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Institute
Eichenauer, Dennis Alexander ; Bühnen, Ina ; Kreissl, Stefanie ; Goergen, Helen ; Fuchs, Michael ; Tresckow, Bastian von ; Rosenwald, Andreas ; Klapper, Wolfram ; Hansmann, Martin-Leo ; Möller, Peter ; Bernd, Heinz-Wolfram ; Feller, Alfred C. ; Engert, Andreas ; Borchmann, Peter ; Hartmann, Sylvia
We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.
Sharma, Sunny ; Hartmann, Johannes David ; Watzinger, Peter ; Klepper, Arvid ; Peifer, Christian ; Kötter, Peter ; Lafontaine, Denis L. J. ; Entian, Karl-Dieter
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Baltes, Peter ; Bota, Marc ; Albert, Jörg Gerhard ; Philipper, Michael ; Hörster, Hans-Georg ; Hagenmüller, Friedrich ; Steinbrück, Ingo ; Jakobs, Ralf ; Bechtler, Matthias ; Hartmann, Dirk ; Neuhaus, Horst ; Charton, Jean-Pierre ; Mayershofer, Rupert ; Hohn, Horst ; Rösch, Thomas ; Groth, Stefan ; Nowak, Tanja ; Wohlmuth, Peter ; Keuchel, Martin
Aim: To evaluate the ability of PillCamColon2 to visualize colonic segments missed by incomplete optical colonoscopy (OC) and to assess the diagnostic yield.
Methods: This prospective multicentre study included 81 patients from nine centres who underwent second-generation colon capsule endoscopy (CCE) following incomplete OC performed by an experienced gastroenterologist (> 1000 colonoscopies). Patients with stenosis were excluded. According to patient preferences, CCE was performed the following day (protocol A) after staying on clear liquids and 0.75 L Moviprep in the morning or within 30 d after new split-dose Moviprep (protocol B). Boosts consisted of 0.75 L and 0.25 L Moviprep, and phospho-soda was given as a rescue if the capsule was not excreted after seven hours.
Results: Seventy-four patients were analysed (51% of them in group A; 49% in group B). Bowel cleansing was adequate in 67% of cases, and CCE could visualize colonic segments missed by incomplete colonoscopy in 90% of patients under protocol A and 97% of patients under protocol B (P = 0.35, n.s.). Significant polyps including adenocarcinoma were detected in 24% of cases. Detection rates for all polyps and significant polyps per patient were similar in both protocols. Polyps were found predominantly in the right colon (86%) in segments that were not reached by OC. Extracolonic findings - such as reflux esophagitis, suspected Barrett esophagus, upper GI-bleeding, gastric polyps, gastric erosions and angiectasia - were detected in eight patients. PillCamColon2 capsule was retained in the ileum of one patient (1.4%) without symptoms and removed during an uneventful resection for unknown Crohn’s disease that was diagnosed as the cause of anemia, which was the indication for colonoscopy. CCE was well tolerated. One patient suffered from self-limiting vomiting after consuming the phospho-soda.
Conclusion: Second-generation CCE using a low-volume preparation is useful after incomplete OC, and it allows for the detection of additional relevant findings, but cleansing efficiency could be improved.
Sharma, Sunny ; David Hartmann, Johannes ; Watzinger, Peter ; Klepper, Arvid ; Peifer, Christian ; Kötter, Peter ; Lafontaine, Denis L. J. ; Entian, Karl-Dieter
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Non-standard errors
(2021)
Menkveld, Albert J. ; Dreber, Anna ; Holzmeister, Felix ; Huber, Jürgen ; Johannesson, Magnus ; Kirchler, Michael ; Razen, Michael ; Weitzel, Utz ; Abad Díaz, David ; Abudy, Menachem ; Adrian, Tobias ; Ait-Sahalia, Yacine ; Akmansoy, Olivier ; Alcock, Jamie ; Alexeev, Vitali ; Aloosh, Arash ; Amato, Livia ; Amaya, Diego ; Angel, James ; Bach, Amadeus ; Baidoo, Edwin ; Bakalli, Gaetan ; Barbon, Andrea ; Bashchenko, Oksana ; Bindra, Parampreet Christopher ; Bjonnes, Geir Hoidal ; Black, Jeff ; Black, Bernard S. ; Bohorquez, Santiago ; Bondarenko, Oleg ; Bos, Charles S. ; Bosch-Rosa, Ciril ; Bouri, Elie ; Brownlees, Christian ; Calamia, Anna ; Cao, Viet Nga ; Capelle-Blancard, Gunther ; Capera, Laura ; Caporin, Massimiliano ; Carrion, Allen ; Caskurlu, Tolga ; Chakrabarty, Bidisha ; Chernov, Mikhail ; Cheung, William M. ; Chincarini, Ludwig Boris ; Chordia, Tarun ; Chow, Sheung Chi ; Clapham, Benjamin ; Colliard, Jean-Edouard ; Comerton-Forde, Carole ; Curran, Edward ; Dao, Thong ; Dare, Wale ; Davies, Ryan J. ; De Blasis, Riccardo ; De Nard, Gianluca ; Declerck, Fany ; Deev, Oleg ; Degryse, Hans ; Deku, Solomon ; Desagre, Christophe ; Dijk, Mathijs van ; Dim, Chukwuma ; Dimpfl, Thomas ; Dong, Yun Jiang ; Drummond, Philip ; Dudda, Tom ; Dumitrescu, Ariadna ; Dyakov, Teodor ; Haubo Dyhrberg, Anne ; Dzieliński, Michał ; Eksi, Asli ; El Kalak, Izidin ; Ellen, Saskia ter ; Eugster, Nicolas ; Evans, Martin D. D. ; Farrell, Michael ; Félez-Viñas, Ester ; Ferrara, Gerardo ; Ferrouhi, El Mehdi ; Flori, Andrea ; Fluharty-Jaidee, Jonathan ; Foley, Sean ; Fong, Kingsley Y. L. ; Foucault, Thierry ; Franus, Tatiana ; Franzoni, Francesco ; Frijns, Bart ; Frömmel, Michael ; Fu, Servanna ; Füllbrunn, Sascha ; Gan, Baoqing ; Gehrig, Thomas ; Gerritsen, Dirk ; Gil-Bazo, Javier ; Glosten, Lawrence R. ; Gomez, Thomas ; Gorbenko, Arseny ; Güçbilmez, Ufuk ; Grammig, Joachim ; Gregoire, Vincent ; Hagströmer, Björn ; Hambuckers, Julien ; Hapnes, Erik ; Harris, Jeffrey H. ; Harris, Lawrence ; Hartmann, Simon ; Hasse, Jean-Baptiste ; Hautsch, Nikolaus ; He, Xuezhong ; Heath, Davidson ; Hediger, Simon ; Hendershott, Terrence ; Hibbert, Ann Marie ; Hjalmarsson, Erik ; Hoelscher, Seth A. ; Hoffmann, Peter ; Holden, Craig W. ; Horenstein, Alex R. ; Huang, Wenqian ; Huang, Da ; Hurlin, Christophe ; Ivashchenko, Alexey ; Iyer, Subramanian Rama ; Jahanshahloo, Hossein ; Jalkh, Naji ; Jones, Charles M. ; Jurkatis, Simon ; Jylha, Petri ; Kaeck, Andreas ; Kaiser, Gabriel ; Karam, Arzé ; Karmaziene, Egle ; Kassner, Bernhard ; Kaustia, Markku ; Kazak, Ekaterina ; Kearney, Fearghal ; Kervel, Vincent van ; Khan, Saad ; Khomyn, Marta ; Klein, Tony ; Klein, Olga ; Klos, Alexander ; Koetter, Michael ; Krahnen, Jan Pieter ; Kolokolov, Aleksey ; Korajczyk, Robert A. ; Kozhan, Roman ; Kwan, Amy ; Lajaunie, Quentin ; Lam, FY Eric C ; Lambert, Marie ; Langlois, Hugues ; Lausen, Jens ; Lauter, Tobias ; Leippold, Markus ; Levin, Vladimir ; Li, Yijie ; Li, Hui ; Liew, Chee Yoong ; Lindner, Thomas ; Linton, Oliver B. ; Liu, Jiacheng ; Liu, Anqi ; Llorente, Guillermo ; Lof, Matthijs ; Lohr, Ariel ; Longstaff, Francis A. ; Lopez-Lira, Alejandro ; Mankad, Shawn ; Mano, Nicola ; Marchal, Alexis ; Martineau, Charles ; Mazzola, Francesco ; Meloso, Debrah ; Mihet, Roxana ; Mohan, Vijay ; Moinas, Sophie ; Moore, David ; Mu, Liangyi ; Muravyev, Dmitriy ; Murphy, Dermot ; Neszveda, Gabor ; Neumeier, Christian ; Nielsson, Ulf ; Nimalendran, Mahendrarajah ; Nolte, Sven ; Norden, Lars L. ; O'Neill, Peter ; Obaid, Khaled ; Ødegaard, Bernt Arne ; Östberg, Per ; Painter, Marcus ; Palan, Stefan ; Palit, Imon ; Park, Andreas ; Pascual, Roberto ; Pasquariello, Paolo ; Pastor, Lubos ; Patel, Vinay ; Patton, Andrew J. ; Pearson, Neil D. ; Pelizzon, Loriana ; Rzeźnik, Aleksandra ; Sanford, Anthony ; Sankaran, Harikumar ; Sarkar, Asani ; Sarno, Lucio ; Scaillet, O. ; Scharnowski, Stefan ; Schenk-Hoppé, Klaus Reiner ; Schertler, Andrea ; Schneider, Michael ; Schroeder, Florian ; Schürhoff, Norman ; Schuster, Philipp ; Schwarz, Marco A. ; Seasholes, Mark S. ; Seeger, Norman ; Shachar, Or ; Shkilko, Andriy ; Shui, Jessica ; Sikic, Mario ; Simion, Giorgia ; Smales, Lee A. ; Söderlind, Paul ; Sojli, Elvira ; Sokolov, Konstantin ; Spokeviciute, Laima ; Stefanova, Denitsa ; Subrahmanyam, Marti G. ; Neusüss, Sebastian ; Szaszi, Barnabas ; Talavera, Oleksandr ; Tang, Yuehua ; Taylor, Nicholas ; Tham, Wing Wah ; Theissen, Erik ; Thimme, Julian ; Tonks, Ian ; Tran, Hai ; Trapin, Luca ; Trolle, Anders B. ; Valente, Giorgio ; Van Ness, Robert A. ; Vasquez, Aurelio ; Verousis, Thanos ; Verwijmeren, Patrick ; Vilhelmsson, Anders ; Vilkov, Grigory ; Vladimirov, Vladimir ; Vogel, Sebastian ; Voigt, Stefan ; Wagner, Wolf ; Walther, Thomas ; Weiss, Patrick ; Wel, Michel van der ; Werner, Ingrid M. ; Westerholm, Joakim ; Westheide, Christian ; Wipplinger, Evert ; Wolf, Michael ; Wolff, Christiaan Cornelis Petrus ; Wolk, Leonard ; Wong, Wing Keung ; Wrampelmeyer, Jan ; Xia, Shuo ; Xiu, Dacheng ; Xu, Ke ; Xu, Caihong ; Yadav, Pradeep ; Yagüe, José ; Yan, Cheng ; Yang, Antti ; Yoo, Woongsun ; Yu, Wenjia ; Yu, Shihao ; Yueshen, Bart Zhou ; Yuferova, Darya ; Zamojski, Marcin ; Zareei, Abalfazl ; Zeisberger, Stefan ; Zhang, Sarah ; Zhang, Xiaoyu ; Zhong, Zhuo ; Zhou, Z. Ivy ; Zhou, Chen ; Zhu, Xingyu Sonya ; Zoican, Marius ; Zwinkels, Remco C. J. ; Chen, Jian ; Duevski, Teodor ; Gao, Ge ; Gemayel, Roland ; Gilder, Dudley ; Kuhle, Paul ; Pagnotta, Emiliano ; Pelli, Michele ; Sönksen, Jantje ; Zhang, Lu ; Ilczuk, Konrad ; Bogoev, Dimitar ; Qian, Ya ; Wika, Hans C. ; Yu, Yihe ; Zhao, Lu ; Mi, Michael ; Bao, Li ; Vaduva, Andreea ; Prokopczuk, Marcel ; Avetikian, Alejandro ; Wu, Zhen-Xing
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
In dieser Studie wird der Einfluss überwiegend historischer atmosphärischer Flugaschedepositionen auf physikalische Eigenschaften von Waldböden und insbesondere deren Humusauflagen untersucht. Es werden sechs Leitprofile der Region Oberlausitz mit und ohne Flugascheanreicherungen vorgestellt. Die flugascheangereicherten Standorte sind geprägt durch 1,0 bis 1,5 dm mächtige Durchmischungshorizonte (Humusauflage mit Flugasche), die extrem stark durchwurzelt sind. Die reinen Humusauflagen sind geringmächtiger (< 0,6 dm) und auch weniger stark durchwurzelt. Im Vergleich mit reinen Humusauflagen zeigen die flugascheangereicherten zum Teil signifikant höhere Luftkapazitäten, gesättigte Wasserleitfähigkeiten und Festsubstanzdichten, wohingegen emittentennah die nutzbaren Feldkapazitäten geringer sind. Für die flugascheangereicherten Standorte wurden mineralische Flugascheanreicherungen von 150 bis 280 t/ha berechnet, wobei emittentennähere Standorte höhere Werte aufweisen. Zeitweise Vernässung und anstehendes Ausgangsgestein schränken die Durchwurzelbarkeit stark ein. Die nutzbare Feldkapazität des effektiven Wurzelraums nFKWe ist daher deutlich von den Eigenschaften der Auflagen und des Oberbodens geprägt. Die flugascheangereicherten Humusauflagen stellen 20 bis 42% der nFKWe, die reinen Humusauflagen nur 8 bis 16%.
Naturschutzorganisationen, wie die Umweltstiftung World Wide Fund for Nature (WWF) -Deutschland und die Deutsche Sektion der Föderation der Natur- und Nationalparke Europas (FÖNAD), fordern seit Jahren die Anerkennung eines eigenständigen Berufsbildes "Schutzgebietsbetreuer/in" und die Schaffung einer einheitlichen Aus- und Fortbildungsregelung für die hauptamtlichen Naturwachtmitarbeiter in den Großschutzgebieten der Bundesrepublik Deutschland [Fleckenstein 1995, FÖNAD 1992a). Seit geraumer Zeit bemüht sich auch das Land Sachsen-Anhalt um die Ausbildung entsprechenden Personals für seine Großschutzgebiete (vgl. Kison; Wegener 1996). In diesem Zusammenhang beantragte die Umweltakademie Sachsen-Anhalt e.V. im vergangenen Jahr beim Ministerium für Raumordnung, Landwirtschaft und Umwelt (MRLU) die Förderung eines Projektes, das unter Berücksichtigung des bundesweiten Diskussionsstandes Empfehlungen für Mindestanforderungen an die Qualität der Fort- und Weiterbildung erarbeiten sollte.
Czowalla, Lucas ; Blechschmidt, Andreas ; Busch, Dahlia ; Fromberg, Andrea ; Grün, Christiane ; Gwiasda, Peter ; Hartmann, Pia ; Wilde, Mathias ; Lanzendorf, Martin
Die Verknüpfung des Fahrrades mit dem Öffentlichen Verkehr (ÖV) kann den Umweltverbund stärken, den Übergang von einem Verkehrssystem auf das andere erleichtern und eine attraktive Alternative zum motorisierten Individualverkehr schaffen. Die vorliegende Arbeit repräsentiert den zweiten umfassenden Projektbericht innerhalb des Forschungsprojektes „Verbesserte Integration des Fahrrads in den öffentlichen Verkehr – Systematische Erschließung von Handlungsoptionen und Bewertung von Best-Practices“. Im ersten Projektbericht (ebenfalls in dieser Arbeitspapierreihe erschienen – Nr. 15) wurden die Entwicklungen der letzten Jahre in den infrastrukturellen Themenfeldern Fahrradmitnahme, Fahrradverleihsysteme und Fahrradabstellanlagen aufgearbeitet und Fragen zu Kommunikation und Marketing der Angebote sowie zu Möglichkeiten der fortschreitenden Digitalisierung zur verbesserten Integration von Fahrrad und Öffentlichem Verkehr diskutiert. Darauf aufbauend werden im vorliegenden Bericht die Ergebnisse vertiefender Fallstudien dargestellt, mit dem Ziel, Erfolgsfaktoren und Hemmnisse für die Integration von Fahrrad mit Öffentlichem Verkehr aufzuzeigen und in einem späteren Schritt daraus Handlungsempfehlungen zur Stärkung dieser Integration für Kommunen und Verkehrsanbieter geben zu können. Für die Fallstudien wurden solche Beispiele ausgewählt, die einen Vorbildcharakter haben und als nachahmenswert für andere Städte und Regionen gelten können bzw. aus denen sich Erkenntnisse für die Stärkung der Integration von Fahrradverkehr mit dem ÖV ziehen lassen. Zudem sollten die verschiedenen infrastrukturellen Themenfelder abgedeckt sein. Neben einer Darstellung der jeweils fallspezifischen Besonderheiten wird zu jedem Fallbeispiel das Betreiber- und Geschäftsmodell dargestellt und es erfolgt eine Bewertung, die sowohl die Sicht der Betreiber als auch die der Nutzenden beachtet.
Folgende Fallbeispiele werden behandelt:
Die hessischen Verkehrsverbünde Rhein-Main-Verkehrsverbund (RMV) und Nordhessischer Verkehrsverbund (NVV) bieten eine kosten- und sperrzeitfreie Mitnahmeregelung für Fahrräder an.
Das MVGmeinRad Mainz ist als Fahrradverleihsystem ein Teil des kommunalen ÖPNV-Unternehmens.
Zu den Fahrradabstellanlagen an Bahnhöfen wurden in der Fallstudie drei unterschiedlich große Anlagen einbezogen: Dein Radschloss des Verkehrsverbundes Rhein-Ruhr (VRR) für kleine, das Radhaus Offenburg für mittelgroße und die Radstation Düsseldorf für große Standorte.
München wurde schließlich für eine kommunale Strategie zur verbesserten Verknüpfung von Fahrrad und Öffentlichem Verkehr ausgewählt, da dort eine Vielzahl von Maßnahmen zur Stärkung der Fahrradmobilität sichtbar sind.
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
(2016)
Regula, Jörg Thomas ; Lundh von Leithner, Peter ; Foxton, Richard ; Barathi, Veluchamy A. ; Gemmy Cheung, Chui Ming ; Tun, Sai Bo Bo ; Wey, Yeo Sia ; Iwata, Daiju ; Dostalek, Miroslav ; Moelleken, Jörg ; Stubenrauch, Kay-Gunnar ; Nogoceke, Everson ; Widmer, Gabriella ; Strassburger, Pamela ; Koss, Michael Janusz ; Klein, Christian ; Shima, David T. ; Hartmann, Guido
Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716’s FcRn and FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye.