TY  - THES
A1  - Bergmann, Anna
T1  - Untersuchungen zur Verwertung proteinhaltiger Substrate als mögliche Virulenzdeterminante des humanpathogenen Schimmelpilzes Aspergillus fumigatus
T1  - Studies on utilisation of proteinaceous substrates as potential virulence determinant of the human pathogen Aspergillus fumigatus
N2  - Die asexuellen Sporen von Aspergillus fumigatus sind ubiquitär verbreitete Luftkeime. Als Saprophyt ist dieser opportunistisch humanpathogene Pilz darauf spezialisiert, polymere Substanzen aus dem umgebenden Milieu zu zersetzen, um daraus die von ihm benötigten Nährstoffe zu generieren und aufzunehmen. Die Fähigkeit, verschiedene Stickstoff- und Kohlenstoffquellen zu verwerten, trägt dabei zu seiner Virulenz bei und hierbei scheint die extrazelluläre Proteolyse eine wichtige Rolle zu spielen. Sekretierte Proteasen, die das umgebende Gewebe während einer Infektion mit A. fumigatus erschließen, könnten somit zu dessen Pathogenität beitragen. Dementsprechend sollte im Rahmen dieser Arbeit die Bedeutung einer Regulation der extrazellulären proteolytischen Aktivität von A. fumigatus für dessen Virulenz untersucht werden. Dies geschah durch Untersuchungen eines konservierten Transkriptionsfaktors, PrtT. Dabei stellte sich heraus, dass PrtT die Expression der drei Hauptproteasen von A. fumigatus, Alp, Mep und Pep stark beeinflusst, in einem murinen Tiermodell der pulmonaren Aspergillose scheint dieser Regulator jedoch keine Rolle für die Pathogenität von A. fumigatus zu spielen. Um einen weiteren Aspekt des pilzlichen Aminosäurestoffwechsels zu beleuchten, wurde die Biosynthese der aromatischen Aminosäuren als mögliche Virulenzdeterminate untersucht. Für den Menschen sind diese Aminosäuren essentiell, weshalb dieser Syntheseweg ein mögliches Ziel für antimykotische Substanzen darstellen könnte. Es konnten mehrere für A. fumigatus essentielle Komponenten des Shikimatweges identifiziert werden, des Weiteren wurden Deletionsmutanten in den Genen aroC und trpA, die für die Chorismatmutase bzw. Anthranilatsynthase der Biosynthese von Phenylalanin und Tyrosin bzw. Tryptophan kodieren, erzeugt und phänotypisch charakterisiert. Deren Untersuchung in einem alternativen Tiermodell der Aspergillose zeigte eine deutlich attenuierte Virulenz. Diese Ergebnisse verdeutlichen, wie wichtig die Biosynthese der aromatischen Aminosäuren für das Wachstum von A. fumigatus ist, und dass ein Eingriff in diesen Syntheseweg eine lohnende Strategie zur Entwicklung neuer Antimykotika sein könnte. Die hier präsentierten Ergebnisse unterstreichen die für den Schimmelpilz A. fumigatus typische Redundanz bezüglich extrazellulärer proteolytischer Enzyme und dass diese nur bedingt hinsichtlich ihres Virulenzbeitrags untersucht werden können. Im Gegensatz hierzu lassen sich bestimmte Stoffwechselwege, die oftmals durch einzigartige Genprodukte katalysiert werden, unter Umständen besser als unspezifische aber vielversprechende Virulenzdeterminanten identifizieren.
N2  - The air-borne spores of Aspergillus fumigatus are ubiquitously distributed. As a saprophyte, this fungus is well adapted to feed from the environment by degradation of polymeric substances and uptake of breakdown products. The nutritional versatility has to be regarded as virulence determinant in the development of pulmonary aspergillosis. Secreted proteolytic activities that degrade the surrounding lung tissue during infection may contribute to pathogenicity. Until now, knowledge on the regulation of the expression and secretion of proteases by A. fumigatus is scarce. Therefore, the role of extracellular proteolytic activity for pathogenicity of A. fumigatus was examined by characterisation of a global regulatory factor, PrtT, that acts on expression of secreted proteases. It could be shown that PrtT regulates the transcription of the major secreted proteases Alp, Mep and Pep. When tested in a leukopenic mouse model, the deletant strain is not attenuated in virulence, suggesting that the PrtT transcription factor - and accordingly extracellular proteolysis - supports virulence of this opportunistic pathogen only to a limited extent. To gain insight into the fungal biosynthesis pathway of amino acids, the aromatic amino acid biosynthesis was investigated concerning the aspect of a virulence determinant. In contrast to mammals, fungi are able for de novo synthesis of the aromatic amino acids. Therefore it might be a usable target for antifungal therapy since such pathway does not exist in humans. Some genes of the shikimate pathway could be shown to be essential for the survival of A. fumigatus. Virulence tests of strains with deletion of the genes aroC or trpA which encodes for the chorismate mutase and anthranilate synthase respectively, showed attenuated virulence of both strains. These results clarify the stringent necessity of the aromatic amino acid biosynthesis for the survival of A. fumigatus, concluding this biosynthesis pathway as a usable target for antimycotic substances. The results of this work emphasise the redundancy of extracellular proteolytic activities. In contrast specific pathways which are mostly catalysed by unique gene products may be identified as virulence determinant rather than unspecific factors.
KW  - Aspergillus fumigatus
KW  - Proteasen
KW  - Proteolyse
KW  - Posttranskriptionelle Regulation
KW  - Biosynthese der aromatischen Aminosäuren
KW  - Aspergillus fumigatus
KW  - Proteases
KW  - Proteolysis
KW  - posttranscriptional regulation
KW  - aromatic amino acid biosynthesis
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67333
ER  - 
TY  - JOUR
A1  - Semmler, Anna-Lena
A1  - Sacconi, Sabrina
A1  - Bach, J. Elisa
A1  - Liebe, Claus
A1  - Bürmann, Jan
A1  - Kley, Rudolf A.
A1  - Ferbert, Andreas
A1  - Anderheiden, Roland
A1  - Van den Bergh, Peter
A1  - Martin, Jean-Jacques
A1  - De Jonghe, Peter
A1  - Neuen-Jacob, Eva
A1  - Müller, Oliver
A1  - Deschauer, Marcus
A1  - Bergmann, Markus
A1  - Schröder, J. Michael
A1  - Vorgerd, Matthias
A1  - Schulz, Jörg B.
A1  - Weis, Joachim
A1  - Kress, Wolfram
A1  - Claeys, Kristl G.
T1  - Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies
JF  - Orphanet Journal of Rare Diseases
N2  - Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. 
Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. 
Results: We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p. Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p. Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). 
Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.
KW  - polyneuropathy
KW  - MFM
KW  - next generation sequencing
KW  - bcl-2 associated athanogene protein 3
KW  - protein aggregation
KW  - hearing impairment
KW  - early respiratory-failure
KW  - myopathy
KW  - muscular-dystrophy
KW  - skeletal myopathy
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115623
SN  - 1750-1172
N1  - Additional files are available here: http://www.ojrd.com/content/9/1/121/additional
VL  - 9
IS  - 121
ER  - 
TY  - JOUR
A1  - Bousquet, Jean
A1  - Anto, Josep M.
A1  - Bachert, Claus
A1  - Haahtela, Tari
A1  - Zuberbier, Torsten
A1  - Czarlewski, Wienczyslawa
A1  - Bedbrook, Anna
A1  - Bosnic‐Anticevich, Sinthia
A1  - Walter Canonica, G.
A1  - Cardona, Victoria
A1  - Costa, Elisio
A1  - Cruz, Alvaro A.
A1  - Erhola, Marina
A1  - Fokkens, Wytske J.
A1  - Fonseca, Joao A.
A1  - Illario, Maddalena
A1  - Ivancevich, Juan‐Carlos
A1  - Jutel, Marek
A1  - Klimek, Ludger
A1  - Kuna, Piotr
A1  - Kvedariene, Violeta
A1  - Le, LTT
A1  - Larenas‐Linnemann, Désirée E.
A1  - Laune, Daniel
A1  - Lourenço, Olga M.
A1  - Melén, Erik
A1  - Mullol, Joaquim
A1  - Niedoszytko, Marek
A1  - Odemyr, Mikaëla
A1  - Okamoto, Yoshitaka
A1  - Papadopoulos, Nikos G.
A1  - Patella, Vincenzo
A1  - Pfaar, Oliver
A1  - Pham‐Thi, Nhân
A1  - Rolland, Christine
A1  - Samolinski, Boleslaw
A1  - Sheikh, Aziz
A1  - Sofiev, Mikhail
A1  - Suppli Ulrik, Charlotte
A1  - Todo‐Bom, Ana
A1  - Tomazic, Peter‐Valentin
A1  - Toppila‐Salmi, Sanna
A1  - Tsiligianni, Ioanna
A1  - Valiulis, Arunas
A1  - Valovirta, Erkka
A1  - Ventura, Maria‐Teresa
A1  - Walker, Samantha
A1  - Williams, Sian
A1  - Yorgancioglu, Arzu
A1  - Agache, Ioana
A1  - Akdis, Cezmi A.
A1  - Almeida, Rute
A1  - Ansotegui, Ignacio J.
A1  - Annesi‐Maesano, Isabella
A1  - Arnavielhe, Sylvie
A1  - Basagaña, Xavier
A1  - D. Bateman, Eric
A1  - Bédard, Annabelle
A1  - Bedolla‐Barajas, Martin
A1  - Becker, Sven
A1  - Bennoor, Kazi S.
A1  - Benveniste, Samuel
A1  - Bergmann, Karl C.
A1  - Bewick, Michael
A1  - Bialek, Slawomir
A1  - E. Billo, Nils
A1  - Bindslev‐Jensen, Carsten
A1  - Bjermer, Leif
A1  - Blain, Hubert
A1  - Bonini, Matteo
A1  - Bonniaud, Philippe
A1  - Bosse, Isabelle
A1  - Bouchard, Jacques
A1  - Boulet, Louis‐Philippe
A1  - Bourret, Rodolphe
A1  - Boussery, Koen
A1  - Braido, Fluvio
A1  - Briedis, Vitalis
A1  - Briggs, Andrew
A1  - Brightling, Christopher E.
A1  - Brozek, Jan
A1  - Brusselle, Guy
A1  - Brussino, Luisa
A1  - Buhl, Roland
A1  - Buonaiuto, Roland
A1  - Calderon, Moises A.
A1  - Camargos, Paulo
A1  - Camuzat, Thierry
A1  - Caraballo, Luis
A1  - Carriazo, Ana‐Maria
A1  - Carr, Warner
A1  - Cartier, Christine
A1  - Casale, Thomas
A1  - Cecchi, Lorenzo
A1  - Cepeda Sarabia, Alfonso M.
A1  - H. Chavannes, Niels
A1  - Chkhartishvili, Ekaterine
A1  - Chu, Derek K.
A1  - Cingi, Cemal
A1  - Correia de Sousa, Jaime
A1  - Costa, David J.
A1  - Courbis, Anne‐Lise
A1  - Custovic, Adnan
A1  - Cvetkosvki, Biljana
A1  - D'Amato, Gennaro
A1  - da Silva, Jane
A1  - Dantas, Carina
A1  - Dokic, Dejan
A1  - Dauvilliers, Yves
A1  - De Feo, Giulia
A1  - De Vries, Govert
A1  - Devillier, Philippe
A1  - Di Capua, Stefania
A1  - Dray, Gerard
A1  - Dubakiene, Ruta
A1  - Durham, Stephen R.
A1  - Dykewicz, Mark
A1  - Ebisawa, Motohiro
A1  - Gaga, Mina
A1  - El‐Gamal, Yehia
A1  - Heffler, Enrico
A1  - Emuzyte, Regina
A1  - Farrell, John
A1  - Fauquert, Jean‐Luc
A1  - Fiocchi, Alessandro
A1  - Fink‐Wagner, Antje
A1  - Fontaine, Jean‐François
A1  - Fuentes Perez, José M.
A1  - Gemicioğlu, Bilun
A1  - Gamkrelidze, Amiran
A1  - Garcia‐Aymerich, Judith
A1  - Gevaert, Philippe
A1  - Gomez, René Maximiliano
A1  - González Diaz, Sandra
A1  - Gotua, Maia
A1  - Guldemond, Nick A.
A1  - Guzmán, Maria‐Antonieta
A1  - Hajjam, Jawad
A1  - Huerta Villalobos, Yunuen R.
A1  - Humbert, Marc
A1  - Iaccarino, Guido
A1  - Ierodiakonou, Despo
A1  - Iinuma, Tomohisa
A1  - Jassem, Ewa
A1  - Joos, Guy
A1  - Jung, Ki‐Suck
A1  - Kaidashev, Igor
A1  - Kalayci, Omer
A1  - Kardas, Przemyslaw
A1  - Keil, Thomas
A1  - Khaitov, Musa
A1  - Khaltaev, Nikolai
A1  - Kleine‐Tebbe, Jorg
A1  - Kouznetsov, Rostislav
A1  - Kowalski, Marek L.
A1  - Kritikos, Vicky
A1  - Kull, Inger
A1  - La Grutta, Stefania
A1  - Leonardini, Lisa
A1  - Ljungberg, Henrik
A1  - Lieberman, Philip
A1  - Lipworth, Brian
A1  - Lodrup Carlsen, Karin C.
A1  - Lopes‐Pereira, Catarina
A1  - Loureiro, Claudia C.
A1  - Louis, Renaud
A1  - Mair, Alpana
A1  - Mahboub, Bassam
A1  - Makris, Michaël
A1  - Malva, Joao
A1  - Manning, Patrick
A1  - Marshall, Gailen D.
A1  - Masjedi, Mohamed R.
A1  - Maspero, Jorge F.
A1  - Carreiro‐Martins, Pedro
A1  - Makela, Mika
A1  - Mathieu‐Dupas, Eve
A1  - Maurer, Marcus
A1  - De Manuel Keenoy, Esteban
A1  - Melo‐Gomes, Elisabete
A1  - Meltzer, Eli O.
A1  - Menditto, Enrica
A1  - Mercier, Jacques
A1  - Micheli, Yann
A1  - Miculinic, Neven
A1  - Mihaltan, Florin
A1  - Milenkovic, Branislava
A1  - Mitsias, Dimitirios I.
A1  - Moda, Giuliana
A1  - Mogica‐Martinez, Maria‐Dolores
A1  - Mohammad, Yousser
A1  - Montefort, Steve
A1  - Monti, Ricardo
A1  - Morais‐Almeida, Mario
A1  - Mösges, Ralph
A1  - Münter, Lars
A1  - Muraro, Antonella
A1  - Murray, Ruth
A1  - Naclerio, Robert
A1  - Napoli, Luigi
A1  - Namazova‐Baranova, Leyla
A1  - Neffen, Hugo
A1  - Nekam, Kristoff
A1  - Neou, Angelo
A1  - Nordlund, Björn
A1  - Novellino, Ettore
A1  - Nyembue, Dieudonné
A1  - O'Hehir, Robyn
A1  - Ohta, Ken
A1  - Okubo, Kimi
A1  - Onorato, Gabrielle L.
A1  - Orlando, Valentina
A1  - Ouedraogo, Solange
A1  - Palamarchuk, Julia
A1  - Pali‐Schöll, Isabella
A1  - Panzner, Peter
A1  - Park, Hae‐Sim
A1  - Passalacqua, Gianni
A1  - Pépin, Jean‐Louis
A1  - Paulino, Ema
A1  - Pawankar, Ruby
A1  - Phillips, Jim
A1  - Picard, Robert
A1  - Pinnock, Hilary
A1  - Plavec, Davor
A1  - Popov, Todor A.
A1  - Portejoie, Fabienne
A1  - Price, David
A1  - Prokopakis, Emmanuel P.
A1  - Psarros, Fotis
A1  - Pugin, Benoit
A1  - Puggioni, Francesca
A1  - Quinones‐Delgado, Pablo
A1  - Raciborski, Filip
A1  - Rajabian‐Söderlund, Rojin
A1  - Regateiro, Frederico S.
A1  - Reitsma, Sietze
A1  - Rivero‐Yeverino, Daniela
A1  - Roberts, Graham
A1  - Roche, Nicolas
A1  - Rodriguez‐Zagal, Erendira
A1  - Rolland, Christine
A1  - Roller‐Wirnsberger, Regina E.
A1  - Rosario, Nelson
A1  - Romano, Antonino
A1  - Rottem, Menachem
A1  - Ryan, Dermot
A1  - Salimäki, Johanna
A1  - Sanchez‐Borges, Mario M.
A1  - Sastre, Joaquin
A1  - Scadding, Glenis K.
A1  - Scheire, Sophie
A1  - Schmid‐Grendelmeier, Peter
A1  - Schünemann, Holger J.
A1  - Sarquis Serpa, Faradiba
A1  - Shamji, Mohamed
A1  - Sisul, Juan‐Carlos
A1  - Sofiev, Mikhail
A1  - Solé, Dirceu
A1  - Somekh, David
A1  - Sooronbaev, Talant
A1  - Sova, Milan
A1  - Spertini, François
A1  - Spranger, Otto
A1  - Stellato, Cristiana
A1  - Stelmach, Rafael
A1  - Thibaudon, Michel
A1  - To, Teresa
A1  - Toumi, Mondher
A1  - Usmani, Omar
A1  - Valero, Antonio A.
A1  - Valenta, Rudolph
A1  - Valentin‐Rostan, Marylin
A1  - Pereira, Marilyn Urrutia
A1  - van der Kleij, Rianne
A1  - Van Eerd, Michiel
A1  - Vandenplas, Olivier
A1  - Vasankari, Tuula
A1  - Vaz Carneiro, Antonio
A1  - Vezzani, Giorgio
A1  - Viart, Frédéric
A1  - Viegi, Giovanni
A1  - Wallace, Dana
A1  - Wagenmann, Martin
A1  - Wang, De Yun
A1  - Waserman, Susan
A1  - Wickman, Magnus
A1  - Williams, Dennis M.
A1  - Wong, Gary
A1  - Wroczynski, Piotr
A1  - Yiallouros, Panayiotis K.
A1  - Yusuf, Osman M.
A1  - Zar, Heather J.
A1  - Zeng, Stéphane
A1  - Zernotti, Mario E.
A1  - Zhang, Luo
A1  - Shan Zhong, Nan
A1  - Zidarn, Mihaela
T1  - ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice
JF  - Allergy
N2  - Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
KW  - ARIA
KW  - asthma
KW  - CARAT
KW  - digital transformation of health and care
KW  - MASK
KW  - rhinitis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228339
VL  - 76
IS  - 1
SP  - 168
EP  - 190
ER  -