TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdel Khalek, S. A1 - Abdelalim, A. A. T1 - Search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν decay mode with 4.7 fb\(^{−1}\) of ATLAS data at \(\sqrt{s}\)=7 TeV JF - Physics Letters B N2 - A search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν (ℓ=e,μℓ=e,μ) decay mode is presented. The search is performed using proton–proton collision data corresponding to an integrated luminosity of 4.7 fb\(^{−1}\) at a centre-of-mass energy of 7 TeV collected during 2011 with the ATLAS detector at the Large Hadron Collider. No significant excess of events over the expected background is observed. An upper bound is placed on the Higgs boson production cross section as a function of its mass. A Standard Model Higgs boson with mass in the range between 133 GeV and 261 GeV is excluded at 95% confidence level, while the expected exclusion range is from 127 GeV to 233 GeV. KW - ATLAS KW - LHC KW - Higgs KW - WW Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127307 VL - 761 IS - 1 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Electron performance measurements with the ATLAS detector using the 2010 LHC proton-proton collision data JF - The European Physical Journal C N2 - Detailed measurements of the electron performance of the ATLAS detector at the LHC are reported, using decays of the Z, W and J/ψ particles. Data collected in 2010 at s√=7 TeV are used, corresponding to an integrated luminosity of almost 40 pb\(^{−1}\). The inter-alignment of the inner detector and the electromagnetic calorimeter, the determination of the electron energy scale and resolution, and the performance in terms of response uniformity and linearity are discussed. The electron identification, reconstruction and trigger efficiencies, as well as the charge misidentification probability, are also presented. KW - electromagnetic calorimeter KW - Atlas detector KW - calorimeter Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127313 VL - 72 IS - 1909 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Performance of the ATLAS Trigger System in 2010 JF - The European Physical Journal C N2 - Proton–proton collisions at √s=7 TeV and heavy ion collisions at \(\sqrt{sNN}\)=2.76 TeV were produced by the LHC and recorded using the ATLAS experiment’s trigger system in 2010. The LHC is designed with a maximum bunch crossing rate of 40 MHz and the ATLAS trigger system is designed to record approximately 200 of these per second. The trigger system selects events by rapidly identifying signatures of muon, electron, photon, tau lepton, jet, and B meson candidates, as well as using global event signatures, such as missing transverse energy. An overview of the ATLAS trigger system, the evolution of the system during 2010 and the performance of the trigger system components and selections based on the 2010 collision data are shown. A brief outline of plans for the trigger system in 2011 is presented. KW - ATLAS KW - Trigger System Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127321 VL - 72 IS - 1849 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Forward-backward correlations and charged-particle azimuthal distributions in pp interactions using the ATLAS detector JF - Journal of High Energy Physics N2 - Using inelastic proton-proton interactions at s√=900 GeV and 7 TeV, recorded by the ATLAS detector at the LHC, measurements have been made of the correlations between forward and backward charged-particle multiplicities and, for the first time, between forward and backward charged-particle summed transverse momentum. In addition, jet-like structure in the events is studied by means of azimuthal distributions of charged particles relative to the charged particle with highest transverse momentum in a selected kinematic region of the event. The results are compared with predictions from tunes of the pythia and herwig++ Monte Carlo generators, which in most cases are found to provide a reasonable description of the data. KW - Hadron-Hadron Scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127336 VL - 7 IS - 19 ER - TY - THES A1 - Abbas, Eid Nagy Eid T1 - Demotic Texts from Medinet Habu (Philological, Paleographical, and Cultural Study) T1 - Demotische Texte aus Medinet Habu (Philologische, paläographische und kulturelle Studie) N2 - The current study presents a new a group of Demotic ostraca in the belongings of the Cairo Museum. A large part of this group stem from Medinet Habu in the western bank of modern Luxor in Upper Egypt and was discovered in the beginning of the thirties of the last century by the Chicago Oriental Institute (recently renamed as Institute for the Study of Ancient Cultures ‘ISAC’). A small portion of the collection under consideration come from other Upper Egyptian provenances including Gebelein, Edfu, Kom Ombo, and possibly elsewhere in Thebes. The main goal of the present dissertation is to decipher, translate, and provide a philological, paleographical, and cultural analysis of the group of texts in question. The results of this study are spread over two main parts, the first of which is dedicated to the main and largest part of the collection, i.e. ostraca from Medinet Habu, while the second is concerned with ostraca from other places. The first part comprises of five sections beginning with receipts of money and in-kind payments including some receipts for the payments of the different capitation charges in the Ptolemaic and Roman Periods, a few for land-related payments, as well as others related to different Ptolemaic monopolies or trades such as a receipt for the price of oil, one for the linen tax, in addition to a unique receipt for the rarely attested fish tax. The second section includes accounts and lists of different kinds be it monetary, in-kind, agriculture, or any other type of lists or accounts that record different everyday transactions. The following section presents a relatively different type of lists, namely lists of personal names. The fourth section incorporates a variety of texts of different concerns, e.g. texts of religious nature, letters, temples oaths, or other private documents. Unidentified texts occupy the fifth and final section of the first part. The second part of the study, which comprises texts that originate from different Upper Egyptian localities, includes three sections, i.e. receipts, accounts, and lists of names. N2 - Die aktuelle Studie stellt eine neue Gruppe demotischer Ostraka im Bestand des Kairoer Museums vor. Ein großer Teil dieser Gruppe stammt aus Medinet Habu am Westufer des heutigen Luxor in Oberägypten und wurde Anfang der dreißiger Jahre des letzten Jahrhunderts vom Chicago Oriental Institute (kürzlich in Institute for the Study of Ancient Cultures „ISAC“ umbenannt) entdeckt. Ein kleiner Teil der untersuchten Sammlung stammt aus anderen oberägyptischen Provenienzen, darunter Gebelein, Edfu, Kom Ombo und möglicherweise anderswo in Theben. Das Hauptziel der vorliegenden Dissertation ist die Entzifferung, Übersetzung und Bereitstellung einer philologischen, paläographischen und kulturellen Analyse der betreffenden Textgruppe. Die Ergebnisse dieser Studie verteilen sich auf zwei Hauptteile, von denen der erste dem Haupt und größten Teil der Sammlung, d.h. Ostraka aus Medinet Habu, gewidmet ist, während sich der zweite mit Ostraka aus anderen oberägyptischen Orten befasst. Der erste Teil besteht aus fünf Abschnitten, beginnend mit Quittungen in Geld oder Naturalien, darunter einige Zahlungsquittungen für die verschiedenen Kopfsteuern in der ptolemäischen und römischen Zeit, einige für landbezogene Zahlungen sowie Zahlungusquittungen über verschiedene ptolemäische Monopole oder Gewerben wie z.B. ein Quittung für den Preis des Öls, eine über Leinensteuer sowie eine einzigartige Quittung über die selten belegete Fischsteuer. Der zweite Abschnitt umfasst Listen und Abrechnungen unterschiedlicher Art, sei es über Geld, Natur, Landwirtschaft, oder jede andere Art, die verschiedene alltägliche Transaktionen aufzeichnen. Im folgenden Abschnitt wird eine andere Art von Listen vorgestellt, nämlich Namenlisten. Der vierte Abschnitt enthält eine Vielzahl von Texten zu unterschiedlichen Themen, wie z.B. Texte religiöser Natur, Briefe, Tempeleide oder andere private Dokumente. Nicht identifizierte Texte belegen den fünften und letzten Abschnitt des ersten Teils der Studie. Der zweite Teil dieser Studie, der Texte umfasst, die aus verschiedenen oberägyptischen Fundorten stammen, enthält drei Abschnitte: Quittungen, Abrechnungen sowie Namenlisten. KW - Demotic KW - Ostraca KW - Medinet Habu KW - Tax Receipts KW - Accounts KW - Lists Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352653 ER - TY - JOUR A1 - Abboud, Tammam A1 - Asendorf, Thomas A1 - Heinrich, Jutta A1 - Faust, Katharina A1 - Krieg, Sandro M. A1 - Seidel, Kathleen A1 - Mielke, Dorothee A1 - Matthies, Cordola A1 - Ringel, Florian A1 - Rohde, Veit A1 - Szelényi, Andrea T1 - Transcranial versus direct cortical stimulation for motor-evoked potentials during resection of supratentorial tumors under general anesthesia (the TRANSEKT-trial): study protocol for a randomized controlled trial JF - Biomedicines N2 - Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we designed this randomized study to compare between both methods regarding the prediction of postoperative motor deficits and extent of tumor resection. Methods: This is a multicenter (six centers in Germany and one in Switzerland), double blind, parallel group, exploratory, randomized controlled clinical trial. Patients without or with mild paresis, who are scheduled for surgical resection of motor-eloquent brain tumors under general anesthesia will be randomized to surgical resection under TES or surgical resection under DCS. The primary endpoint is sensitivity and specificity in prognosis of motor function 7 days after surgery. The main secondary endpoint is the extent of tumor resection. The study is planned to include 120 patients within 2 years. Discussion: The present exploratory study should compare TES and DCS regarding sensitivity and specificity in predicting postoperative motor deficit and extent of tumor resection to calculate the required number of patients in a confirmatory trial to test the superiority of one method over the other. KW - threshold criterion KW - amplitude criterion KW - intraoperative monitoring KW - transcranial motor-evoked potentials KW - direct cortical stimulation KW - threshold level Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248513 SN - 2227-9059 VL - 9 IS - 10 ER - TY - JOUR A1 - Abd El-Aziz, Asmaa M. A1 - El-Maghraby, Azza A1 - Ewald, Andrea A1 - Kandil, Sherif H. T1 - In-vitro cytotoxicity study: cell viability and cell morphology of carbon nanofibrous scaffold/hydroxyapatite nanocomposites JF - Molecules N2 - Electrospun carbon nanofibers (CNFs), which were modified with hydroxyapatite, were fabricated to be used as a substrate for bone cell proliferation. The CNFs were derived from electrospun polyacrylonitrile (PAN) nanofibers after two steps of heat treatment: stabilization and carbonization. Carbon nanofibrous (CNF)/hydroxyapatite (HA) nanocomposites were prepared by two different methods; one of them being modification during electrospinning (CNF-8HA) and the second method being hydrothermal modification after carbonization (CNF-8HA; hydrothermally) to be used as a platform for bone tissue engineering. The biological investigations were performed using in-vitro cell counting, WST cell viability and cell morphology after three and seven days. L929 mouse fibroblasts were found to be more viable on the hydrothermally-modified CNF scaffolds than on the unmodified CNF scaffolds. The biological characterizations of the synthesized CNF/HA nanofibrous composites indicated higher capability of bone regeneration. KW - HA modifiedCNF membranes KW - cytotoxicity KW - WST test KW - cell counting KW - cell viability KW - cell morphology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234037 SN - 1420-3049 VL - 26 IS - 6 ER - TY - JOUR A1 - Abda, Ebrahim M. A1 - Krysciak, Dagmar A1 - Krohn-Molt, Ines A1 - Mamat, Uwe A1 - Schmeisser, Christel A1 - Förstner, Konrad U. A1 - Schaible, Ulrich E. A1 - Kohi, Thomas A. A1 - Nieman, Stefan A1 - Streit, Wolfgang R. T1 - Phenotypic Heterogeneity Affects Stenotrophomonas maltophilia K279a Colony Morphotypes and \(\beta\)-Lactamase Expression JF - Frontiers in Microbiology N2 - Phenotypic heterogeneity at the cellular level in response to various stresses, e.g., antibiotic treatment has been reported for a number of bacteria. In a clonal population, cell-to-cell variation may result in phenotypic heterogeneity that is a mechanism to survive changing environments including antibiotic therapy. Stenotrophomonas rnaltophilia has been frequently isolated from cystic fibrosis patients, can cause numerous infections in other organs and tissues, and is difficult to treat due to antibiotic resistances. S. maltophilia K279a produces the Li and L2 beta-lactamases in response to beta-lactam treatment. Here we report that the patient isolate S. rnaltophilia K279a diverges into cellular subpopulations with distinct but reversible morphotypes of small and big colonies when challenged with ampicillin. This observation is consistent with the formation of elongated chains of bacteria during exponential growth phase and the occurrence of mainly rod-shaped cells in liquid media. RNA-seq analysis of small versus big colonies revealed differential regulation of at least seven genes among the colony morphotypes. Among those, bleu and bla(L2) were transcriptionally the most strongly upregulated genes. Promoter fusions of b/a(L1) and b/a(L2) genes indicated that expression of both genes is also subject to high levels of phenotypic heterogeneous expression on a single cell level. Additionally, the comE homolog was found to be differentially expressed in homogenously versus heterogeneously bla(L2) expressing cells as identified by RNA(seq) analysis. Overexpression of cornE in S. maltophilia K279a reduced the level of cells that were in a bla(L2)-ON mode to 1% or lower. Taken together, our data provide strong evidence that S. maltophilia K279a populations develop phenotypic heterogeneity in an ampicillin challenged model. This cellular variability is triggered by regulation networks including b/a(L1), b/a(L2), and comE. KW - xanthomonas maltophilia KW - gram-negative bacteria KW - RNA-seq KW - pseudomas aeruginosa KW - antibiotic resistance KW - colony morphotypes KW - beta-lactamases KW - K279a KW - Stenotrophomonas maltophilia KW - phenotypic heterogeneity KW - persister cells KW - streptococcus pneumoniae KW - nosocomial pathogen KW - membrane vesicles KW - sinorhizobium fredii NGR234 KW - red fluorescent protein KW - escherichia coli Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136446 VL - 6 IS - 1373 ER - TY - JOUR A1 - Abdali, Narges A1 - Barth, Enrico A1 - Norouzy, Amir A1 - Schulz, Robert A1 - Nau, Werner M. A1 - Kleinekathofer, Ulrich A1 - Tauch, Andreas A1 - Benz, Roland T1 - Corynebacterium jeikeium jk0268 Constitutes for the 40 Amino Acid Long PorACj, Which Forms a Homooligomeric and Anion- Selective Cell Wall Channel JF - PLoS ONE N2 - Corynebacterium jeikeium, a resident of human skin, is often associated with multidrug resistant nosocomial infections in immunodepressed patients. C. jeikeium K411 belongs to mycolic acid-containing actinomycetes, the mycolata and contains a channel-forming protein as judged from reconstitution experiments with artificial lipid bilayer experiments. The channel-forming protein was present in detergent treated cell walls and in extracts of whole cells using organic solvents. A gene coding for a 40 amino acid long polypeptide possibly responsible for the pore-forming activity was identified in the known genome of C. jeikeium by its similar chromosomal localization to known porH and porA genes of other Corynebacterium strains. The gene jk0268 was expressed in a porin deficient Corynebacterium glutamicum strain. For purification temporarily histidine-tailed or with a GST-tag at the N-terminus, the homogeneous protein caused channel-forming activity with an average conductance of 1.25 nS in 1M KCl identical to the channels formed by the detergent extracts. Zero-current membrane potential measurements of the voltage dependent channel implied selectivity for anions. This preference is according to single-channel analysis caused by some excess of cationic charges located in the channel lumen formed by oligomeric alpha-helical wheels. The channel has a suggested diameter of 1.4 nm as judged from the permeability of different sized hydrated anions using the Renkin correction factor. Surprisingly, the genome of C. jeikeium contained only one gene coding for a cell wall channel of the PorA/PorH type found in other Corynebacterium species. The possible evolutionary relationship between the heterooligomeric channels formed by certain Corynebacterium strains and the homooligomeric pore of C. jeikeium is discussed. KW - antibiotics KW - detergents KW - anions KW - corynebacterium diphtheriae KW - membrane potential KW - corynebacteria KW - cell walls KW - permeability Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129989 VL - 8 IS - 10 ER - TY - JOUR A1 - Abdali, Narges A1 - Younas, Farhan A1 - Mafakheri, Samaneh A1 - Pothula, Karunakar R. A1 - Kleinekathöfer, Ulrich A1 - Tauch, Andreas A1 - Benz, Roland T1 - Identification and characterization of smallest pore-forming protein in the cell wall of pathogenic Corynebacterium urealyticum DSM 7109 JF - BMC Biochemistry N2 - Background: Corynebacterium urealyticum, a pathogenic, multidrug resistant member of the mycolata, is known as causative agent of urinary tract infections although it is a bacterium of the skin flora. This pathogenic bacterium shares with the mycolata the property of having an unusual cell envelope composition and architecture, typical for the genus Corynebacterium. The cell wall of members of the mycolata contains channel-forming proteins for the uptake of solutes. Results: In this study, we provide novel information on the identification and characterization of a pore-forming protein in the cell wall of C. urealyticum DSM 7109. Detergent extracts of whole C. urealyticum cultures formed in lipid bilayer membranes slightly cation-selective pores with a single-channel conductance of 1.75 nS in 1 M KCl. Experiments with different salts and non-electrolytes suggested that the cell wall pore of C. urealyticum is wide and water-filled and has a diameter of about 1.8 nm. Molecular modelling and dynamics has been performed to obtain a model of the pore. For the search of the gene coding for the cell wall pore of C. urealyticum we looked in the known genome of C. urealyticum for a similar chromosomal localization of the porin gene to known porH and porA genes of other Corynebacterium strains. Three genes are located between the genes coding for GroEL2 and polyphosphate kinase (PKK2). Two of the genes (cur_1714 and cur_1715) were expressed in different constructs in C. glutamicum Delta porA Delta porH and in porin-deficient BL21 DE3 Omp8 E. coli strains. The results suggested that the gene cur_1714 codes alone for the cell wall channel. The cell wall porin of C. urealyticum termed PorACur was purified to homogeneity using different biochemical methods and had an apparent molecular mass of about 4 kDa on tricine-containing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Conclusions: Biophysical characterization of the purified protein (PorACur) suggested indeed that cur_1714 is the gene coding for the pore-forming protein in C. urealyticum because the protein formed in lipid bilayer experiments the same pores as the detergent extract of whole cells. The study is the first report of a cell wall channel in the pathogenic C. urealyticum. KW - cell wall channel KW - mycolic acid KW - porin KW - Corynebacterium urealyticum KW - lipid bilayer membrane Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226959 VL - 19 ER - TY - THES A1 - Abdel Rahman, Faisal Mirghani T1 - Systematic analysis of genes expressed in the retinal pigment epithelium (RPE) and identification of candidates for genetic susceptibility to age-related macular degeneration (AMD) N2 - Age related macular degeneration (AMD) is the leading cause of visual impairment in the elderly and the major cause of blindness in the developed world. To date, the molecular mechanisms underlying the disease are not well understood although in recent years a primary involvement of the retinal pigment epithelium (RPE) has become evident. The aim of the present study is to systematically analyse genes which are differentially expressed in the RPE, and to assess their possible association with mechanisms and pathways likely to be related to retinal disease, in particular AMD. Towards this goal, 2379 expressed sequence tags (ESTs) were established from an inhouse generated RPE cDNA library. This library was constructed by using the suppression subtraction hybridization (SSH) technique which normalises redundant sequences and ensures enrichment of rare transcripts. In a first phase, 1002 ESTs were sequenced and subjected to comprehensive alignment with public nucleotide and protein databases. A search of the 1002 ESTs against the human genome draft sequence yielded 168 known genes, 51 predicted genes, 15 unknown transcripts and 41 clones with no significant similarity. Reverse Northern blot hybridization was performed for 318 EST clusters to identify abundantly expressed genes in the RPE and to prioritize subsequent analyses. Representative clones were spotted onto a nylon membrane and hybridized with cDNA probes of driver (heart and liver) and tester (RPE) used in the cDNA library construction. Subsequently, 107 EST clusters were subjected to Northern blot hybridizations. These analyses identified 7 RPE-specific, 3 retina-specific, 7 RPE/retina-specific, and 7 tissue restricted transcripts, while 29 EST clusters were ubiquitously expressed, and evaluation was not possible for another 54 EST clusters. Of the 24 transcripts with specific or restricted expression, 16 clones were selected for further characterization. The predicted gene MGC2477 and 2 novel isoforms of the human transient receptor potential cation channel, subfamily M, member 3 (TRPM3) were cloned and further described in detail. In addition, polymorphic variations for these 2 genes as well as for the human MT-Protocadherin gene were determined. For MGC2477, 15 single nucleotide polymorphisms (SNPs) were identified, with 13 having a frequency of the minor allele greater than 20%. 10 of the 15 SNPs have not been reported in so far in public SNP repertoires. Partial assessment of the TRPM3 gene yielded 35 SNPs. Of these, 30 (85.7%) were highly frequent (0.17-0.5%), and 14 (40%) were novel. The MT-Protocadherin gene revealed 35 SNPs, including 28 (80%) with high frequency of the minor allele. 23 (65.7%) were novel SNPs. These SNPs will be used to construct the most common haplotypes. These will be used in case/control association studies in 400 AMD patients and 200 ethnically and aged matched controls to assess a possible contribution of these genes in the etiology of AMD. N2 - Die altersabhängige Makuladegeneration (AMD) ist die häufigste Ursache von gravierenden Einschränkungen des Sehvermögens im fortgeschrittenen Lebensalter. In den Industriestaaten ist die AMD zudem die Hauptursache für Altersblindheit. Die molekularen Mechanismen, die zur Entstehung der AMD führen, sind bisher nur unzureichend bekannt. In den letzten Jahren hat es sich jedoch herausgestellt, dass das retinale Pigmentepithel (RPE) eine primäre Rolle in der Pathogenese der AMD spielt. Ziel dieser Arbeit war die systematische Analyse von Genen, welche im RPE differentiell exprimiert werden. Entsprechende Kandidatengene sollten auf deren mögliche Beteiligung an der Entstehung von Erkrankungen der Retina, insbesondere der AMD, untersucht werden. Zunächst wurden 2379 ESTs aus einer innerhalb der Arbeitsgruppe generierten RPE cDNA Bibliothek definiert. Die dazu verwendete cDNA Bibliothek wurde durch die Suppressions- Subtraktions Hybridisierungs-Technik (SSH) konstruiert. Diese Technik gestattet eine Normalisierung gegenüber redundanten Sequenzen und begünstigt gleichzeitig die Anreicherung von seltenen Transkripten. In einer ersten Phase wurden 1002 ESTs sequenziert und einer umfassenden bioinformatischen Analyse mit Hilfe der verfügbaren DNA- und Protein Datenbanken unterzogen. Der Vergleich der 1002 ESTs mit der Draft Sequenz des menschlichen Genoms ergab den Hinweis auf 168 bereits bekannte Gene, 51 mögliche Gene, 15 völlig unbekannte Transkripte und 41 nicht weiter zuordenbare cDNA Klone. 318 EST Cluster wurden einer reversen Northen-Blot Analyse unterzogen um hochexprimierte Gene zu identifizieren und damit Prioritäten für die weiteren Analysen zu setzen. Im Rahmen der Northern-Analyse wurden repräsentative Klone von 107 EST-Klustern mit cDNA Sonden der ursprünglichen cDNA-Bibliothek hybridisiert. Als Ergebnis dieser Analyse fanden sich 7 RPE-spezifische, 3 Retina-spezifische, 7 sowohl RPE- als auch Retinaspezifische sowie 7 auf einzelne Gewebe limitierte Transkripte. 29 EST Cluster erwiesen sich als ubiquitär exprimiert, und 54 Kluster konnten nicht näher zugeordnet werden. Von den 24 Transkripten mit spezifischer oder zumindest begrenzter Expression wurden 16 Klone zur weiteren Charakterisierung ausgewählt. Aus diesen Material wurden im Rahmen dieser Arbeit das Kandidatengen MGC2477 sowie 2 neue Isoformen des menschlichen TRPM3-Gens kloniert und näher charakterisiert. Weiterhin wurden polymorphe Varianten dieser beiden Isoformen und des menschlichen MTProtocadherin- Gens definiert. Im Gen MGC2477 wurden 15 SNPs identifiziert, wovon die Allelhäufigkeit des selteneren Allels bei 13 der SNPs über 20% lag. Für 10 der insgesamt 15 vii SNPs dieses Gens fanden sich bisher keine Einträge in den entprechenden Datenbanken. Die SNP-Suche wurde auch für das TRPM3-Gen durchgeführt und ergab 35 SNPs, wovon 30 (85,7%) als hochfrequent eingestuft werden konnten. 14 dieser 35 SNPs waren bisher nicht in den Datenbanken verzeichnet. Beim MT-Protocadherin-Gen fanden sich ebenfalls 35 SNPs, wobei 80% eine hohe Frequenz des selteneren Allels aufwiesen. In diesem Fall handelte es sich bei 23 der insgesamt 35 SNPs um bisher unbekannte Allele. Diese SNPs bilden den Ausgangspunkt zur Konstruktion der häufigsten Haplotypen der genannten Gene. Mit der Charakterisierung der Einzel-Nukleotid Polymorphismen der Kandidatengene wurde die Grundlage zur Durchführung von Fall/Kontrollstudien gelegt, in deren Rahmen die Bedeutung der jeweiligen Kandidatengene in der Pathogense der AMD untersucht werden kann. KW - Senile Makuladegeneration / Pigmentepithel / Genexpression KW - RPE KW - AMD KW - RPE specific genes Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-7053 ER - TY - JOUR A1 - Abdel-Latif, Rania A1 - Fathy, Moustafa A1 - Anwar, Hend Ali A1 - Naseem, Muhammad A1 - Dandekar, Thomas A1 - Othman, Eman M. T1 - Cisplatin-induced reproductive toxicity and oxidative stress: ameliorative effect of kinetin JF - Antioxidants N2 - Cisplatin is a commonly used chemotherapeutic agent; however, its potential side effects, including gonadotoxicity and infertility, are a critical problem. Oxidative stress has been implicated in the pathogenesis of cisplatin-induced testicular dysfunction. We investigated whether kinetin use at different concentrations could alleviate gonadal injury associated with cisplatin treatment, with an exploration of the involvement of its antioxidant capacity. Kinetin was administered in different doses of 0.25, 0.5, and 1 mg/kg, alone or along with cisplatin for 10 days. Cisplatin toxicity was induced via a single IP dose of 7 mg/kg on day four. In a dose-dependent manner, concomitant administration of kinetin with cisplatin significantly restored testicular oxidative stress parameters, corrected the distorted sperm quality parameters and histopathological changes, enhanced levels of serum testosterone and testicular StAR protein expression, as well as reduced the up-regulation of testicular TNF-α, IL-1β, Il-6, and caspase-3, caused by cisplatin. It is worth noting that the testicular protective effect of the highest kinetin dose was comparable/more potent and significantly higher than the effects of vitamin C and the lowest kinetin dose, respectively. Overall, these data indicate that kinetin may offer a promising approach for alleviating cisplatin-induced reproductive toxicity and organ damage, via ameliorating oxidative stress and reducing inflammation and apoptosis. KW - cytokinins KW - kinetin KW - cisplatin KW - reproductive toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271223 SN - 2076-3921 VL - 11 IS - 5 ER - TY - JOUR A1 - Abdelhafez, Omnia Hesham A1 - Fawzy, Michael Atef A1 - Fahim, John Refaat A1 - Desoukey, Samar Yehia A1 - Krischke, Markus A1 - Mueller, Martin J. A1 - Abdelmohsen, Usama Ramadan T1 - Hepatoprotective potential of Malvaviscus arboreus against carbon tetrachloride-induced liver injury in rats JF - PLoS ONE N2 - Malvaviscus arboreus Cav. is a medicinal plant belonging to family Malvaceae with both ethnomedical and culinary value; however, its phytochemical and biological profiles have been scarcely studied. Accordingly, this work was designed to explore the chemical composition and the hepatoprotective potential of M. arboreus against carbon tetrachloride (CCl\(_4\))-induced hepatotoxicity. The total extract of the aerial parts and its derived fractions (petroleum ether, dichloromethane, ethyl acetate, and aqueous) were orally administered to rats for six consecutive days, followed by injection of CCl\(_4\) (1:1 v/v, in olive oil, 1.5 ml/kg, i.p.) on the next day. Results showed that the ethyl acetate and dichloromethane fractions significantly alleviated liver injury in rats as indicated by the reduced levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB), and malondialdehyde (MDA), along with enhancement of the total antioxidant capacities of their livers, with the maximum effects were recorded by the ethyl acetate fraction. Moreover, the protective actions of both fractions were comparable to those of silymarin (100 mg/kg), and have been also substantiated by histopathological evaluations. On the other hand, liquid chromatography-high resolution electrospray ionization mass spectrometry (LC‒HR‒ESI‒MS) metabolomic profiling of the crude extract of M. arboreus aerial parts showed the presence of a variety of phytochemicals, mostly phenolics, whereas the detailed chemical analysis of the most active fraction (i.e. ethyl acetate) resulted in the isolation and identification of six compounds for the first time in the genus, comprising four phenolic acids; β-resorcylic, caffeic, protocatechuic, and 4-hydroxyphenylacetic acids, in addition to two flavonoids; trifolin and astragalin. Such phenolic principles, together with their probable synergistic antioxidant and liver-protecting properties, seem to contribute to the observed hepatoprotective potential of M. arboreus. KW - high performance liquid chromatography KW - phenols KW - phytochemicals KW - antioxidants KW - metabolomics KW - medicinal plants KW - Egypt KW - xenobiotic metabolism KW - Malvaviscus arboreus Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177243 VL - 13 IS - 8 ER - TY - JOUR A1 - Abdelhameed, Reda F. A. A1 - Eltamany, Enas E. A1 - Hal, Dina M. A1 - Ibrahim, Amany K. A1 - AboulMagd, Asmaa M. A1 - Al-Warhi, Tarfah A1 - Youssif, Khayrya A. A1 - Abd El-kader, Adel M. A1 - Hassanean, Hashim A. A1 - Fayez, Shaimaa A1 - Bringmann, Gerhard A1 - Ahmed, Safwat A. A1 - Abdelmohsen, Usama Ramadan T1 - New cytotoxic cerebrosides from the Red Sea cucumber Holothuria spinifera supported by in-silico studies JF - Marine Drugs N2 - Bioactivity-guided fractionation of a methanolic extract of the Red Sea cucumber Holothuria spinifera and LC-HRESIMS-assisted dereplication resulted in the isolation of four compounds, three new cerebrosides, spiniferosides A (1), B (2), and C (3), and cholesterol sulfate (4). The chemical structures of the isolated compounds were established on the basis of their 1D NMR and HRMS spectral data. Metabolic profiling of the H. spinifera extract indicated the presence of diverse secondary metabolites, mostly hydroxy fatty acids, diterpenes, triterpenes, and cerebrosides. The isolated compounds were tested for their in vitro cytotoxicities against the breast adenocarcinoma MCF-7 cell line. Compounds 1, 2, 3, and 4 displayed promising cytotoxic activities against MCF-7 cells, with IC\(_{50}\) values of 13.83, 8.13, 8.27, and 35.56 µM, respectively, compared to that of the standard drug doxorubicin (IC\(_{50}\) 8.64 µM). Additionally, docking studies were performed for compounds 1, 2, 3, and 4 to elucidate their binding interactions with the active site of the SET protein, an inhibitor of protein phosphatase 2A (PP2A), which could explain their cytotoxic activity. This study highlights the important role of these metabolites in the defense mechanism of the sea cucumber against fouling organisms and the potential uses of these active molecules in the design of new anticancer agents. KW - LC-HRESIMS KW - Holothuria spinifera KW - cerebrosides KW - molecular docking KW - cytotoxicity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211089 SN - 1660-3397 VL - 18 IS - 8 ER - TY - JOUR A1 - Abdelhameed, Reda F. A. A1 - Habib, Eman S. A1 - Eltahawy, Nermeen A. A1 - Hassanean, Hashim A. A1 - Ibrahim, Amany K. A1 - Mohammed, Anber F. A1 - Fayez, Shaimaa A1 - Hayallah, Alaa M. A1 - Yamada, Koji A1 - Behery, Fathy A. A1 - Al-Sanea, Mohammad M. A1 - Alzarea, Sami I. A1 - Bringmann, Gerhard A1 - Ahmed, Safwat A. A1 - Abdelmohsen, Usama Ramadan T1 - New cytotoxic natural products from the Red Sea sponge Stylissa carteri JF - Marine Drugs N2 - Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract’s metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC\(_{50}\) values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC\(_{50}\) at 36.8 ± 0.16 µM for 1 and IC\(_{50}\) 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents. KW - LC-HRESIMS KW - Stylissa carteri KW - ceramide KW - cerebroside KW - docking KW - cytotoxic activity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205795 SN - 1660-3397 VL - 18 IS - 5 ER - TY - JOUR A1 - Abdelhameed, Reda F. A. A1 - Habib, Eman S. A1 - Goda, Marwa S. A1 - Fahim, John Refaat A1 - Hassanean, Hashem A. A1 - Eltamany, Enas E. A1 - Ibrahim, Amany K. A1 - AboulMagd, Asmaa M. A1 - Fayez, Shaimaa A1 - Abd El-kader, Adel M. A1 - Al-Warhi, Tarfah A1 - Bringmann, Gerhard A1 - Ahmed, Safwat A. A1 - Abdelmohsen, Usama Ramadan T1 - Thalassosterol, a New Cytotoxic Aromatase Inhibitor Ergosterol Derivative from the Red Sea Seagrass Thalassodendron ciliatum JF - Marine Drugs N2 - Thalassodendron ciliatum (Forssk.) Den Hartog is a seagrass belonging to the plant family Cymodoceaceae with ubiquitous phytoconstituents and important pharmacological potential, including antioxidant, antiviral, and cytotoxic activities. In this work, a new ergosterol derivative named thalassosterol (1) was isolated from the methanolic extract of T. ciliatum growing in the Red Sea, along with two known first-reported sterols, namely ergosterol (2) and stigmasterol (3), using different chromatographic techniques. The structure of the new compound was established based on 1D and 2D NMR spectroscopy and high-resolution mass spectrometry (HR-MS) and by comparison with the literature data. The new ergosterol derivative showed significant in vitro antiproliferative potential against the human cervical cancer cell line (HeLa) and human breast cancer (MCF-7) cell lines, with IC\(_{50}\) values of 8.12 and 14.24 µM, respectively. In addition, docking studies on the new sterol 1 explained the possible binding interactions with an aromatase enzyme; this inhibition is beneficial in both cervical and breast cancer therapy. A metabolic analysis of the crude extract of T. ciliatum using liquid chromatography combined with high-resolution electrospray ionization mass spectrometry (LC-ESI-HR-MS) revealed the presence of an array of phenolic compounds, sterols and ceramides, as well as di- and triglycerides. KW - cytotoxic activity KW - ergosterol derivative KW - metabolic analysis KW - docking studies KW - seagrass KW - Thalassodendron ciliatum Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236085 VL - 18 IS - 7 ER - TY - THES A1 - Abdelmohsen, Usama Ramadan T1 - Antimicrobial Activities from Plant Cell Cultures and Marine Sponge-Associated Actinomycetes T1 - Antimikrobielle Aktivitäten aus Pflanzenzellkulturen und marinen Schwamm-assoziierten Actinomyceten N2 - This thesis is divided into three parts with the main goal allocating novel antimicrobial compounds that could be used as future antibiotics. The first part aimed to evaluate the potential of plant suspension cultures for the production of antimicrobial proteins. The extracellular, intracellular and cell wall bound fractions of seven heterotrophic and photomixotrophic plant cell suspension cultures treated with nine different elicitors were tested for the elicitor dependent production of antimicrobial proteins. Bioactivities were tested against a selected panel of human isolates including Gram-positive and Gram-negative bacteria as well as fungi using the disc diffusion assay. The intracellular fractions of elicited cell cultures were more active than extracellular fractions while the cell wall bound fractions showed lowest activities. Among the 21 fractions tested, the intracellular fraction of Lavendula angustifolia elicited with DC3000 was most active against Candida maltosa. The second most active fraction was the intracellular fraction of Arabidopsis thaliana elicited with salicylic acid which was moreover active against all test strains. The antimicrobial activity of elicited Arabidopsis thaliana cell cultures was tested by bioautography to locate the antimicrobial proteins in the crude extract. The intracellular fraction of photomixotrophic Arabidopsis thaliana cells elicited with salicylic acid was selected for further gel filtration chromatography on S-200 column leading to the purification of one 19 kDa antimicrobially active protein, designated, AtAMP. Our findings suggest that elicited plant cell cultures may present a new promising alternative source of antimicrobial proteins. The second part comprises the isolation of actinomycetes associated with marine sponges and testing the bioactivities of new species for further investigations. Actinobacterial communities of eleven taxonomically different sponges that had been collected from offshore Ras Mohamed (Egypt) and from Rovinj (Croatia) were investigated by a culture-based approach using different standard media for isolation of actinomycetes and media enriched with aqueous sponge extract to target rare and new actinomycete species. Phylogenetic characterization of 52 representative isolates out of 90 based on almost complete sequences of genes encoding 16S rRNA supported their assignment to 18 different actinomycete genera. Altogether 14 putatively new species were identified based on sequence similarity values below 98.2% to other strains in the NCBI database. The use of M1 agar amended with aqueous sponge extract yielded a putative new genus related to Rubrobacter which highlighting the need for innovative cultivation protocols. Biological activity testing showed that five isolates were active against Gram-positives only, one isolate was active against Candida albicans only and one isolate showed activity against both groups of pathogens. Moreover, the antiparasistic activity was documented for four isolates. These results showed a high diversity of actinomycetes associated with marine sponges as well as highlighted their potential to produce anti-infective agents. The third part of the thesis focused on the isolation and structure elucidation of new bioactive compounds. Streptomyces strain RV15 recovered from sponge Dysidea tupha, was selected for further chemical analysis by virtue of the fact that it exhibited the greatest antimicrobial potential against Staphylococcus aureus as well as Candida albicans among the all tested strains. Moreover, members of the genus Streptomyces are well known as prolific producers of interesting pharmacologically active metabolites. Chemical analysis of the methanolic crude extract using different chromatographic tools yielded four new compounds. The structures of the new compounds were spectroscopically elucidated to be four new cyclic peptides, namely, cyclodysidins A-D. Their bioactivity was tested against different proteases, bacteria and Candida as well as tumor cell lines. The compounds did not show any significant activities at this point. N2 - Die hier vorliegende Dissertation ist in drei Kapitel gegliedert und hatte die Bereitstellung neuer antimikrobieller Substanzen, die zukünftig als Antibiotika genutzt werden könnten, zum Hauptziel. Das erste Kapitel befasst sich mit dem Potenzial von Pflanzen zur Produktion von Proteinen mit antimikrobieller Wirkung. Pflanzenzellkulturen wurden mit neun verschiedenen Induktoren stimuliert und anschließend auf die Produktion von Proteinen mit antimikrobieller Wirkung hin untersucht. Dafür wurden die extra-, intrazellulären sowie die membrangebundenen Proteinfraktionen von sieben heterotrophen und photomixotrophen Pflanzenzellkulturen extrahiert. Mittels Diffusionstests wurden die Wirkung der Proteine gegen eine Sammlung menschlicher Pathogene inklusive Gram-positiver und Gram-negativer Bakterien, sowie Pilze getestet. Die intrazellulären Fraktionen zeigten dabei höhere Aktivitäten als die extrazellulären, wohingegen die membrangebundenen Proteine die geringsten Aktivitäten aufwiesen. Von den insgesamt 21 getesteten Proteinfraktionen wies die mit DC3000 induzierte intrazelluläre Fraktion von Lavendula angustifolia die größte Wirkung gegen Candida maltosa auf. Die mit Salicylsäure induzierte intrazelluläre Proteinfraktion von Arabidopsis thaliana zeigte eine Hemmung aller getesteten pathogenen Stämme. Die antimikrobielle Aktivität der induzierten Arabidopsis thaliana-Zellkultur wurde mittels Bioautography weiter untersucht, um das wirksame Protein im Gesamt-(Roh-) extrakt einzugrenzen. Die intrazelluläre Fraktion der photomixotrophen Arabidopsis thaliana-Zellkultur wurde ausgewählt, um ein 19 kDa Protein mit antimikrobieller Wirkung, genannt AtAMP, mittels Gelfitrationschromatography über eine S-200 Säule aufzureinigen. Unsere Ergebnisse weisen darauf hin, dass induzierte Pflanzenzellkulturen zukünftig als aussichtsreiche alternative Quelle für antimikrobiell wirksame Proteine herangezogen werden können. Der zweite Teil dieser Dissertation beinhaltet die Isolation von mit marinen Schwämmen assoziierten Actinomyceten und deren Testung auf Bioaktivität. Aus 11 taxonomisch verschiedenen, an den Küsten von Ras Mohamed (Ägypten) und Rovinj (Kroatien) gesammelten Schwammspezies, wurden Actinobakterien auf verschiedenen Standardmedien kultiviert. Um seltene, neue Stämme zu isolieren, wurden diese Medien mit wässrigen Schwammextrakten angereichert. Die auf der 16S rRNA-Gensequenz basierenden phylogenetischen Charakterisierung von 52 der insgesamt 90 Isolate, zeigte die Zugehörigkeit zu 18 verschiedenen Actinomyceten-Gattungen. Die 16S rRNA-Gene von 14 Isolaten zeigten Homologien von weniger als 98,2% zu denen anderer in Datenbanken abgelegten Bakterien und stellen somit vermutlich neue Arten dar. Die Verwendung von mit Schwammextrakt angereichertem M1-Agar resultierte in der Kultivierung einer mutmaßlich neuen, mit Rubrobacter verwandten Gattung und bestätigt die Notwendigkeit der Entwicklung neuer innovativer Kultivierungsprotokolle. Aktivitätstests von fünf Isolaten zeigten deren hemmende Wirkung nur gegen Gram-positive Bakterien, ein Isolat zeigte Aktivität nur gegen Candida albicans und ein Isolat war wirksam gegen beide genannten Pathogengruppen. Desweiteren konnten antiparasitäre Wirkungen von vier Isolaten dokumentiert werden. Die hier beschriebenen Ergebnisse zeigen die große Diversität von mit Schwämmen assoziierten Actinomyceten und deren Potential Antiinfektiva zu produzieren. Der dritte Teil dieser Arbeit fokussierte sich auf die Isolation und Strukturaufklärung neuer bioaktiver Substanzen. Streptomyceten sind bekannt für die Produktion von interessanten, pharmakologisch aktiven Metaboliten. Der aus dem Schwamm Dysidea tupha isolierte Stamm Streptomyces RV 15 zeigte eine hohe Aktivität gegen Staphylococcus aureus und C. albicans und wurde deshalb für nähere Untersuchungen ausgewählt. Die chemische Analyse des Methanol-Rohextrakts unter der Verwendung verschiedener Chromatographie-Verfahren resultierte in der Isolation von vier Substanzen. Die spektroskopische Analyse zeigte, dass diese neuen Substanzen zyklische Peptidstrukturen aufweisen und wurden daraufhin als Cyclodysidin A-D benannt. Die Bioaktivitäten dieser Substanzen wurden gegen verschiedene Proteasen, Bakterien und Candida sowie gegen verschiedene Tumorzelllinien getestet. Bis zum jetzigen Zeitpunkt zeigte keine der getesteten Peptide eine aussagekräftige Wirkung. KW - Antimikrobieller Wirkstoff KW - Pflanzenzelle KW - Zellkultur KW - Antimikrobielle Aktivitäten KW - Pflanzenzellkulturen KW - Proteinen mit antimikrobieller Wirkung KW - Actinomyceten KW - zyklische Peptide KW - Antimicrobial activities KW - Plant cell cultures KW - Antimicrobial proteins KW - Actinomycetes KW - Cyclic peptides Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-51483 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Cheng, Cheng A1 - Viegelmann, Christina A1 - Zhang, Tong A1 - Grkovic, Tanja A1 - Ahmed, Safwat A1 - Quinn, Ronald J. A1 - Hentschel, Ute A1 - Edrada-Ebel, RuAngelie T1 - Dereplication Strategies for Targeted Isolation of New Antitrypanosomal Actinosporins A and B from a Marine Sponge Associated-Actinokineospora sp EG49 JF - Marine Drugs N2 - High resolution Fourier transform mass spectrometry (HRFTMS) and nuclear magnetic resonance (NMR) spectroscopy were employed as complementary metabolomic tools to dereplicate the chemical profile of the new and antitrypanosomally active sponge-associated bacterium Actinokineospora sp. EG49 extract. Principal Component (PCA), hierarchical clustering (HCA), and orthogonal partial least square-discriminant analysis (OPLS-DA) were used to evaluate the HRFTMS and NMR data of crude extracts from four different fermentation approaches. Statistical analysis identified the best culture one-strain-many-compounds (OSMAC) condition and extraction procedure, which was used for the isolation of novel bioactive metabolites. As a result, two new O-glycosylated angucyclines, named actinosporins A (1) and B (2), were isolated from the broth culture of Actinokineospora sp. strain EG49, which was cultivated from the Red Sea sponge Spheciospongia vagabunda. The structures of actinosporins A and B were determined by 1D- and 2D-NMR techniques, as well as high resolution tandem mass spectrometry. Testing for antiparasitic properties showed that actinosporin A exhibited activity against Trypanosoma brucei brucei with an IC₅₀ value of 15 µM; however no activity was detected against Leishmania major and Plasmodium falciparum, therefore suggesting its selectivity against the parasite Trypanosoma brucei brucei; the causative agent of sleeping sickness. KW - dereplication KW - secondary metabolomics KW - anti-trypanosoma KW - Actinokineospora KW - Spheciospongia vagabunda KW - actinosporins Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119876 SN - 1660-3397 VL - 12 IS - 3 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Pimentel-Elardo, Sheila M. A1 - Hanora, Amro A1 - Radwan, Mona A1 - Abou-El-Ela, Soad H. A1 - Ahmed, Safwat A1 - Hentschel, Ute T1 - Isolation, Phylogenetic Analysis and Anti-infective Activity Screening of Marine Sponge-Associated Actinomycetes N2 - Terrestrial actinomycetes are noteworthy producers of a multitude of antibiotics, however the marine representatives are much less studied in this regard. In this study, 90 actinomycetes were isolated from 11 different species of marine sponges that had been collected from offshore Ras Mohamed (Egypt) and from Rovinj (Croatia). Phylogenetic characterization of the isolates based on 16S rRNA gene sequencing supported their assignment to 18 different actinomycete genera representing seven different suborders. Fourteen putatively novel species were identified based on sequence similarity values below 98.2% to other strains in the NCBI database. A putative new genus related to Rubrobacter was isolated on M1 agar that had been amended with sponge extract, thus highlighting the need for innovative cultivation protocols. Testing for anti-infective activities was performed against clinically relevant, Gram-positive (Enterococcus faecalis, Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, fungi (Candida albicans) and human parasites (Leishmania major, Trypanosoma brucei). Bioactivities against these pathogens were documented for 10 actinomycete isolates. These results show a high diversity of actinomycetes associated with marine sponges as well as highlight their potential to produce anti-infective agents. KW - Biologie KW - actinomycetes KW - marine sponges KW - anti-infective KW - anti-parasitic KW - phylogenetic Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68307 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Szesny, Matthias A1 - Othman, Eman Maher A1 - Schirmeister, Tanja A1 - Grond, Stepanie A1 - Stopper, Helga A1 - Hentschel, Ute T1 - Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115 N2 - Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70–90 μM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 μM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate. KW - Biologie KW - diazepinomicin KW - anti-protease KW - antioxidant KW - actinomycetes KW - Micromonospora Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76279 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Yang, Chen A1 - Horn, Hannes A1 - Hajjar, Dina A1 - Ravasi, Timothy A1 - Hentschel, Ute T1 - Actinomycetes from Red Sea Sponges: Sources for Chemical and Phylogenetic Diversity N2 - The diversity of actinomycetes associated with marine sponges collected off Fsar Reef (Saudi Arabia) was investigated in the present study. Forty-seven actinomycetes were cultivated and phylogenetically identified based on 16S rRNA gene sequencing and were assigned to 10 different actinomycete genera. Eight putatively novel species belonging to genera Kocuria, Mycobacterium, Nocardia, and Rhodococcus were identified based on sequence similarity values below 98.2% to other 16S rRNA gene sequences available in the NCBI database. PCR-based screening for biosynthetic genes including type I and type II polyketide synthases (PKS-I, PKS-II) as well as nonribosomal peptide synthetases (NRPS) showed that 20 actinomycete isolates encoded each at least one type of biosynthetic gene. The organic extracts of nine isolates displayed bioactivity against at least one of the test pathogens, which were Gram-positive and Gram-negative bacteria, fungi, human parasites, as well as in a West Nile Virus protease enzymatic assay. These results emphasize that marine sponges are a prolific resource for novel bioactive actinomycetes with potential for drug discovery. KW - PKS I KW - Meeresschwämme KW - PKS II KW - NRPS KW - Red sea KW - sponges KW - actinomycetes KW - bioactivity Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112882 ER - TY - JOUR A1 - Abdullahi, Sahra A1 - Wessel, Birgit A1 - Huber, Martin A1 - Wendleder, Anna A1 - Roth, Achim A1 - Kuenzer, Claudia T1 - Estimating penetration-related X-band InSAR elevation bias: a study over the Greenland ice sheet JF - Remote Sensing N2 - Accelerating melt on the Greenland ice sheet leads to dramatic changes at a global scale. Especially in the last decades, not only the monitoring, but also the quantification of these changes has gained considerably in importance. In this context, Interferometric Synthetic Aperture Radar (InSAR) systems complement existing data sources by their capability to acquire 3D information at high spatial resolution over large areas independent of weather conditions and illumination. However, penetration of the SAR signals into the snow and ice surface leads to a bias in measured height, which has to be corrected to obtain accurate elevation data. Therefore, this study purposes an easy transferable pixel-based approach for X-band penetration-related elevation bias estimation based on single-pass interferometric coherence and backscatter intensity which was performed at two test sites on the Northern Greenland ice sheet. In particular, the penetration bias was estimated using a multiple linear regression model based on TanDEM-X InSAR data and IceBridge laser-altimeter measurements to correct TanDEM-X Digital Elevation Model (DEM) scenes. Validation efforts yielded good agreement between observations and estimations with a coefficient of determination of R\(^2\) = 68% and an RMSE of 0.68 m. Furthermore, the study demonstrates the benefits of X-band penetration bias estimation within the application context of ice sheet elevation change detection. KW - InSAR height KW - penetration bias KW - cryosphere KW - TanDEM-X KW - Greenland ice sheet KW - DEM Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193902 SN - 2072-4292 VL - 11 IS - 24 ER - TY - JOUR A1 - Abendroth, Johanna A1 - Nauroth, Peter A1 - Richter, Tobias A1 - Gollwitzer, Mario T1 - Non-strategic detection of identity-threatening information: Epistemic validation and identity defense may share a common cognitive basis JF - PLoS ONE N2 - Readers use prior knowledge to evaluate the validity of statements and detect false information without effort and strategic control. The present study expands this research by exploring whether people also non-strategically detect information that threatens their social identity. Participants (N = 77) completed a task in which they had to respond to a “True” or “False” probe after reading true, false, identity-threatening, or non-threatening sentences. Replicating previous studies, participants reacted more slowly to a positive probe (“True”) after reading false (vs. true) sentences. Notably, participants also reacted more slowly to a positive probe after reading identity-threatening (vs. non-threatening) sentences. These results provide first evidence that identity-threatening information, just as false information, is detected at a very early stage of information processing and lends support to the notion of a routine, non-strategic identity-defense mechanism. KW - social identity KW - cognitive basis KW - identity defense Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301019 VL - 17 IS - 1 ER - TY - CHAP A1 - Abendschein, Robin A1 - Desai, Shital A1 - Astell, Arlene J. T1 - Towards Accessibility Guidelines for the Metaverse : A Synthesis of Recommendations for People Living With Dementia T2 - Conference on Human Factors in Computing Systems (CHI’23) : Workshop "Towards an Inclusive and Accessible Metaverse" N2 - Given the growing interest of corporate stakeholders in Metaverse applications, there is a need to understand accessibility of these technologies for marginalized populations such as people living with dementia to ensure inclusive design of Metaverse applications. We assessed the accessibility of extended reality technology for people living with mild cognitive impairment and dementia to develop accessibility guidelines for these technologies. We used four strategies to synthesize evidence for barriers and facilitators of accessibility: (1) Findings from a non-systematic literature review, (2) guidelines from well-researched technology, (3) exploration of selected mixed reality technologies, and (4) observations from four sessions and video data of people living with dementia using mixed reality technologies. We utilized template analysis to develop codes and themes towards accessibility guidelines. Future work can validate our preliminary findings by applying them on video recordings or testing them in experiments. KW - CHI Conference KW - Accessibility KW - Metaverse KW - extended reality KW - dementia KW - cognitive impairment KW - Human-centered computing / Access KW - Human-centered computing / Human computer interaction (HCI) / Interaction paradigms / Mixed / augmented reality KW - Human-centered computing / Human computer interaction (HCI) / Interaction paradigms / Virtual reality KW - Human-centered computing / Human computer interaction (HCI) / Interactiondevices KW - Human-centered computing / Human computerinteraction (HCI) / Interaction techniques Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320199 UR - https://sites.google.com/view/accessiblemetaverse ER - TY - JOUR A1 - Abimannan, Nagarajan A1 - Sumathi, G. A1 - Krishnarajasekhar, O. R. A1 - Sinha, Bhanu A1 - Krishnan, Padma T1 - Clonal Clusters and Virulence Factors of Methicillin-Resistant \(Staphylococcus\) \(Aureus\): Evidence for Community-Acquired Methicillin-Resistant \(Staphylococcus\) \(Aureus\) Infiltration into Hospital Settings in Chennai, South India JF - Indian Journal of Medical Microbiology N2 - Background and Objective: Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. Methods: S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance. Results and Conclusion: A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17%, 81.67%, 58.33% and 22.85% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings. KW - Community-acquired methicillin-resistant Staphylococcus aureus KW - HIV KW - hospital-acquired methicillin-resistant Staphylococcus aureus KW - innate immune evasions KW - MLST KW - microbial surface component recognising adhesive matrix molecules KW - spa typing KW - ST 772 KW - Inducible Clindamycin Resistance KW - Valentine Leukocidin Genes KW - Multiplex PCR KW - Nasal Carriage KW - Colonization KW - Prevalence KW - Emergence KW - Skin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226963 VL - 37 IS - 3 ER - TY - JOUR A1 - Ablin, Jacob A1 - Fitzcharles, Mary-Ann A1 - Buskila, Dan A1 - Shir, Yoram A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Treatment of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines with Special Emphasis on Complementary and Alternative Therapies JF - Evidence-Bayed Complementary and Alternative Medicine N2 - Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM-recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self-management strategies (exercise, and psychological techniques). KW - metaanalysis KW - management KW - care Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122235 SN - 1741-427X ER - TY - JOUR A1 - Aboagye, B. A1 - Weber, T. A1 - Merdian, H. L. A1 - Bartsch, D. A1 - Lesch, K. P. A1 - Waider, J. T1 - Serotonin deficiency induced after brain maturation rescues consequences of early life adversity JF - Scientific Reports N2 - Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKOxMS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders. KW - emotion KW - molecular medicine KW - neuroscience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258626 SN - 2045-2322 VL - 11 IS - 1 ER - TY - THES A1 - Aboagye, Benjamin T1 - Behavioral and physiologic consequences of inducible inactivation of the \(Tryptophan\) \(hydroxylase\) 2 gene in interaction with early-life adversity T1 - Verhaltens- und physiologische Konsequenzen einer induzierbaren Inaktivierung des \(Tryptophan\) \(hydroxylase\) 2-Gens Interaktion mit frühkindlichen Stresses N2 - Disruptions in brain serotonin (5-hydroxytryptamine, 5-HT) signaling pathways have been associated with etiology and pathogenesis of various neuropsychiatric disorders, but specific neural mechanisms of 5-HT function are yet to be fully elucidated. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme for brain 5-HT synthesis. Therefore, in this study a tamoxifen (Tam)-inducible cre-mediated conditional gene (Tph2) knockout in adult mouse brain (Tph2icKO) has been established to decipher the specific role of brain 5-HT in the regulation of behavior in adulthood. Immunohistochemistry and high-performance liquid chromatography (HPLC) were used first to test the efficacy of Tam-inducible inactivation of Tph2 and consequential reduction of 5-HT in adult mouse brain. Tam treatment resulted in ≥90% reduction in the number of 5-HT immuno-reactive cells in the anterior raphe nuclei. HPLC revealed a significant reduction in concentration of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in selected brain regions of Tph2icKO, indicating the effectiveness of the protocol used. Second, standard behavioral tests were used to assess whether reduced brain 5-HT concentrations could alter anxiety-, fear- and depressive-like behavior in mice. No altered anxiety- and depressive-like behaviors were observed in Tph2icKO compared to control mice (Tph2CON) in all indices measured, but Tph2icKO mice exhibited intense and sustained freezing during context-dependent fear memory retrieval. Tph2icKO mice also exhibited locomotor hyperactivity in the aversive environments, such as the open field, and consumed more food and fluid than Tph2CON mice. Lastly, the combined effect of maternal separation (MS) stress and adult brain 5-HT depletion on behavior was assessed in male and female mice. Here, MS stress, 5-HT depletion and their interaction elicited anxiety-like behavior in a sex-dependent manner. MS reduced exploratory behavior in both male and female mice. Reduced 5-HT enhanced anxiety in female, but not in male mice. Furthermore, expression of genes related to the 5-HT system and emotionality (Tph2, Htr1a, Htr2a, Maoa and Avpr1a) was assessed by performing a quantitative real-time PCR. In Tph2icKO mice there was a reduction in expression of Tph2 in the raphe nuclei of both male and female mice. Interaction between MS stress and 5-HT deficiency was detected showing increased Htr2a and Maoa expression in raphe and hippocampus respectively of female mice. In male mice, MS stress and 5-HT depletion interaction effects reduced Avpr1a expression in raphe, while the expression of Htr1a, Htr2a and Maoa was differentially altered by 5-HT depletion and MS in various brain regions. N2 - Unterbrechungen der Serotonin-Stoffwechselwege (5-Hydroxytryptamin, 5-HT) im Gehirn wurden mit der Ätiologie und der Pathogenese von verschiedenen neuropsychiatrischen Erkrankungen assoziiert, wobei die neuronalen Mechanismen der 5-HT Funktionen noch vollständig entschlüsselt werden müssen. Die Tryptophan-Hydroxylase 2 (TPH2) ist das limitierende Enzym für die 5-HT Synthese im Gehirn, weshalb der durch Tamoxifen (Tam) induzierbare, cre-vermittelte Tph2 Gen-Knockout (Tph2icKO) im adulten Mausgehirn möglicherweise helfen könnte die spezifische Rolle von 5-HT im Gehirn in der Regulation von adultem Verhalten zu entschlüsseln. Zuerst wurden Hochleistungsflüssigkeitschromatographie (HPLC) und Immunhistochemische Analysen durchgeführt um die Effizienz der Tam induzierten Inaktivierung des Tph2 und die daraus folgende Reduktion von 5-HT im Gehirn zu überprüfen. Die Behandlung mit Tam resultierte in einer ≥86% Reduktion der Anzahl von 5-HT immunoreaktiven Zellen in der anterioren Raphe im Gehirn. Die HPLC zeigte eine signifikante Reduktion der 5-HT Konzentration und dessen Stoffwechselprodukts 5-Hydroxyindolylessigsäure (5-HIAA) in ausgewählten Gehirn regionen von Tph2icKO, was auf die Effektivität des benutzten Protokolls hindeutet. Danach wurden standarisierte Verhaltens tests durchgeführt um festzustellen, ob eine reduzierte 5-HT Konzentrationen im Gehirn zu einer Veränderung in der Angstreaktion, Depression und im Furchtverhalten der Mäuse führt. Bei allen Tests konnte sowohl in den Tph2icKO-Mäusen als auch in den Kontrolltieren kein offensichtliches angstbezogenes und depressionsähnliches Verhalten festgestellt werden, wobei die Tph2icKO-Mäuse intensive und anhaltende Furcht im Kontext „dependent fear retrieval“ zeigten. Tph2icKO-Mäuse zeigten zudem lokomotorische Hyperaktivität und konsumierten mehr Futter und Flüssigkeit als die Kontrolltiere. Zuletzt wurde der kombinierte Effekt von Stress durch mütterliche Trennung (MS) und adulter 5-HT Reduktion im Gehirn auf das Verhalten von männlichen und weiblichen Mäusen untersucht. Wieder rief nicht der depressionsähnliche Phänotyp, sondernder Stress durch die mütterliche Trennung (MS) und 5-HT Verarmung und deren Interaktion ein angstähnliches Verhalten in Abhängigkeit vom Geschlecht hervor. Reduziertes 5-HT vergrößerte die Angst in weiblichen, aber nicht in männlichen Mäusen. Stress durch mütterliche Trennung (MS) reduzierte das explorative Verhalten sowohl in Männchen als auch in Weibchen. Die Expression von Genen, welche im Bezug zum 5-HT System stehen (Tph2, Htr1a, Htr2a, Maoa und Avpr1a) wurden mit Hilfe von quantitativer Real-Time PCR untersucht. Die Tam Behandlung reduzierte dasTph2 Level in der Raphe bei beiden Geschlechtern signifikant. In weiblichen Mäusen steigertedie Interaktion zwischen Stress durch mütterliche Trennung (MS) und 5-HT Verarmung das Htr2a und Maoa Expressions level in der Raphe und im Hippokampus. In männlichen Mäusen reduzierte die Interaktion von Stress durch mütterliche Trennung (MS) und 5-HT Reduktion die Avpr1a Expression in der Raphe. Die Expression von Htr1a, Htr2a und Maoa wurde in verschiedenen Gehirn regionen unterschiedlich von Tam und Mütterliche Trennung MS verändert. In der Amygdala wurde nur ein MS Effekt auf die Tph2 Expression in den Mäusen sichtbar. KW - Anxiety KW - Angst KW - Depression KW - Serotonin KW - Tamoxifen KW - Tryptophan hydroxylase Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173581 ER - TY - THES A1 - Abt, Raimond T1 - Implementing Aspects of Quantum Information into the AdS/CFT Correspondence T1 - Aspekte der Quanteninformation in der AdS/CFT-Korrespondenz N2 - In recent years many discoveries have been made that reveal a close relation between quantum information and geometry in the context of the AdS/CFT correspondence. In this duality between a conformal quantum field theory (CFT) and a theory of gravity on Anti-de Sitter spaces (AdS) quantum information quantities in CFT are associated with geometric objects in AdS. Subject of this thesis is the examination of this intriguing property of AdS/CFT. We study two central elements of quantum information: subregion complexity -- which is a measure for the effort required to construct a given reduced state -- and the modular Hamiltonian -- which is given by the logarithm of a considered reduced state. While a clear definition for subregion complexity in terms of unitary gates exists for discrete systems, a rigorous formulation for quantum field theories is not known. In AdS/CFT, subregion complexity is proposed to be related to certain codimension one regions on the AdS side. The main focus of this thesis lies on the examination of such candidates for gravitational duals of subregion complexity. We introduce the concept of \textit{topological complexity}, which considers subregion complexity to be given by the integral over the Ricci scalar of codimension one regions in AdS. The Gauss-Bonnet theorem provides very general expressions for the topological complexity of CFT\(_2\) states dual to global AdS\(_3\), BTZ black holes and conical defects. In particular, our calculations show that the topology of the considered codimension one bulk region plays an essential role for topological complexity. Moreover, we study holographic subregion complexity (HSRC), which associates the volume of a particular codimension one bulk region with subregion complexity. We derive an explicit field theory expression for the HSRC of vacuum states. The formulation of HSRC in terms of field theory quantities may allow to investigate whether this bulk object indeed provides a concept of subregion complexity on the CFT side. In particular, if this turns out to be the case, our expression for HSRC may be seen as a field theory definition of subregion complexity. We extend our expression to states dual to BTZ black holes and conical defects. A further focus of this thesis is the modular Hamiltonian of a family of states \(\rho_\lambda\) depending on a continuous parameter \(\lambda\). Here \(\lambda\) may be associated with the energy density or the temperature, for instance. The importance of the modular Hamiltonian for quantum information is due to its contribution to relative entropy -- one of the very few objects in quantum information with a rigorous definition for quantum field theories. The first order contribution in \(\tilde{\lambda}=\lambda-\lambda_0\) of the modular Hamiltonian to the relative entropy between \(\rho_\lambda\) and a reference state \(\rho_{\lambda_0}\) is provided by the first law of entanglement. We study under which circumstances higher order contributions in \(\tilde{\lambda}\) are to be expected. We show that for states reduced to two entangling regions \(A\), \(B\) the modular Hamiltonian of at least one of these regions is expected to provide higher order contributions in \(\tilde{\lambda}\) to the relative entropy if \(A\) and \(B\) saturate the Araki-Lieb inequality. The statement of the Araki-Lieb inequality is that the difference between the entanglement entropies of \(A\) and \(B\) is always smaller or equal to the entanglement entropy of the union of \(A\) and \(B\). Regions for which this inequality is saturated are referred to as entanglement plateaux. In AdS/CFT the relation between geometry and quantum information provides many examples for entanglement plateaux. We apply our result to several of them, including large intervals for states dual to BTZ black holes and annuli for states dual to black brane geometries. N2 - In den letzten Jahren wurden viele Entdeckungen gemacht, welche eine enge Beziehung zwischen Quanteninformation und Geometrie im Kontext der AdS/CFT-Korrespondenz aufzeigen. In dieser Dualität zwischen einer konformen Quantenfeldtheorie (CFT) und einer Gravitationstheorie auf Anti-de-Sitter-Räumen (AdS) werden Quanteninformationsgrößen der CFT mit geometrischen Objekten in AdS assoziiert. In der vorliegenden Arbeit wird dieser faszinierende Aspekt von AdS/CFT untersucht. Wir studieren zwei Objekte welche eine zentrale Rolle in der Quanteninformation spielen: Die Teilregionkomplexität (subregion complexity) -- welche ein Maß für den nötigen Aufwand zur Konstruktion eines vorgegebenen reduzierten Zustandes ist -- und den modularen Hamiltonoperator -- welcher durch den Logarithmus eines reduzierten Zustandes gegeben ist. Während eine klare Definition der Teilregionkomplexität mittels unitärer Gatter für diskrete Systeme angegeben werden kann, ist eine präzise Formulierung für Quantenfeldtheorien nicht bekannt. In der AdS/CFT-Korrespondenz wird angenommen, dass die Teilregionkomplexität mit bestimmten Regionen der Kodimension eins in AdS-Räumen in Beziehung stehen. Der Hauptfokus der vorliegenden Arbeit ist die Untersuchung derartiger Kandidaten für Gravitationsduale der Teilregionkomplexität. Wir führen das Konzept der \textit{topologischen Komplexität} (topological complexity) ein, welches das Integral über den Ricci-Skalar bestimmter Teilregionen von AdS-Räumen als das Gravitationsdual der Teilregionkomplexität ansieht. Der Satz von Gauss-Bonnet erlaubt es uns sehr allgemeine Ausdrücke für die Teilregionkomplexität von CFT\(_2\)-Zuständen mit globalem AdS\(_3\), BTZ-Schwarzen-Löchern oder konischen Defekten als Gravitationsdual zu konstruieren. Unsere Berechnungen zeigen insbesondere, dass die Topologie der betrachteten Kodimension-Eins-Regionen eine große Rolle für die topologische Komplexität spielt. Weiterhin befassen wir uns mit der holographischen Teilregionkomplexität (holographic subregion complexity, HSRC), welche annimmt, dass die Teilregionkomplexität durch das Volumen bestimmter Kodimension-Eins-Regionen in AdS-Räumen gegeben ist. Wir leiten einen expliziten Ausdruck für die HSRC von Vakuumzuständen in Größen der Feldtheorie her. Die Formulierung der HSRC in Feldtheoriegrößen könnte es ermöglichen zu untersuchen ob diese Größe tatsächlich als die Teilregionkomplexität der CFT interpretiert werden kann. Sollte sich dies bestätigen, kann unser Feldtheorieausdruck für HSRC als Definition für die Teilregionkomplexität der CFT angesehen werden. Wir verallgemeinern unseren Ausdruck für HSRC dahingehend, dass er auch für Zustände dual zu BTZ-Schwarzen-Löchern und konischen Defekten gültig ist. Ein weiterer Fokus der vorliegenden Arbeit ist der modulare Hamiltonoperator einer Familie von Zuständen \(\rho_\lambda\), welche von einem kontinuierlichen Parameter \(\lambda\) abhängen. Hierbei kann \(\lambda\) beispielsweise der Energiedichte oder der Temperatur entsprechen. Die Bedeutung des modularen Hamiltonoperator für die Quanteninformation ist auf seinen Beitrag zur relativen Entropie zurückzuführen -- eine der wenigen Größen der Quanteninformation für welche eine formale Definition für Quantenfeldtheorien bekannt ist. Der Beitrag erster Ordnung in \(\tilde{\lambda}=\lambda-\lambda_0\) des modularen Hamiltonoperators zur relativen Entropie zwischen \(\rho_\lambda\) und einem Referenzzustand \(\rho_{\lambda_0}\) ist gegeben durch den ersten Hauptsatz der Verschränkung (first law of entanglement). Wir untersuchen unter welchen Umständen Beiträge höherer Ordnung in \(\tilde{\lambda}\) zu erwarten sind. Wir zeigen, dass für Zustände die auf zwei Teilregionen \(A\), \(B\) reduziert wurden in der Regel mindestens einer dieser Beiträge höherer Ordnung in \(\tilde{\lambda}\) zur relativen Entropie liefert, wenn \(A\) und \(B\) die Araki-Lieb-Ungleichung saturieren. Die Araki-Lieb-Ungleichung besagt, dass die Differenz der Verschränkungsentropien von \(A\) und \(B\) stets kleiner oder gleich der Verschränkungsentropie der Vereinigung von \(A\) und \(B\) ist. Regionen für welche die Araki-Lieb-Ungleichung saturiert ist werden als Verschränkungsplateaus (entanglement plateaux) bezeichnet. In der AdS/CFT-Korrespondenz gibt es aufgrund der Beziehung zwischen Quanteninformation und Geometrie viele Beispiele für derartige Plateaus. Wir wenden unser Resultat auf einige dieser an. Unter anderem diskutieren wir große Intervalle für Zustände dual zu BTZ-Schwarzen-Löchern und Annuli für Zustände dual zu schwarzen Branen. KW - AdS-CFT-Korrespondenz KW - AdS/CFT KW - Complexity KW - Quantum Information KW - Modular Hamiltonian KW - AdS/CFT KW - Komplexität KW - Quanteninformation KW - Modularer Hamiltonoperator Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188012 ER - TY - JOUR A1 - Abt, Raimond A1 - Erdmenger, Johanna T1 - Properties of modular Hamiltonians on entanglement plateaux JF - Journal of High Energy Physics N2 - The modular Hamiltonian of reduced states, given essentially by the logarithm of the reduced density matrix, plays an important role within the AdS/CFT correspondence in view of its relation to quantum information. In particular, it is an essential ingredient for quantum information measures of distances between states, such as the relative entropy and the Fisher information metric. However, the modular Hamiltonian is known explicitly only for a few examples. For a family of states rho(lambda) that is parametrized by a scalar lambda, the first order contribution in (lambda) over tilde = lambda-lambda(0) of the modular Hamiltonian to the relative entropy between rho(lambda) and a reference state rho(lambda 0) is completely determined by the entanglement entropy, via the first law of entanglement. For several examples, e.g. for ball-shaped regions in the ground state of CFTs, higher order contributions are known to vanish. In these cases the modular Hamiltonian contributes to the Fisher information metric in a trivial way. We investigate under which conditions the modular Hamiltonian provides a non-trivial contribution to the Fisher information metric, i.e. when the contribution of the modular Hamiltonian to the relative entropy is of higher order in (lambda) over tilde. We consider one-parameter families of reduced states on two entangling regions that form an entanglement plateau, i.e. the entanglement entropies of the two regions saturate the Araki-Lieb inequality. We show that in general, at least one of the relative entropies of the two entangling regions is expected to involve (lambda) over tilde contributions of higher order from the modular Hamiltonian. Furthermore, we consider the implications of this observation for prominent AdS/CFT examples that form entanglement plateaux in the large N limit. KW - AdS-CFT Correspondence KW - Gauge-gravity correspondence KW - Conformal Field Theory KW - Relative Entropy KW - Complexity Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227693 VL - 11 IS - 2 ER - TY - JOUR A1 - Abt, Raimond A1 - Erdmenger, Johanna A1 - Gerbershagen, Marius A1 - Melby-Thompson, Charles M. A1 - Northe, Christian T1 - Holographic subregion complexity from kinematic space JF - Journal of High Energy Physics N2 - We consider the computation of volumes contained in a spatial slice of AdS(3) in terms of observables in a dual CFT. Our main tool is kinematic space, defined either from the bulk perspective as the space of oriented bulk geodesics, or from the CFT perspective as the space of entangling intervals. We give an explicit formula for the volume of a general region in a spatial slice of AdS(3) as an integral over kinematic space. For the region lying below a geodesic, we show how to write this volume purely in terms of entangling entropies in the dual CFT. This expression is perhaps most interesting in light of the complexity = volume proposal, which posits that complexity of holographic quantum states is computed by bulk volumes. An extension of this idea proposes that the holographic subregion complexity of an interval, defined as the volume under its Ryu-Takayanagi surface, is a measure of the complexity of the corresponding reduced density matrix. If this is true, our results give an explicit relationship between entanglement and subregion complexity in CFT, at least in the vacuum. We further extend many of our results to conical defect and BTZ black hole geometries. KW - AdS-CFT Correspondence KW - Gauge-gravity correspondence KW - Black Holes in String Theory KW - Black-hole KW - Entanglement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227711 VL - 1 IS - 12 ER - TY - JOUR A1 - Abu-Halima, Masood A1 - Häusler, Sebastian A1 - Backes, Christina A1 - Fehlmann, Tobias A1 - Staib, Claudia A1 - Nestel, Sigrun A1 - Nazarenko, Irina A1 - Meese, Eckart A1 - Keller, Andreas T1 - Micro-ribonucleic acids and extracellular vesicles repertoire in the spent culture media is altered in women undergoing \(In\) \(Vitro\) Fertilization JF - Scientific Reports N2 - MicroRNAs (miRNAs) are class of small RNA molecules with major impact on gene regulation. We analyzed the potential of miRNAs secreted from pre-implantation embryos into the embryonic culture media as biomarkers to predict successful pregnancy. Using microarray analysis, we profiled the miRNome of the 56 spent culture media (SCM) after embryos transfer and found a total of 621 miRNAs in the SCM. On average, we detected 163 miRNAs in SCM of samples with failed pregnancies, but only 149 SCM miRNAs of embryos leading to pregnancies. MiR-634 predicted an embryo transfer leading to a positive pregnancy with an accuracy of 71% and a sensitivity of 85%. Among the 621 miRNAs, 102 (16.4%) showed a differential expression between positive and negative outcome of pregnancy with miR-29c-3p as the most significantly differentially expressed miRNA. The number of extracellular vehicles was lower in SCM with positive outcomes (3.8 × 10\(^9\)/mL EVs), as compared to a negative outcome (7.35 × 10\(^9\)/mL EVs) possibly explaining the reduced number of miRNAs in the SCM associated with failed pregnancies. The analysis of the miRNome in the SCM of couples undergoing fertility treatment lays the ground towards development of biomarkers to predict successful pregnancy and towards understanding the role of embryonic miRNAs found in the SCM. KW - Medicine KW - miRNAs KW - Molecular biology KW - Non-coding RNAs Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173632 VL - 7 ER - TY - JOUR A1 - Achenbach, Leonard A1 - Huppertz, Gunnar A1 - Zeman, Florian A1 - Weber, Johannes A1 - Luig, Patrick A1 - Rudert, Maximilian A1 - Krutsch, Werner T1 - Multicomponent stretching and rubber band strengthening exercises do not reduce overuse shoulder injuries: a cluster randomised controlled trial with 579 handball athletes JF - BMJ Open Sport & Exercise Medicine N2 - Objectives Handball is associated with a high risk of overuse shoulder injury. This study investigated if an injury prevention programme effectively reduces overuse injury to the throwing shoulder of handball athletes. Methods 61 men’s and women’s handball teams (u-19 and senior athletes) were cluster-randomised into an intervention and a control group in the 2019–2020 season. Players of the intervention group regularly carried out an injury prevention programme. Both groups documented overuse shoulder injuries via an online questionnaire every second week. The primary endpoint was the prevalence of overuse injury to the throwing shoulder. Secondary endpoints were the influence of compliance on the primary endpoint and intensity of overuse shoulder symptoms measured by a shortened, handball-specific Western Ontario Shoulder Index (WOSI). Results 31 teams (295 players) in the intervention group and 30 teams (284 players) in the control group were included for analyses. The overall questionnaire response rate was 61%. The average prevalence of overuse shoulder injury did not significantly differ between the intervention group (n=109, 38.4% (95% CI 32.9% to 44.2%)) and the control group (n=106, 35.9% (95% CI 30.7% to 41.6%), p=0.542). Compliance with the intervention programme did not significantly affect overuse shoulder injury (p=0.893). Using generalised estimating equations for WOSI, the estimated mean for the intervention group was 44.6 points (95% CI 42.0 to 47.1) and 47.6 points for the control group (95% CI 44.9 to 50.3, p=0.111). Conclusions A multicomponent exercise programme using rubber bands and stretching did not significantly reduce the prevalence or symptoms of overuse throwing shoulder injury in handball athletes of both sexes. Randomised controlled study; level of evidence I. KW - handball KW - multicomponent stretching KW - shoulder injuries Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300770 SN - 2055-7647 VL - 8 IS - 1 ER - TY - JOUR A1 - Achenbach, Leonard A1 - Klein, Christian A1 - Luig, Patrick A1 - Bloch, Hendrik A1 - Schneider, Dominik A1 - Fehske, Kai T1 - Collision with opponents - but not foul play - dominates injury mechanism in professional men's basketball JF - BMC Sports Science Medicine and Rehabilitation N2 - Background To identify injury patterns and mechanisms in professional men’s basketball by means of video match analysis. Methods In Germany, injuries are registered with the statutory accident insurance for professional athletes (VBG) by clubs or club physicians as part of occupational accident reporting. Moderate and severe injuries (absence of > 7 days) sustained during basketball competition in one of four seasons (2014–2017 and 2018–2019) in the first or second national men’s league in Germany were prospectively analyzed using a newly developed standardized observation form. Season 2017–2018 was excluded because of missing video material. Results Video analysis included 175 (53%) of 329 moderate and severe match injuries. Contact patterns categorized according to the different body sites yielded eight groups of typical injury patterns: one each for the head, shoulders, and ankles, two for the thighs, and three for the knees. Injuries to the head (92%), ankles (76%), shoulders (70%), knees (47%), and thighs (32%) were mainly caused by direct contact. The injury proportion of foul play was 19%. Most injuries (61%) occurred in the central zone below the basket. More injuries occurred during the second (OR 1.8, p = 0.018) and fourth quarter (OR 1.8, p = 0.022) than during the first and third quarter of the match. Conclusion The eight identified injury patterns differed substantially in their mechanisms. Moderate and severe match injuries to the head, shoulders, knees, and ankles were mainly caused by collision with opponents and teammates. Thus, stricter rule enforcement is unlikely to facilitate safer match play. KW - epidemiology KW - mechanism KW - contact KW - non-contact´ KW - injury prevention KW - match load Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261765 VL - 13 ER - TY - JOUR A1 - Achenbach, Leonard A1 - Le Hanneur, Malo A1 - Camenzind, Roland S. A1 - Bouyer, Michael A1 - Pottecher, Pierre A1 - Lafosse, Thibault T1 - Systematic bifocal decompression for isolated long thoracic nerve paresis: A case series of 12 patients JF - Interdisciplinary Neurosurgery N2 - To date, no consensus exists regarding the best surgical management of isolated, micro-traumatic long thoracic nerve (LTN) paresis. Our hypothesis was that a combined decompression of the LTN at two potential locations for entrapment would be effective in the management of dynamic LTN paresis. We report on twelve patients with isolated LTN parersis, with tenderness at two entrapment sites, who underwent bifocal LTN decompression after undergoing unsuccessful conservative treatment for at least 6 months; all patients had preoperative electrodiagnostic studies that confirmed the paresis and ruled out peripheral neuritis. Clinical and electrical improvements were observed in eight patients (67%) regarding shoulder flexion, shoulder abduction, and Quick-DASH scores. Four patients (33%) did not improve after surgery. The results corroborate our hypothesis that a bifocal LTN decompression can be an effective and reliable therapeutic option in more than half of a very selective patient population suffering from serratus anterior muscle deficiency. KW - entrapment, traction KW - serratus anterior KW - scapular winging KW - scapula alata KW - dyskinesia KW - peripheral nerve KW - nerve compression KW - micro-traumatic KW - neurolysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265085 VL - 27 ER - TY - BOOK A1 - Ackermann, Zeno A1 - Karremann, Isabel A1 - Malhotra, Simi A1 - Zaidi, Nishat T1 - Terrains of Consciousness: Multilogical Perspectives on Globalization N2 - TERRAINS OF CONSCIOUSNESS emerges from an Indian-German-Swiss research collaboration. The book makes a case for a phenomenology of globalization that pays attention to locally situated socioeconomic terrains, everyday practices, and cultures of knowledge. This is exemplified in relation to three topics: - the tension between ‘terrain’ and ‘territory’ in Defoe’s ‘Robinson Crusoe’ as a pioneering work of the globalist mentality (chapter 1) - the relationship between established conceptions of feminism and the concrete struggles of women in India since the 19th century (chapter 2) - the exploration of urban space and urban life in writings on India’s capital – from Ahmed Ali to Arundhati Roy (chapter 3). N2 - TERRAINS OF CONSCIOUSNESS emerges from a transnational research project in which scholars from Jamia Millia Islamia (New Delhi), the JMU Würzburg, and the University of Zurich collaborated to evolve new multilogical perspectives on what is usually referred to as globalization. The book makes a case for a PHENOMENOLOGY OF GLOBALIZATION that pays particular attention to the transformation of locally situated and individually experienced socioeconomic terrains, everyday practices, and cultures of knowledge. This perspective is exemplified in relation to three concrete research topics: - the tension between the concepts of ‘TERRAIN’ and ‘TERRITORY’ in parts one and two of Daniel Defoe’s "Robinson Crusoe as" a pioneering work of the globalist mentality (chapter 1) - the relationship between established abstract conceptions of FEMINISM and the concrete emancipatory struggles and life practices of women in India since the early 19th century (chapter 2) - the exploration of URBAN SPACE and URBAN LIFE as a socio-sensorial terrain in fictional and non-fictional writings on or of Delhi – from Ahmed Ali’s "Twilight in Delhi" (1940) to Arundhati Roy’s "The Ministry of Utmost Happiness" (2017). Throughout, the approach of Terrains of Consciousness is informed by the uncomfortable question of how the ‘liberating’ effects of globalization relate to its limiting and disrupting consequences. In these respects, it is vital to ask how globalization affects the dispossessed inhabitants of the world and its various societies. KW - Globalisierung KW - Sinne KW - Kulturtheorie KW - Literaturwissenschaft KW - Stadtforschung KW - Globalization KW - Sensory Studies KW - Phenomenology KW - Mondialization KW - Articulation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243936 SN - 978-3-95826-168-6 SN - 978-3-95826-169-3 N1 - Parallel erschienen als Druckausgabe in Würzburg University Press, 978-3-95826-168-6, 24,90 Euro. PB - Würzburg University Press CY - Würzburg ET - 1. Auflage ER - TY - CHAP A1 - Ackermann, Zeno A1 - Snyder-Körber, MaryAnn ED - Jetter, Tobias T1 - Series Foreword : JMU Cultural Studies – Strategies for Struggling with the Obvious T2 - Global Cultural Studies? Engaged Scholarship between National and Transnational Frames N2 - No abstract available. KW - Kulturwissenschaften KW - Hall, Stuart KW - Globalisierung KW - Kulturwissenschaft KW - cultural studies KW - Nationale Traditionen KW - national traditions KW - Transnationalismus KW - transnationalism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305801 PB - Würzburg University Press CY - Würzburg ER - TY - JOUR A1 - Acqualagna, Laura A1 - Botrel, Loic A1 - Vidaurre, Carmen A1 - Kübler, Andrea A1 - Blankertz, Benjamin T1 - Large-Scale Assessment of a Fully Automatic Co-Adaptive Motor Imagery-Based Brain Computer Interface JF - PLoS ONE N2 - In the last years Brain Computer Interface (BCI) technology has benefited from the development of sophisticated machine leaning methods that let the user operate the BCI after a few trials of calibration. One remarkable example is the recent development of co-adaptive techniques that proved to extend the use of BCIs also to people not able to achieve successful control with the standard BCI procedure. Especially for BCIs based on the modulation of the Sensorimotor Rhythm (SMR) these improvements are essential, since a not negligible percentage of users is unable to operate SMR-BCIs efficiently. In this study we evaluated for the first time a fully automatic co-adaptive BCI system on a large scale. A pool of 168 participants naive to BCIs operated the co-adaptive SMR-BCI in one single session. Different psychological interventions were performed prior the BCI session in order to investigate how motor coordination training and relaxation could influence BCI performance. A neurophysiological indicator based on the Power Spectral Density (PSD) was extracted by the recording of few minutes of resting state brain activity and tested as predictor of BCI performances. Results show that high accuracies in operating the BCI could be reached by the majority of the participants before the end of the session. BCI performances could be significantly predicted by the neurophysiological indicator, consolidating the validity of the model previously developed. Anyway, we still found about 22% of users with performance significantly lower than the threshold of efficient BCI control at the end of the session. Being the inter-subject variability still the major problem of BCI technology, we pointed out crucial issues for those who did not achieve sufficient control. Finally, we propose valid developments to move a step forward to the applicability of the promising co-adaptive methods. KW - large-scale assessment KW - Brain Computer Interface KW - machine leaning KW - fully automatic KW - co-adaptive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167230 VL - 11 IS - 2 ER - TY - JOUR A1 - Adaku Chilaka, Cynthia A1 - Mally, Angela T1 - Mycotoxin Occurrence, Exposure and Health Implications in Infants and Young Children in Sub-Saharan Africa: A Review JF - Foods N2 - Infants and young children (IYC) remain the most vulnerable population group to environmental hazards worldwide, especially in economically developing regions such as sub-Saharan Africa (SSA). As a result, several governmental and non-governmental institutions including health, environmental and food safety networks and researchers have been proactive toward protecting this group. Mycotoxins, toxic secondary fungal metabolites, contribute largely to the health risks of this young population. In SSA, the scenario is worsened by socioeconomic status, poor agricultural and storage practices, and low level of awareness, as well as the non-establishment and lack of enforcement of regulatory limits in the region. Studies have revealed mycotoxin occurrence in breast milk and other weaning foods. Of concern is the early exposure of infants to mycotoxins through transplacental transfer and breast milk as a consequence of maternal exposure, which may result in adverse health effects. The current paper presents an overview of mycotoxin occurrence in foods intended for IYC in SSA. It discusses the imperative evidence of mycotoxin exposure of this population group in SSA, taking into account consumption data and the occurrence of mycotoxins in food, as well as biomonitoring approaches. Additionally, it discusses the health implications associated with IYC exposure to mycotoxins in SSA. KW - mycotoxin KW - occurrence KW - exposure KW - child health KW - sub-Saharan Africa Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219250 SN - 2304-8158 VL - 9 IS - 11 ER - TY - JOUR A1 - Adam, Alexander A1 - Deimel, Stephan A1 - Pardo-Medina, Javier A1 - García-Martínez, Jorge A1 - Konte, Tilen A1 - Limón, M. Carmen A1 - Avalos, Javier A1 - Terpitz, Ulrich T1 - Protein activity of the \(Fusarium\) \(fujikuroi\) rhodopsins CarO and OpsA and their relation to fungus−plant interaction JF - International Journal of Molecular Sciences N2 - Fungi possess diverse photosensory proteins that allow them to perceive different light wavelengths and to adapt to changing light conditions in their environment. The biological and physiological roles of the green light-sensing rhodopsins in fungi are not yet resolved. The rice plant pathogen Fusarium fujikuroi exhibits two different rhodopsins, CarO and OpsA. CarO was previously characterized as a light-driven proton pump. We further analyzed the pumping behavior of CarO by patch-clamp experiments. Our data show that CarO pumping activity is strongly augmented in the presence of the plant hormone indole-3-acetic acid and in sodium acetate, in a dose-dependent manner under slightly acidic conditions. By contrast, under these and other tested conditions, the Neurospora rhodopsin (NR)-like rhodopsin OpsA did not exhibit any pump activity. Basic local alignment search tool (BLAST) searches in the genomes of ascomycetes revealed the occurrence of rhodopsin-encoding genes mainly in phyto-associated or phytopathogenic fungi, suggesting a possible correlation of the presence of rhodopsins with fungal ecology. In accordance, rice plants infected with a CarO-deficient F. fujikuroi strain showed more severe bakanae symptoms than the reference strain, indicating a potential role of the CarO rhodopsin in the regulation of plant infection by this fungus. KW - fungal rhodopsins KW - CarO KW - OpsA KW - Fusarium fujikuroi KW - Oryza sativa KW - rice–plant infection KW - green light perception KW - indole-3-acetic acid (IAA) KW - bakanae KW - patch-clamp Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285125 SN - 1422-0067 VL - 19 IS - 1 ER - TY - JOUR A1 - Adam, Christian A1 - Baeurle, Anne A1 - Brodsky, Jeffrey L. A1 - Schrama, David A1 - Wipf, Peter A1 - Becker, Jürgen Christian A1 - Houben, Roland T1 - The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma N2 - Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future. KW - apoptosis KW - cancer treatment KW - cell staining KW - cultured fibroplasts KW - heat shock response KW - membrans proteins KW - polymerase chain reaction Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112795 ER - TY - CHAP A1 - Adam, D. A1 - Schartl, A. A1 - Andexinger, S. A1 - Hölter, S. A1 - Wilde, B. A1 - Schartl, Manfred T1 - Genetic factors in tumour formation: The melanoma-inducing gene of Xiphophorus N2 - No abstract available. KW - Humangenetik KW - Tumor KW - Entstehung Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86388 ER - TY - JOUR A1 - Adam, D. A1 - Wittbrodt, J. A1 - Telling, A. A1 - Schartl, Manfred T1 - RFLP for an EGF-receptor related gene associated with the melanoma oncogene locus of Xiphophorus maculatus N2 - No abstract available KW - Physiologische Chemie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61822 ER - TY - JOUR A1 - Adam, Dieter A1 - Dimitrijevic, Nicola A1 - Schartl, Manfred T1 - Tumor suppression in Xiphophorus by an accidentally acquired promoter N2 - Melanoma formation in the teleost Xiphophorus is caused by a dominant genetic locus, Tu. This locus includes the Xmrk oncogene, which encodes a receptor tyrosine kinase. Tumor induction is. suppressed in wild-type fish by a tumor suppressor locus, R. Molecular genetic analyses revealed that the Tu locus emerged by nonhomologaus recombination of the Xmrk proto-oncogene with a previously uncharacterized sequence, D. This event generated an additional copy of Xmrk with a new promoter. Suppression of the new Xmrk promoter by R in parental fish and its deregulation in hybrids explain the genetics of melanoma formation in Xiphophorus. KW - Physiologische Chemie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61630 ER - TY - JOUR A1 - Adam, Dieter A1 - Maueler, Winfried A1 - Schartl, Manfred T1 - Transcriptional activation of the melanoma inducing Xmrk oncogene in Xiphophorus N2 - The melanoma inducing locus of Xiphophorus encodes a tumorigenic version of a novel putative receptor tyrosine kinase (Xmrk). To elucidate the mechanism of oncogenic activation of Xmrk, we compared the structure and expression of two oncogenic loci with the corresponding proto-oncogene. Only minor structural alterations were found to be specific for the oncogenic Xmrk genes. Marked overexpression of the oncogene transcripts in melanoma, which are approximately 1 kb shorter than the proto-oncogene transcript, correlates with the malignancy of the tumors. The tumor transcripts are derived from an alternative transcription start site that is used only in the oncogenic loci. Thus, oncogenic activation of the melanoma inducing Xmrk gene appears primarily to be due to novel transcriptional control and overexpression. KW - Schwertkärpfling KW - Onkogen KW - Melanom Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-87584 ER - TY - JOUR A1 - Adam, Pia A1 - Kircher, Stefan A1 - Sbiera, Iuliu A1 - Koehler, Viktoria Florentine A1 - Berg, Elke A1 - Knösel, Thomas A1 - Sandner, Benjamin A1 - Fenske, Wiebke Kristin A1 - Bläker, Hendrik A1 - Smaxwil, Constantin A1 - Zielke, Andreas A1 - Sipos, Bence A1 - Allelein, Stephanie A1 - Schott, Matthias A1 - Dierks, Christine A1 - Spitzweg, Christine A1 - Fassnacht, Martin A1 - Kroiss, Matthias T1 - FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale JF - Frontiers in Endocrinology N2 - Background Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation. KW - tyrosine kinase inhibitor (TKI) KW - immune checkpoint inhibitor (ICI) KW - immunohistochemistry KW - immunotherapy KW - PD-L1 KW - FGFR Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244653 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Adam, W. A1 - Ahrweiler, M. A1 - Saha-Möller, C. R. A1 - Sauter, M. A1 - Schönberger, A. A1 - Epe, B. A1 - Müller, E. A1 - Schiffmann, D. A1 - Stopper, Helga A1 - Wild, D. T1 - Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells N2 - 1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system. KW - Toxikologie KW - 1 KW - 2-Dioxetane KW - Benzefuran dioxetane KW - Benzefuran epoxide KW - DNA damage KW - Mutagenicity KW - DNA adduct . Repair endonuclease KW - FPG protein Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63420 ER - TY - THES A1 - Adamek, Julian T1 - Classical and Quantum Aspects of Anisotropic Cosmology T1 - Klassische und Quantentheoretische Gesichtspunkte der Anisotropen Kosmologie N2 - The idea that our observable Universe may have originated from a quantum tunneling event out of an eternally inflating false vacuum state is a cornerstone of the multiverse paradigm. Modern theories that are considered as an approach towards the ultraviolet-complete fundamental theory of particles and gravity, such as the various types of string theory, even suggest that a vast landscape of different vacuum configurations exists, and that gravitational tunneling is an important mechanism with which the Universe can explore this landscape. The tunneling scenario also presents a unique framework to address the initial conditions of our observable Universe. In particular, it allows to introduce deviations from the cosmological concordance model in a controlled and well-motivated way. These deviations are a central topic of this work. An important feature in most of the theories mentioned above is the presumed existence of additional space dimensions in excess of the three which we observe in our every-day experience. It was realized that these extra dimensions could avoid our detection if they are compactified to microscopic length scales far beyond the reach of current experiments. There also seem to be natural mechanisms available for dynamical compactification in those theories. These typically lead to a vast landscape of different vacuum configurations which also may differ in the number of macroscopic dimensions, only the total number of dimensions being determined by the theory. Transitions between these vacuum configurations may hence open up new directions which were previously compact, spontaneously compactify some previously macroscopic directions, or otherwise re-arrange the configuration of compact and macroscopic dimensions in a more general way. From within the bubble Universe, such a process may be perceived as an anisotropic background spacetime - intuitively, the dimensions which open up may give rise to preferred directions. If our 3+1 dimensional observable Universe was born in a process as described above, one may expect to find traces of a preferred direction in cosmological observations. For instance, two directions could be curved like on a sphere, while the third space direction is flat. Using a scenario of gravitational tunneling to fix the initial conditions, I show how the primordial signatures in such an anisotropic Universe can be obtained in principle and work out a particular example in more detail. A small deviation from isotropy also has phenomenological consequences for the later evolution of the Universe. I discuss the most important effects and show that backreaction can be dynamically important. In particular, under certain conditions, a buildup of anisotropic stress in different components of the cosmic fluid can lead to a dynamical isotropization of the total stress-energy tensor. The mechanism is again demonstrated with the help of a physical example. N2 - Die Vorstellung von einem Multiversum baut unter anderem auf dem Gedanken auf, dass unser beobachtbares Universum in einem Tunnelprozess entstanden sein könnte. Demzufolge hätte es sich dabei von einem ewig währenden, inflationären Vakuumzustand abgekoppelt. Die so entstehende Blase gleicht einer bewohnbaren Insel inmitten eines gewaltigen Ozeans. Moderne Theorien, die als gute Ansätze bezüglich einer fundamentalen und ultraviolett-vollständigen Beschreibung von Elementarteilchen und Gravitation angesehen werden, wie etwa die verschiedenen Ausprägungen der Stringtheorie, legen sogar nahe, dass eine ganze "Landschaft" (im Englischen "landscape") verschiedener Vakuumzustände existiert, und dass Tunnelprozesse einen wichtigen Mechanismus darstellen, mit dem das Universum die Vielzahl an Möglichkeiten erforschen und realisieren kann. Das Tunnelszenario stellt auch einen einzigartigen Rahmen zur Verfügung, um die Anfangsbedingungen unseres beobachtbaren Universums zu untersuchen. Insbesondere besteht damit die Möglichkeit, geringfügige Abweichungen vom kosmologischen Standardmodell in kontrollierter und gut motivierter Art und Weise zu realisieren. Solche Abweichungen stellen eines der zentralen Themen dieser Arbeit dar. Eine wichtige Besonderheit der eben erwähnten Theorien ist die Annahme, dass neben den drei uns bekannten Raumdimensionen eine Vielzahl weiterer existieren könnte. Diese Zusatzdimensionen könnten vor uns verborgen sein, wenn sie kompakt sind und nur extrem mikroskopische Ausmaße haben, so dass sie sich weit unterhalb des Auflösungsvermögens heutiger Experimente befinden. Mechanismen, welche eine solche mikroskopische Gestalt dynamisch erklären könnten, sind in den gängigen Theorien auf ganz natürliche Weise verfügbar. Typischerweise ergibt sich daraus das eben gezeichnete Bild einer ausgedehnten "Landschaft" verschiedener Konfigurationen. Die Vakuumzustände können sich nun auch in der Anzahl und Gestalt der mikroskopischen Dimensionen unterscheiden, da nur die Gesamtzahl an Raumdimensionen von der Theorie vorgegeben wird. Übergänge zwischen diesen Zuständen können also dazu führen, dass neue Raumrichtungen entstehen, indem mikroskopische Dimensionen sich plötzlich aufblähen, alte Raumrichtungen verschwinden, indem sie sich spontan ins Mikroskopische zusammenziehen, oder dass die Konfiguration der Raumdimensionen auf eine noch kompliziertere Art und Weise verändert wird. Aus Sicht des neu entstehenden "Universums" in der Blase führt ein solcher Prozess effektiv zu einem anisotropen Hintergrund - vereinfacht ausgedrückt können die neu entstehenden Raumrichtungen eine Vorzugsrichtung ausweisen. Wenn unser 3+1 dimensionales beobachtbares Universum in einem solchen Prozess entstanden ist, kann man vermuten, dass sich in kosmologischen Beobachtungen Hinweise auf eine Vorzugsrichtung finden lassen müssten. Zum Beispiel könnten zwei Raumrichtungen gekrümmt wie eine Kugeloberfläche sein, während die dritte Richtung keinerlei Krümmung aufweist. Indem ich ein Tunnelszenario benutze, um die Anfangsbedingungen festzulegen, gelingt es mir zu zeigen wie die primordialen Spuren eines solchen anisotropen Universums prinzipiell auszusehen haben und führe eine Berechnung anhand eines speziellen Beispiels explizit vor. Eine geringfügige Abweichung von Isotropie hat ebenfalls phänomenologische Auswirkungen auf die spätere Entwicklung des Universums. Ich gehe auf die wichtigsten Effekte ein und zeige außerdem, dass Rückkopplung dynamisch relevant sein kann. Insbesondere kann sich unter gewissen Voraussetzungen ein Ungleichgewicht der Druckkräfte in verschiedenen Komponenten der "kosmischen Flüssigkeit" aufbauen, das insgesamt zu einer dynamischen Isotropisierung des kollektiven Energie-Impuls-Tensors führt. Dieser Mechanismus wird ebenfalls anhand eines konkreten Beispiels beleuchtet. KW - Kosmologie KW - Anisotropes Universum KW - Quantenkosmologie KW - Bianchi-Kosmologie KW - Anisotropic Universe Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-65908 ER - TY - JOUR A1 - Adami, Hans-Olov A1 - Dragsted, Lars A1 - Enig, Bent A1 - Hansen, Jens A1 - Haraldsdóttir, Jóhanna A1 - Hill, Michael J. A1 - Holm, Lars Erik A1 - Knudsen, Ib A1 - Larsen, Jens-Jorgen A1 - Lutz, Werner K. A1 - Osler, Merete A1 - Overvad, Kim A1 - Sabroe, Svend A1 - Sanner, Tore A1 - Strube, Michael A1 - Sorensen, Thorkild I. A. A1 - Thorling, Eivind B. T1 - Report from the working group on diet and cancer. N2 - No abstract available. KW - Krebs KW - Ernährung Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71601 ER - TY - THES A1 - Adel Abdelrehim Mohamed Soliman, Hadya T1 - Structural Equation Modeling of Factors Influencing EFL Reading comprehension: Comparative study between Egypt and Germany T1 - Strukturgleichungsmodellierung von Faktoren, die das EFL-Leseverständnis beeinflussen: Vergleichende Studie zwischen Ägypten und Deutschland N2 - In most foreign language learning contexts, there are only rare chance for contact with native speakers of the target language. In such a situation, reading plays an important role in language acquisition as well as in gaining cultural information about the target language and its speakers. Previous research indicated that reading in foreign language is a complex process, which is influenced by various linguistic, cognitive and affective factors. The aim of the present study was to test two structural models of the relationship between reading comprehension in native language (L1), English language (L2) reading motivation, metacognitive awareness of L2 reading strategies, and reading comprehension of English as a foreign language among the two samples. Furthermore, the current study aimed to examine the differences between Egyptian and German students in their perceived usage of reading strategies during reading English texts, as well as to explore the pattern of their motivation toward reading English texts. For this purpose, 401 students were recruited from Germany (n=200) and Egypt (n=201) to participate in the current study. In order to have information about metacognitive awareness of reading strategies, a self-report questionnaire (SORS) developed by Moktari and Sheory (2002) was used. While the L2 reading motivation variable, was measured by a reading motivation survey (L2RMQ) which was based on reviewed reading motivation research. In addition, two reading tests were administrated one to measure reading comprehension for native language (German/Arabic) and the other to measure English reading comprehension. To analyze the collected data, descriptive statistics and independent t-tests were performed. In addition, further analysis using structural equation modeling was applied to test the strength of relationships between the variables under study. The results from the current research revealed that L1 reading comprehension, whether in a German or Arabic language, had the strongest relationship with L2 reading comprehension. However, the relationship between L2 intrinsic reading motivation was not proven to be significant in either the German or Egyptian models. On the other hand, the relationship between L2 extrinsic reading motivation, metacognitive awareness of reading strategies, and L2 reading comprehension was only proven significant in the German sample. The discussion of these results along with their pedagogical implications for education and practice will be illustrated in the following study. N2 - In den meisten Kontexten des Fremdsprachenlernens gibt es nur selten eine Chance auf Kontakt mit Muttersprachlern der Zielsprache. In einer solchen Situation spielt das Lesen eine wichtige Rolle beim Spracherwerb sowie bei der Gewinnung kultureller Informationen über die Zielsprache und ihre Sprecher. Frühere Untersuchungen haben gezeigt, dass das Lesen in der Fremdsprache ein komplexer Prozess ist, der von verschiedenen linguistischen, kognitiven und affektiven Faktoren beeinflusst wird. Ziel der vorliegenden Studie war es, zwei Strukturmodelle der Beziehung zwischen Leseverständnis in der Muttersprache (L1), englischer Sprache (L2) Lesemotivation, metakognitivem Bewusstsein für L2-Lesestrategien und Leseverständnis von Englisch als Fremdsprache zwischen den beiden Stichproben zu testen. Zur Analyse der gesammelten Daten wurden deskriptive Statistiken und unabhängige t-Tests durchgeführt. Darüber hinaus wurde eine weitere Analyse mit Hilfe der Strukturgleichungsmodellierung durchgeführt, um die Stärke der Beziehungen zwischen den untersuchten Variablen zu testen. Die Ergebnisse der aktuellen Forschung zeigten, dass das L1-Leseverständnis, ob in deutscher oder arabischer Sprache, die stärkste Beziehung zum L2-Leseverständnis hatte. Der Zusammenhang zwischen L2 intrinsischer Lesemotivation wurde jedoch weder im deutschen noch im ägyptischen Modell nachgewiesen. Andererseits war der Zusammenhang zwischen L2 extrinsischer Lesemotivation, metakognitivem Bewusstsein für Lesestrategien und L2-Leseverständnis nur in der deutschen Stichprobe signifikant. Die Diskussion dieser Ergebnisse sowie ihre pädagogischen Implikationen für Bildung und Praxis werden in der folgenden Studie dargestellt. KW - L1 reading comprehension KW - metacognition KW - L2 reading motivation KW - L2 reading comprehension KW - Leseverstehen Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186957 ER - TY - JOUR A1 - Adelfinger, Marion A1 - Bessler, Simon A1 - Cecil, Alexander A1 - Langbein-Laugwitz, Johanna A1 - Frentzen, Alexa A1 - Gentschev, Ivaylo A1 - Szalay, Aladar A. T1 - Preclinical Testing Oncolytic Vaccinia Virus Strain GLV-5b451 Expressing an Anti-VEGF Single-Chain Antibody for Canine Cancer Therapy JF - Viruses N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for canine cancer therapy. Here we describe, for the first time, the characterization and the use of VACV strain GLV-5b451 expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as therapeutic agent against different canine cancers. Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1). The GLV-5b451 virus-mediated production of GLAF-2 antibody was observed in all four cancer cell lines. In addition, this antibody specifically recognized canine VEGF. Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth. A CD31-based immuno-staining showed significantly decreased neo-angiogenesis in GLV-5b451-treated tumors compared to the controls. In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS. KW - canine cancer therapy KW - canine soft tissue sarcoma (CSTS) KW - oncolytic virus KW - cancer KW - canine cancer cell lines KW - antibody production KW - angiogenesis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125705 VL - 7 ER - TY - JOUR A1 - Adelfinger, Marion A1 - Gentschev, Ivaylo A1 - de Guibert, Julio Grimm A1 - Weibel, Stephanie A1 - Langbein-Laugwitz, Johanna A1 - Härtl, Barbara A1 - Escobar, Hugo Murua A1 - Nolte, Ingo A1 - Chen, Nanhai G. A1 - Aguilar, Richard J. A1 - Yu, Yong A. A1 - Zhang, Qian A1 - Frentzen, Alexa A1 - Szalay, Aladar A. T1 - Evaluation of a New Recombinant Oncolytic Vaccinia Virus Strain GLV-5b451 for Feline Mammary Carcinoma Therapy JF - PLoS ONE N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis. In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model. KW - antibodies KW - cancer treatment KW - carcinomas KW - vaccinia virus KW - oncolytic viruses KW - viral replication KW - cell cultures KW - enzyme-linked immunoassays Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119387 VL - 9 IS - 8 ER - TY - JOUR A1 - Ademmer, Martin A1 - Horn, Wolfram A1 - Quast, Josefine T1 - Stock market dynamics and the relative importance of domestic, foreign, and common shocks JF - International Journal of Finance & Economics N2 - We quantify the contemporaneous relationships among stock markets in the euro area, the United States, and a group of emerging economies over the period from 2008 to 2017. Exploiting the heteroskedasticity in the stock market data, we identify shocks that originated in the respective domestic markets and shocks that are common to all markets. Our results underline the leading role of the United States in international equity markets, but also point to the importance of indirect spillovers for all economies. Variance decompositions show that while domestic shocks explain the bigger part of the variation in each stock market, a substantial part of the variation in the euro area and the emerging economies can be attributed to foreign shocks. A comparison with a sample covering the pre‐crisis period from 1999 to 2007 suggests a strengthening of the linkages among global stock markets in recent years. In particular, the spillovers from advanced to emerging economies have become more pronounced. KW - financial linkages KW - heteroskedasticity KW - identification KW - spillovers KW - stock markets Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225729 VL - 27 IS - 4 SP - 3911 EP - 3923 ER - TY - THES A1 - Adenugba, Akinbami Raphael T1 - Functional analysis of the gene organization of the pneumoviral attachment protein G T1 - Funktionelle Analyse der Genorganisation des pneumoviralen Attachment-Protein G N2 - The putative attachment protein G of pneumonia virus of mice (PVM), a member of the Pneumoviruses, is an important virulence factor with so far ambiguous function in a virus-cell as well as in virus-host context. The sequence of the corresponding G gene is characterized by significant heterogeneity between and even within strains, affecting the gene and possibly the protein structure. This accounts in particular for the PVM strain J3666 for which two differing G gene organizations have been described: a polymorphism in nucleotide 65 of the G gene results in the presence of an upstream open reading frame (uORF) that precedes the main ORF in frame (GJ366665A) or extension of the major G ORF for 18 codons (GJ366665U). Therefore, this study was designed to analyse the impact of the sequence variations in the respective G genes of PVM strains J3666 and the reference strain 15 on protein expression, replication and virulence. First, the controversy regarding the consensus sequence of PVM J3666 was resolved. The analysis of 45 distinct cloned fragments showed that the strain separated into two distinct virus populations defined by the sequence and structure of the G gene. This division was further supported by nucleotide polymorphisms in the neighbouring M and SH genes. Sequential passage of this mixed strain in the cell line standardly used for propagation of virus stocks resulted in selection for the GJ366665A-containing population in one of two experiments pointing towards a moderate replicative advantage. The replacement of the G gene of the recombinant PVM 15 with GJ366665A or GJ366665U, respectively, using a reverse genetic approach indicated that the presence of uORF within the GJ366665A significantly reduced the expression of the main G ORF on translational level while the potential extension of the ORF in GJ366665U increased G protein expression. In comparison, the effect of the G gene-structure on virus replication was inconsistent and dependent on cell line and type. While the presence of uORF correlated with a replication advantage in the standardly used BHK-21 cells and primary murine embryonic fibroblasts, replication in the murine macrophage cell line RAW 264.7 did not. In comparison, the GJ366665U variant was not associated with any effect on replication in cultured cells at all. Nonetheless, in-vivo analysis of the recombinant viruses associated the GJ366665U gene variant, and hence an increased G expression, with higher virulence whereas the GJ366665A gene, and therefore an impaired G expression, conferred an attenuated phenotype to the virus. To extend the study to other G gene organizations, a recombinant PVM expressing a G protein without the cytoplasmic domain and for comparison a G-deletion mutant, both known to be attenuated in vivo, were studied. Not noticed before, this structure of the G gene was associated with a 75% reduction in G protein expression and a significant attenuation of replication in macrophage-like cells. This attenuation was even more prominent for the virus lacking G. Taking into consideration the higher reduction in G protein levels compared to the GJ366665A variant indicates that a threshold amount of G is required for efficient replication in these cells. In conclusion, the results gathered indicated that the expression levels of the G protein were modulated by the sequence of the 5’ untranslated region of the gene. At the same time the G protein levels modulated the virulence of PVM. N2 - Das mutmaßliche „attachment“ Protein G des Pneumonievirus der Maus (PVM), einem Mitglied des Genus Pneumovirus, ist ein bedeutender Virulenzfaktor, mit allerdings noch nicht vollständig verstandener Funktion. Dabei zeichnet sich die Sequenz des G-Gens durch Nukleotid-Polymorphismen und damit verbundenen Variationen in der Genorganisation und möglicherweise der Proteinstruktur sowohl zwischen als auch innerhalb von PVM-Stämmen aus. Insbesondere für den PVM-Stamm J3666 wurden zwei verschiedene Organisationen des G-Gens beschrieben: ein Polymorphismus des Nukleotids 65 des G-Genes erzeugt einen neuen „upstream Open reading frame“ (uORF), der dem eigentlichen G-ORF vorausgeht (GJ366665A), oder führt zu einer Verlängerung des eigentlichen G-ORF von G um 18 Kodons (GJ366665U). Ziel dieser Studie war es deshalb, die Auswirkung dieser Sequenzvariabilitäten der für PVM J3666 beschriebenen G-Gene im Vergleich zu dem des Referenzstamms PVM 15 bezüglich Proteinexpression, der Virusreplikation und der Virulenz zu untersuchen. Als erstes wurden die beschriebenen Sequenzunterschiede bezüglich des PVM-Stamms J3666 untersucht. Die Analyse von 45 verschiedenen klonierten Fragmenten von PVM J3666 zeigte, dass es sich bei diesem Stamm eigentlich um zwei separate Viruspopulationen handelt, die sich durch die Sequenz und Struktur des G-Genes definieren lassen. Diese Unterscheidung wird durch weitere Nukleotid-Polymorphismen in den benachbarten Genen, M und SH, gestärkt. Sequenzielle Passagierung dieses gemischten Stammes in der standardmäßig zur Virusanzucht verwendeten BHK-21-Zelllinie resultierte in einem von zwei Experimenten in der Selektion der GJ366665A-Population, das ein Hinweis auf einen moderaten Replikationsvorteil darstellt. Der Austausch des G-Gens des Referenzstamms PVM 15 durch GJ366665A oder GJ366665U mithilfe der Reversen Genetik, zeigte, dass der uORF innerhalb von GJ366665A zu einer deutlich reduzierten Expression des eigentlichen G-ORF führt. Andererseits führte die potenzielle Verlängerung des ORF in GJ366665U zu einer im gleichen Maße erhöhten Expression des G-Proteins. Dagegen war der Einfluss der G-Genorganisation auf die Virusvermehrung in Zellkultur in Abhängigkeit von Zelllinie und Zelltyp inkonsistent. Während ein uORF mit einem Replikationsvorteil in BHK-21-Zellen und primären murinen embryonen Fibroblasten korrelierte, war dies in der murinen Makrophagen-Zelllinie RAW 264.7 nicht zu beobachten. Im Vergleich dazu konnte die GJ366665U-Variante nicht mit einem Einfluss auf die Virusvermehrung in Verbindung gebracht werden. Nichtsdestotrotz, konnte die GJ366665U-Variante, und damit eine erhöhte Expression von G, mit einer gesteigerten Virulenz assoziiert werden, während die GJ366665A-Variante, d. h. eine verringerte G-Expression zur Attenuierung des Virus führte. Die Untersuchungen wurden auf weitere G-Genstrukturen, d.h. ein rekombinantes PVM, rPVM-Gt, das ein N-terminal verkürztes G-Protein exprimiert, ausgeweitet. Zum Vergleich wurde eine Deletionsmutante des kompletten G-Gens, rPVM-ΔG, mit einbezogen. Von beiden Viren war bereits bekannt, dass sie in vivo attenuiert sind. Die Organisation des Gt-Gens war mit einer um 75 % verringerten Expression des entsprechenden Proteins assoziiert, was zuvor nicht beobachtet worden war. Zugleich zeigte rPVM-Gt eine deutliche Attenuierung der Replikation in RAW 264.7-Zellen und primären Mausmakrophagen, die von der G-Deletionsmutante noch übertroffen wurde. Die im Vergleich zu der GJ366665A-Variante deutlich höhere Reduktion der G-Expression dieser beiden G-Mutanten in Betracht ziehend, scheint dies darauf hinzuweisen, dass eine bestimmte Mindestexpression von G für eine effiziente Virusvermehrung in diesen Zellen benötigt wird. Zusammenfassend deuten die erhaltenen Ergebnisse darauf hin, dass die Expression des G-Proteins durch die jeweiligen 5’ nicht-translatierte Region des Gens moduliert wird, was einen neuen Mechanismus für Negativstrang-RNA-Viren darstellt. Zugleich moduliert die Expressionsrate von G die Virulenz von PVM. KW - G glycoprotein KW - protein regulation and expression KW - Pneumoviruses KW - regulation KW - expression KW - replication KW - virulence KW - 5`-UTR KW - PVM KW - RSV Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128146 ER - TY - JOUR A1 - Adeyemo, M. A1 - Sirén, Anna-Leena T1 - Cardio-respiratory changes and mortality in the conscious rat induced by (+)- and (±)- anatoxin-a N2 - 0. M. ADEYEMO and A.-L. SIREN. Cardio-respiratory changes and mortality in the conscious rat induced by ( + )- and ( ± )-anatoxin-a. Toxicon 30, 899-905, 1992.-Anatoxin-a (AnTx-a) isapotent nicotinic cholinergic receptor agonist. The relative potencies of the ( + )-AnTx-a and the racemic mixture ( ± )-AnTxa were investigated in the conscious rat by comparing their effects on mean arterial blood pressure (BP), heart rate (HR), blood oxygen and carbon dioxide pressures (p02 and pC02, respective1y), acid-base balance (pH) and mortality. The present experiments show that while both forms of AnTx-a produce dose-dependent increases in BP and decreases in HR, ( + )-AnTx-a is about IO-fo1d morepotent than the optically inactive isomer. ( + )-AnTx-a was also 6-fo1d more potent than ( ± )-AnTx-a in produclog severe hypoxemia, and more than 4-fold as potent as the (±}-AnTx-a in producing significant hypercapnia accompanied with severe acidosis. The approximate median Iethai dose (Ln so) of ( + )-AnTx-a was about 5-fold less than that of ( ± )-AnTx-a. We conclude that ( + )-AnTx-a is more potent than the ( ± )-AnTx-a racemic mixture in causing detrimental cardio-respiratory changes and therefore increased mortality in the rat. KW - Neurobiologie Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63027 ER - TY - JOUR A1 - Adeyemo, O. M. A1 - Shapira, S. A1 - Tombaccini, D. A1 - Pollard, H. A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - A goldfish model for evaluation of the neurotoxicit of \(\omega\)-conotoxin GVIA and screening of monoclonal antibodies N2 - A Goldfish Model for Evaluation of the Neurotaxicity of \(\omega\)-Conotoxin GVI A and Screening of Monoclonal Antibodies. ADEYEMO, 0. M .. SHAPIRA, S., TOMBACCINI, D., POLLARD, H. 8 .• FEUERSTEIN, G .. AND SIREN, A-L. ( 1991 ). Toxicol. App/. Pharmaco/. 108, 489-496. The neurotoxicity of \(\omega\)-conotoxin (\(\omega\)-CgTx), a potent neuronal voltage-sensitive calcium channel blocker, was measured using a new bioassay. \(\omega\)-CgTx was administered intraperitoneally (ip) to goldfish weighing approximately 1.6 g, and dose-related changes were observed over a 2-hr period. \(\omega\)CgTx induced time- and dose-dependent abnormal swimming behavior (ASB) and mortality. The antitoxin activity of the antiborlies was investigated in vivo by either ( l) preincubation of the antibody with w-CgTx at 4°C overnight, or (2) pretreatment with antibody, 30 min before \(\omega\)CgTx injection in a 10:1 antibody/\(\omega\)-CgTx molar ratio. The LD50 dose of \(\omega\)-CgTx in goldfish was 5 nmol/kg ip, and preincubation of monoclonal antibody (50 nmol/kg ip) with \(\omega\)-CgTx (5 nmol/kg ip) significantly (p < 0.05) reduced mortality. ASB, and toxicity time. The antitoxin activity of the monoclonal antiborlies evidenced in the goldfish bioassay was further tested in the conscious rat. In the rat, the increases in mean arterial pressure and heart rate induced by \(\omega\)-CgTx (0.03 nmol/rat icv) were significantly (p < 0.02 and p < 0.0 l, respectively) attenuated by preincubation of the toxin with the antibody (0.3 nmol/rat). We conclude that the goldfish bioassay provides a simple. accurate, and inexpensive in vivo model for the study of the toxicity of \(\omega\)CgTx KW - Neurobiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63087 ER - TY - THES A1 - Adhikari, Bikash T1 - Targeted degradation of Myc-interacting oncoproteins T1 - Gezielte Degradation von mit Myc interagierenden Onkoproteinen N2 - The hallmark oncoprotein Myc is a major driver of tumorigenesis in various human cancer entities. However, Myc’s structural features make it challenging to develop small molecules against it. A promising strategy to indirectly inhibit the function of Myc is by targeting its interactors. Many Myc-interacting proteins have reported scaffolding functions which are difficult to target using conventional occupancy- driven inhibitors. Thus, in this thesis, the proteolysis targeting chimera (PROTAC) approach was used to target two oncoproteins interacting with Myc which promote the oncogenicity of Myc, Aurora-A and WDR5. PROTACs are bifunctional small molecules that bind to the target protein with one ligand and recruit a cellular E3- ligase with the other ligand to induce target degradation via the ubiquitin- proteasome system. So far, the most widely used E3-ligases for PROTAC development are Cereblon (CRBN) and von Hippel–Lindau tumor suppressor (VHL). Furthermore, there are cases of incompatibility between some E3-ligases and proteins to bring about degradation. Hence there is a need to explore new E3- ligases and a demand for a tool to predict degradative E3-ligases for the target protein in the PROTAC field. In the first part, a highly specific mitotic kinase Aurora-A degrader, JB170, was developed. This compound utilized Aurora-A inhibitor alisertib as the target ligand and thalidomide as the E3-ligase CRBN harness. The specificity of JB170 and the ternary complex formation was supported by the interactions between Aurora-A and CRBN. The PROTAC-mediated degradation of Aurora-A induced a distinct S- phase defect rather than mitotic arrest, shown by its catalytic inhibition. The finding demonstrates that Aurora-A has a non-catalytic role in the S-phase. Furthermore, the degradation of Aurora-A led to apoptosis in various cancer cell lines. In the second part, two different series of WDR5 PROTACs based on two protein- protein inhibitors of WDR5 were evaluated. The most efficient degraders from both series recruited VHL as a E3-ligase and showed partial degradation of WDR5. In addition, the degradation efficiency of the PROTACs was significantly affected by the linker nature and length, highlighting the importance of linker length and composition in PROTAC design. The degraders showed modest proliferation defects at best in cancer cell lines. However, overexpression of VHL increased the degradation efficiency and the antiproliferative effect of the PROTACs. In the last part, a rapamycin-based assay was developed to predict the degradative E3-ligase for a target. The assay was validated using the WDR5/VHL and Aurora- A/CRBN pairs. The result that WDR5 is degraded by VHL but not CRBN and Aurora-A is degraded by CRBN, matches observations made with PROTACs. This technique will be used in the future to find effective tissue-specific and essential E3-ligases for targeted degradation of oncoproteins using PROTACs. Collectively, the work presented here provides a strategy to improve PROTAC development and a starting point for developing Aurora-A and WDR5 PROTACs for cancer therapy. N2 - Das Onkoprotein Myc ist ein wichtiger Faktor bei der Tumorentstehung in verschiedenen menschlichen Krebsarten. Die strukturellen Merkmale von Myc machen es jedoch schwierig, kleine Moleküle gegen dieses Protein zu entwickeln. Eine vielversprechende Strategie zur indirekten Hemmung der Funktion von Myc besteht darin, auf seine Interaktoren abzuzielen. Viele Proteine, die mit Myc interagieren, haben Gerüstfunktionen, die mit herkömmlichen Inhibitoren nur schwer zu hemmen sind. Daher wurde in dieser Arbeit der PROTAC-Ansatz (Proteolysis Targeting Chimera) verwendet, um zwei Onkoproteine, die mit Myc interagieren und die Onkogenität von Myc fördern, ins Visier zu nehmen: Aurora-A und WDR5. PROTACs sind bifunktionale kleine Moleküle, die mit einem Liganden an das Zielprotein binden und mit dem anderen Liganden eine zelluläre E3-Ligase rekrutieren, um den Abbau des Zielproteins über das Ubiquitin-Proteasom-System einzuleiten. Die bisher am häufigsten verwendeten E3-Ligasen für die Entwicklung von PROTACs sind Cereblon (CRBN) und der von Hippel-Lindau-Tumorsuppressor (VHL). Außerdem gibt es Fälle von Inkompatibilität zwischen einigen E3-Ligasen und Proteinen, die abgebaut werden sollen. Daher besteht die Notwendigkeit, neue E3-Ligasen zu erforschen und Werkzeuge zur Vorhersage abbauender E3-Ligasen für das Zielprotein zu entwickeln. Im ersten Teil wurde ein hochspezifischer Degrader der mitotischen Kinase Aurora-A, JB170, entwickelt. Bei dieser Verbindung wurde der Aurora-A-Inhibitor Alisertib als Zielligand und Thalidomid als Binder für die E3-Ligase CRBN verwendet. Die Spezifität von JB170 und die ternäre Komplexbildung wurden durch die Wechselwirkungen zwischen Aurora-A und CRBN unterstützt. Der durch PROTAC vermittelte Abbau von Aurora-A führte zu einem deutlichen Defekt in der S-Phase und nicht zu einem mitotischen Stillstand, wie es für dessen katalytische Hemmung beobachtet wurde. Dies zeigt, dass Aurora-A eine nicht-katalytische Funktion in der S-Phase hat. Außerdem führte der Abbau von Aurora-A in verschiedenen Krebszelllinien zur Apoptose. Im zweiten Teil wurden zwei verschiedene Serien von WDR5 PROTACs auf der Grundlage von zwei Protein-Protein-Inhibitoren von WDR5 untersucht. Die effizientesten Degrader aus beiden Serien rekrutierten VHL als E3-Ligase und zeigten einen teilweisen Abbau von WDR5. Darüber hinaus wurde die Abbaueffizienz der PROTACs erheblich von der Art und Länge des Linkers beeinflusst, was die Bedeutung der Linkerlänge und -zusammensetzung bei der Entwicklung von PROTACs unterstreicht. Die Abbauprodukte zeigten bestenfalls bescheidene Proliferationsdefekte in Krebszelllinien. Eine Überexpression von VHL erhöhte jedoch die Abbaueffizienz und den antiproliferativen Effekt der PROTACs. Im letzten Teil wurde ein auf Rapamycin basierender Assay entwickelt, um die abbauende E3-Ligase für ein Target vorherzusagen. Der Assay wurde anhand der Paare WDR5/VHL und Aurora-A/CRBN validiert. Das Ergebnis, dass WDR5 von VHL, aber nicht von CRBN abgebaut wird und Aurora-A von CRBN abgebaut wird, stimmt mit den Beobachtungen überein, die mit PROTACs gemacht wurden. Diese Technik wird in Zukunft eingesetzt werden, um wirksame gewebespezifische und essentielle E3-Ligasen für den gezielten Abbau von Onkoproteinen mit Hilfe von PROTACs zu finden. Insgesamt bieten die hier vorgestellten Arbeiten eine Strategie zur Verbesserung der PROTAC-Entwicklung und einen Ausgangspunkt für die Entwicklung von Aurora-A- und WDR5-PROTACs für die Krebstherapie. KW - Degradation KW - PROTACs KW - Oncoprotein KW - Cancer KW - Onkoprotein Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317326 ER - TY - THES A1 - Adler, Florian Rudolf T1 - Electronic Correlations in Two-dimensional Triangular Adatom Lattices T1 - Elektronische Korrelationen in zweidimensionalen Adatom-Dreiecksgittern N2 - Two-dimensional triangular lattices of group IV adatoms on semiconductor substrates provide a rich playground for the investigation of Mott-Hubbard physics. The possibility to combine various types of adatoms and substrates makes members of this material class versatile model systems to study the influence of correlation strength, band filling and spin-orbit coupling on the electronic structure - both experimentally and with dedicated many-body calculation techniques. The latter predict exotic ground states such as chiral superconductivity or spin liquid behavior for these frustrated lattices, however, experimental confirmation is still lacking. In this work, three different systems, namely the \(\alpha\)-phases of Sn/SiC(0001), Pb/Si(111), and potassium-doped Sn/Si(111) are investigated with scanning tunneling microscopy and photoemission spectroscopy in this regard. The results are potentially relevant for spintronic applications or quantum computing. For the novel group IV triangular lattice Sn/SiC(0001), a combined experimental and theoretical study reveals that the system features surprisingly strong electronic correlations because they are boosted by the substrate through its partly ionic character and weak screening capabilities. Interestingly, the spectral function, measured for the first time via angle-resolved photoemission, does not show any additional superstructure beyond the intrinsic \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) reconstruction, thereby raising curiosity regarding the ground-state spin pattern. For Pb/Si(111), preceding studies have noted a phase transition of the surface reconstruction from \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) to \(3 \times 3\) at 86 K. In this thesis, investigations of the low-temperature phase with high-resolution scanning tunneling microscopy and spectroscopy unveil the formation of a charge-ordered ground state. It is disentangled from a concomitant structural rearrangement which is found to be 2-up/1-down, in contrast to previous predictions. Applying an extended variational cluster approach, a phase diagram of local and nonlocal Coulomb interactions is mapped out. Based on a comparison of theoretical spectral functions with scattering vectors found via quasiparticle interference, Pb/Si(111) is placed in said phase diagram and electronic correlations are found to be the driving force of the charge-ordered state. In order to realize a doped Mott insulator in a frustrated geometry, potassium was evaporated onto the well-known correlated Sn/Si(111) system. Instead of the expected insulator-to-metal transition, scanning tunneling spectroscopy data indicates that the electronic structure of Sn/Si(111) is only affected locally around potassium atoms while a metallization is suppressed. The potassium atoms were found to be adsorbed on empty \(T_4\) sites of the substrate which eventually leads to the formation of two types of K-Sn alloys with a relative potassium content of 1/3 and 1/2, respectively. Complementary measurements of the spectral function via angle-resolved photoemission reveal that the lower Hubbard band of Sn/Si(111) gradually changes its shape upon potassium deposition. Once the tin and potassium portion on the surface are equal, this evolution is complete and the system can be described as a band insulator without the need to include Coulomb interactions. N2 - Zweidimensionale Dreiecksgitter aus Adatomen der vierten Hauptgruppe auf Halbleitersubstraten bieten eine reichhaltige Spielwiese für die Untersuchung von Mott-Hubbard-Physik. Die Möglichkeit, verschiedene Adatomsorten und Substrate zu kombinieren, macht die Mitglieder dieser Materialklasse zu vielseitigen Modellsystemen, um den Einfluss von Korrelationsstärke, Bandfüllung und Spin-Bahn-Kopplung auf die elektronische Struktur zu untersuchen - sowohl im Experiment als auch mit Vielkörper-Rechnungen. Letztere prognostizieren exotische Grundzustände, wie z.B. chirale Supraleitung oder eine Spin-Flüssigkeit, wobei eine experimentelle Bestätigung jeweils noch aussteht. In dieser Dissertation werden drei derartige Systeme, nämlich die \(\alpha\)-Phasen von Sn/SiC(0001), Pb/Si(111) und kaliumdotiertem Sn/Si(111) mittels Rastertunnelmikroskopie und Photoemissionsspektroskopie diesbezüglich untersucht. Die Resultate sind potentiell relevant für Anwendungen im Bereich der Spintronik oder Quantencomputer. Für das erst kürzlich realisierte Gruppe-IV-Dreiecksgitter Sn/SiC(0001) zeigt diese Studie, bei der experimentelle und theoretische Methoden kombiniert werden, dass das System unerwartet starke Korrelationen aufweist, weil sie durch den teilweise ionischen Charakter und das geringe Abschirmungsvermögen des Substrats verstärkt werden. Die Spektralfunktion, die erstmals mit winkelaufgelöster Photoemission gemessen wird, zeigt keine überstruktur außer der intrinsischen \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) Rekonstruktion des Gitters, was die Frage nach der Anordnung der Spins im Grundzustand aufwirft. Bei Pb/Si(111) haben bereits frühere Veröffentlichungen einen Phasenübergang bei der Oberflächenrekonstruktion von \(\sqrt{3}\times\sqrt{3}R30^{\circ}\) auf \(3 \times 3\) bei 86 K festgestellt. In dieser Arbeit zeigen Untersuchungen der Niedrigtemperaturphase mit hochaufgelöster Rastertunnelmikroskopie und -spektroskopie die Entstehung eines ladungsgeordneten Zustands. Dieser wird von der begleitend auftretenden strukturellen Neuordnung getrennt, welche entgegen bisheriger Voraussagen eine 2-hoch/1-tief-Anordnung aufweist. Mit Hilfe einer neu entwickelten Cluster-Rechenmethode wird ein Phasendiagramm erstellt, in dem die lokale und nichtlokale Coulomb-Wechselwirkung gegeneinander aufgetragen sind. Durch einen Vergleich zwischen theoretischen Spektralfunktionen mit Streuvektoren, die mittels Quasiteilchen-Interferenz bestimmt werden, kann Pb/Si(111) in besagtem Phasendiagramm platziert werden. Dadurch stellt sich heraus, dass elektronische Korrelationen die treibende Kraft für den ladungsgeordneten Zustand in Pb/Si(111) sind. Um einen dotierten Mott-Isolator in einem frustrierten System zu verwirklichen, wird Kalium auf das bekannte, korrelierte System Sn/Si(111) aufgebracht. Statt des erwarteten Isolator-Metall übergangs zeigen Messungen mit Rastertunnelspektroskopie, dass die elektronische Struktur von Sn/Si(111) nur lokal in der unmittelbaren Umgebung der Kaliumatome beeinflusst wird, ohne dass das System metallisch wird. Die Kaliumatome werden auf freien \(T_4\)-Plätzen des Substrats adsorbiert, was letztendlich zur Ausbildung von zwei unterschiedlichen Kalium-Zinn-Legierungen mit einem Kaliumanteil von 1/3 bzw. 1/2 führt. Komplementäre Messungen der Spektralfunktion mit winkelaufgelöster Photoemission zeigen, dass das untere Hubbardband von Sn/Si(111) durch die Kalium-Deposition allmählich seine Form verändert. Sobald Zinn und Kalium zu gleichen Teilen auf der Oberfläche vorliegen, ist diese Transformation beendet und das System kann als einfacher Bandisolator ohne die Notwendigkeit, elektronische Korrelationen zu berücksichtigen, beschrieben werden. KW - Rastertunnelmikroskopie KW - ARPES KW - Elektronenkorrelation KW - Oberflächenphysik Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241758 ER - TY - THES A1 - Adler, Melanie T1 - New approaches to improve prediction of drug-induced liver injury T1 - Neue Ansätze zur verbesserten Vorhersage arzneimittelinduzierter Leberschäden N2 - Das häufige Scheitern neuer Arzneistoffkandidaten aufgrund von Lebertoxizität in präklinischen und klinischen Studien stellt ein erhebliches Problem in der Entwicklung von neuen Arzneimitteln dar. Deshalb ist es wichtig, neue Ansätze zu entwickeln, mit deren Hilfe unerwünschte Wirkungen von Arzneimitteln früher und zuverlässiger erkannt werden können. Um die Vorhersage von Lebertoxizität in präklinischen Studien zu verbessern, wurden im Rahmen dieser Arbeit zwei wesentliche Ansätze gewählt: 1) die Evaluierung neuer Biomarker, durch die Lebertoxizität zuverlässiger und empfindlicher detektiert werden könnte und 2.) wirkmechanistische Untersuchungen mittels Toxcicogenomics für ein besseres Verständnis der zugrunde liegenden Mechanismen der Arzneimittel-induzierten Toxizität. Ein Ziel dieser Arbeit war, die Fähigkeit einiger neuer potenzieller Biomarker (NGAL, Thiostatin, Clusterin und PON1) zu bewerten, Arzmeimittel-induzierte Lebertoxizität in Ratten frühzeitig zu erkennen. Die Ergebnisse zeigen, dass PON1 und Clusterin infolge eines durch die verabreichten Arzneistoffkandidaten verursachten Leberschadens nicht konsistent verändert waren. Diese beiden Marker sind daher, verglichen mit bestehenden klinisch-chemischen Markern, nicht für eine sichere Vorhersage von Arzneistoff-induzierten Leberschäden geeignet. Bei Thiostatin und NGAL zeigte sich hingegen ein zeit- und dosisabhängiger Anstieg im Serum und Urin behandelter Tiere. Diese Veränderungen, die gut mit der mRNA Expression im Zielorgan übereinstimmten, korrelierten mit dem Schweregrad der Arzneistoff-induzierten Leberschäden. Die Analyse mittels ROC zeigte, Thiostatin im Serum, nicht aber NGAL, ein besserer Indikator für Arzneimittel-induzierte hepatobiliäre Schäden ist als die routinemäßig verwendeten klinische-chemischen Marker, wie z.B. die Leberenzyme ALP, ALT und AST. Thiostatin wird jedoch als Akute-Phase-Protein in einer Vielzahl von Geweben exprimiert und kann somit nicht spezifisch als Lebermarker betrachtet werden. Dennoch zeigen unsere Ergebnisse, dass Thiostatin als sensitiver, minimal-invasiver diagnostischer Marker für Entzündungsprozesse und Gewebeschäden eine sinnvolle Ergänzung in der präklinischen Testung auf Lebertoxizität darstellt. Im zweiten Teil dieser Arbeit wurde mittels RNA-Interferenz das pharmakologische Target des Arzneistoffkandidaten BAY16, der Glukagonrezeptor, auf mRNA-Ebene gehemmt und anhand von Genexpressionsanalysen untersucht, ob die pharmakologisch-bedingte Modulation des Glukagonrezeptors eine Rolle in der Toxizität von BAY16 spielt. Desweiteren sollten diese Arbeiten Aufschluss geben, welche molekularen Veränderungen auf die pharmakologische Wirkung des Arzneistoffs zurückzuführen sind, und daher für den Mechanismus der Toxizität möglicherweise wenig relevant sind. Während BAY16 in Konzentrationen von 75 µM starke zytotoxische Wirkungen aufwies, hatte die siRNA vermittelte Depletion des Glukagonrezeptors keinen Einfluss auf die Vitalität primärer Rattenhepatozyten. Daraus lässt sich ableiten, dass die Hepatotoxiziät von BAY16 in vitro und in vivo nicht mit der pharmakologischen Modulation des Glukagonrezeptors assoziiert ist. Diese Ergebnisse wurden durch die Tatsache gestützt, dass die meisten der durch BAY16 induzierten Genexpressionsveränderungen unabhängig von der pharmakologischen Modulation des Glucagonrezeptors auftraten. Diese beobachteten off-target-Effekte beinhalteten Veränderungen im Fremdstoffmetabolismus, oxidativer Stress, erhöhte Fettsäuresynthese und Veränderungen im Cholesterol- und Gallensäuremetabolismus. Obwohl Veränderungen in diesen molekularen Mechanismen zum Fortschreiten eines Leberschadens beitragen können, ist es anhand dieser Daten nicht möglich einen eindeutigen Mechanismus für die Toxizität von BAY16 abzuleiten. In dieser Arbeit konnte jedoch gezeigt werden, dass die Anwendung der siRNA-Technologie einen neuen methodischen Ansatz darstellt, um Mechanismen arzneimittelbedingter Toxizität besser verstehen zu können. N2 - The high failure rate of new drug candidates in preclinical or clinical studies due to hepatotoxicity represents a considerable problem in the drug development. Hence, there is an urgent need to develop new approaches for early and reliable prediction of drug-induced hepatotoxicity that enables a better identification of drug candidates with high potential for toxicity at early stages of drug development. Therefore, the aim of this work was to improve the prediction of drug-induced liver injury in preclinical studies through evaluation of more reliable and sensitive biomarkers of hepatotoxicity and a better understanding of the underlying mechanistic basis for drug-induced toxicity. First, the ability of a set of potential markers (NGAL, thiostatin, clusterin, PON1) to detect early signs of liver injury was assessed in rats treated with drug candidates that were dropped from further development, in part due to toxic adverse effects in the liver. In summary, PON1 and clusterin were not consistently altered in response to liver injury and thus provide no additive information to the traditional liver enzymes in detecting drug-induced hepatotoxicity. In contrast, thiostatin and NGAL were increased in serum and urine of treated animals in a time- and dose-dependent manner. These changes correlated well with mRNA expression in the target organ and generally reflected the onset and degree of drug-induced liver injury. Receiver-operating characteristics analyses supported serum thiostatin, but not NGAL, as a better indicator of drug-induced hepatobiliary injury than conventional clinical chemistry parameters, such as ALP, ALT and AST. Although thiostatin, an acute phase protein expressed in a range of tissues, may not be specific for liver injury, our results indicate that thiostatin may serve as a sensitive, minimally-invasive diagnostic marker of inflammation and tissue damage in preclinical safety assessment. In the second part of this work, combined application of genomics profiling technology and RNAi to inhibit the pharmacological target of a drug candidate BAY16, a glucagon receptor (GCGR) antagonist, was used to determine if interference with the pharmacological target plays a role in the toxic response to BAY16, and to narrow down those molecular changes that are associated with toxicity, and not the pharmacological action of BAY16. In contrast to Bay 16, which was found to be cytotoxic at concentrations of 75 µM, silencing of the glucagon receptor did not affect cell viability in primary rat hepatocytes. Thus, it can be concluded that hepatotoxicity of Bay 16 was not related to the drugs inhibitory effect on the glucagon receptor in vitro and in vivo. These findings were supported by the fact that most of BAY16-induced changes in gene expression occurred independently of the pharmacological modulation of GCGR. These off-target effects include altered xenobiotic metabolism, oxidative stress, increased fatty acid synthesis, and alterations in cholesterol and bile acid metabolic processes. Although it was not possible to draw a final conclusion about the mechanism of BAY16 hepatotoxicity, changes in these molecular mechanisms appear contribute to progression of hepatic injury. With regard to drug safety assessment in preclinical studies, the utilization of siRNA technology in vitro represents a new approach to improve mechanistic understanding of the nature of drug’s toxicity, being either chemically mediated or due to primary or secondary pharmacological mode of action. KW - Biomarker KW - Leber KW - Hepatotoxizität KW - Lebertoxizität KW - biomarker KW - liver KW - hepatotoxicity Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69512 ER - TY - JOUR A1 - Adolf, Christian A1 - Braun, Leah T. A1 - Fuss, Carmina T. A1 - Hahner, Stefanie A1 - Künzel, Heike A1 - Handgriff, Laura A1 - Sturm, Lisa A1 - Heinrich, Daniel A. A1 - Schneider, Holger A1 - Bidlingmaier, Martin A1 - Reincke, Martin T1 - Spironolactone reduces biochemical markers of bone turnover in postmenopausal women with primary aldosteronism JF - Endocrine N2 - Context Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis. Patients and methods We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment. Study design Observational longitudinal cohort study. Setting Tertiary care hospital. Results Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers. Conclusion This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy. KW - aldosterone KW - osteocalcin KW - osteoporosis KW - hyperparathyroidism KW - cortisol Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-315966 SN - 1355-008X SN - 1559-0100 VL - 69 IS - 3 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Carreira, Ana C. O. A1 - Jesus, Lázaro W. O. A1 - Bogerd, Jan A1 - Funes, Rejane M. A1 - Schartl, Manfred A1 - Sogayar, Mari C. A1 - Borella, Maria I. T1 - Molecular cloning and expression analysis of dmrt1 and sox9 during gonad development and male reproductive cycle in the lambari fish, Astyanax altiparanae JF - Reproductive Biology and Endocrinology N2 - Background The dmrt1 and sox9 genes have a well conserved function related to testis formation in vertebrates, and the group of fish presents a great diversity of species and reproductive mechanisms. The lambari fish (Astyanax altiparanae) is an important Neotropical species, where studies on molecular level of sex determination and gonad maturation are scarce. Methods Here, we employed molecular cloning techniques to analyze the cDNA sequences of the dmrt1 and sox9 genes, and describe the expression pattern of those genes during development and the male reproductive cycle by qRT-PCR, and related to histology of the gonad. Results Phylogenetic analyses of predicted amino acid sequences of dmrt1 and sox9 clustered A. altiparanae in the Ostariophysi group, which is consistent with the morphological phylogeny of this species. Studies of the gonad development revealed that ovary formation occurred at 58 days after hatching (dah), 2 weeks earlier than testis formation. Expression studies of sox9 and dmrt1 in different tissues of adult males and females and during development revealed specific expression in the testis, indicating that both genes also have a male-specific role in the adult. During the period of gonad sex differentiation, dmrt1 seems to have a more significant role than sox9. During the male reproductive cycle dmrt1 and sox9 are down-regulated after spermiation, indicating a role of these genes in spermatogenesis. Conclusions For the first time the dmrt1 and sox9 were cloned in a Characiformes species. We show that both genes have a conserved structure and expression, evidencing their role in sex determination, sex differentiation and the male reproductive cycle in A. altiparanae. These findings contribute to a better understanding of the molecular mechanisms of sex determination and differentiation in fish. KW - spermatogenesis KW - SOX9 KW - DMRT1 KW - sex differentiation KW - teleostei Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126486 VL - 13 IS - 2 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Du, Kang A1 - Kneitz, Susanne A1 - Cabau, Cédric A1 - Zahm, Margot A1 - Klopp, Christophe A1 - Feron, Romain A1 - Paixão, Rômulo V. A1 - Varela, Eduardo S. A1 - de Almeida, Fernanda L. A1 - de Oliveira, Marcos A. A1 - Nóbrega, Rafael H. A1 - Lopez-Roques, Céline A1 - Iampietro, Carole A1 - Lluch, Jérôme A1 - Kloas, Werner A1 - Wuertz, Sven A1 - Schaefer, Fabian A1 - Stöck, Matthias A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - A duplicated copy of id2b is an unusual sex-determining candidate gene on the Y chromosome of arapaima (Arapaima gigas) JF - Scientific Reports N2 - Arapaima gigas is one of the largest freshwater fish species of high ecological and economic importance. Overfishing and habitat destruction are severe threats to the remaining wild populations. By incorporating a chromosomal Hi-C contact map, we improved the arapaima genome assembly to chromosome-level, revealing an unexpected high degree of chromosome rearrangements during evolution of the bonytongues (Osteoglossiformes). Combining this new assembly with pool-sequencing of male and female genomes, we identified id2bbY, a duplicated copy of the inhibitor of DNA binding 2b (id2b) gene on the Y chromosome as candidate male sex-determining gene. A PCR-test for id2bbY was developed, demonstrating that this gene is a reliable male-specific marker for genotyping. Expression analyses showed that this gene is expressed in juvenile male gonads. Its paralog, id2ba, exhibits a male-biased expression in immature gonads. Transcriptome analyses and protein structure predictions confirm id2bbY as a prime candidate for the master sex-determiner. Acting through the TGF beta signaling pathway, id2bbY from arapaima would provide the first evidence for a link of this family of transcriptional regulators to sex determination. Our study broadens our current understanding about the evolution of sex determination genetic networks and provide a tool for improving arapaima aquaculture for commercial and conservation purposes. KW - evolutionary genetics KW - genetic markers KW - genome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265672 VL - 11 IS - 1 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Herpin, Amaury A1 - Martinez-Bengochea, Anabel A1 - Kneitz, Susanne A1 - Regensburger, Martina A1 - Grunwald, David J. A1 - Schartl, Manfred T1 - Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka JF - Frontiers in Cell and Developmental Biology N2 - Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes. KW - sex determination KW - retinoic acid KW - meiosis KW - gametogenesis KW - medaka Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222669 SN - 2296-634X VL - 8 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Herpin, Amaury A1 - Regensburger, Martina A1 - Sacquegno, Jacopo A1 - Waxman, Joshua S. A1 - Schartl, Manfred T1 - Retinoic acid and meiosis induction in adult versus embryonic gonads of medaka JF - Scientific Reports N2 - In vertebrates, one of the first recognizable sex differences in embryos is the onset of meiosis, known to be regulated by retinoic acid (RA) in mammals. We investigated in medaka a possible meiotic function of RA during the embryonic sex determination (SD) period and in mature gonads. We found RA mediated transcriptional activation in germ cells of both sexes much earlier than the SD stage, however, no such activity during the critical stages of SD. In adults, expression of the RA metabolizing enzymes indicates sexually dimorphic RA levels. In testis, RA acts directly in Sertoli, Leydig and pre-meiotic germ cells. In ovaries, RA transcriptional activity is highest in meiotic oocytes. Our results show that RA plays an important role in meiosis induction and gametogenesis in adult medaka but contrary to common expectations, not for initiating the first meiosis in female germ cells at the SD stage. KW - developmental biology KW - molecular biology Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147843 VL - 6 ER - TY - JOUR A1 - Adolph, Jonas E. A1 - Fleischhack, Gudrun A1 - Gaab, Christine A1 - Mikasch, Ruth A1 - Mynarek, Martin A1 - Rutkowski, Stefan A1 - Schüller, Ulrich A1 - Pfister, Stefan M. A1 - Pajtler, Kristian W. A1 - Milde, Till A1 - Witt, Olaf A1 - Bison, Brigitte A1 - Warmuth-Metz, Monika A1 - Kortmann, Rolf-Dieter A1 - Dietzsch, Stefan A1 - Pietsch, Torsten A1 - Timmermann, Beate A1 - Tippelt, Stephan T1 - Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies JF - Journal of Neuro-Oncology N2 - Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation. KW - ependymoma KW - chemotherapy KW - recurrence KW - children KW - sirolimus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308302 SN - 0167-594X SN - 1573-7373 VL - 155 IS - 2 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Ageron, M. A1 - Aharonian, F. A1 - Aiello, S. A1 - Albert, A. A1 - Ameli, F. A1 - Annasontzis, E. A1 - Andre, M. A1 - Androulakis, G. A1 - Anghinolfi, M. A1 - Anton, G. A1 - Ardid, M. A1 - Avgitas, T. A1 - Barbarino, G. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Belhorma, B. A1 - Belias, A. A1 - Berbee, A. A1 - van den Berg, A. A1 - Bertin, V. A1 - Beurthey, S. A1 - van Beeveren, V. A1 - Beverini, N. A1 - Biagi, S. A1 - Biagioni, A. A1 - Billault, M. A1 - Bondì, M. A1 - Bormuth, R. A1 - Bouhadef, B. A1 - Bourlis, G. A1 - Bourret, S. A1 - Boutonnet, C. A1 - Bouwhuis, M. A1 - Bozza, C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Buis, E. A1 - Busto, J. A1 - Cacopardo, G. A1 - Caillat, L. A1 - Calmai, M. A1 - Calvo, D. A1 - Capone, A. A1 - Caramete, L. A1 - Cecchini, S. A1 - Celli, S. A1 - Champion, C. A1 - Cherkaoui El Moursli, R. A1 - Cherubini, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Classen, L. A1 - Cocimano, R. A1 - Coelho, J. A. B. A1 - Coleiro, A. A1 - Colonges, S. A1 - Coniglione, R. A1 - Cordelli, M. A1 - Cosquer, A. A1 - Coyle, P. A1 - Creusot, A. A1 - Cuttone, G. A1 - D'Amico, A. A1 - De Bonis, G. A1 - De Rosa, G. A1 - De Sio, C. A1 - Di Capua, F. A1 - Di Palma, I. A1 - Díaz García, A. F. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Dorosti-Hasankiadeh, Q. A1 - Drakopoulou, E. A1 - Drouhin, D. A1 - Drury, L. A1 - Durocher, M. A1 - Eberl, T. A1 - Eichie, S. A1 - van Eijk, D. A1 - El Bojaddaini, I. A1 - El Khayati, N. A1 - Elsaesser, D. A1 - Enzenhöfer, A. A1 - Fassi, F. A1 - Favali, P. A1 - Fermani, P. A1 - Ferrara, G. A1 - Filippidis, C. A1 - Frascadore, G. A1 - Fusco, L. A. A1 - Gal, T. A1 - Galatà, S. A1 - Garufi, F. A1 - Gay, P. A1 - Gebyehu, M. A1 - Giordano, V. A1 - Gizani, N. A1 - Gracia, R. A1 - Graf, K. A1 - Grégoire, T. A1 - Grella, G. A1 - Habel, R. A1 - Hallmann, S. A1 - van Haren, H. A1 - Harissopulos, S. A1 - Heid, T. A1 - Heijboer, A. A1 - Heine, E. A1 - Henry, S. A1 - Hernández-Rey, J. J. A1 - Hevinga, M. A1 - Hofestädt, J. A1 - Hugon, C. M. F. A1 - Illuminati, G. A1 - James, C. W. A1 - Jansweijer, P. A1 - Jongen, M. A1 - de Jong, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Kappes, A. A1 - Katz, U. F. A1 - Keller, P. A1 - Kieft, G. A1 - Kießling, D. A1 - Koffeman, E. N. A1 - Kooijman, P. A1 - Kouchner, A. A1 - Kulikovskiy, V. A1 - Lahmann, R. A1 - Lamare, P. A1 - Leisos, A. A1 - Leonora, E. A1 - Lindsey Clark, M. A1 - Liolios, A. A1 - Llorenz Alvarez, C. D. A1 - Lo Presti, D. A1 - Löhner, H. A1 - Lonardo, A. A1 - Lotze, M. A1 - Loucatos, S. A1 - Maccioni, E. A1 - Mannheim, K. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Mariş, O. A1 - Markou, C. A1 - Martínez-Mora, J. A. A1 - Martini, A. A1 - Mele, R. A1 - Melis, K. W. A1 - Michael, T. A1 - Migliozzi, P. A1 - Migneco, E. A1 - Mijakowski, P. A1 - Miraglia, A. A1 - Mollo, C. M. A1 - Mongelli, M. A1 - Morganti, M. A1 - Moussa, A. A1 - Musico, P. A1 - Musumeci, M. A1 - Navas, S. A1 - Nicoleau, C. A. A1 - Olcina, I. A1 - Olivetto, C. A1 - Orlando, A. A1 - Papaikonomou, A. A1 - Papaleo, R. A1 - Păvălaş, G. E. A1 - Peek, H. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Pfutzner, M. A1 - Piattelli, P. A1 - Pikounis, K. A1 - Poma, G. E. A1 - Popa, V. A1 - Pradier, T. A1 - Pratolongo, F. A1 - Pühlhofer, G. A1 - Pulvirenti, S. A1 - Quinn, L. A1 - Racca, C. A1 - Raffaelli, F. A1 - Randazzo, N. A1 - Rapidis, P. A1 - Razis, P. A1 - Real, D. A1 - Resvanis, L. A1 - Reubelt, J. A1 - Riccobene, G. A1 - Rossi, C. A1 - Rovelli, A. A1 - Saldaña, M. A1 - Salvadori, I. A1 - Samtleben, D. F. E. A1 - Sánchez García, A. A1 - Sánchez Losa, A. A1 - Sanguineti, M. A1 - Santangelo, A. A1 - Santonocito, D. A1 - Sapienza, P. A1 - Schimmel, F. A1 - Schmelling, J. A1 - Sciacca, V. A1 - Sedita, M. A1 - Seitz, T. A1 - Sgura, I. A1 - Simeone, F. A1 - Siotis, I. A1 - Sipala, V. A1 - Spisso, B. A1 - Spurio, M. A1 - Stavropoulos, G. A1 - Steijger, J. A1 - Stellacci, S. M. A1 - Stransky, D. A1 - Taiuti, M. A1 - Tayalati, Y. A1 - Tézier, D. A1 - Theraube, S. A1 - Thompson, L. A1 - Timmer, P. A1 - Tönnis, C. A1 - Trasatti, L. A1 - Trovato, A. A1 - Tsirigotis, A. A1 - Tzamarias, S. A1 - Tzamariudaki, E. A1 - Vallage, B. A1 - Van Elewyk, V. A1 - Vermeulen, J. A1 - Vicini, P. A1 - Viola, S. A1 - Vivolo, D. A1 - Volkert, M. A1 - Voulgaris, G. A1 - Wiggers, L. A1 - Wilms, J. A1 - de Wolf, E. A1 - Zachariadou, K. A1 - Zornoza, J. D. A1 - Zúñiga, J. T1 - Letter of intent for KM3NeT 2.0 JF - Journal of Physics G-Nuclear and Particle Physics N2 - The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the high-energy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a three-dimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and KW - neutrino astronomy KW - eutrino physics KW - deep sea neutrino telescope KW - neutrino mass hierarchy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188050 VL - 43 IS - 8 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anghinolfi, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coleiro, A. A1 - Coniglione, R. A1 - Constantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Fehn, K. A1 - Felis, I. A1 - Fusco, L.A. A1 - Galatà, S. A1 - Gay, P. A1 - Geißelsöder, S. A1 - Geyer, K. A1 - Giordano, V. A1 - Gleixner, A. A1 - Glotin, H. A1 - Gracia-Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A.J. A1 - Hello, Y. A1 - Hernández-Rey, J.J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Hugon, C. A1 - Illuminati, G. A1 - James, C.W. A1 - de Jong, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Kießling, D. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J.A. A1 - Mathieu, A. A1 - Michael, T. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Mueller, C. A1 - Nezri, E. A1 - Pavalas, G.E. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Racca, C. A1 - Riccobene, G. A1 - Roensch, K. A1 - Saldaña, M. A1 - Samtleben, D.F.E. A1 - Sánchez-Losa, A. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schnabel, J. A1 - Schüssler, F. A1 - Seitz, T. A1 - Sieger, C. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Taiuti, M. A1 - Trovato, A. A1 - Tselengidou, M. A1 - Turpin, D. A1 - Tönnis, C. A1 - Vallage, B. A1 - Vallée, C. A1 - Van Elewyck, V. A1 - Visser, E. A1 - Vivolo, D. A1 - Wagner, S. A1 - Wilms, J. A1 - Zornoza, J.D. A1 - Zúñiga, J. T1 - Constraints on the neutrino emission from the Galactic Ridge with the ANTARES telescope JF - Physics Letters B N2 - A highly significant excess of high-energy astrophysical neutrinos has been reported by the IceCube Collaboration. Some features of the energy and declination distributions of IceCube events hint at a North/South asymmetry of the neutrino flux. This could be due to the presence of the bulk of our Galaxy in the Southern hemisphere. The ANTARES neutrino telescope, located in the Mediterranean Sea, has been taking data since 2007. It offers the best sensitivity to muon neutrinos produced by galactic cosmic ray interactions in this region of the sky. In this letter a search for an extended neutrino flux from the Galactic Ridge region is presented. Different models of neutrino production by cosmic ray propagation are tested. No excess of events is observed and upper limits for different neutrino flux spectral indices Γ are set. For Γ=2.4 the 90% confidence level flux upper limit at 100 TeV for one neutrino flavour corresponds to Φ\(^{1f}_{0}\) (100 TeV) = 2.0 · 10\(^{−17}\) GeV\(^{−1}\) cm\(^{−2}\)s\(^{−1}\)sr\(^{−1}\). Under this assumption, at most two events of the IceCube cosmic candidates can originate from the Galactic Ridge. A simple power-law extrapolation of the Fermi-LAT flux to account for IceCube High Energy Starting Events is excluded at 90% confidence level. KW - neutrino emission KW - Galactic Ridge KW - ANTARES telescope Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166608 VL - 760 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anghinolfi, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Baret, B. A1 - Barrios-Marti, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Buto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coniglione, R. A1 - Costantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Dekeyser, I. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. T1 - Stacked search for time shifted high energy neutrinos from gamma ray bursts with the ANTARES neutrino telescope JF - European Physical Journal C N2 - A search for high-energy neutrino emission correlated with gamma-ray bursts outside the electromagnetic prompt-emission time window is presented. Using a stacking approach of the time delays between reported gamma-ray burst alerts and spatially coincident muon-neutrino signatures, data from the Antares neutrino telescope recorded between 2007 and 2012 are analysed. One year of public data from the IceCube detector between 2008 and 2009 have been also investigated. The respective timing profiles are scanned for statistically significant accumulations within 40 days of the Gamma Ray Burst, as expected from Lorentz Invariance Violation effects and some astrophysical models. No significant excess over the expected accidental coincidence rate could be found in either of the two data sets. The average strength of the neutrino signal is found to be fainter than one detectable neutrino signal per hundred gamma-ray bursts in the Antares data at 90% confidence level. KW - Search window KW - Neutrino data KW - Neutrino telescope KW - Neutrino emission KW - Accidental coincidence KW - Gamma-ray bursts Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181251 VL - 77 IS - 1 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bou-Cabo, M. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coleiro, A. A1 - Coniglione, R. A1 - Costantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Fehn, K. A1 - Felis, I. A1 - Fusco, L.A. A1 - Galatà, S. A1 - Gay, P. A1 - Geißelsöder, S. A1 - Geyer, K. A1 - Giordano, V. A1 - Gleixner, A. A1 - Glotin, H. A1 - Gracia-Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A.J. A1 - Hello, Y. A1 - Hernández-Rey, J.-J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Hugon, C. A1 - Illuminati, G. A1 - James, C.W. A1 - de Jong, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Kießling, D. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J.A. A1 - Mathieu, A. A1 - Michael, T. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Mueller, C. A1 - Nezri, E. A1 - Păvălaș, G.E. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Racca, C. A1 - Riccobene, G. A1 - Roensch, K. A1 - Saldaña, M. A1 - Samtleben, D.F.E. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schnabel, J. A1 - Schüssler, F. A1 - Seitz, T. A1 - Sieger, C. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Sánchez-Losa, A. A1 - Taiuti, M. A1 - Trovato, A. A1 - Tselengidou, M. A1 - Turpin, D. A1 - Tönnis, C. A1 - Vallage, B. A1 - Vallée, C. A1 - Van Elewyck, V. A1 - Vivolo, D. A1 - Wagner, S. A1 - Wilms, J. A1 - Zornoza, J.D. A1 - Zúñiga, J. T1 - A search for Secluded Dark Matter in the Sun with the ANTARES neutrino telescope JF - Journal of Cosmology and Astroparticle Physics N2 - A search for Secluded Dark Matter annihilation in the Sun using 2007-2012 data of the ANTARES neutrino telescope is presented. Three different cases are considered: a) detection of dimuons that result from the decay of the mediator, or neutrino detection from: b) mediator that decays into a dimuon and, in turn, into neutrinos, and c) mediator that decays directly into neutrinos. As no significant excess over background is observed, constraints are derived on the dark matter mass and the lifetime of the mediator. KW - dark matter experiments KW - neutrino detectors KW - dark matter detectors KW - neutrino astronomy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189035 VL - 2016 IS - 5 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coleiro, A. A1 - Coniglione, R. A1 - Costantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Fehn, K. A1 - Felis, I. A1 - Fusco, L.A. A1 - Galatà, S. A1 - Gay, P. A1 - Geißelsöder, S. A1 - Geyer, K. A1 - Giordano, V. A1 - Gleixner, A. A1 - Glotin, H. A1 - Gracia-Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A.J. A1 - Hello, Y. A1 - Hernández-Rey, J.J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Hugon, C. A1 - Illuminati, G. A1 - James, C.W. A1 - de Jong, M. A1 - Jongen, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Kießling, D. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J.A. A1 - Mathieu, A. A1 - Melis, K. A1 - Michael, T. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Mueller, C. A1 - Nezri, E. A1 - Pavalas, G.E. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Racca, C. A1 - Riccobene, G. A1 - Roensch, K. A1 - Saldaña, M. A1 - Samtleben, D.F.E. A1 - Sánchez-Losa, A. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schnabel, J. A1 - Schüssler, F. A1 - Seitz, T. A1 - Sieger, C. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Taiuti, M. A1 - Tönnis, C. A1 - Trovato, A. A1 - Tselengidou, M. A1 - Turpin, D. A1 - Vallage, B. A1 - Vallée, C. A1 - Van Elewyck, V. A1 - Vivolo, D. A1 - Wagner, S. A1 - Wilms, J. A1 - Zornoza, J.D. A1 - Zúñiga, J. T1 - Limits on dark matter annihilation in the sun using the ANTARES neutrino telescope JF - Physics Letters B N2 - A search for muon neutrinos originating from dark matter annihilations in the Sun is performed using the data recorded by the ANTARES neutrino telescope from 2007 to 2012. In order to obtain the best possible sensitivities to dark matter signals, an optimisation of the event selection criteria is performed taking into account the background of atmospheric muons, atmospheric neutrinos and the energy spectra of the expected neutrino signals. No significant excess over the background is observed and 90% C.L. upper limits on the neutrino flux, the spin-dependent and spin-independent WIMP-nucleon cross-sections are derived for WIMP masses ranging from 50 GeV to 5 TeV for the annihilation channels WIMP + WIMP→ b\(\overline{b}\), W\(^{+}\)W\(^{−}\) and τ\(^{+}\)τ\(^{−}\). KW - dark matter KW - WIMP KW - neutralino KW - indirect detection KW - neutrino telescope KW - sun Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166642 VL - 759 ER - TY - JOUR A1 - Aerts, An A1 - Eberlein, Uta A1 - Holm, Sören A1 - Hustinx, Roland A1 - Konijnenberg, Mark A1 - Strigari, Lidia A1 - van Leeuwen, Fijs W. B. A1 - Glatting, Gerhard A1 - Lassmann, Michael T1 - EANM position paper on the role of radiobiology in nuclear medicine JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine. KW - radionuclide therapy KW - radiobiology KW - dosimetry KW - biodosimetry KW - biomarkers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265595 VL - 48 IS - 11 ER - TY - JOUR A1 - Aeschlimann, Martin A1 - Bauer, Michael A1 - Bayer, Daniela A1 - Brixner, Tobias A1 - Cunovic, Stefan A1 - Fischer, Alexander A1 - Melchior, Pascal A1 - Pfeiffer, Walter A1 - Rohmer, Martin A1 - Schneider, Christian A1 - Strüber, Christian A1 - Tuchscherer, Philip A1 - Voronine, Dimitri V. T1 - Optimal open-loop near-field control of plasmonic nanostructures N2 - Optimal open-loop control, i.e. the application of an analytically derived control rule, is demonstrated for nanooptical excitations using polarization-shaped laser pulses. Optimal spatial near-field localization in gold nanoprisms and excitation switching is realized by applying a shift to the relative phase of the two polarization components. The achieved near-field switching confirms theoretical predictions, proves the applicability of predefined control rules in nanooptical light–matter interaction and reveals local mode interference to be an important control mechanism. KW - Chemie Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75256 ER - TY - JOUR A1 - Aeschlimann, Martin A1 - Brixner, Tobias A1 - Cinchetti, Mirko A1 - Frisch, Benjamin A1 - Hecht, Bert A1 - Hensen, Matthias A1 - Huber, Bernhard A1 - Kramer, Christian A1 - Krauss, Enno A1 - Loeber, Thomas H. A1 - Pfeiffer, Walter A1 - Piecuch, Martin A1 - Thielen, Philip T1 - Cavity-assisted ultrafast long-range periodic energy transfer between plasmonic nanoantennas JF - Light: Science & Applications N2 - Radiationless energy transfer is at the core of diverse phenomena, such as light harvesting in photosynthesis\(^1\), energy-transfer-based microspectroscopies\(^2\), nanoscale quantum entanglement\(^3\) and photonic-mode hybridization\(^4\). Typically, the transfer is efficient only for separations that are much shorter than the diffraction limit. This hampers its application in optical communication and quantum information processing, which require spatially selective addressing. Here, we demonstrate highly efficient radiationless coherent energy transfer over a distance of twice the excitation wavelength by combining localized and delocalized\(^5\) plasmonic modes. Analogous to the Tavis-Cummings model, two whispering-gallery-mode antennas\(^6\) placed in the foci of an elliptical plasmonic cavity\(^7\) fabricated from single-crystal gold plates act as a pair of oscillators coupled to a common cavity mode. Time-resolved two-photon photoemission electron microscopy (TR 2P-PEEM) reveals an ultrafast long-range periodic energy transfer in accordance with the simulations. Our observations open perspectives for the optimization and tailoring of mesoscopic energy transfer and long-range quantum emitter coupling. KW - chemistry KW - nanocavities KW - nanophotonics and plasmonics KW - photonic devices Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173265 VL - 6 ER - TY - THES A1 - Afify, Samar T1 - Drug targeting delivery systems for treatment of Raf-1 induced lung tumors in mice T1 - Trägersystem der Medikamente für Raf1- induzierte Lungentumor in Mäusen anzuzielen N2 - The aim of the present study was to design different dosage forms as carrier systems to deliver sorafenib to the lung of BXB-23 transgenic mice using different routes of administration. Three dosage forms were used one of them was an oil-in-water emulsion and the oral route was chosen for this experiment. The other delivery system was a liposome preparation for intratracheal instillation. In this case the oral route was considered as a control experiment. The last dosage form was PLGA microspheres. Before sorafenib administration it was important to develop a HPLC method to assess sorafenib absorption after its administration and to determine its concentrations in mouse serum. The HPLC method allowed sorafenib quantification in small volumes (30 µl) of mouse serum and tissues. The developed HPLC method was validated resulting in satisfactory selectivity, good linearity, good accuracy and precision over the concentration range examined. Sorafenib was successfully incorporated in a fat emulsion (o/w) using a traditional method resulting in a white homogenous emulsion and no particle aggregation was observed. Sorafenib exhibited antitumor activity on the lung adenoma in BXB-23 transgenic mice when administered orally (2 mg sorafenib per mouse) in the emulsion preparation. The determined effect was an approximately 29 % reduction in the tumor area of the adenoma foci and a proliferation reduction. In order to improve the pharmacological effects of sorafenib on the lung adenoma in BXB-23 mice, the targeting of sorafenib directly to the site of action (the lung) was an attractive concept. For this purpose the intratracheal route was used. Since sorafenib administration by instillation required incorporation of sorafenib in a dosage form suitable for its lipophilic nature, a liposome suspension was the second dosage form used. A lyophilization method was employed for sorafenib liposome preparation utilizing dilauroylphosphatidylcholine (DLPC) which is safe and tolerable for the lung. Incorporation of sorafenib in the liposomes did not influence the particle size and its distribution. The sorafenib liposomes showed high encapsulation efficiency, good stability at 4 °C for one month and satisfactory in vitro release properties and inhibited Raf-1 mediated activation of ERK in cell culture assay. In a pharmacokinetic experiment sorafenib loaded liposomes were instilled directly into the lung. The results revealed that a significant level of sorafenib was achieved in the lung tissues after 2 hours and then reduced after 48 h and remained nearly constant for one week. On the other hand, only traces of sorafenib were found in the mice serum up to 48 h. Subsequently, the pharmacological activity of sorafenib (1 mg per mouse) was studied when delivered in a liposomal suspension intratracheally to treat the lung adenoma of BXB-23 mice. The data of this experiment demonstrated that sorafenib intratracheal instillation resulted in a reduction of tumor area of adenoma foci (67 %) and an elevation of the percent of apoptotic cells. In contrast, prolongation of the treatment period did not further enhance sorafenib activity on the lung adenoma. This previous finding suggested a development of multidrug resistance (MDR) by the adenoma foci cells against sorafenib instillation, which was examined by immunohistochemistry staining. The percent of MDR positive cells was higher after two and three weeks sorafenib liposome instillation treatment than that after one week treatment. The last dosage form used for sorafenib was microspheres, which were prepared by emulsion-diffusion-evaporation method using biodegradable PLGA 50:50 resulting in a white lyophilized powder. The system was characterized physicochemically and revealed a good microspheres yield, high encapsulation efficiency, a homogenous particle size distribution and slow in vitro release of sorafenib. The other strategy studied in the present research project was gene delivery to target the lung bearing tumor of BXB-23 mice using a non-viral vector (polyethylenimine). Polyethylenimine (PEI) was used to investigate its efficiency in transfecting lung bearing tumor of BXB-23 mice model and its ability to transfect the adenoma foci cells. LacZ, which encodes Beta-galactosidase was used in the present study as a reporter gene and was complexed with PEI before delivered intravenously. A high LacZ expression in the alveolar region with some expression in the adenoma foci was observed. On contrary, a low LacZ expression in the alveoli and in the adenoma foci was achieved after instillation of the same polyplex intratracheally. N2 - Das Ziel der vorliegenden Dissertation war es, verschiedene galenische Darreichungsformen als Trägersystem für Sorafenib zu entwickeln, um den direkten Transport des Arzneistoffes zum Zielorgan Lunge von BXB-23 transgenen Mäusen zu ermöglichen. Für die verschiedenen Applikationswege wurden drei Darreichungsformen gewählt. Eine Öl-in-Wasser-Emulsion sollte oral verabreicht werden. Für die intratracheale Instillation wurde ein liposomales Präparat gewählt. Die letzte Darreichungsform stellten PLGA Mikrosphären dar. Um die Absorption von Sorafenib nach Administration bestimmen zu können, wurde die Konzentration des Arzneistoffes im Mäuseserum gemessen. Zur Quantifizierung von Sorafenib in einem geringen Volumen Serum und in Gewebe wurde eine HPLC-Methode entwickelt und validiert. Sorafenib wurde erfolgreich in eine Fettemulsion (o/w) mittels einer traditionellen Methode eingearbeitet. Nach oraler Verabreichung der Emulsion (2 mg/Maus) zeigte Sorafenib auf Lungenadenome eine Antitumor-Aktivität, wobei eine Reduktion der Tumorfläche der Adenomfoci um etwa 29 % und eine Reduktion der Proliferation verzeichnet werden konnte. Zur Verbesserung der pharmakologischen Effekte von Sorafenib auf die Lungenadenome in BXB-23 Mäusen zu verbessern, sollte Sorafenib direkt dem Zielorgan Lunge zugeführt werden. Zu diesem Zweck wurde der intratracheale Administrationsweg gewählt. Da die Instillation von Sorafenibaufgrund seiner lipophilen Natur nur durch Einschluß in eine andere Darreichungsform zu erreichen ist, wurde für die zweite Darreichungsform eine Liposomen-Suspension verwendet. Für die Zubereitung von Sorafenib in Liposomen wurde eine Lyophilisierungsmethode unter Verwendung von DPLC erarbeitet. Die Einschluss-Effektivität der Sorafenib-beladenen Liposomen war hoch und zeigte bei 4°C eine gute Stabilität für einen Monat. Die erzielten Effekte bei der in vitro Freisetzung und die Hemmung der von Raf1-induzierten Aktivierung von ERK in Zellkulturexperimenten lieferten zufrieden stellende Ergebnisse. In einem pharmakokinetischen Experiment wurden mit Sorafenib beladenen Liposomen direkt in die Lunge appliziert. Die Ergebnisse zeigten, dass nach 2 h eine signifikante Konzentration von Sorafenib im Lungengewebe erreicht wurde. Nach 48 h nahm diese Konzentration ab und blieb dann für eine Woche fast konstant. Andererseits wurden bis zu 48 h nach Gabe des Arzneistoffes nur Spuren von Sorafenib im Mäuseserum gefunden. Folglich wurde die pharmakologische Aktivität von Sorafenib (1 mg/Maus) bei intratrachealer Verabreichung in einer liposomalen Suspension untersucht. Die Ergebnisse zeigten, dass die intratracheale Gabe von Sorafenib eine Reduktion der Tumorfläche der Adenomfoci um 67 % bewirkte, sowie eine Erhöhung des prozentualen Anteils apoptotischer Zellen. Eine Verlängerung der Behandlungszeit zeigte keine zusätzliche Verbesserung der Effekte. Dies lies vermuten, dass hier eine Entwicklung von Multidrug-Resistenz in den Adenomfocizellen gegenüber der Instillation von Sorafenib erfolgte. Dies wurde in immunochemischen Anfärbe-Experimenten untersucht. Die Prozentzahl von MDR-positiven Zellen war nach zwei und drei Wochen Instillation von Sorafenib-Liposomen höher als nach einer Woche. Die letzte verwendete Darreichungsform für Sorafenib waren Mikrosphären, die durch Emulsions-Diffusions-Evaporations-Methoden in biologisch abbaubarem PLGA 50:50 hergestellt wurden. Dies ergab ein weißes, lyophilisiertes Pulver. Das System wurde physiochemisch charakterisiert und ergab ein gutes Mikrosphären-Ergebnis, hohe Einschluss-Effektivität, eine homogene Verteilung der Partikelgrößen und eine langsame in vitro Freisetzung von Sorafenib. Die andere untersuchte Strategie war Gen-Delivery, um den Lungentumor von BXB-23 Mäusen mittels eines nicht-viralen Vektors (Polyethylenimin, PEI) anzuzielen. PEI wurde verwendet, um die Effektivität der Transfektion des Lungentumors zu untersuchen und seine Fähigkeit, die Adenomfocizellen zu transfizieren. LacZ, das Beta-Galactosidase codiert, diente bei diesem Experiment als Reportergen und wurde vor intravenöser Gabe mit PEI komplexiert. Eine hohe LacZ-Expression in der alveolaren Region, aber nur eine geringe Expression in den Adenomfoci wurde beobachtet. Im Gegensatz dazu wurde eine geringe Expression von LacZ in den Alveolen und den Adenomfoci nach intratrachealer Instillation des gleichen Polyplex erreicht. KW - Maus KW - Transgene Tiere KW - Targeted drug delivery KW - Lungenkrebs KW - Sorafenib KW - Liposomen KW - MDR KW - Mikrosphären KW - Antitumor KW - Sorafenib KW - liposomes KW - MDR KW - microspheres KW - Antitumor Y1 - 2007 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-22249 ER - TY - JOUR A1 - Afonso-Grunz, Fabian A1 - Hoffmeier, Klaus A1 - Müller, Sören A1 - Westermann, Alexander J. A1 - Rotter, Björn A1 - Vogel, Jörg A1 - Winter, Peter A1 - Kahl, Günter T1 - Dual 3'Seq using deepSuperSAGE uncovers transcriptomes of interacting Salmonella enterica Typhimurium and human host cells JF - BMC Genomics N2 - Background: The interaction of eukaryotic host and prokaryotic pathogen cells is linked to specific changes in the cellular proteome, and consequently to infection-related gene expression patterns of the involved cells. To simultaneously assess the transcriptomes of both organisms during their interaction we developed dual 3'Seq, a tag-based sequencing protocol that allows for exact quantification of differentially expressed transcripts in interacting pro-and eukaryotic cells without prior fixation or physical disruption of the interaction. Results: Human epithelial cells were infected with Salmonella enterica Typhimurium as a model system for invasion of the intestinal epithelium, and the transcriptional response of the infected host cells together with the differential expression of invading and intracellular pathogen cells was determined by dual 3'Seq coupled with the next-generation sequencing-based transcriptome profiling technique deepSuperSAGE (deep Serial Analysis of Gene Expression). Annotation to reference transcriptomes comprising the operon structure of the employed S. enterica Typhimurium strain allowed for in silico separation of the interacting cells including quantification of polycistronic RNAs. Eighty-nine percent of the known loci are found to be transcribed in prokaryotic cells prior or subsequent to infection of the host, while 75% of all protein-coding loci are represented in the polyadenylated transcriptomes of human host cells. Conclusions: Dual 3'Seq was alternatively coupled to MACE (Massive Analysis of cDNA ends) to assess the advantages and drawbacks of a library preparation procedure that allows for sequencing of longer fragments. Additionally, the identified expression patterns of both organisms were validated by qRT-PCR using three independent biological replicates, which confirmed that RELB along with NFKB1 and NFKB2 are involved in the initial immune response of epithelial cells after infection with S. enterica Typhimurium. KW - complete genome sequence KW - secretion systems KW - RNA-Seq KW - deepSuperSAGE KW - transcriptome KW - gene expression KW - serovar Typhimurium KW - human macrophages KW - epithelial cells KW - infection KW - SuperSAGE KW - receptors KW - Dual 3'seq KW - MACE KW - tag based KW - simultaneous KW - genome wide KW - gene expression profiling KW - host pathogen interaction KW - Salmonella enterica Typhimurium strain SL1344 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143230 VL - 16 IS - 323 ER - TY - JOUR A1 - Agarwal, Shailesh R. A1 - Yang, Pei-Chi A1 - Rice, Monica A1 - Singer, Cherie A. A1 - Nikolaev, Viacheslav O. A1 - Lohse, Martin J. A1 - Clancy, Colleen E. A1 - Harvey, Robert D. T1 - Role of Membrane Microdomains in Compartmentation of cAMP Signaling JF - PLOS ONE N2 - Spatially restricting cAMP production to discrete subcellular locations permits selective regulation of specific functional responses. But exactly where and how cAMP signaling is confined is not fully understood. Different receptors and adenylyl cyclase isoforms responsible for cAMP production are not uniformly distributed between lipid raft and non-lipid raft domains of the plasma membrane. We sought to determine the role that these membrane domains play in organizing cAMP responses in HEK293 cells. The freely diffusible FRET-based biosensor Epac2-camps was used to measure global cAMP responses, while versions of the probe targeted to lipid raft (Epac2-MyrPalm) and non-raft (Epac2-CAAX) domains were used to monitor local cAMP production near the plasma membrane. Disruption of lipid rafts by cholesterol depletion selectively altered cAMP responses produced by raft-associated receptors. The results indicate that receptors associated with lipid raft as well as non-lipid raft domains can contribute to global cAMP responses. In addition, basal cAMP activity was found to be significantly higher in non-raft domains. This was supported by the fact that pharmacologic inhibition of adenylyl cyclase activity reduced basal cAMP activity detected by Epac2-CAAX but not Epac2-MyrPalm or Epac2-camps. Responses detected by Epac2-CAAX were also more sensitive to direct stimulation of adenylyl cyclase activity, but less sensitive to inhibition of phosphodiesterase activity. Quantitative modeling was used to demonstrate that differences in adenylyl cyclase and phosphodiesterase activities are necessary but not sufficient to explain compartmentation of cAMP associated with different microdomains of the plasma membrane. KW - protein-coupled-receptors KW - adenylyl-cyclase isoforms KW - adult cardiac myocytes KW - plasma membrane KW - lipid rafts KW - cholesterol depletion KW - BETA(2)-adrenergic receptor KW - living vells KW - cyclic-AMP KW - domains Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116673 SN - 1932-6203 VL - 9 IS - 4 ER - TY - THES A1 - Agarwal, Shruti T1 - Functional characterization of four CDK-like kinases and one Calmodulin-dependent kinase of the human malaria parasite, Plasmodium falciparum T1 - Funktionelle Charakterisierung von vier CDK-like kinasen und eine Calmodulin-dependent kinasen des human Malaria parasite, Plasmodium falciparum N2 - Malaria still persists as one of the deadliest infectious disease in addition to AIDS and tuberculosis. lt is a leading cause of high mortality and morbidity rates in the developing world despite of groundbreaking research on global eradication of the disease initiated by WHO, about half a century ago. Lack of a commercially available vaccine and rapid spread of drug resistance have hampered the attempts of extinguishing malaria, which still leads to an annual death toll of about one million people. Resistance to anti-malarial compounds thus renders search for new target proteins imperative. The kinome of the human malaria parasite Plasmodium falciparum comprises representatives of most eukaryotic protein kinase groups, including kinases which regulate proliferation and differentiation processes. Several reports till date have suggested involvement of parasite kinases in the human host and as well as in the mosquito vector. Kinases essential for life cycle stages of the parasite represent promising targets for anti-malarial compounds thus, provoking characterization of additional malarial kinases. Despite extensive research on most plasmodial enzymes, very little information is available regarding the four identified members of the cyclin dependent kinase like kinase (CLK) family. Thus, the present thesis dealt with the functional characterization of four members of the PfCLK kinase family of the parasite denoted as PfCLK-1/Lammer, PfCLK-2, PfCLK-3 and PfCLK-4 with a special focus on the first two kinases. Additionally, one Ca2+/Calmodulin dependent putative kinase-related protein, PfPKRP, presumed to be involved in sexual stage development of the parasite, was investigated for its expression in the life cycle of the parasite. In other eukaryotes, CLK kinases regulate mRNA splicing through phosphorylation of Serine/Arginine-rich proteins. Transcription analysis revealed abundance of PfCLK kinase genes throughout the asexual blood stages and in gametocytes. By reverse genetics approach it was demonstrated that all four kinases are essential for completion of the asexual replication cycle of P. falciparum. PfCLK 1/Lammer possesses two nuclear localization signals and PfCLK-2 possesses one of these signals upstream of the C-terminal catalytic domains. Protein level expression and sub-cellular localization of the two kinases was determined by generation of antiserum directed against the kinase domains of the respective kinase. Indirect immunofluorescence, Western blot and electron microscopy data confirm that the kinases are primarily localized in the parasite nucleus, and in vitro assays show that both enzymes are associated with phosphorylation activity. Finally, mass spectrometric analysis of co immunoprecipitated proteins shows interactions of the two PfCLK kinases with proteins, which have putative nuclease, phosphatase or helicase functions. PfPKRP on the other hand is predominantly expressed during gametocyte differentiation as identified from transcriptional analysis. Antiserum directed against the catalytic domain of PfPKRP detected the protein expression profile in both asexual and gametocyte parasite lysates. Via immunofluorescence assay, the kinase was localized in the parasite cytoplasm in a punctuated manner, mostly in the gametocyte stages. Reverse genetics resulted in the generation of PfPKRP gene-disruptant parasites, thus demonstrating that unlike CLK kinases, PfPKRP is dispensable for asexual parasite survival and hence might have crucial role in sexual development of the parasite. On one hand, characterization of PfCLK kinases exemplified the kinases involved in parasite replication cycle. Successful gene-disruption and protein expression of PfPKRP kinase on the other hand, demonstrated a role of the kinase in sexual stage development of the parasite. Both kinase families therefore, represent potential candidates for anti-plasmodial compounds. N2 - Malaria stellt neben AIDS und Tuberkulose weiterhin eine der bedeutendsten Infektionskrankheiten dar. Trotz intensiver, auf die Auslöschung der Krankheit abzielender Forschung, welche vor etwa 50 Jahren durch die Weltgesundheitsorganisation initiiert wurde, bleibt Malaria einer der Hauptgründe für hohe Mortalität und Morbidität in Entwicklungsländern. Das Fehlen eines Impfstoffes und die schnelle Ausbreitung von Resistenzen erschweren die Versuche, Malaria zu eliminieren, welche jährlich weiterhin eine Todesrate von einer Millionen Menschen aufweist. Aufgrund der Zunahme an Resistenzen ist die Suche nach neuen Angriffspunkten für Antimalariamedikamente zwingend erforderlich. Das Kinom des humanpathogen Parasiten Plasmodium falciparum besteht aus Vertretern der meisten eukaryotischen Proteinkinasegruppen, einschließlich einiger Kinasen, welche Proliferations- und Differenzierungsprozesse regulieren. Verschiedenen Berichten zufolge ist eine Rolle von Parasitenkinasen sowohl im menschlichen Wirt als auch in der die Krankenheit übertragende Mücke denkbar. Kinasen, welche für verschiedene Parasitenstadien essentiell sind, stellen viel versprechende Angriffspunkte für Malariamedikamente dar. Dies bestätigt die Bedeutung der Erforschung von weiteren, bisher uncharakterisierten Kinasen. Trotz extensiver Forschungsarbeit an den meisten Enzymen des Parasiten ist bisher sehr wenig über die vier identifizierten Mitglieder der Proteinfamilie Zyklin-abhängige Kinase-ähnlicher Kinasen (cyclin-dependent kinase like kinases, CLK) bekannt. Aufgrund dessen war die Charakterisierung der vier Mitglieder der PfCLK Kinasefamilie, PfCLK-1/PfLAMMER, PfCLK-2, PfCLK-3 und PfCLK-4 Bestandteil dieser Arbeit. Der Forschungsschwerpunkt lag hierbei auf den beiden erstgenannten Kinasen. Zusätzlich wurde die stadienspezifische Expression von PfPKRP, einer Kinase, welche vermutlich in der Entwicklung der Sexualstadien des Parasiten beteiligt ist, untersucht. In anderen Eukaryoten regulieren die CLK kinases das Spleißen von mRNA durch die Phosphorylierung von Serin-/Arginin-reichen Proteinen. Untersuchungen hinsichtlich der Expression der CLK kinase zeigten eine Transkriptabundanz in allen asexuellen Blutstadien sowie in Gametozyten. Mit Hilfe der Reverse-Genetics-Technik, wurde festgestellt, dass alle vier Kinasen essentiell sind für die asexuelle Replikation von P. falciparum. PfCLK-1/Lammer besitzt zwei Kernlokalisationssequenzen, während PfCLK-2 ein solches Signal stromaufwärts der C-terminalen katalytischen Domäne aufweist. Die Expression auf Proteinebene sowie die subzelluläre Lokalisation der beiden Kinasen wurde durch die Herstellung von Antiseren gegen die jeweilige Kinasedomainen hergestellt. Indirekte Immunfluoreszenzstudien, Westernblots und elektronenmikroskopische Daten bestätigten die Lokalisation vornehmlich in Zellkern des Parasiten. In-vitro-Studien demonstrierten, das beide Enzyme mit Phosphorylierungsaktivität assoziierte sind. Die massenspektrometrische Analyse von ko-immunopräzipitierten Proteinen zeigten Interaktionen der beiden PfCLK Kinasen mit Proteinen, welche vermutlich Nuklease-, Phosphatase- oder Helikase-Funktion besitzen. Im Gegensatz zu den CLK-Kinasen wird PfPKRP wird hauptsächlich während der Differenzierung der Gametozyten exprimiert wie Transkriptanalysen zeigten. Antiseren gegen die katalytische Domäne von PfPKRP detektierten jedoch Proteinexpression sowohl in Lysaten asexueller Parasiten als auch in Gametozytenlysaten. In Immunfluoreszenzstudien wurde ein punktiertes Expressionsmuster im Zytoplasma beobachtet, wobei die Expression vornehmlich in Gametozyten stattfand. Die Tatsache, dass die Herstellung einer PfPKRP-Knock out Mutante möglich war, zeigt, dass PfPKRP für das Überleben asexueller Parasiten entbehrlich ist, weshalb eine wichtige Rolle in der sexuellen Entwicklung der Parasiten möglich ist. Zum Einen dient die Charakterisierung der PfCLK-Kinasen als Beispiel für Kinasen, welche eine wichtige Rolle im Replikationszyklus der Parasiten spielen. Das erfolgreiche Ausschalten von PfPKRP sowie Untersuchungen zur Expression der PfPKRP-Kinase lassen zum Anderen eine Rolle in den Sexual- oder Transmissionstadien vermuten. Aufgrund dessen stellen beide Kinasefamilien viel versprechende Kandidaten für die Herstellung von malariamedikamenten dar. KW - Plasmodium falciparum KW - Kinasen KW - RNS-Spleißen KW - Malaria KW - Kinase KW - Calcium KW - Splicing Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-48522 ER - TY - THES A1 - Agarwal, Vaibhav T1 - Role of PspC interaction with human polymeric immunoglobulin receptor and Factor H in Streptococcus pneumoniae infections and host cell induced signalling N2 - Streptococcus pneumoniae ist ein Gram-positives Bakterium und ein Kommensale des humanen Nasenrachenraums. Pneumokokken sind andererseits auch die Verursacher schwerer lokaler Infektionen wie der Otitis media, Sinusitis und von lebensbedrohenden invasiven Erkrankungen. So sind Pneumokokken die wichtigsten Erreger einer ambulant erworbenen Pneumonie und sie sind häufige Verursacher von Septikämien und bakteriellen Meningitiden. Die initiale Phase der Pathogenese ist verbunden mit der Besiedelung der mukosalen Epithelzellen des Rachenraumes. Diese Kolonisierung erleichtert die Aufnahme der Bakterien in die Zelle bzw. deren Dissemination in submukosale Bereiche und den Blutstrom. Die Konversion des Kommensalen zu einem invasiven Mikroorganismus ist assoziiert mit der Anpassung des Krankheitserregers an die verschiedenen Wirtsnischen und wird auf der Wirtsseite durch die Zerstörung der transepithelialen Barriere begleitet. Die Anpassung des Erregers ist vermutlich ein in hohem Grade regulierter Prozess. Die Oberfläche von Streptococcus pneumoniae ist mit Proteinen bedeckt, die kovalent oder nicht kovalent mit der Zellwand verknüpft sind. Eine einzigartige Gruppe von Oberflächenproteinen in der Zellwand der Pneumokokken sind die cholinbindenden Proteine (CBPs). Für einige der CBPs konnte bereits die Bedeutung für die Virulenz gezeigt werden. PspC, auch als SpsA oder CbpA bezeichnet, ist ein multifunktionales Oberflächenprotein, das als Adhesin und Faktor H-Bindungsprotein eine wichtige Rolle in der Pathogenese der Pneumokokken hat. PspC vermittelt als Adhesin die Anheftung der Bakterien an die mukosalen Epithelzellen, indem es human-spezifisch an die sekretorische Komponente (SC) des polymeren Immunoglobulinrezeptors (pIgR) bindet. SC ist die Ektodomäne des pIgR und PspC kann ebenso die freie SC binden oder an die SC des sekretorischen IgA Moleküls binden. PspC interagiert auch mit dem löslichen Komplement Faktor H. Die SC und der Faktor erkennen zwei verschiedene Epitope im bakteriellen PspC Protein. Der genaue Mechanismus der jeweiligen Interaktionen unter physiologischen- bzw. wirtspezifischen Bedingungen ist noch nicht vollständig verstanden. In dieser Arbeit wurde die Auswirkung der PspC Interaktion mit dem humanen pIgR (hpIgR) bzw. dem Faktor H auf die Virulenz der Pneumokokken und die Wirtszellantwort, d.h. die induzierten Signalkaskaden in den eukaryotischen Zellen untersucht. Die molekulare Analyse und die Verwendung von spezifischen pharmakologischen Inhibitoren der Signalmoleküle zeigten, dass verschiedene Signalmoleküle an der PspC-pIgR vermittelten Internalisierung beteiligt sind. Die Aktivierung, d.h. die Phosphorylierung der Signalmoleküle wurde in Immunblots demonstriert. Die Studien zeigten, dass das Aktinzytoskelett und die Mikrotubuli für die bakterielle Aufnahme essentiell sind. Es konnte auch zum ersten Mal nachgewiesen werden, dass Cdc42 die entscheidende GTPase für die Invasion der Pneumokokken in die Wirtsepithelzellen, vermittelt über den PspC-hpIgR Mechanismus, ist. Der Einsatz von PI3-kinase und Akt Kinase Inhibitoren reduzierte signifikant die hpIgR-vermittelte Aufnahme der Pneumokokken in die Wirtszelle. Zusätzlich durchgeführte Infektionen von hpIgR exprimierenden Zellen zeigten eine zeitabhängige Phosphorylierung von Akt und der p85α Untereinheit der PI3-Kinase. Damit ist neben der GTPase Cdc42 der PI3K und Akt Signalweg entscheidend für die PspC-pIgR vermittelte Invasion der Pneumokokken. Des Weiteren sind an der Infektion mit Pneumokokken auch die Protein Tyrosin Kinasen Src, ERK1/2 und JNK beteiligt. Dabei wird die Src Kinase unabhängig von der PI3K in hpIgR exprimierenden Zellen aktiviert. Inhibitionsexperimente und genetische Knockdown Versuche mit siRNA bewiesen, dass die Endozytose der Pneumokokken über PspC-pIgR ein Clathrin und Dynamin abhängiger Mechanismus ist. Im weiterenn Teil der Arbeit wurde der Einfluss des PspC gebundenen Faktor H auf die Anheftung an und Invasion in die Epithelzellen analysiert. Die Bindung von Faktor H erfolgte unabhängig vom PspC-Subtyp. Die Bindungsversuche bewiesen, dass die Kapselmenge negativ korreliert mit der Bindung des Faktor H. Der Einsatz von Faktor H aus Maus oder Ratte zeigte keine typische Bindung. Daraus kann abgeleitet werden, dass diese Interaktion humanspezifisch ist. Die Infektionsexperimente demonstrierten, dass Faktor H die Adhärenz und die Invasion der Bakterien in die Nasenrachenraumzellen (Detroit562), alveolären Lungenepithelzellen (A549) und humanen Hirnendothelzellen (HBMEC) steigert. Der Faktor H hat Heparin Bindestellen. Diese Bindestellen vermitteln die Adhärenz der Faktor H gebundenen Pneumokokken mit Epithelzellen. Inhibitionsstudien mit spezifischen monoklonalen Antikörpern, die gegen die short consensus repeats (SCRs) von Faktor H gerichtet waren, konnten die essentielle Bedeutung der SCR19-20 für die Anheftung der Pneumokokken über Faktor H an die Wirtszellen nachweisen. Die Faktor H vermittelte Assoziation der Pneumokokken an polymorphonukleäre Leukozyten (PMNs) erfolgt über das Integrin CD11b/CD18. Die weiteren Inhibitionsstudien zeigten dann auch zum ersten Mal den Einfluss des Aktinzytoskeletts der Wirtszelle auf die Faktor H-vermittelten bakterieller Internalisierung und den dabei bedeutsamen Signaltransduktionswegen in der eukaryotischen Zelle. Dabei wurden insbesondere die Proteintyrosinkinasen und die PI3K als wichtige Signalmoleküle für die Faktor H vermittelte Invasion der Pneumokokken identifiziert. Die in dieser Arbeit erhaltenen Resultate belegen, dass die Faktor H vermittelte Infektion der Zellen mit S. pneumoniae ein konzertierter Mechanismus ist, bei dem Oberflächen-Glycosaminoglycane, Integrine und Signaltransduktionswege der Wirtsepithelzellen involviert sind. Des Weiteren wurde aufgezeigt, dass die PspC-pIgR-vermittelte Invasion in mukosale Epithelzellen unterschiedliche Signalwege wie z.B. den PI3K und Akt Weg induziert und abhängig von Cdc42 und einer Clathrin vermittelten Endozytosemechanismus ist. N2 - Streptococcus pneumoniae (pneumococci) are Gram-positive bacteria and commensals of the nasopharyngeal cavity. Besides colonization, pneumococci are responsible for severe local infections such as otitis media, sinusitis and life-threatening invasive diseases, including pneumonia, sepsis and meningitis. The surface of pneumococci is decorated with proteins that are covalently or non-covalently anchored to the cell wall. The most unique group of cell wall associated proteins in pneumococci are the choline-binding proteins (CBPs). PspC, also known as SpsA or CbpA, is a multifunctional choline-binding protein that plays an essential role in pneumococcal pathogenesis by functioning as an adhesin. PspC promotes adherence of pneumococci to mucosal epithelial cells by interacting in a human specific manner with the free secretory component (SC) or to SC as part of the secretory IgA (SIgA) or polymeric immunoglobulin receptor (pIgR). PspC also interacts specifically with the soluble complement Factor H. Apparently, PspC uses two different epitopes for binding the soluble host protein Factor H and SC of pIgR. However, the mechanism by which these independent interactions facilitate pneumococcal infections under physiological and host specific conditions have not yet been completely elucidated. This study aims to explore the impact of the PspC interaction with human pIgR (hpIgR) or complement regulator Factor H on pneumococcal virulence. Here the cellular and molecular basis of PspC-mediated adherence to and invasion of host epithelial and endothelial cells was demonstrated. The genetic approach, specific pharmacological inhibitors and immunoblot analysis demonstrated the complexity of the induced signal transduction pathways during PspC-hpIgR mediated pneumococcal uptake by host cells. Inhibition studies with specific inhibitors of actin cytoskeleton and microtubules demonstrated that the dynamics of host cell cytoskeleton are essential for pneumococcal uptake by mucosal epithelial cells. Moreover, this study reports for the first time that the small GTPase Cdc42 is essential for pneumococcal internalization into epithelial cells via the PspC-hpIgR mechanism. In addition, in infection experiments performed in presence of specific inhibitors of PI3-kinase/Akt and protein tyrosine kinase (PTKs), hpIgR-mediated pneumococcal uptake by host cells was significantly blocked. Amongst PTKs the Src kinase pathway, ERK1/2 and JNK pathways were implicated during pneumococcal ingestion by hpIgR expressing cells. In addition, inhibition experiments performed in the presence of individual inhibitors or with a combination of inhibitors suggested the independent activation of PI3-kinase/Akt and Src kinase pathways during pneumococcal infections of hpIgR expressing cells. By employing specific inhibitors and siRNA in cell culture infection experiments it was further demonstrated that pneumococcal endocytosis by host epithelial cells via the PspC-hpIgR mechanism depends on clathrin and dynamin. PspC recruits also Factor H to the pneumococcal cell surface. Consequently, the impact of pneumococcal cell surface bound Factor H on adherence to host cells and the molecular mechanism facilitating the uptake of Factor H bound pneumococci by epithelial cells was investigated. Flow cytometry and immunoblots revealed that S. pneumoniae has evolved the ability to recruit both purified Factor H as well as Factor H from human plasma or serum. Moreover, it was demonstrated that the recruitment of Factor H is independent of the PspC-subtypes and that capsular polysaccharide (CPS) interferes with its recruitment. Factor H bound to pneumococci significantly increased bacterial attachment to and invasion of host epithelial cells including nasopharyngeal cells (Detroit562), lung epithelial cells (A549), and human brain-derived endothelial cells (HBMEC). Blocking experiments demonstrated that bacteria bound Factor H interacts via the heparin binding sites on Factor H with eukaryotic cell surface glycosaminoglycans and that this interaction promotes pneumococcal adherence to host cells. In addition, inhibition studies with mAbs recognizing specifically different short consensus repeats (SCR) of Factor H suggested that SCR 19-20 of Factor H are essential for the pneumococcal interaction with host epithelial cells via Factor H. In the presence of Factor H, attachment of pneumococci to human polymorphonuclear leukocytes (PMNs) is enhanced. The integrin CD11b/CD18 was identified as the cellular receptor on PMNs. By using pharmacological inhibitors the impact of host cell cytoskeleton and signalling molecules, such as PTKs and PI3-kinase, for Factor H-mediated pneumococcal internalization into eukaryotic cells was shown. Taken together, the results revealed that Factor-H mediated pneumococcal infection requires a concerted role of host epithelial cell surface glycosaminoglycans, integrins and host cell signalling pathways. KW - Streptococcus pneumoniae KW - Polymeric Immunoglobulin receptor KW - Factor H Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-36526 ER - TY - BOOK A1 - Agbokhan, Serena A1 - Sandig, Anna A1 - Haas, Thea A1 - Valentin, Francesca A1 - Gasteiger, Annika A1 - von Keller, Anna A1 - Friedmann, Fiona A1 - Wicht, Rebecca A1 - Wintermeyer, Nina A1 - Hofmann, Anna-Lena A1 - Liebich, Alexander A1 - Bördlein, Sophie A1 - Lüderitz, Cathrin A1 - Philipp, Sonja A1 - Watermann, Anne A1 - Hercher, Anna ED - Nelson-Teutsch, Hannah T1 - Insights; N2 - The cluster of texts assembled here were imagined, crafted, and brought together as a collaborative writing project that emerged from the seminar titled "Words Matter Worlds: Activist Scholarship and Literary Praxis," which convened over the course of the 2021/22 winter semester as an offering of the American Studies department of the Julius-Maximilians-Universität Würzburg. Like the seminar that nurtured the considerations that evolve here, these contributions engage with how scholarly writing practices in general, and literary and cultural studies in particular, can remake the world. KW - Aktivist KW - Literaturwissenschaft KW - Amerikanistik KW - Feminist KW - Kreatives Schreiben KW - Activist Scholarship KW - Literary and Cultural Studies KW - American Studies Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317007 SN - 978-3-945459-44-7 ER - TY - JOUR A1 - Aghai, Fatemeh A1 - Zimmermann, Sebastian A1 - Kurlbaum, Max A1 - Jung, Pius A1 - Pelzer, Theo A1 - Klinker, Hartwig A1 - Isberner, Nora A1 - Scherf-Clavel, Oliver T1 - Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma JF - Analytical and Bioanalytical Chemistry N2 - A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients. KW - kinase inhibitors KW - therapeutic drug monitoring KW - liquid chromatography tandem mass spectrometry (LC-MS/MS KW - afatinib KW - osimertinib Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231925 SN - 1618-2642 VL - 413 ER - TY - THES A1 - Agnetta, Luca T1 - Novel Photoswitchable and Dualsteric Ligands Acting on Muscarinic Acetylcholine Receptors for Receptor Function Investigation T1 - Neue lichtschaltbare und dualstere Liganden für die muskarinischen Acetylcholin Rezeptoren zur Untersuchung der Rezeptorfunktion N2 - G protein-coupled receptor research looks out for new technologies to elucidate the complex processes of receptor activation, function and downstream signaling with spatiotemporal resolution, preferably in living cells and organisms. A thriving approach consists in making use of the unsurpassed properties of light, including its high precision in space and time, noninvasiveness and high degree of orthogonality regarding biological processes. This is realized by the incorporation of molecular photoswitches, which are able to effectively respond to light, such as azobenzene, into the structure of a ligand of a given receptor. The muscarinic acetylcholine receptors belong to class A GPCRs and have received special attention in this regard due to their role as a prototypic pharmacological system and their therapeutic potential. They mediate the excitatory and inhibitory effects of the neurotransmitter acetylcholine and thus regulate diverse important biological processes, especially many neurological functions in our brain. In this work, the application of photopharmacological tool compounds to muscarinic receptors is presented, consisting of pharmacophores extended with azobenzene as light-responsive motif. Making use of the dualsteric concept, such photochromic ligands can be designed to bind concomitantly to the orthosteric and allosteric binding site of the receptor, which is demonstrated for BQCAAI (M1) and PAI (M2) and may lead to subtype- and functionalselective photoswitchable ligands, suitable for further ex vivo and in vivo studies. Moreover, photoswitchable ligands based on the synthetic agonist iperoxo were investigated extensively with regard to their photochemical behavior and pharmacological profile, outlining the advantages and challenges of using red-shifted molecular photoswitches, such as tetraortho- fluoro azobenzene. For the first time on a GPCR it was examined, which impact the different substitution pattern has on both the binding and the activity on the M1 receptor. Results show that substituted azobenzenes in photopharmacological compounds (F4-photoiperoxo and F4-iper-azo-iper) not just represent analogs with other photophysical properties but can exhibit a considerably different biological profile that has to be investigated carefully. The achievements gained in this study can give important new insights into the binding mode and time course of activation processes, enabling precise spatial and temporal resolution of the complex signaling pathway of muscarinic receptors. Due to their role as exemplary model system, these findings may be useful for the investigation into other therapeutically relevant GPCRs. N2 - Die Forschung an G-Protein-gekoppelten Rezeptoren verlangt nach neuen Technologien zur Aufklärung der komplexen Prozesse der Rezeptoraktivierung, -funktion und ihrer nachgeschalteten Signalwege mit räumlicher und zeitlicher Auflösung, vorzugsweise in lebenden Zellen und Organismen. Ein erfolgreicher Ansatz besteht darin, die unübertroffenen Eigenschaften des Lichts zu nutzen, welche die hohe Präzision in Raum und Zeit, die Nicht- Invasivität und die hohe Orthogonalität in Bezug auf biologische Prozesse einschließt. Dies wird durch den Einbau von molekularen Photoschaltern, wie z. B. Azobenzolen, in die Struktur eines Liganden eines bestimmten Rezeptors realisiert, welche effektiv auf Licht reagieren. Die muskarinischen Acetylcholin Rezeptoren gehören zur Klasse A der GPCRs und haben aufgrund ihrer Rolle als prototypisches pharmakologisches System und ihres therapeutischen Potenzials diesbezüglich besondere Beachtung gefunden. Sie vermitteln die stimulierenden und hemmenden Wirkungen des Neurotransmitters Acetylcholin und regulieren somit verschiedene wichtige biologische Prozesse, insbesondere viele neurologische Funktionen in unserem Gehirn. In dieser Arbeit wird die Anwendung photopharmakologischer „Tool“-Verbindungen auf die muskarinischen Rezeptoren vorgestellt, die aus Pharmakophoren bestehen, welche mit Azobenzol als lichtempfindlichem Motiv modifiziert wurden. Mit Hilfe des Konzepts der Dualsterie können solche photochromen Liganden so gestaltet werden, dass sie gleichzeitig an die orthosterische und allosterische Bindungsstelle des Rezeptors binden, was für BQCAAI (M1) und PAI (M2) gezeigt wurde und zu subtypen- und funktionsselektiven photoschaltbaren Liganden führen kann, die für weitere Ex- und In-Vivo-Studien geeignet sind. Darüber hinaus wurden photoschaltbare Liganden auf Basis des synthetischen Agonisten Iperoxo hinsichtlich ihres photochemischen Verhaltens und ihres pharmakologischen Profils ausführlich untersucht, um die Vorteile und Herausforderungen der Verwendung rotverschobener molekularer Photoschalter wie tetra-ortho-Fluor-azobenzol zu erläutern. Es wurde erstmals an einem GPCR untersucht, welche Auswirkungen das unterschiedliche Substitutionsmuster sowohl auf die Bindung, als auch auf die Aktivität am M1-Rezeptor hat. Diese Ergebnisse zeigen, dass substituierte Azobenzole in photopharmakologischen Verbindungen (F4-Photoiperoxo und F4-Iper-azo-iper) nicht nur Analoga mit anderen photophysikalischen Eigenschaften darstellen, sondern auch ein deutlich unterschiedliches biologisches Profil aufweisen können, das sorgfältig untersucht werden muss. Die in dieser Studie erzielten Ergebnisse geben neue und wichtige Einblicke in den Bindungsmodus und den zeitlichen Verlauf von Aktivierungsprozessen und ermöglichen eine präzise räumliche und zeitliche Auflösung der komplexen Signalwege von muskarinischen Rezeptoren. Aufgrund ihrer Rolle als exemplarisches Modellsystem können diese Befunde für die Untersuchung anderer therapeutisch relevanter GPCRs sehr nützlich sein. KW - Muscarinrezeptor KW - G-Protein gekoppelte Rezeptor KW - G Protein-coupled receptor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187170 ER - TY - JOUR A1 - Agoston, Zsuzsa A1 - Li, Naixin A1 - Haslinger, Anja A1 - Wizenmann, Andrea A1 - Schulte, Dorothea T1 - Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development JF - BMC Developmental Biology N2 - Background: During early stages of brain development, secreted molecules, components of intracellular signaling pathways and transcriptional regulators act in positive and negative feed-back or feed-forward loops at the mid-hindbrain boundary. These genetic interactions are of central importance for the specification and subsequent development of the adjacent mid-and hindbrain. Much less, however, is known about the regulatory relationship and functional interaction of molecules that are expressed in the tectal anlage after tectal fate specification has taken place and tectal development has commenced. Results: Here, we provide experimental evidence for reciprocal regulation and subsequent cooperation of the paired-type transcription factors Pax3, Pax7 and the TALE-homeodomain protein Meis2 in the tectal anlage. Using in ovo electroporation of the mesencephalic vesicle of chick embryos we show that (i) Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle, (ii) Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins, and (iii) Meis2 physically interacts with Pax3 and Pax7. These results extend our previous observation that Meis2 cooperates with Otx2 in tectal development to include Pax3 and Pax7 as Meis2 interacting proteins in the tectal anlage. Conclusion: The results described here suggest a model in which interdependent regulatory loops involving Pax3 and Pax7 in the dorsal mesencephalic vesicle modulate Meis2 expression. Physical interaction with Meis2 may then confer tectal specificity to a wide range of otherwise broadly expressed transcriptional regulators, including Otx2, Pax3 and Pax7. KW - dosage KW - quali-chick chimeras KW - drosophila embryo KW - neural crest KW - transcription activation KW - hindbrain boundary KW - isthmic oragnizer KW - sonic hedghog KW - expression KW - induction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132626 VL - 12 IS - 10 ER - TY - JOUR A1 - Agranovsky, A. A. A1 - Dolya, V. V. A1 - Gorboulev, Valentin G. A1 - Kozlov, J. V. A1 - Atabekov, J. G. T1 - Aminoacylation of barley stripe mosaic virus RNA: polyadenylate-containing RNA has a 3'-terminal tyrosine-accepting structure N2 - Barley stripe mosaic virus (BSMV) RNA which was previously reported to contain poly(A) sequences (Agranovsky et al., 1978) can be specifically esterified with tyrosine in vitro in the presence of an aminoacyl-tRNA synthetase fraction from wheat embryos. All the three RNA components of the BSMV strain with a three-component genome (Norwich) and both RNA components of a two-component strain (Russian) can be tyrosylated. The poly(A)-containing (bound to oligo(dT)-cellulose) and poly(A)-deficient(not bound to oligo(dT)-cellulose) fractions of BSMV RNA display a similar amino acidaccepting ability. The nucleotide sequence which accepts tyrosine is coupled with the intact genomic polyadenylated BSMV RNA. The viral RNA isolated after sucrose density gradient centrifugation under drastic denaturing conditions retains its aminoacylating activity, which suggests that this activity is not due to the presence in a BSMV RNA preparation of a tyrosine tRNA associated with BSMV RNA. Inhibition of aminoacylation of the 3’-oxidized (treated with sodium metaperiodate) BSMV RNA suggests that the tyrosine-accepting structure is localized at the 3’ terminus of BSMV RNA molecules. It is shown that segments of different lengths obtained upon random fragmentation can be tyrosylated. The 3’-terminal (tyrosine-accepting) poly(A)+ segments can be isolated. The shortest segments of viral RNA capable of being aminoacylated [i.e., containing both tRNA-like structure and poly(A)] consists of approximately 150-200 nucleotides. The analysis of the oligonucleotides derived from individual BSMV RNA components labeled with 32P at the 3’ end revealed two types of 3’-terminal sequences different from poly(A). It is suggested that a poly(A) sequence is intercalated between a 3’-terminal tyrosineaccepting structure and the 5’-terminal portion of poly(A)+ BSMV RNA. Y1 - 1981 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-32566 ER - TY - JOUR A1 - Aguzzi, A. A1 - Both, K. A1 - Anhauser, I. A1 - Horak, I. A1 - Rethwilm, Axel A1 - Wagner, EF. T1 - Expression of human foamy virus is differentially regulated during development in transgenic mice N2 - Tbe human foamy virus (HFV) is a recently characterized member ofthe spumavirus family. Although no diseases have been unequivocally associated with HFV infection, expression of HFV regulatory genes in transgenie mice induces a characteristic aeute neuro degenerative disease and a myopathy. To better eharaeterize the sequenee of events leading to disease, and to gain a better understanding of the underlying pathogenetic meehanisms, we have analyzed in detail the transgene expression pattern during development. Transcription of a construet containing all regulatory elements and aneillary genes of mv was analyzed by in situ hybridization and was shown to occur in two distinct phases. At midgestation, low but widespread expression was first deteeted in eells of extraembryonie tissues. Later, various tissues originating from embryonie mesoderm, neuroeetoderm, and neural erest transeribed the transgene at moderate levels. However, expression deereased dramatically during late gestation and was suppressed shortly after birth. After a latency period of up to 5 weeks, transeription of the transgene resumed in single eelJs distributed irregularly in the central nervous system and in the skeletal museIe. By the age of 8 weeks, an increasing number of eells displayed much higher expression levels than in embryonie Iife and eventually underwent severe degenerative ehanges. These findings demonstrate that HFV transgene expression is differentially regulated in development and that HFV cytotoxicity may be dose-dependent. Such biphasic pattern of expression differs from that of murine retroviruses and may be explained by the specificity of HFV regulatory elements in combination with cellular faetors. Future studies of this model system should, therefore, provide novel insights in the mechanisms controlling retrovirallatency. KW - Virologie Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-55290 ER - TY - JOUR A1 - Aguzzi, A. A1 - Wagner, E. F. A1 - Netzer, K. O. A1 - Bothe, K. A1 - Anhauser, I. A1 - Rethwilm, Axel T1 - Human foamy virus proteins accumulate in neurons and induce multinucleated giant cells in the brain of transgenic mice N2 - Humanfoamy virus (HFV) is a retrovirus encoding structural genes and, like human immunodeficiency virus and human T ceU leukemia virus I, several anciUary reading frames collectively termed the belgenes. We have previously shown that HFV transgenic mice develop an encephalopathy with neuronal loss in hippocampus and cerebral cortex. We have now raised and characterized rabbit antisera to various recombinant portions of gag, pot, env, and bel-I, the viraltransactivator. Immunoreactivity for gag and bel-I was observed in nuclei and processes of hippocampal and cortical neurons before the onset of morphological lesions and correlated with the appearance of HFV mRNA. Astrocyte-derived multinucleated giant ceUs containing HFV proteins were present in the brain oftransgenic mice coexpressingfuU- length HFV genes but not in mice expressing truncated gag and env, suggesting that these genes contain afusogenic domain. Expression of fuU-length structural genes decreased the life expectancy oftransgenic mice, implying an a4Juvant rolefor these proteins in HFV-induced brain damage. (Am] Pathol 1993, 142:1061-1072) KW - Molekularpathologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47356 ER - TY - THES A1 - Ahmad, Ruhel T1 - Neurogenesis from parthenogenetic human embryonic stem cells T1 - Neurogenese von parthenogenetischen humanen embryonalen Stammzellen N2 - Imprinted genes play important roles in brain development. As the neural developmental capabilities of human parthenogenetic embryonic stem cells (hpESCs) with only a maternal genome were not assessed in great detail, hence here the potential of hpESCs to differentiate into various neural subtypes was determined. In addition DNA methylation and expression of imprinted genes upon neural differentiation was also investigated. The results demonstrated that hpESC-derived neural stem cells (hpNSCs) showed expression of NSC markers Sox1, Nestin, Pax6, and Musashi1 (MS1), the silencing of pluripotency genes (Oct4, Nanog) and the absence of activation of neural crest (Snai2, FoxD3) and mesodermal (Acta1) markers. Moreover, confocal images of hpNSC cultures exhibited ubiquitous expression of NSC markers Nestin, Sox1, Sox2 and Vimentin. Differentiating hpNSCs for 28 days generated neural subtypes with neural cell type-specific morphology and expression of neuronal and glial markers, including Tuj1, NeuN, Map2, GFAP, O4, Tau, Synapsin1 and GABA. hpNSCs also responded to region-specific differentiation signals and differentiated into regional phenotypes such as midbrain dopaminergic- and motoneuron-type cells. hpESC-derived neurons showed typical neuronal Na+/K+ currents in voltage clamp mode, elicited multiple action potentials with a maximum frequency of 30 Hz. Cell depicted a typical neuron-like current pattern that responded to selective pharmacological blockers of sodium (tetrodotoxin) and potassium (tetraethylammonium) channels. Furthermore, in hpESCs and hpNSCs the majority of CpGs of the differentially methylated regions (DMRs) KvDMR1 were methylated whereas DMR1 (H19/Igf2 locus) showed partial or complete absence of CpG methylation, which is consistent with a parthenogenetic (PG) origin. Upon differentiation parent-of-origin-specific gene expression was maintained in hpESCs and hpNSCs as demonstrated by imprinted gene expression analyses. Together this shows that despite the lack of a paternal genome, hpNSCs are proficient in differentiating into glial- and neuron-type cells, which exhibit electrical activity similar to newly formed neurons. Moreover, maternal-specific gene expression and imprinting-specific DNA-methylation are largely maintained upon neural differentiation. hpESCs are a means to generate histocompatible and disease allele-free ESCs. Additionally, hpESCs are a unique model to study the influence of imprinting on neurogenesis. N2 - Imprinted Gene spielen eine wichtige Rolle bei der Gehirnentwicklung. Da das neurale Entwicklungspotenzial von hpESCs bisher noch nicht ausführlich untersucht wurde, war das Ziel dieser Arbeit das Differenzierungspotenzial von hpESCs zu verschiedenen neuralen Subtypen zu untersuchen. Außerdem wurden die DNA-Methylierung und Expression imprinted Gene in hpESCs während der neuralen Differenzierung analysiert. Die Ergebnisse zeigten, dass von hpESCs abgeleitete neurale Stammzellen (hpNSCs) die NSC-Marker Sox1, Nestin, Pax6 und Musashi1 (MS1) exprimierten, Pluripotenzmarker-Gene (Oct4, Nanog) abschalteten und keine Aktivierung von Markern der Neuralleistenzellen (Snai2, FoxD3) sowie dem mesodermalen Marker Acta1 stattfand. Immunfärbungen zeigten weiterhin, dass aus hpESCs abgeleitete Stammzellen die NSC-Marker Nestin, Sox1, Sox2 und Vimentin auf Proteinebene exprimierten. Durch gerichtete neurale Differenzierung für 28 Tage konnten aus hpESCs neurale Subtypen abgeleitet werden, die eine neurale Zelltyp-spezifische Morphologie aufweisen und positiv für neuronale und gliale Marker wie Tuj1, NeuN, Map2, GFAP, O4, Tau, Synapsin1 und GABA sind. Um aus hpNSCs dopaminerge und Motoneuronen abzuleiten, wurden während der Differenzierung Morphogene und trophische Faktoren zugegeben. Elektrophysiologische Analysen konnten zeigen, dass die in vitro differenzierten Neuronen, die von hpESCs abgeleitet wurden, für Neurone typische Na+/K+ Ströme sowie Aktionspotentiale (30 Hz) vorweisen ausbilden und auf ausgewählte pharmakologische Natrium- (Tetrodotoxin) und Kalium- (Tetraethylammonium) Kanal-Blocker reagierten. Desweiteren war der Großteil der CpGs von differentiell methylierten Regionen (DMRs) KvDMR1 in hpESCs und hpNSCs methyliert, während DMR1 (H19/Igf2 Locus) eine partiell oder komplett abwesende CpG-Methylierung zeigte, was dem parthenogenetischen Ursprung entspricht. Während der Differenzierung wurde die elternabhängige (parent-of-origin) spezifische Genexpression in hpESCs und hpNSCs aufrechterhalten, wie mit Genexpressionsanalysen imprinted Gene gezeigt werden konnte. In der Summe zeigen die hier dargestellten Ergebnisse, dass hpESCs, die kein paternales Genom besitzen, keine Beeinträchtigung im neuralen Differenzierungspotential zeigten und zu Gliazellen und Neurone differenziert werden konnten. Elektrophysiologische Analysen zeigten ferner, dass von hpESCs abgeleitete Neurone funktionell sind. Zudem wird die Expression maternal-spezifischer Gene und die Imprinting-spezifische DNA-Methylierung während der Differenzierung größtenteils aufrechterhalten. In der Summe stellen hpESCs ein einzigartiges Modell dar, um den Einfluss des Imprintings auf die Neurogenese zu untersuchen. KW - Embryonale Stammzelle KW - Neurogenese KW - Zelldifferenzierung KW - Stammzelle KW - human parthenogenetic stem cells KW - in vitro neural differentiation KW - human parthenogenetic neural stem cells KW - PG neurons KW - imprinting. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75935 ER - TY - JOUR A1 - Ahmad, Ruhel A1 - Wolber, Wanja A1 - Eckardt, Sigrid A1 - Koch, Philipp A1 - Schmitt, Jessica A1 - Semechkin, Ruslan A1 - Geis, Christian A1 - Heckmann, Manfred A1 - Brüstle, Oliver A1 - McLaughlin, John K. A1 - Sirén, Anna-Leena A1 - Müller, Albrecht M. T1 - Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells JF - PLoS One N2 - Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases. KW - methylation KW - derivation KW - blastocysts KW - pluripotent KW - differentiation KW - lines KW - brain development KW - in-vitro KW - mice KW - specification Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130268 VL - 7 IS - 8 ER - TY - THES A1 - Ahmed, Arabe T1 - Assessing particle deposition in a representative in vitro model of the rat respiratory tract T1 - Entwicklung eines in vitro Modells (IVR) der Rattenlunge für die Untersuchung der Deposition von Wirkstoffpartikeln in den Atemwegen der Ratte N2 - The aim of this thesis was to develop an in vitro model (IVR) of the rat lung for the purpose of investigating the deposition of drug particles in the rat airways. The model attempted to account for the affect of drug product characteristics and physiological parameters on deposition in the lungs. In addition, the model outputs were compared with in vivo lung deposition results from live rats and in silico predictions using published computer model of lung deposition in pre-clinical species. Initial work focussed on developing an aerosol exposure system capable of dosing small rodent to a range of airborne test materials. The system consists of two main parts; a fluidised bed aerosol generator and connection of the generator output to a nose only exposure chamber capable of accommodating 12 small animals in a single layer. In addition, an aerodynamic particle spectrometer (APS) was installed for continuously measuring the size distribution and airborne concentration of aerosol particles generated in the exposure chamber. System validation showed acceptable degree of variation of the test material tested, Fluorescent Microspheres (FMS) throughout the exposure chamber (CV < 15.0%). Particle size (MMAD ± GSD) using the APS was shown to be stable throughout the exposure periods. The IVR model developed in this project was based on a number of euthanased (n=7), female Sprague-Dawley rats (weight: 372 ± 56 g), which underwent high-resolution micro-CT scans. The physical model consisted of five sub sections; Extra-Thoracic region containing the snout and nasophyarynx, trachea-bronchial region containing the trachea, bronchi, and bronchioles. All sections of the model were attached to one another in numerical order and housed within a containment unit. At the rear end of the cast, a flexible diaphragm was attached in order to collect the fraction of inhaled particles exiting the TB section and possibly reaching the lung, referred to as the Post-TB section. A study was conducted to assess the influence of inhalation parameters such as the breathing frequency and tidal volume on total and regional dose distribution using FMS as test material. The major finding of this study was the demonstration of the model sensitivity to changes in breathing parameters especially respiratory frequency, where the data showed increased deposition in the peripheral regions of the model with decreased respiratory frequency. Other studies assessed the effect of particle characteristics on deposition on the IVR model, such as particle size, dose increase and formulation changes. The results assessing particle size effect showed a slightly higher deposition levels for the 4µm sized particles versus 2µm sized particles in the head region; 90.8 ± 3.6% and 88.2 ± 6.6%. However, this difference did not reach statistical significance (P> 0.05) probably due to the polydispersity of aerosolised FMS particles. In addition, the regional deposition analysis showed an increased lung peripheral deposition with the smaller particles. In addition, the model was shown to be sensitive to changes in formulation composition mediated by inclusion of MgSt. The next stage of work was to validate the model in terms of comparison with lung deposition for in vivo rats. For lung deposition comparison, the absolute amount deposited in the IVR lung model (expressed as µg/kg) was shown to have a reasonably strong correlation with in vivo lung concentration measures (µg/kg); R2= 0.66, P < 0.05. Compounds were predicted well and within 2-folds of the measured lung deposition values. However, knowing the variability in biological systems and the multiple components required to estimate lung doses, predictions within 2-fold of the measured values would seem reasonable In terms of comparison with in silico model predictions using MPPD, similar deposition levels were noted between the two models, particularly when the data was expressed as percentage of total particles inhaled. The data showed the highest deposition levels were noted in the head region (> 80%) and less than 5.0% deposition for the peripheral lung fractions. With regards to using the IVR model to assess the relationship between dose, particle size and efficacy, an in vivo study using FP with different particle sizes (2.0 and 4.0 µm) but same doses ( 100 and 1000 µg/kg). This study demonstrated that exposure of rat to FP powder resulted in a dose-dependent inhibition of neutrophils in BAL fluids. However, a clear difference in neutrophils suppression was demonstrated for equivalent doses but different particle sizes of FP, where the smaller FP particles (2.0 µm) induced a greater level of neutrophils suppression in comparison with larger FP particles (4.0 µm). In addition, a reasonably good correlation for the relationship between lung deposition in the IVR model and a neutrophils suppression level was demonstrated. Furthermore this data support the hypothesis that regional deposition is an important determinant in efficacy. Therefore, this suggests that the IVR model may be a useful as a tool to describe in vivo efficacy with in vitro data. However, further studies should be conducted to evaluate the validity of this model and relationship. The IVR model has a number of important limitations. First, the model is based on scans up to generation four of the rat respiratory tract as this represented the limits of the micro-CT scanning technology at the time of this study. Therefore deposition in the deeper region of the lung may not be reflected precisely in the IVR model. Second, the regional deposition data generated using the model tended to show an overestimation of deposition in head region and an underestimation of deposition in the peripheral regions of the lung, in comparison with in vivo lung deposition data. Third, the current model does not take into account lung clearance. However, the amount of the drug present in the in vivo lungs is dependent on numerous physiological processes such as dissolution, passive or active absorption into the systemic circulation, binding to lung tissue and mucociliary clearance. Consequently, the results generated using this IVR model for drug molecules with high lung clearance rate should be treated with some caution. Future work extending this research could go in a number of directions. In this research, a representative model of the rat respiratory tract was constructed from analysis of imaging data from a number of euthanised Sprague-Dawley rats. This model represented the “average respiratory tract” in terms of dimensions of Sprague-Dawley rats. However, there is considerable variability in the airway dimensions between rats. This variability encompasses a number of factors such as the strains of rats, sex and age, and disease state. Thus, it may be possible to produce a small number of airway models to represent small and large rats and scaled to represent the extrathoracic and peripheral regions based on literature reports of their dimensions in different rat populations. This approach will then enable the effect of intersubject airway dimensions for different rat populations on aerosol deposition to be thoroughly examined. In addition, due to the limitation of the micro-CT technology used to construct the physical IVR model, detailed morphology only up to generation 4 were captured. However, recent advances in MRI technology, such as the use of in situ-MRI based scanning technology have enabled rat airway morphometry to be extended to 16 airway generation. This coupled with improvements in the resolutions of rapid-prototyping process means it may be possible to construct a rat model that reflects the in vivo lung morphology more accurately, and thus enable greater understanding of the link between aerosol deposition and airway geometry. In conclusion, a model cast of the rat lung was developed and validated to allow the deposition of inhaled particles in the rat lung to be investigated. The model may be used to estimate the lung concentration in vivo rats in preference to exposure concentration measurements based on filter samples which have been shown to be a poor indicator of the lung concentration immediately after exposure. In addition, the model has the potential to be used along with live rats in an inhalation rig in pulmonary pharmaceutics research and may facilitate in development of inhaled formulations to target specific regions within the lung as well as screening of inhaled drugs in preclinical setting. N2 - Das Ziel dieser Arbeit war es, ein in vitro Modell (IVR) der Rattenlunge für die Untersuchung der Deposition von Wirkstoffpartikeln in den Atemwegen der Ratte zu entwickeln. Das Modell sollte dabei den Einfluss der Arzneistoffeigenschaften und physiologischer Parameter auf die pulmonale Deposition berücksichtigen. Darüber hinaus wurden die Modellergebnisse mit in vivo Daten aus Versuchen mit Ratten und in silico Vorhersagen eines etablierten Computermodells der Partikeldeposition in präklinischen Spezies verglichen. Erste Arbeiten konzentrierten sich auf die Entwicklung eines Aerosol-Expositionssystems, das in der Lage war, kleine Nagetiere einer Reihe von inhalativ verabreichten Testmaterialien auszusetzen. Das System bestand aus zwei Hauptteilen, einem Wirbelbett-Aerosolgenerator und einer Verabreichungskammer, die eine nasale Partikelexposition und –inhalation („Nose only Inhalation“) bei 12 Kleintieren auf einer Etage ermöglichte. Darüber hinaus wurde ein aerodynamisches Partikelspektrometer (APS) zur kontinuierlichen Messung der Größenverteilung und Konzentration der erzeugten Aerosolpartikel eingebaut. Die Systemvalidierung zeigte einen akzeptablen Grad der Variabilität des Testmaterials, Fluoreszenz-Mikrosphären (FMS), in der gesamten Expositionskammer (VK < 15,0%). Es konnte gezeigt werden, dass die aerodynamische Partikelgröße (MMAD ± GSD) der APS über die Expositionszeiten konstant blieb. Das IVR-Modell, das in diesem Projekt entwickelt wurde, basierte auf einer Anzahl euthanasierter, weiblicher Sprague-Dawley-Ratten (Gewicht: 372 ± 56 g), die hochauf¬lösenden Mikro-CT-Scans unterzogen wurden. Das physikalische Modell gliederte sich in fünf Teilabschnitte, dem extrathorakalen Bereich bestehend aus der Schnauze und dem Nasopharynx, und dem tracheo-bronchialen Bereich (TB), der die Luftröhre, Bronchien und Bronchiolen umfasste. Alle Abschnitte des Modells wurden miteinander in numerische Reihenfolge gebracht und innerhalb einer Behältereinheit untergebracht. Am hinteren Ende des Gusses wurde eine flexible Membran angebracht, um den Anteil der inhalierten Partikel, der den TB-Abschnitt verlässt und möglicherweise die Lunge erreicht, zu sammeln. Dieses wurde als Post-TB-Anteil bezeichnet. Eine Untersuchung sollte zeigen, welchen Einfluss Inhalationsparameter wie die Atem¬frequenz und –volumen auf die gesamte und regionale Dosisverteilung der FMS als Test¬material hatten. Das wichtigste Ergebnis dieser Studie war der Nachweis, dass das Modell empfindlich gegenüber Änderungen in der Respirationsparameter, vor allem der Atem¬frequenz, war. Die Daten zeigten, dass es unter verminderter Atemfrequenz zu einer verstärkten Partikeldeposition in den peripheren Modellbereichen kam. In weiteren Versuchsansätzen wurden die Wirkung von Partikeleigenschaften, wie Partikelgröße, Dosiserhöhung und Formulierungsänderungen auf die Deposition in dem IVR-Modell ermittelt. Die Ergebnisse der Untersuchung des Partikelgrößeneffektes zeigten eine etwas höhere Deposition der 4 µm großen Partikel, verglichen mit den 2 µm Partikeln, im Kopfbereich, 90,8 ± 3,6% bzw. 88,2 ± 6,6%. Allerdings war dieser Unterschied statistisch nicht signifikant (P > 0,05), wahrscheinlich aufgrund der Polydispersität der FMS-Aerosolpartikel. Darüber hinaus zeigte die Analyse der regionalen Verteilung eine erhöhte periphere Lungendeposition bei kleineren Partikeln. Zudem war das Modell empfindlich gegenüber Veränderungen in der Formulierungszusammensetzung durch Zugabe von Magnesium¬stearat. In nächsten Schritt sollte das Modell in Bezug auf den Vergleich mit der Lungendeposition bei Ratten in vivo validiert werden. Es zeigte sich, dass die absolut im IVR-Lungenmodell deponierte Menge (ausgedrückt in µg/kg) eine annehmbar starke Korrelation mit in vivo Daten (µg/kg) aufwies; R2 = 0,66, p < 0,05. Substanzen konnten gut innerhalb des 2-fachen Bereiches der gemessenen Lungendepositionsrate vorhergesagt werden. Angesichts der bekannt hohen Variabilität in biologischen Systemen und der Komplexität der Schätzung der Lungendeposition erscheinen Schwankungen der Vorhersagen innerhalb des 2-fachen Bereiches der tatsächlichen Werte akzeptabel. Der Vergleich der in silico Vorhersagen mit den IVR-Resultaten zeigte ähnliche Depositions¬raten in beiden Modellen, insbesondere dann, wenn die Daten als Prozentsatz der insgesamt inhalierten Partikel ausgedrückt wurden. Die höchste Deposition fand im Kopfbereich (> 80%) statt und weniger als 5,0 % der Partikel erreichte den peripheren Lungenbereich. Das IVR-Modell wurde nachfolgend auch in einer in vivo Studie mit Fluticasonpropionat (FP) eingesetzt, um die Beziehung zwischen der Dosis, Partikelgröße und Wirksamkeit unterschiedlicher Teilchengrößen (2,0 und 4,0 µm) bei gleichen Dosen (100 und 1000 µg/kg) zu beurteilen. Diese Studie zeigte eine dosisabhängige Hemmung der Neutrophilen in der bronchoalveolären Lavage. Es wurde jedoch ein deutlicher Unterschied in der Neutrophilensuppression unter äquivalenten Dosen unterschiedlicher Partikelgrößen beobachtet. Kleinere Partikel (2,0 µm) von FP hemmten die Neutrophilen stärker als die größeren FP-Partikel (4,0 µm). Darüber hinaus konnte eine recht gute Korrelation zwischen der Lungendepositionsrate im IVR-Modell und der Neutrophilensuppression gezeigt werden. Diese Daten unterstützen die Hypothese, dass die regionale Deposition eine wichtige Determinante der Wirksamkeit ist. Die Ergebnisse legen die mögliche Eignung des IVR-Modells als Hilfsmittel zur Beschreibung der in vivo Effektivität, ausgehend von in vitro Daten, nahe. Allerdings sollten weitere Studien durchgeführt werden, um die Valididtät dieses Modells und der gefundenen Beziehung zu bestätigen. Das IVR-Modell hat eine Reihe von wichtigen Einschränkungen. Erstens basiert das Modell auf Scans lediglich bis zu vierten Generation der Atemwege, was zum Zeitpunkt dieser Studie die Grenze der Mikro-CT-Scan-Technik darstellte. Daher wird in dem IVR-Modell eine Deposition in tieferen Bereichen der Lunge nicht präzise beschrieben. Zweitens zeigten die regionalen Depositionsdaten, die unter Verwendung des Modells ermittelt wurden, im Vergleich zu in vivo Ergebnissen eine Überschätzung der Deposition im Kopfbereich und eine Unterschätzung der Deposition in den peripheren Regionen der Lunge. Drittens berücksichtigt das Modell nicht die Clearance des Arzneistoffes. Die Arzneistoffkonzentration in der Lunge hängt in vivo von zahlreichen physiologischen Prozessen ab, wie Auflösung, aktive und passive Absorption in den systemischen Kreislauf, die Bindung an das Lungengewebe und mukoziliäre Clearance. Daher sollten die Ergebnisse, die unter Verwendung dieses IVR-Modells gewonnen werden, für Wirkstoff¬moleküle mit hoher Clearance-Rate mit einer gewissen Vorsicht behandelt werden. Zukünftige weiterführende Arbeiten könnten in eine Reihe von Richtungen gehen. In der vorliegenden Untersuchung wurde ein repräsentatives Modell des Rattenrespirationstraktes aus der Analyse der Bilddaten mehrerer anästhesierter Sprague-Dawley-Ratten erstellt. Dieses Modell repräsentiert die "durchschnittlichen Atemwege " in Bezug auf Abmessungen der Sprague-Dawley-Ratten. Es gibt jedoch eine beträchtliche Variabilität basierend auf einer Reihe von Faktoren wie den Rattenstamm, Geschlecht, Alter und Krankheitszustand. Es wäre möglich, mehrere verschiedene Atemwegsmodelle zu erstellen, um kleine und große Ratten zu repräsentieren. Es könnten, basierend auf Literaturangaben, die extra¬thorakalen und peripheren Regionen in ihren Abmessungen skaliert werden, um verschiedenen Rattenpopulationen zu repräsentieren. Dieser Ansatz würde dann die detaillierte Untersuchung des Einflusses interindividueller Unterschiede der Atemwegs¬dimensionen verschiedener Rattenpopulationen auf die Aerosoldeposition ermöglichen. Aufgrund der Beschränkung der Mikro-CT-Technologie, die eingesetzt wurde, um das IVR-Modell zu erstellen, konnte eine detaillierte Morphologie nur bis zur vierten Atemwegs¬generation abgebildet werden. Jüngste Fortschritte in der MRI-Technologie, wie die in situ MRI-Scan-Technologie, ermöglichen die Erfassung der Atemwegsmorphometrie bis zu 16 Atemwegsgenerationen. Dieser Ansatz, in Verbindung mit Verbesserungen in den räumlichen Auflösungen der „Rapid-Prototyping“-Verfahren, könnte die Konstruktion eines Rattenmodells ermöglichen, das die in vivo Lungenmorphologie genauer widerspiegelt, und so zu einem besseren Verständnis für den Zusammenhang zwischen Aerosoldeposition und Atemwegsgeometrie führen. Zusammenfassend lässt sich sagen, dass in der vorliegenden Arbeit ein Modellguss der Rattenlunge entwickelt und validiert wurde, um die Untersuchung der Deposition von inhalierten Partikel in der Rattenlunge zu ermöglichen. Das Modell kann verwendet werden, um die in vivo Lungenkonzentrationen von Arzneistoffen in Ratten abzuschätzen. Es bietet Vorteile gegenüber der Expositionsabschätzung auf der Basis von Filterproben, die ein schlechter Indikator der Lungenkonzentrationen unmittelbar nach der Exposition sind. Darüber hinaus hat das Modell das Potenzial, zusammen mit lebenden Ratten in einer Inhalationskammer in der Forschung verwendet zu werden und könnte in der Entwicklung von inhalativen Formulierungen erleichtern, die in bestimmten Regionen innerhalb der Lunge deponiert werden sollen. Darüber hinaus ermöglicht das Modell ein Screening inhalativ verabreichter Arzneistoffe in der präklinischen Phase. KW - In vitro rat KW - Ratte KW - in silico models KW - lung KW - deposition KW - Atemwege KW - In vitro KW - Wirkstoff KW - Inhalation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-104912 ER - TY - JOUR A1 - Ahmed, Bilal A1 - Ojha, Animesh K. A1 - Hirsch, Florian A1 - Fischer, Ingo A1 - Patrice, Donfack A1 - Materny, Arnulf T1 - Tailoring of enhanced interfacial polarization in WO\(_3\) nanorods grown over reduced graphene oxide synthesized by a one-step hydrothermal method JF - RSC Advances N2 - In the present report, well-defined WO3 nanorods (NRs) and a rGO–WO\(_3\) composite were successfully synthesized using a one-pot hydrothermal method. The crystal phase, structural morphology, shape, and size of the as-synthesized samples were studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM) measurements. The optical properties of the synthesized samples were investigated by Raman, ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. Raman spectroscopy and TEM results validate the formation of WO\(_3\) (NRs) on the rGO sheet. The value of the dielectric constant (ε′) of WO3 NRs and rGO–WO\(_3\) composite is decreased with an increase in frequency. At low frequency (2.5 to 3.5 Hz), the value of ε′ for the rGO–WO3 composite is greater than that of pure WO\(_3\) NRs. This could be due to the fact that the induced charges follow the ac signal. However, at higher frequency (3.4 to 6.0), the value of ε′ for the rGO–WO\(_3\) composite is less compared to that of the pure WO3 NRs. The overall decrease in the value of ε′ could be due to the occurrence of a polarization process at the interface of the rGO sheet and WO3 NRs. Enhanced interfacial polarization in the rGO–WO\(_3\) composite is observed, which may be attributed to the presence of polar functional groups on the rGO sheet. These functional groups trap charge carriers at the interface, resulting in an enhancement of the interfacial polarization. The value of the dielectric modulus is also calculated to further confirm this enhancement. The values of the ac conductivity of the WO\(_3\) NRs and rGO–WO\(_3\) composite were calculated as a function of the frequency. The greater value of the ac conductivity in the rGO–WO\(_3\) composite compared to that of the WO\(_3\) NRs confirms the restoration of the sp:\(^{++}\) network during the in situ synthesis of the rGO–WO\(_3\) composite, which is well supported by the results obtained by Raman spectroscopy. KW - chemistry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181829 VL - 7 IS - 23 ER - TY - JOUR A1 - Ahmed, Zeeshan A1 - Zeeshan, Saman A1 - Dandekar, Thomas T1 - Mining biomedical images towards valuable information retrieval in biomedical and life sciences JF - Database - The Journal of Biological Databases and Curation N2 - Biomedical images are helpful sources for the scientists and practitioners in drawing significant hypotheses, exemplifying approaches and describing experimental results in published biomedical literature. In last decades, there has been an enormous increase in the amount of heterogeneous biomedical image production and publication, which results in a need for bioimaging platforms for feature extraction and analysis of text and content in biomedical images to take advantage in implementing effective information retrieval systems. In this review, we summarize technologies related to data mining of figures. We describe and compare the potential of different approaches in terms of their developmental aspects, used methodologies, produced results, achieved accuracies and limitations. Our comparative conclusions include current challenges for bioimaging software with selective image mining, embedded text extraction and processing of complex natural language queries. KW - humans KW - software KW - image processing KW - animals KW - computer-assisted KW - data mining/methods KW - natural language processing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162697 VL - 2016 ER - TY - JOUR A1 - Ahmed, Zeeshan A1 - Zeeshan, Saman A1 - Huber, Claudia A1 - Hensel, Michael A1 - Schomburg, Dietmar A1 - Münch, Richard A1 - Eylert, Eva A1 - Eisenreich, Wolfgang A1 - Dandekar, Thomas T1 - ‘Isotopo’ a database application for facile analysis and management of mass isotopomer data JF - Database N2 - The composition of stable-isotope labelled isotopologues/isotopomers in metabolic products can be measured by mass spectrometry and supports the analysis of pathways and fluxes. As a prerequisite, the original mass spectra have to be processed, managed and stored to rapidly calculate, analyse and compare isotopomer enrichments to study, for instance, bacterial metabolism in infection. For such applications, we provide here the database application ‘Isotopo’. This software package includes (i) a database to store and process isotopomer data, (ii) a parser to upload and translate different data formats for such data and (iii) an improved application to process and convert signal intensities from mass spectra of \(^{13}C\)-labelled metabolites such as tertbutyldimethylsilyl-derivatives of amino acids. Relative mass intensities and isotopomer distributions are calculated applying a partial least square method with iterative refinement for high precision data. The data output includes formats such as graphs for overall enrichments in amino acids. The package is user-friendly for easy and robust data management of multiple experiments. KW - stable-isotope Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120102 VL - 2014 IS - bau077 ER - TY - THES A1 - Ahrens, Lea Marlen T1 - The Role of Attentional Control and Fear Acquisition and Generalization in Social Anxiety Disorder T1 - Die Rolle von Aufmerksamkeitskontrolle und Furchtlernen und Generalisierung bei Sozialer Angststörung N2 - Although Social Anxiety Disorder (SAD) is one of the most prevalent mental disorders, still little is known about its development and maintenance. Cognitive models assume that deviations in attentional as well as associative learning processes play a role in the etiology of SAD. Amongst others, deficits in inhibitory attentional control as well as aberrations during fear generalization, which have already been observed in other anxiety disorders, are two candidate mechanisms that might contribute to the onset and retention of SAD. However, a review of the literature shows that there is a lack of research relating to these topics. Thus, the aim of the present thesis was to examine in which way individuals with SAD differ from healthy controls regarding attentional control and generalization of acquired fear during the processing of social stimuli. Study 1 tested whether impairment in the inhibitory control of attention is a feature of SAD, and how it might be influenced by emotional expression and gaze direction of an interactional partner. For this purpose, individuals with SAD and healthy controls (HC) participated in an antisaccade task with faces displaying different emotional expressions (angry, neutral and happy) and gaze directions (direct and averted) serving as target stimuli. While the participants performed either pro- or antisaccades in response to the peripherally presented faces, their gaze behavior was recorded via eye-tracking, and ratings of valence and arousal were obtained. Results revealed that both groups showed prolonged latencies and increased error rates in trials with correct anti- compared to prosaccades. However, there were no differences between groups with regard to response latency or error rates, indicating that SAD patients did not exhibit impairment on inhibitory attentional control in comparison to HC during eye-tracking. Possible explanations for this finding could be that reduced inhibitory attentional control in SAD only occurs under certain circumstances, for example, when these individuals currently run the risk of being negatively evaluated by others and not in the mere presence of phobic stimuli, or when the cognitive load of a task is so high that it cannot be unwound by compensatory strategies, such as putting more effort into a task. As not only deviations in attentional, but also associative learning processes might be pathogenic markers of SAD, these mechanisms were further addressed in the following experiments. Study 2 is the first that attempted to investigate the generalization of conditioned fear in patients with SAD. To this end, patients with SAD and HC were conditioned to two neutral female faces serving as conditioned stimuli (CS+: reinforced; CS-: non-reinforced) and a fearful face paired with a loud scream serving as unconditioned stimulus (US). Fear generalization was tested by presenting morphs of the two faces (GS: generalization stimuli), which varied in their similarity to the original faces. During the whole experiment, self-report ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results demonstrated that SAD patients rated all stimuli as less pleasant and more arousing, and overestimated the occurrence of the US compared to HC, indicating a general hyperarousal in individuals with SAD. In addition, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to intermediate GSs as a function of their similarity to the CS+. However, except for the HR data, which indicated that only SAD patients but not HC displayed a generalization response in this measure, most of the results did not support the hypothesis that SAD is characterized by overgeneralization. A plausible reason for this finding could be that overgeneralization is just a key characteristic of some anxiety disorders and SAD is not one of them. Still, other factors, such as comorbidities in the individuals with SAD, could also have had an influence on the results, which is why overgeneralization was further examined in study 3. The aim of study 3 was to investigate fear generalization on a neuronal level. Hence, high (HSA) and low socially anxious participants (LSA) underwent a conditioning paradigm, which was an adaption of the experimental design used study 2 for EEG. During the experiment, steady-state visually evoked potentials (ssVEPs) and ratings of valence and arousal were recorded. Analyses revealed significant generalization gradients in all ratings with highest fear responses to the CS+ and a progressive decline of these reactions with increasing similarity to the CS-. In contrast, the generalization gradient on a neuronal level showed highest amplitudes for the CS+ and a reduction in amplitude to the most proximal, but not distal GSs in the ssVEP signal, which might be interpreted as lateral inhibition in the visual cortex. The observed dissociation among explicit and implicit measures points to different functions of behavioral and sensory cortical processes during fear generalization: While the ratings might reflect an individual’s consciously increased readiness to react to threat, the lateral inhibition pattern in the occipital cortex might serve to maximize the contrast among stimuli with and without affective value and thereby improve adaptive behavior. As no group differences could be observed, the finding of study 2 that overgeneralization does not seem to be a marker of SAD is further consolidated. In sum, the conducted experiments suggest that individuals with SAD are characterized by a general hyperarousal during the exposition to disorder-relevant stimuli as indicated by enhanced arousal and reduced valence ratings of the stimuli compared to HC. However, the hypotheses that reduced inhibitory attentional control and overgeneralization of conditioned fear are markers of SAD were mostly not confirmed. Further research is required to elucidate whether they only occur under certain circumstances, such as high cognitive load (e.g. handling two tasks simultaneously) or social stress (e.g. before giving a speech), or whether they are not characteristics of SAD at all. With the help of these findings, new interventions for the treatment of SAD can be developed, such as attentional bias modification or discrimination learning. N2 - Obwohl die Soziale Angststörung (SAS) eine der häufigsten psychischen Erkrankungen ist, ist über ihre Entstehung und Aufrechterhaltung noch wenig bekannt. Kognitive Modelle nehmen an, dass Abweichungen sowohl in Aufmerksamkeits- als auch assoziativen Lernprozessen eine Rolle bei ihrer Entwicklung spielen. Unter anderem werden Defizite in der Aufmerksamkeitskontrolle sowie Abweichungen während der Generalisierung von konditionierter Furcht als für die Ätiologie potentiell bedeutsame Faktoren gehandelt, da diese Auffälligkeiten bereits bei anderen Angststörungen beobachtet wurden. Eine Literaturübersicht zeigt jedoch, dass zu dieser Thematik ein Mangel an Forschung besteht. Das Ziel der vorliegenden Doktorarbeit war es daher zu untersuchen, auf welche Weise sich Individuen mit Sozialer Angststörung bei der Verarbeitung sozialer Stimuli von gesunden Kontrollprobanden in Hinblick auf ihre Aufmerksamkeitskontrolle und die Generalisierung gelernter Furchtreaktionen unterscheiden. Studie 1 testete, ob das Vorliegen einer Beeinträchtigung der inhibitorischen Aufmerksamkeitskontrolle ein Merkmal der SAS ist, und auf welche Weise diese vom emotionalen Gesichtsausdruck sowie der Blickrichtung von Interaktionspartnern beeinflusst werden kann. Zu diesem Zweck nahmen Patienten mit SAS und eine gesunde Kontrollgruppe (KG) an einer Antisakkaden-Aufgabe teil, bei welcher Gesichter mit unterschiedlichem emotionalen Ausdruck (wütend, neutral und fröhlich) und unterschiedlicher Blickrichtung (direkter und abgewandter Blick) als Stimuli dienten. Während die Probanden in Abhängigkeit eines Hinweisreizes entweder Pro- oder Antisakkaden in Reaktion auf die peripher präsentierten Gesichter ausübten, wurde ihr Blickverhalten mittels Eye-Tracking aufgezeichnet. Außerdem wurden anschließend Valenz- und Arousal-Ratings der Stimuli erfasst. Die Ergebnisse zeigten, dass beide Gruppen erhöhte Latenzzeiten sowie Fehlerraten in Durchgängen mit korrekt ausgeführten Antisakkaden im Vergleich zu Prosakkaden aufwiesen. Jedoch gab es keinen Gruppenunterschied in Bezug auf die Antwortlatenz und Fehlerrate, was darauf hindeutet, dass Patienten mit SAS im Vergleich zur KG kein Defizit der inhibitorischen Aufmerksamkeitskontrolle während des Eye-Trackings erkennen ließen. Eine mögliche Ursache für diesen Befund könnte sein, dass eine reduzierte inhibitorische Aufmerksamkeitskontrolle bei SAS nur unter bestimmten Umständen auftritt, beispielsweise, wenn betroffene Individuen akut Gefahr laufen von anderen negativ bewertet zu werden, und nicht bloß phobischen Stimuli ausgesetzt sind, oder wenn die kognitive Belastung durch eine Aufgabe so groß ist, dass sie nicht durch kompensatorische Strategien, wie beispielsweise mehr Anstrengung, ausgeglichen werden kann. Da nicht nur abweichende Aufmerksamkeitsprozesse, sondern auch abweichende assoziative Lernprozesse pathogene Marker von SAS sein könnten, wurden letztere in den folgenden Experimenten genauer untersucht. Studie 2 stellt den ersten Versuch dar die Generalisierung konditionierter Furcht in Patienten mit SAS zu erforschen. Hierfür wurden sowohl SAS Patienten als auch eine KG auf zwei neutrale, weibliche Gesichter konditioniert, welche als Konditionierungsstimuli (conditioned stimuli [CS]: CS+: verstärkt; CS-: unverstärkt) dienten. Bei dem unkonditionierten Stimulus (unconditioned stimulus [US]) handelte es sich um die bereits bekannten Gesichter mit ängstlichem Ausdruck, die mit einem lauten Schrei gepaart wurden. Die Furchtgeneralisierung wurde mittels der Präsentation von Gesichtern, welche aus den beiden Ursprungsgesichtern gemorpht worden waren und als Generalisierungsstimuli (generalization stimuli [GS]) dienten, getestet. Während des Experiments wurden Selbstauskunftsratings sowie Herzrate (heart rate [HR]) und Hautleitfähigkeit (skin conductance response [SCR]) aufgezeichnet. Die Ergebnisse zeigten, dass Patienten mit SAS im Vergleich zur KG alle Stimuli als unangenehmer und aufregender bewerteten sowie die Auftretenswahrscheinlichkeit des US überschätzten, was auf eine generelle Übererregung in Individuen mit SAS hinweist. Darüber hinaus ergaben die Ergebnisse, dass beide Gruppen ihre erworbene Furcht vom CS+ in Abhängigkeit ihrer Ähnlichkeit mit dem CS+ auf intermediäre GSs übertrugen. Allerdings stützen abgesehen von den Daten der Herzrate, in denen nur SAS Patienten und nicht die KG eine Generalisierungsreaktion zeigten, die meisten Befunde nicht die Hypothese, dass Übergeneralisierung ein Merkmal von SAS ist. Eine mögliche Ursache dieses Ergebnisses könnte sein, dass Übergeneralisierung nur ein wichtiges Merkmal einiger bestimmter Angststörungen ist und SAS nicht zu ihnen gehört. Dennoch könnten auch andere Faktoren, wie beispielsweise die Komorbiditäten der untersuchten SAS Patienten, einen Einfluss auf die Ergebnisse gehabt haben. Aus diesem Grund wurde Übergeneralisierung in Studie 3 näher untersucht. Das Ziel von Studie 3 war es Furchtgeneralisierung auf neuronaler Ebene zu untersuchen. Folglich wurde das Paradigma der zweiten Studie an einen Versuchsplan, der für die Messung von neuronaler Aktivität mittels EEG geeignet war, angepasst und auf eine hoch (high socially anxious [HSA])- sowie eine niedrig sozialängstliche Gruppe (low socially anxious [LSA]) angewandt. Während des Experiments wurden sowohl steady-state visually evoked potentials (ssVEPs) als auch Valenz- und Arousal-Ratings erfasst. Die Analyse ergab signifikante Generalisierungsgradienten in allen Ratings mit der höchsten Furchtreaktion auf den CS+ und einem fortschreitenden Abfall der Reaktion auf die GSs mit zunehmender Ähnlichkeit zum CS-. Im Gegensatz dazu zeigte sich in der ssVEP-Amplitude ein anderes Muster: hier erreichte der Generalisierungsgradient zwar auch die höchste Amplitude in Reaktion auf den CS+, jedoch eine anschließende Reduktion der Amplitude auf den nächst proximalen, nicht jedoch distale GS, was ein Hinweis auf laterale Hemmungsprozesse im visuellen Kortex sein könnte. Die beobachtete Dissoziation zwischen expliziten und impliziten Maßen könnte auf unterschiedliche Funktionen von behavioralen und sensorischen kortikalen Prozessen während der Generalisierung von Furcht hinweisen: Während die Ratings möglicherweise die bewusste Bereitschaft eines Individuums auf Bedrohung zu reagieren widerspiegeln, könnte das Muster lateraler Hemmung im okzipitalen Kortex dazu dienen den Kontrast zwischen Stimuli mit und ohne affektivem Wert zu maximieren und somit adaptives Verhalten verbessern. Da zwischen beiden Gruppen keine signifikanten Unterschiede gefunden wurden, untermauerte Studie 3 das Ergebnis von Studie 2, welches bereits eher dagegen sprach, dass Übergeneralisierung von Furcht ein Merkmal von Individuen mit SAS sei. Insgesamt suggerieren die Ergebnisse der durchgeführten Studien, dass Individuen mit SAS während der Exposition von störungsspezifischen Reizen im Vergleich zu Kontrollprobanden durch eine generelle Übererregung gekennzeichnet sind, was an erhöhten Arousal- und verringerten Valenz-Ratings erkennbar war. Jedoch konnten die Hypothesen, dass reduzierte Aufmerksamkeitskontrolle sowie Übergeneralisierung Merkmale von Individuen mit SAS sind, zum größten Teil nicht bestätigt werden. Weitere Forschung ist nötig um herauszufinden, ob diese Phänomene nur unter besonderen äußeren Umständen, wie beispielsweise hohen kognitiven Anforderungen (e.g. bei der Bearbeitung zweier Aufgaben gleichzeitig) oder sozialem Stress (e.g. vor dem Halten einer Rede), auftreten, oder ob sie gar kein Merkmal von SAS darstellen. Mit Hilfe der sich daraus ergebenden Befunde könnten neue Interventionen für die Behandlung von SAS entwickelt werden, wie beispielsweise Aufmerksamkeitsbias-Modifikations-Trainings oder Diskriminationslernen. KW - Sozialangst KW - Aufmerksamkeit KW - social anxiety KW - fear generalization KW - visual attention KW - Psychologie KW - Visuelle Aufmerksamkeit KW - Aversive Konditionierung Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171622 ER - TY - JOUR A1 - Aich, Valentin A1 - Akhundzadah, Noor Ahmad A1 - Knuerr, Alec A1 - Khoshbeen, Ahmad Jamshed A1 - Hattermann, Fred A1 - Paeth, Heiko A1 - Scanlon, Andrew A1 - Paton, Eva Nora T1 - Climate change in Afghanistan deduced from reanalysis and coordinated regional climate downscaling experiment (CORDEX)—South Asia Simulations JF - Climate N2 - Past and the projected future climate change in Afghanistan has been analyzed systematically and differentiated with respect to its different climate regions to gain some first quantitative insights into Afghanistan’s vulnerability to ongoing and future climate changes. For this purpose, temperature, precipitation and five additional climate indices for extremes and agriculture assessments (heavy precipitation; spring precipitation; growing season length (GSL), the Heat Wave Magnitude Index (HWMI); and the Standardized Precipitation Evapotranspiration Index (SPEI)) from the reanalysis data were examined for their consistency to identify changes in the past (data since 1950). For future changes (up to the year 2100), the same parameters were extracted from an ensemble of 12 downscaled regional climate models (RCM) of the Coordinated Regional Climate Downscaling Experiment (CORDEX)-South Asia simulations for low and high emission scenarios (Representative Concentration Pathways 4.5 and 8.5). In the past, the climatic changes were mainly characterized by a mean temperature increase above global level of 1.8 °C from 1950 to 2010; uncertainty with regard to reanalyzed rainfall data limited a thorough analysis of past changes. Climate models projected the temperature trend to accelerate in the future, depending strongly on the global carbon emissions (2006–2050 Representative Concentration Pathways 4.5/8.5: 1.7/2.3 °C; 2006–2099: 2.7/6.4 °C, respectively). Despite the high uncertainty with regard to precipitation projections, it became apparent that the increasing evapotranspiration is likely to exacerbate Afghanistan’s already existing water stress, including a very strong increase of frequency and magnitude of heat waves. Overall, the results show that in addition to the already extensive deficiency in adaptation to current climate conditions, the situation will be aggravated in the future, particularly in regard to water management and agriculture. Thus, the results of this study underline the importance of adequate adaptation to climate change in Afghanistan. This is even truer taking into account that GSL is projected to increase substantially by around 20 days on average until 2050, which might open the opportunity for extended agricultural husbandry or even additional harvests when water resources are properly managed. KW - climate change KW - Afghanistan KW - Coordinated Regional Climate Downscaling Experiment (CORDEX)-South Asia KW - trend analysis KW - Heat Wave Magnitude Index (HWMI) KW - Standardized Precipitation Evapotranspiration Index (SPEI) KW - growing season length (GSL) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198024 SN - 2225-1154 VL - 5 IS - 2 ER - TY - THES A1 - Aido, Ahmed T1 - Development of anti-TNF antibody-gold nanoparticles (anti-TNF-AuNPs) T1 - Entwicklung von Anti-TNF-Antikörper-Gold-Nanopartikeln N2 - Gold nanoparticles of diameter ca. 60 nm have been synthesized based on Turkevich and Frens protocols. We have demonstrated that the carboxyl-modified gold nanoparticles can be coupled covalently with antibodies (Ab) of interest using the EDC/NHS coupling procedure. Binding studies with Ab-grafted AuNPs and GpL fusion proteins proved that conjugation of AuNPs with antibodies enables immobilization of antibodies with preservation of a significant antigen binding capacity. More importantly, our findings showed that the conjugation of types of anti-TNF receptors antibodies such as anti-Fn14 antibodies (PDL192 and 5B6) (Aido et al., 2021), anti-CD40, anti-4-1BB and anti-TNFR2 with gold nanoparticles confers them with potent agonism. Thus, our results suggest that AuNPs can be utilized as a platform to immobilize anti-TNFR antibodies which, on the one hand, helps to enhance their agonistic activity in comparison to “free” inactive antibodies by mimicking the effect of cell-anchored antibodies or membrane-bound TNF ligands and, on the other hand, allows to develop new generations of drug delivery systems. These constructs are characterized with their biocompatibility and their tunable synthesis process. In a further work part, we combined the benefits of the established system of Ab-AuNPs with materials used widely in the modern biofabrication approaches such as the photo-crosslinked hydrogels, methacrylate-modified gelatin (GelMA), combined with embedded variants of human cell lines. The acquired results demonstrated clearly that the attaching of proteins like antibodies to gold nanoparticles might reduce their release rate from the crosslinked hydrogels upon the very low diffusion of gold nanoparticles from the solid constructs to the surrounding medium yielding long-term local functioning proteins-attached particles. Moreover, our finding suggests that hydrogel-embedded AuNP-immobilized antibodies, e.g. anti-TNFα-AuNPs or anti-IL1-AuNPs enable local inhibitory functions, To sum up, our results demonstrate that AuNPs can act as a platform to attach anti-TNFR antibodies to enhance their agonistic activity by resembling the output of cell-anchoring or membrane bounding. Gold nanoparticles are considered, thus, as promising tool to develop the next generation of drug delivery systems, which may contribute to cancer therapy. On top of that, the embedding of anti-inflammatory-AuNPs in the biofabricated hydrogel presents new innovative strategy of the treatment of autoinflammatory diseases. N2 - Gold-Nanopartikel mit einem Durchmesser von ca. 60 nm wurden auf Basis der Turkevich- und Frens-Protokolle synthetisiert. Bindungsstudien mit Ab-verankerten AuNPs und GpL-Fusionsproteinen haben gezeigt, dass die Konjugation von AuNPs mit Antikörpern die Immobilisierung von Antikörpern mit Erhaltung einer signifikanten Antigenbindungs-Kapazität ermöglicht. Noch wichtiger ist, dass unsere Ergebnisse zeigen, dass die Konjugation von Typen von Antikörpern gegen TNFRs wie anti-Fn14-Antikörper (PDL192 und 5B6), anti-CD40, anti-4-1BB und anti-TNFR2 mit Gold-Nanopartikeln ihnen eine starke agonistische Wirkung verleiht. Unsere Ergebnisse legen nahe, dass AuNPs als Plattform genutzt werden können, um Antikörper gegen TNFR zu immobilisieren, was einerseits dazu beiträgt, ihre agonistische Aktivität im Vergleich zu "freien" inaktiven Antikörpern zu erhöhen, indem sie die Wirkung von zellgebundenen Antikörpern oder membranverankerten TNF-Liganden nachahmen und andererseits die Entwicklung neuer Generationen von Wirkstoffabgabe Systemen ermöglicht. Diese Konstrukte zeichnen sich durch ihre Biokompatibilität und ihren einstellbaren Syntheseprozess aus. In einem weiteren Teil der Arbeit haben wir die Vorteile des etablierten Systems von Ab-AuNPs mit Materialien kombiniert, die in modernen Biofabrikationsansätzen weit verbreitet sind, nämlich Hydrogele, z.b. methacrylatmodifiziertes Gelatine (GelMA), kombiniert mit eingebetteten Varianten von menschlichen Zelllinien. Die erzielten Ergebnisse zeigten deutlich, dass die Anbindung von Proteinen wie Antikörpern an Gold-Nanopartikel ihre Freisetzung aus den vernetzten Hydrogelen reduzieren könnte, da die Diffusion von Gold-Nanopartikeln aus den festen Konstrukten in das umgebende Medium sehr gering ist und so langfristig Konstrukte mit lokalem Proteine load - erzeugt werden können. Darüber hinaus legt unser Befund nahe, dass in das Hydrogel eingebettete AuNP-immobilisierte Antikörper wie Anti-TNFα-AuNPs oder Anti-IL1-AuNPs eine lokal Immunsuppression erlauben. Diese können als vielversprechende Ansätze betrachtet werden, um verschiedene Arten von Autoimmunerkrankungen zu behandeln. Zusammenfassend zeigen unsere Ergebnisse, dass AuNPs als Plattform dienen können, um Anti-TNFR-Antikörper anzubinden und ihre agonistische Aktivität zu erhöhen. Goldnanopartikel werden daher als vielversprechendes Werkzeug zur Entwicklung der nächsten Generation von Wirkstofftransportsystemen angesehen, die zur Krebstherapie beitragen können. Darüber hinaus stellt die Einbettung von entzündungshemmenden-AuNPs in das biofabrizierte Hydrogel eine neue innovative Strategie für die Behandlung von autoinflammatorischen Erkrankungen dar. KW - AuNPs KW - TNF KW - Nanoparticles KW - Antibody KW - Gold Nanoparticles KW - Drug delivery system (DDS) KW - Nanopartikel Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349212 ER - TY - JOUR A1 - Aido, Ahmed A1 - Zaitseva, Olena A1 - Wajant, Harald A1 - Buzgo, Matej A1 - Simaite, Aiva T1 - Anti-Fn14 antibody-conjugated nanoparticles display membrane TWEAK-like agonism JF - Pharmaceutics N2 - Conventional bivalent IgG antibodies targeting a subgroup of receptors of the TNF superfamily (TNFSF) including fibroblast growth factor-inducible 14 (anti-Fn14) typically display no or only very limited agonistic activity on their own and can only trigger receptor signaling by crosslinking or when bound to Fcγ receptors (FcγR). Both result in proximity of multiple antibody-bound TNFRSF receptor (TNFR) molecules, which enables engagement of TNFR-associated signaling pathways. Here, we have linked anti-Fn14 antibodies to gold nanoparticles to mimic the “activating” effect of plasma membrane-presented FcγR-anchored anti-Fn14 antibodies. We functionalized gold nanoparticles with poly-ethylene glycol (PEG) linkers and then coupled antibodies to the PEG surface of the nanoparticles. We found that Fn14 binding of the anti-Fn14 antibodies PDL192 and 5B6 is preserved upon attachment to the nanoparticles. More importantly, the gold nanoparticle-presented anti-Fn14 antibody molecules displayed strong agonistic activity. Our results suggest that conjugation of monoclonal anti-TNFR antibodies to gold nanoparticles can be exploited to uncover their latent agonism, e.g., for immunotherapeutic applications. KW - Fn14 KW - nanoparticles KW - surface modification KW - drug-delivery KW - anti-TNFRSF receptor (TNFR) antibodies Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242710 SN - 1999-4923 VL - 13 IS - 7 ER - TY - THES A1 - Aigner, Max T1 - Establishing successful protocols and imaging pipelines for Expansion Microscopy in murine blood platelets T1 - Etablierung erfolgreicher Protokolle zur Probenpräparation und Bildgebung für die ‚Expansion Microscopy‘ in murinen Thrombozyten N2 - Platelets play an important role in the body, since they are part of the hemostasis system, preventing and stopping blood loss. Nevertheless, when platelet or coagulation system function are impaired, uncontrolled bleedings but also irreversible vessel occlusion followed by ischemic tissue damage can occur. Therefore, understanding platelet function and activation, mechanisms which are controlled by a variety of platelet membrane receptors and other factors is important to advance out knowledge of hemostasis and platelet malfunction. For a complete picture of platelet function and their modulating behavior it is desired to be able to quantify receptor distributions and interactions of these densely packed molecular ensembles in the membrane. This challenges scientists for several reasons. Most importantly, platelets are microscopically small objects, challenging the spatial resolution of conventional light microscopy. Moreover, platelet receptors are highly abundant on the membrane so even super-resolution microscopy struggles with quantitative receptor imaging on platelets. With Expansion microscopy (ExM), a new super-resolution technique was introduced, allowing resolutions to achieve super-resolution without using a super-resolution microscope, but by combining a conventional confocal microscopy with a highly processed sample that has been expanded physically. In this doctoral thesis, I evaluated the potential of this technique for super-resolution platelet imaging by optimizing the sample preparation process and establishing an imaging and image processing pipeline for dual-color 3D images of different membrane receptors. The analysis of receptor colocalization using ExM demonstrated a clear superiority compared to conventional microscopy. Furthermore, I identified a library of fluorescently labeled antibodies against different platelet receptors compatible with ExM and showed the possibility of staining membrane receptors and parts of the cytoskeleton at the same time. N2 - Thrombozyten spielen eine wichtige Rolle im Körper, denn als Teil des Gerinnungssystems, sind sie daran beteiligt Blutverlust vorzubeugen und zu stoppen. Gleichwohl können sie bei Störungen des Gerinnungssystems zu unkontrollierbaren Blutungen und auch durch Aggregation zu kardiovaskulären Ereignissen, wie Herzinfarkt und Schlaganfällen führen. Für ein besseres Verständnis von Hämostase und Gerinnungsstörungen ist es deshalb nötig die Funktion und Aktivierung von Thrombozyten zu verstehen, welche durch eine Vielzahl von Membranrezeptoren und anderen Faktoren gesteuert wird. Eine Methode, um weitere Einblicke in diese Prozesse zu bekommen ist die mikroskopische Darstellung von Rezeptorverteilungen auf der Zellmembran und deren Interaktionen. Dies zu realisieren ist aus verschiedenen Gründen anspruchsvoll. Der mikroskopisch kleine Durchmesser der Thrombozyten macht es konventioneller Lichtmikroskopie schwer, einzelne Rezeptoren auf der Membran darzustellen. Außerdem befinden sich sehr viele Rezeptoren dicht gepackt auf der Membran, sodass sogar superhochauflösende Mikroskope Schwierigkeiten haben, die Rezeptoren quantitativ zu beurteilen. Mit ‚Expansion microscopy‘ (ExM) wurde eine relativ junge superhochaufösende Technik auf Thrombozyten angewendet. Diese Technik erreicht Auflösungen vergleichbar mit sogenannten ‚super-resolution‘ Mikroskopen, ohne die Benutzung selbiger, sondern durch die Kombination von konfokaler Mikroskopie mit einer physikalisch expandierten Probe. In dieser Arbeit evaluierte ich das Potential dieser Technik für superhochauflösende Bilder von Thrombozytenrezeptoren und optimierte die Probenvorbereitung, sodass zweifarbige 3D Bilder von verschiedenen Membranrezeptoren möglich waren. Die Ergebnisse der Kolokationsanalyse zeigten einen deutlich vergrößerten Dynamikumfang durch ExM. Außerdem katalogisierte ich fluoreszenzmarkierte Antikörper gegen verschiedene Thrombozyten Rezeptoren bezüglich ihrer Tauglichkeit mit ExM und zeigte, dass es möglich ist Membranrezeptoren und Bestandteile des Zytoskeletts gleichzeitig zu färben. KW - Expansion Microscopy KW - platelets KW - Mikroskopie KW - Microscopy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309003 ER - TY - JOUR A1 - Aintablian, Arpa A1 - Strozniak, Sandra A1 - Heuer, Marion A1 - Lutz, Manfred B. T1 - M-MDSC in vitro generation from mouse bone marrow with IL-3 reveals high expression and functional activity of arginase 1 JF - Frontiers in Immunology N2 - Myeloid-derived suppressor cells (MDSC) represent major regulators of immune responses, which can control T cells via their inducible nitric oxide synthase (iNOS)- and arginase 1 (Arg1)-mediated effector functions. While GM-CSF is well documented to promote MDSC development, little is known about this potential of IL-3, an established growth factor for mast cells. Here, we show that IL-3, similar to GM-CSF, generates monocytic MDSC (M-MDSC) from murine bone marrow (BM) cells after 3 days of in vitro culture. At this time point, predominantly CD11b+ CD49a+ monocytic and CD11b+ CD49a- FcεR I- neutrophilic cells were detectable, while CD11blow/neg FcεR I+ mast cells accumulated only after extended culture periods. Both growth factors were equivalent in generating M-MDSC with respect to phenotype, cell yield and typical surface markers. However, IL-3 generated M-MDSC produced less TNF, IL-1β and IL-10 after activation with LPS + IFN-γ but showed higher Arg1 expression compared to GM-CSF generated M-MDSC. Arg1 was further induced together with iNOS after MDSC activation. Accordingly, an increased Arg1-dependent suppressor activity by the IL-3 generated M-MDSC was observed using respective iNOS and Arg1 inhibitors. Together, these data indicate that M-MDSC can be generated in vitro by IL-3, similar to GM-CSF, but with increased Arg1 expression and Arg1-mediated suppression capacity. This protocol now allows further in vitro studies on the role of IL-3 for MDSC biology. KW - myeloid-derived suppressor cells (MDSC) KW - bone marrow KW - IL-3 KW - GM-CSF KW - in vitro culture KW - protocol Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317769 VL - 14 ER - TY - JOUR A1 - Aistleitner, Karin A1 - Heinz, Christian A1 - Hoermann, Alexandra A1 - Heinz, Eva A1 - Montanaro, Jacqueline A1 - Schulz, Frederik A1 - Maier, Elke A1 - Pichler, Peter A1 - Benz, Roland A1 - Horn, Matthias T1 - Identification and Characterization of a Novel Porin Family Highlights a Major Difference in the Outer Membrane of Chlamydial Symbionts and Pathogens JF - PLoS ONE N2 - The Chlamydiae constitute an evolutionary well separated group of intracellular bacteria comprising important pathogens of humans as well as symbionts of protozoa. The amoeba symbiont Protochlamydia amoebophila lacks a homologue of the most abundant outer membrane protein of the Chlamydiaceae, the major outer membrane protein MOMP, highlighting a major difference between environmental chlamydiae and their pathogenic counterparts. We recently identified a novel family of putative porins encoded in the genome of P. amoebophila by in silico analysis. Two of these Protochlamydia outer membrane proteins, PomS (pc1489) and PomT (pc1077), are highly abundant in outer membrane preparations of this organism. Here we show that all four members of this putative porin family are toxic when expressed in the heterologous host Escherichia coli. Immunofluorescence analysis using antibodies against heterologously expressed PomT and PomS purified directly from elementary bodies, respectively, demonstrated the location of both proteins in the outer membrane of P. amoebophila. The location of the most abundant protein PomS was further confirmed by immuno-transmission electron microscopy. We could show that pomS is transcribed, and the corresponding protein is present in the outer membrane throughout the complete developmental cycle, suggesting an essential role for P. amoebophila. Lipid bilayer measurements demonstrated that PomS functions as a porin with anion-selectivity and a pore size similar to the Chlamydiaceae MOMP. Taken together, our results suggest that PomS, possibly in concert with PomT and other members of this porin family, is the functional equivalent of MOMP in P. amoebophila. This work contributes to our understanding of the adaptations of symbiotic and pathogenic chlamydiae to their different eukaryotic hosts. KW - cell wall KW - protochlamydia amoebophila KW - escherichia coli KW - matrix protein porin KW - gram negative bacteria KW - single channel analysis KW - developmental cycle KW - mycobacterium smegmatis KW - monoclonal antibodies KW - signal peptides Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131176 VL - 8 IS - 1 ER - TY - THES A1 - Akakpo, Martin Gameli T1 - The influence of learner characteristics on interactions to seek and share information in e-learning: A media psychology perspective T1 - Der Einfluss von Lernendenmerkmale auf die Interaktionen zur Suche und zum Austausch von Informationen im E-Learning: Eine medienpsychologische Perspektive N2 - Research on the deployment and use of technology to assist learning has seen a significant rise over the last decades (Aparicio et al., 2017). The focus on course quality, technology, learning outcome and learner satisfaction in e-learning has led to insufficient attention by researchers to individual characteristics of learners (Cidral et al., 2017 ; Hsu et al., 2013). The current work aims to bridge this gap by investigating characteristics identified by previous works and backed by theory as influential individual differences in e-learning. These learner characteristics have been suggested as motivational factors (Edmunds et al., 2012) in decisions by learners to interact and exchange information (Luo et al., 2017). In this work e-learning is defined as interaction dependent information seeking and sharing enabled by technology. This is primarily approached from a media psychology perspective. The role of learner characteristics namely, beliefs about the source of knowledge (Schommer, 1990), learning styles (Felder & Silverman, 1988), need for affect (Maio & Esses, 2001), need for cognition (Cacioppo & Petty, 1982) and power distance (Hofstede, 1980) on interactions to seek and share information in e-learning are investigated. These investigations were shaped by theory and empirical lessons as briefly mentioned in the next paragraphs. Theoretical support for investigations is derived from the technology acceptance model(TAM) by psychologist Davis (1989) and the hyper-personal model by communication scientist Walther (1996). The TAM was used to describe the influence of learner characteristics on decisions to use e-learning systems (Stantchev et al., 2014). The hyper-personal model described why computer-mediated communication thrives in e-learning (Kaye et al., 2016) and how learners interpret messages exchanged online (Hansen et al., 2015). This theoretical framework was followed by empirical reviews which justified the use of interaction and information seeking-sharing as key components of e-learning as well as the selection of learner characteristics. The reviews provided suggestions for the measurement of variables (Kühl et al., 2014) and the investigation design (Dascalau et al., 2015). Investigations were designed and implemented through surveys and quasi experiments which were used for three preliminary studies and two main studies. Samples were selected from Germany and Ghana with same variables tested in both countries. Hypotheses were tested with interaction and information seeking-sharing as dependent variables while beliefs about the source of knowledge, learning styles, need for affect, need for cognition and power distance were independent variables. Firstly, using analyses of variance, the influence of beliefs about the source of knowledge on interaction choices of learners was supported. Secondly, the role of need for cognition on interaction choices of learners was supported by results from a logistic regression. Thirdly, results from multiple linear regressions backed the influence of need for cognition and power distance on information seeking-sharing behaviour of learners. Fourthly, the relationship between need for affect and need for cognition was supported. The findings may have implications for media psychology research, theories used in this work, research on e-learning, measurement of learner characteristics and the design of e-learning platforms. The findings suggest that, the beliefs learners have about the source of knowledge, their need for cognition and their power distance can influence decisions to interact and seek or share information. The outlook from reviews and findings in this work predicts more research on learner characteristics and a corresponding intensity in the use of e-learning by individuals. It is suggested that future studies investigate the relationship between learner autonomy and power distance. Studies on inter-cultural similarities amongst e-learners in different populations are also suggested. N2 - Forschungsbemühungen zur Bereitstellung und die Nutzung von Technologien zur Unterstützung des Lernens nahm in den letzten Jahrzehnten erheblich zu (Aparicio et al., 2017). Der Fokus auf Kursqualität, Technologie, Lernergebnisse und Zufriedenheit der Lernenden im E-Learning führte dazu, dass die Forschenden den individuellen Eigenschaften der Lernenden nicht genügend Aufmerksamkeit schenkten (Cidral et al., 2017; Hsu et al., 2013). Die vorliegende Arbeit ist bestrebt, diese Lücke zu schließen. Sie untersucht Lernendenmerkmale, die in früheren Arbeiten identifiziert und theoretisch als einflussreiche individuelle Unterschiede beim E-Learning unterstrichen wurden. Diese Eigenschaften des Lernenden wurden als Motivationsfaktoren (Edmunds et al., 2012) in Entscheidungen des Lernenden bei Interaktion mit und zum Austausch von Informationen vorgeschlagen (Luo et al., 2017). In der vorliegenden Arbeit wird E-Learning definiert als Informationssuche und -austausch, der durch Technologie ermöglicht wird und auf Interaktionen basiert. Diese Ideen werden vor allem aus medienpsychologischer Sicht angegangen. Die Rolle der Merkmale des Lernenden, nämlich seine jeweiligen Überzeugungen über die Quelle des Wissens (Schommer, 1990), Lernstile (Felder & Silverman, 1988), Bedürfnis nach Zuwendung (Maio & Esses, 2001), Erkenntnisdrang (Cacioppo & Petty, 1982) und Machtdistanz (Hofstede, 1980) werden bzgl. der Interaktionen, die zur Suche und zum Austausch von Informationen dienen, untersucht. Diese Untersuchungen berücksichtigen theoretische Annahmen und empirische Erkenntnisse, die hier kurz skizziert werden. Das ‚Technology Acceptance Model‘ (TAM) des Psychologen Davis (1989) und das ‚Hyper-Personal Model‘ des Kommunikationswissenschaftlers Walther (1996) liegen den durchgeführten Untersuchungen zugrunde. Mit dem TAM wurde der Einfluss der Eigenschaften eines Lernenden auf Entscheidungen zur Verwendung von E-Learning-Systemen erklärt (Stantchev et al., 2014). Das ‚Hyper-Personal Model‘ skizzierte Ursachen, warum computervermittelte Kommunikation im E-Learning gelingt (Kaye et al., 2016) und wie Lernende online ausgetauschte Nachrichten interpretieren (Hansen et al., 2015). Diesem theoretischen Rahmen folgend, werden empirische Arbeiten umrissen, die die Verwendung von Interaktion, zur Suche und zum Austausch von Informationen als Schlüsselkomponenten des E-Learning beschreiben sowie die Auswahl der zu untersuchenden Eigenschaften der Lernenden rechtfertigten. Aus diesen Arbeiten wurden Ideen für die Messung der Variablen (Kühl et al., 2014) und das Untersuchungsdesign (Dascalau et al., 2015) abgeleitet. Umfragen und Quasi-Experimente wurden hierzu durchgeführt. Diese Instrumente wurden für drei Vorstudien und zwei Hauptstudien verwendet. Probanden wurden aus Deutschland und Ghana ausgewählt, wobei in beiden Ländern die gleichen Variablen getestet wurden. Die Hypothesentestung berücksichtigte Interaktion und Informationssuche und -austausch als abhängige Variablen, während die Überzeugungen bzgl. der Quellen des Wissens, Lernstile, Bedürfnis nach Zuwendung, Erkenntnisdrang und Machtdistanz als unabhängige Variablen dienten. Durchgeführte Varianzanalysen (1.) belegen die Annahme, dass Überzeugungen über die Wissensquelle Einfluss auf die Interaktionswahl der Lernenden haben. Zudem konnte ein Effekt (2.) des Erkenntnisdrangs auf die Wahlentscheidung der Lernenden durch die Ergebnisse einer logistischen Regression unterstützt werden. Des Weiteren (3.) unterstützten die Ergebnisse mehrerer linearer Regressionen den Einfluss des Erkenntnisdrangs und der Machtdistanz auf das Verhalten der Lernenden bezüglich Informationssuche und -austausch. Schließlich (4.) wurde die Wechselbeziehung zwischen Bedürfnis nach Zuwendung und Erkenntnisdrang unterstützt. Die Ergebnisse sind relevant für die medienpsychologische Forschung, Theorien, die in dieser Arbeit verwendet werden, die Untersuchung von E-Learning, die Messung der Merkmale der Lernenden, sowie für die Gestaltung von E-Learning-Plattformen. Die Ergebnisse deuten darauf hin, dass die Überzeugungen der Lernenden über die Wissensquelle, ihr Erkenntnisdrang (NfC) und ihre Machtdistanz, die Entscheidungen, wie sie interagieren und Informationen suchen oder sie auszutauschen, beeinflussen können. Schlußfolgerungen aus der erarbeiteten Theorie und Empirie sowie aus dieser Arbeit befürworten eine stärkere Erforschung der Eigenschaften der Lernenden. Es erscheint darüber hinaus ratsam, dass zukünftige Studien den Zusammenhang zwischen der Autonomie der Lernenden und der Machtdistanz untersuchen. Es werden außerdem weitere Studien zu interkulturellen Ähnlichkeiten zwischen E-Learning-Lernenden in verschiedenen Bevölkerungsgruppen vorgeschlagen. KW - e-learning KW - Individualität KW - E-Learning KW - Media Psychology KW - Interactions KW - Information seeking and sharing KW - information sharing KW - learner characteristics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-185934 ER - TY - JOUR A1 - Akhoon, Bashir A. A1 - Gupta, Shishir K. A1 - Tiwari, Sudeep A1 - Rathor, Laxmi A1 - Pant, Aakanksha A1 - Singh, Nivedita A1 - Gupta, Shailendra K. A1 - Dandekar, Thomas A1 - Pandey, Rakesh T1 - C. elegans protein interaction network analysis probes RNAi validated pro-longevity effect of nhr-6, a human homolog of tumor suppressor Nr4a1 JF - Scientific Reports N2 - Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function. KW - Computer modelling KW - Embryonic induction KW - RNAi Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202666 VL - 9 ER -