TY  - JOUR
A1  - Postema, Merel C.
A1  - Hoogman, Martine
A1  - Ambrosino, Sara
A1  - Asherson, Philip
A1  - Banaschewski, Tobias
A1  - Bandeira, Cibele E.
A1  - Baranov, Alexandr
A1  - Bau, Claiton H.D.
A1  - Baumeister, Sarah
A1  - Baur‐Streubel, Ramona
A1  - Bellgrove, Mark A.
A1  - Biederman, Joseph
A1  - Bralten, Janita
A1  - Brandeis, Daniel
A1  - Brem, Silvia
A1  - Buitelaar, Jan K.
A1  - Busatto, Geraldo F.
A1  - Castellanos, Francisco X.
A1  - Cercignani, Mara
A1  - Chaim‐Avancini, Tiffany M.
A1  - Chantiluke, Kaylita C.
A1  - Christakou, Anastasia
A1  - Coghill, David
A1  - Conzelmann, Annette
A1  - Cubillo, Ana I.
A1  - Cupertino, Renata B.
A1  - de Zeeuw, Patrick
A1  - Doyle, Alysa E.
A1  - Durston, Sarah
A1  - Earl, Eric A.
A1  - Epstein, Jeffery N.
A1  - Ethofer, Thomas
A1  - Fair, Damien A.
A1  - Fallgatter, Andreas J.
A1  - Faraone, Stephen V.
A1  - Frodl, Thomas
A1  - Gabel, Matt C.
A1  - Gogberashvili, Tinatin
A1  - Grevet, Eugenio H.
A1  - Haavik, Jan
A1  - Harrison, Neil A.
A1  - Hartman, Catharina A.
A1  - Heslenfeld, Dirk J.
A1  - Hoekstra, Pieter J.
A1  - Hohmann, Sarah
A1  - Høvik, Marie F.
A1  - Jernigan, Terry L.
A1  - Kardatzki, Bernd
A1  - Karkashadze, Georgii
A1  - Kelly, Clare
A1  - Kohls, Gregor
A1  - Konrad, Kerstin
A1  - Kuntsi, Jonna
A1  - Lazaro, Luisa
A1  - Lera‐Miguel, Sara
A1  - Lesch, Klaus‐Peter
A1  - Louza, Mario R.
A1  - Lundervold, Astri J.
A1  - Malpas, Charles B
A1  - Mattos, Paulo
A1  - McCarthy, Hazel
A1  - Namazova‐Baranova, Leyla
A1  - Nicolau, Rosa
A1  - Nigg, Joel T.
A1  - Novotny, Stephanie E.
A1  - Oberwelland Weiss, Eileen
A1  - O'Gorman Tuura, Ruth L.
A1  - Oosterlaan, Jaap
A1  - Oranje, Bob
A1  - Paloyelis, Yannis
A1  - Pauli, Paul
A1  - Picon, Felipe A.
A1  - Plessen, Kerstin J.
A1  - Ramos‐Quiroga, J. Antoni
A1  - Reif, Andreas
A1  - Reneman, Liesbeth
A1  - Rosa, Pedro G.P.
A1  - Rubia, Katya
A1  - Schrantee, Anouk
A1  - Schweren, Lizanne J.S.
A1  - Seitz, Jochen
A1  - Shaw, Philip
A1  - Silk, Tim J.
A1  - Skokauskas, Norbert
A1  - Soliva Vila, Juan C.
A1  - Stevens, Michael C.
A1  - Sudre, Gustavo
A1  - Tamm, Leanne
A1  - Tovar‐Moll, Fernanda
A1  - van Erp, Theo G.M.
A1  - Vance, Alasdair
A1  - Vilarroya, Oscar
A1  - Vives‐Gilabert, Yolanda
A1  - von Polier, Georg G.
A1  - Walitza, Susanne
A1  - Yoncheva, Yuliya N.
A1  - Zanetti, Marcus V.
A1  - Ziegler, Georg C.
A1  - Glahn, David C.
A1  - Jahanshad, Neda
A1  - Medland, Sarah E.
A1  - Thompson, Paul M.
A1  - Fisher, Simon E.
A1  - Franke, Barbara
A1  - Francks, Clyde
T1  - Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets
JF  - Journal of Child Psychology and Psychiatry
N2  - Objective
Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods
We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results
There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing.

Conclusion
Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
KW  - attention‐deficit
KW  - hyperactivity disorder
KW  - brain asymmetry
KW  - brain laterality
KW  - structural MRI
KW  - large‐scale data
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239968
VL  - 62
IS  - 10
SP  - 1202
EP  - 1219
ER  - 
TY  - JOUR
A1  - Manchia, Mirko
A1  - Adli, Mazda
A1  - Akula, Nirmala
A1  - Arda, Raffaella
A1  - Aubry, Jean-Michel
A1  - Backlund, Lena
A1  - Banzato, Claudio E. M.
A1  - Baune, Bernhard T.
A1  - Bellivier, Frank
A1  - Bengesser, Susanne
A1  - Biernacka, Joanna M.
A1  - Brichant-Petitjean, Clara
A1  - Bui, Elise
A1  - Calkin, Cynthia V.
A1  - Cheng, Andrew Tai Ann
A1  - Chillotti, Caterina
A1  - Cichon, Sven
A1  - Clark, Scott
A1  - Czerski, Piotr M.
A1  - Dantas, Clarissa
A1  - Del Zompo, Maria
A1  - DePaulo, J. Raymond
A1  - Detera-Wadleigh, Sevilla D.
A1  - Etain, Bruno
A1  - Falkai, Peter
A1  - Frisén, Louise
A1  - Frye, Mark A.
A1  - Fullerton, Jan
A1  - Gard, Sébastien
A1  - Garnham, Julie
A1  - Goes, Fernando S.
A1  - Grof, Paul
A1  - Gruber, Oliver
A1  - Hashimoto, Ryota
A1  - Hauser, Joanna
A1  - Heilbronner, Urs
A1  - Hoban, Rebecca
A1  - Hou, Liping
A1  - Jamain, Stéphane
A1  - Kahn, Jean-Pierre
A1  - Kassem, Layla
A1  - Kato, Tadafumi
A1  - Kelsoe, John R.
A1  - Kittel-Schneider, Sarah
A1  - Kliwicki, Sebastian
A1  - Kuo, Po-Hsiu
A1  - Kusumi, Ichiro
A1  - Laje, Gonzalo
A1  - Lavebratt, Catharina
A1  - Leboyer, Marion
A1  - Leckband, Susan G.
A1  - López Jaramillo, Carlos A.
A1  - Maj, Mario
A1  - Malafosse, Alain
A1  - Martinsson, Lina
A1  - Masui, Takuya
A1  - Mitchell, Philip B.
A1  - Mondimore, Frank
A1  - Monteleone, Palmiero
A1  - Nallet, Audrey
A1  - Neuner, Maria
A1  - Novák, Tomás
A1  - O'Donovan, Claire
A1  - Ösby, Urban
A1  - Ozaki, Norio
A1  - Perlis, Roy H.
A1  - Pfennig, Andrea
A1  - Potash, James B.
A1  - Reich-Erkelenz, Daniela
A1  - Reif, Andreas
A1  - Reininghaus, Eva
A1  - Richardson, Sara
A1  - Rouleau, Guy A.
A1  - Rybakowski, Janusz K.
A1  - Schalling, Martin
A1  - Schofield, Peter R.
A1  - Schubert, Oliver K.
A1  - Schweizer, Barbara
A1  - Seemüller, Florian
A1  - Grigoroiu-Serbanescu, Maria
A1  - Severino, Giovanni
A1  - Seymour, Lisa R.
A1  - Slaney, Claire
A1  - Smoller, Jordan W.
A1  - Squassina, Alessio
A1  - Stamm, Thomas
A1  - Steele, Jo
A1  - Stopkova, Pavla
A1  - Tighe, Sarah K.
A1  - Tortorella, Alfonso
A1  - Turecki, Gustavo
A1  - Wray, Naomi R.
A1  - Wright, Adam
A1  - Zandi, Peter P.
A1  - Zilles, David
A1  - Bauer, Michael
A1  - Rietschel, Marcella
A1  - McMahon, Francis J.
A1  - Schulze, Thomas G.
A1  - Alda, Martin
T1  - Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report
JF  - PLoS ONE
N2  - Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. 
Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. 
Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). 
Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
KW  - age
KW  - observer agreement
KW  - prophylactic lithium
KW  - mapping susceptibility genes
KW  - mood disorders
KW  - onset
KW  - association
KW  - reliability
KW  - morality
KW  - illness
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130938
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - Redlich, Sarah
A1  - Zhang, Jie
A1  - Benjamin, Caryl
A1  - Dhillon, Maninder Singh
A1  - Englmeier, Jana
A1  - Ewald, Jörg
A1  - Fricke, Ute
A1  - Ganuza, Cristina
A1  - Haensel, Maria
A1  - Hovestadt, Thomas
A1  - Kollmann, Johannes
A1  - Koellner, Thomas
A1  - Kübert‐Flock, Carina
A1  - Kunstmann, Harald
A1  - Menzel, Annette
A1  - Moning, Christoph
A1  - Peters, Wibke
A1  - Riebl, Rebekka
A1  - Rummler, Thomas
A1  - Rojas‐Botero, Sandra
A1  - Tobisch, Cynthia
A1  - Uhler, Johannes
A1  - Uphus, Lars
A1  - Müller, Jörg
A1  - Steffan‐Dewenter, Ingolf
T1  - Disentangling effects of climate and land use on biodiversity and ecosystem services—A multi‐scale experimental design
JF  - Methods in Ecology and Evolution
N2  - Climate and land-use change are key drivers of environmental degradation in the Anthropocene, but too little is known about their interactive effects on biodiversity and ecosystem services. Long-term data on biodiversity trends are currently lacking. Furthermore, previous ecological studies have rarely considered climate and land use in a joint design, did not achieve variable independence or lost statistical power by not covering the full range of environmental gradients.
    
Here, we introduce a multi-scale space-for-time study design to disentangle effects of climate and land use on biodiversity and ecosystem services. The site selection approach coupled extensive GIS-based exploration (i.e. using a Geographic information system) and correlation heatmaps with a crossed and nested design covering regional, landscape and local scales. Its implementation in Bavaria (Germany) resulted in a set of study plots that maximise the potential range and independence of environmental variables at different spatial scales.
    
Stratifying the state of Bavaria into five climate zones (reference period 1981–2010) and three prevailing land-use types, that is, near-natural, agriculture and urban, resulted in 60 study regions (5.8 × 5.8 km quadrants) covering a mean annual temperature gradient of 5.6–9.8°C and a spatial extent of ~310 × 310 km. Within these regions, we nested 180 study plots located in contrasting local land-use types, that is, forests, grasslands, arable land or settlement (local climate gradient 4.5–10°C). This approach achieved low correlations between climate and land use (proportional cover) at the regional and landscape scale with |r ≤ 0.33| and |r ≤ 0.29| respectively. Furthermore, using correlation heatmaps for local plot selection reduced potentially confounding relationships between landscape composition and configuration for plots located in forests, arable land and settlements.
    
The suggested design expands upon previous research in covering a significant range of environmental gradients and including a diversity of dominant land-use types at different scales within different climatic contexts. It allows independent assessment of the relative contribution of multi-scale climate and land use on biodiversity and ecosystem services. Understanding potential interdependencies among global change drivers is essential to develop effective restoration and mitigation strategies against biodiversity decline, especially in expectation of future climatic changes. Importantly, this study also provides a baseline for long-term ecological monitoring programs.
KW  - study design
KW  - biodiversity
KW  - climate change
KW  - ecosystem functioning
KW  - insect monitoring
KW  - land use
KW  - space-for-time approach
KW  - spatial scales
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258270
VL  - 13
IS  - 2
ER  - 
TY  - JOUR
A1  - Zaho, Huaying
A1  - Ghirlando, Rodolfo
A1  - Alfonso, Carlos
A1  - Arisaka, Fumio
A1  - Attali, Ilan
A1  - Bain, David L.
A1  - Bakhtina, Marina M.
A1  - Becker, Donald F.
A1  - Bedwell, Gregory J.
A1  - Bekdemir, Ahmet
A1  - Besong, Tabot M. D.
A1  - Birck, Catherine
A1  - Brautigam, Chad A.
A1  - Brennerman, William
A1  - Byron, Olwyn
A1  - Bzowska, Agnieszka
A1  - Chaires, Jonathan B.
A1  - Chaton, Catherine T.
A1  - Coelfen, Helmbut
A1  - Connaghan, Keith D.
A1  - Crowley, Kimberly A.
A1  - Curth, Ute
A1  - Daviter, Tina
A1  - Dean, William L.
A1  - Diez, Ana I.
A1  - Ebel, Christine
A1  - Eckert, Debra M.
A1  - Eisele, Leslie E.
A1  - Eisenstein, Edward
A1  - England, Patrick
A1  - Escalante, Carlos
A1  - Fagan, Jeffrey A.
A1  - Fairman, Robert
A1  - Finn, Ron M.
A1  - Fischle, Wolfgang
A1  - Garcia de la Torre, Jose
A1  - Gor, Jayesh
A1  - Gustafsson, Henning
A1  - Hall, Damien
A1  - Harding, Stephen E.
A1  - Hernandez Cifre, Jose G.
A1  - Herr, Andrew B.
A1  - Howell, Elizabeth E.
A1  - Isaac, Richard S.
A1  - Jao, Shu-Chuan
A1  - Jose, Davis
A1  - Kim, Soon-Jong
A1  - Kokona, Bashkim
A1  - Kornblatt, Jack A.
A1  - Kosek, Dalibor
A1  - Krayukhina, Elena
A1  - Krzizike, Daniel
A1  - Kusznir, Eric A.
A1  - Kwon, Hyewon
A1  - Larson, Adam
A1  - Laue, Thomas M.
A1  - Le Roy, Aline
A1  - Leech, Andrew P.
A1  - Lilie, Hauke
A1  - Luger, Karolin
A1  - Luque-Ortega, Juan R.
A1  - Ma, Jia
A1  - May, Carrie A.
A1  - Maynard, Ernest L.
A1  - Modrak-Wojcik, Anna
A1  - Mok, Yee-Foong
A1  - Mücke, Norbert
A1  - Nagel-Steger, Luitgard
A1  - Narlikar, Geeta J.
A1  - Noda, Masanori
A1  - Nourse, Amanda
A1  - Obsil, Thomas
A1  - Park, Chad K
A1  - Park, Jin-Ku
A1  - Pawelek, Peter D.
A1  - Perdue, Erby E.
A1  - Perkins, Stephen J.
A1  - Perugini, Matthew A.
A1  - Peterson, Craig L.
A1  - Peverelli, Martin G.
A1  - Piszczek, Grzegorz
A1  - Prag, Gali
A1  - Prevelige, Peter E.
A1  - Raynal, Bertrand D. E.
A1  - Rezabkova, Lenka
A1  - Richter, Klaus
A1  - Ringel, Alison E.
A1  - Rosenberg, Rose
A1  - Rowe, Arthur J.
A1  - Rufer, Arne C.
A1  - Scott, David J.
A1  - Seravalli, Javier G.
A1  - Solovyova, Alexandra S.
A1  - Song, Renjie
A1  - Staunton, David
A1  - Stoddard, Caitlin
A1  - Stott, Katherine
A1  - Strauss, Holder M.
A1  - Streicher, Werner W.
A1  - Sumida, John P.
A1  - Swygert, Sarah G.
A1  - Szczepanowski, Roman H.
A1  - Tessmer, Ingrid
A1  - Toth, Ronald T.
A1  - Tripathy, Ashutosh
A1  - Uchiyama, Susumu
A1  - Uebel, Stephan F. W.
A1  - Unzai, Satoru
A1  - Gruber, Anna Vitlin
A1  - von Hippel, Peter H.
A1  - Wandrey, Christine
A1  - Wang, Szu-Huan
A1  - Weitzel, Steven E
A1  - Wielgus-Kutrowska, Beata
A1  - Wolberger, Cynthia
A1  - Wolff, Martin
A1  - Wright, Edward
A1  - Wu, Yu-Sung
A1  - Wubben, Jacinta M.
A1  - Schuck, Peter
T1  - A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation
JF  - PLoS ONE
N2  - Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304\(\pm\)0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of \(\pm\)0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies.
KW  - fluorescence-detected sedimentation
KW  - size exclusion chromatography
KW  - field flow fractionation
KW  - spinco ultracentrifuge
KW  - aggregation
KW  - bead models
KW  - velocity
KW  - hydrodynamics
KW  - biopharmaceuticals
KW  - proteins
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151903
VL  - 10
IS  - 5
ER  - 
TY  - CHAP
A1  - Schwaneck, Stefan
A1  - Welge, Christopher
A1  - Bopp, Ann-Kathrin
A1  - Faulhaber, Sarah
A1  - Hampel, Susanne
A1  - Pfletschinger, Maike
A1  - Nebelung, Lisa
A1  - Hamme, Berit
A1  - Priddat, Birger
A1  - Salmen, Thomas
A1  - Rosenthal, Georg
A1  - Neumann, Bernd
A1  - Deeg, Steffen
A1  - Buytendijk, Frank
A1  - Gonzalez, Thomas
A1  - Träger, Gloria
A1  - Mayer, Benjamin
A1  - Mohamad, Christoph
A1  - Reinders, Heinz
A1  - Bohmeier, Bernhard
T1  - Chef, lass uns mal Kultur machen! Festschrift zum 6. Würzburger Wirtschaftssymposium
N2  - Am Montag, den 29. November 2010 fand das 6. Würzburger Wirtschaftssymposium unter dem Leitmotiv "Chef, lass uns mal Kultur machen!" statt. Die gemeinnützige Veranstaltung versteht sich seit jeher als Ort der Begegnung und des gemeinsamen Gedankenaustauschs, Studenten und Mitarbeiter aller Fachbereiche nahmen ebenso teil wie interessierte Bürger außerhalb der Würzburger Hochschulen. Die Festschrift enthält Interviews mit sowie Gastbeiträge von Referenten des 6. Würzburger Wirtschaftssymposiums. Darüber hinaus greifen Gastbeiträge von Experten aus Wissenschaft, Wirtschaft, Politik und Gesellschaft weitere Facetten auf und stellen das Thema damit auf eine breitere Grundlage.
KW  - Festschrift
KW  - Unternehmenskultur
KW  - Kulturwirtschaft
KW  - Geistiges Eigentum
KW  - Jugendkultur
KW  - Wirtschaft
KW  - Kultur
KW  - Unternehmenskultur
KW  - Kreativ- und Kulturwirtschaft
KW  - Mainfranken Theater
KW  - business culture
KW  - economics
KW  - intellectual property
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-53329
SN  - 978-3-923959-66-2
ER  - 
TY  - JOUR
A1  - Dech, Stefan
A1  - Holzwarth, Stefanie
A1  - Asam, Sarah
A1  - Andresen, Thorsten
A1  - Bachmann, Martin
A1  - Boettcher, Martin
A1  - Dietz, Andreas
A1  - Eisfelder, Christina
A1  - Frey, Corinne
A1  - Gesell, Gerhard
A1  - Gessner, Ursula
A1  - Hirner, Andreas
A1  - Hofmann, Matthias
A1  - Kirches, Grit
A1  - Klein, Doris
A1  - Klein, Igor
A1  - Kraus, Tanja
A1  - Krause, Detmar
A1  - Plank, Simon
A1  - Popp, Thomas
A1  - Reinermann, Sophie
A1  - Reiners, Philipp
A1  - Roessler, Sebastian
A1  - Ruppert, Thomas
A1  - Scherbachenko, Alexander
A1  - Vignesh, Ranjitha
A1  - Wolfmueller, Meinhard
A1  - Zwenzner, Hendrik
A1  - Kuenzer, Claudia
T1  - Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience
JF  - Remote Sensing
N2  - Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper.
KW  - AVHRR
KW  - Earth Observation
KW  - harmonization
KW  - time series analysis
KW  - climate related trends
KW  - automatic processing
KW  - Europe
KW  - TIMELINE
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246134
SN  - 2072-4292
VL  - 13
IS  - 18
ER  - 
TY  - JOUR
A1  - Willeke, Kristina
A1  - Janson, Patrick
A1  - Zink, Katharina
A1  - Stupp, Carolin
A1  - Kittel-Schneider, Sarah
A1  - Berghöfer, Anne
A1  - Ewert, Thomas
A1  - King, Ryan
A1  - Heuschmann, Peter U.
A1  - Zapf, Andreas
A1  - Wildner, Manfred
A1  - Keil, Thomas
T1  - Occurrence of mental illness and mental health risks among the self-employed: a systematic review
JF  - International Journal of Environmental Research and Public Health
N2  - We aimed to systematically identify and evaluate all studies of good quality that compared the occurrence of mental disorders in the self-employed versus employees. Adhering to the Cochrane guidelines, we conducted a systematic review and searched three major medical databases (MEDLINE, Web of Science, Embase), complemented by hand search. We included 26 (three longitudinal and 23 cross-sectional) population-based studies of good quality (using a validated quality assessment tool), with data from 3,128,877 participants in total. The longest of these studies, a Swedish national register evaluation with 25 years follow-up, showed a higher incidence of mental illness among the self-employed compared to white-collar workers, but a lower incidence compared to blue-collar workers. In the second longitudinal study from Sweden the self-employed had a lower incidence of mental illness compared to both blue- and white-collar workers over 15 years, whereas the third longitudinal study (South Korea) did not find a difference regarding the incidence of depressive symptoms over 6 years. Results from the cross-sectional studies showed associations between self-employment and poor general mental health and stress, but were inconsistent regarding other mental outcomes. Most studies from South Korea found a higher prevalence of mental disorders among the self-employed compared to employees, whereas the results of cross-sectional studies from outside Asia were less consistent. In conclusion, we found evidence from population-based studies for a link between self-employment and increased risk of mental illness. Further longitudinal studies are needed examining the potential risk for the development of mental disorders in specific subtypes of the self-employed.
KW  - incidence
KW  - mental disorders
KW  - mental health
KW  - mental illness
KW  - prevalence
KW  - self-employed
KW  - small business
KW  - systematic review
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245085
SN  - 1660-4601
VL  - 18
IS  - 16
ER  - 
TY  - JOUR
A1  - Breuer, René
A1  - Mattheisen, Manuel
A1  - Frank, Josef
A1  - Krumm, Bertram
A1  - Treutlein, Jens
A1  - Kassem, Layla
A1  - Strohmaier, Jana
A1  - Herms, Stefan
A1  - Mühleisen, Thomas W.
A1  - Degenhardt, Franziska
A1  - Cichon, Sven
A1  - Nöthen, Markus M.
A1  - Karypis, George
A1  - Kelsoe, John
A1  - Greenwood, Tiffany
A1  - Nievergelt, Caroline
A1  - Shilling, Paul
A1  - Shekhtman, Tatyana
A1  - Edenberg, Howard
A1  - Craig, David
A1  - Szelinger, Szabolcs
A1  - Nurnberger, John
A1  - Gershon, Elliot
A1  - Alliey-Rodriguez, Ney
A1  - Zandi, Peter
A1  - Goes, Fernando
A1  - Schork, Nicholas
A1  - Smith, Erin
A1  - Koller, Daniel
A1  - Zhang, Peng
A1  - Badner, Judith
A1  - Berrettini, Wade
A1  - Bloss, Cinnamon
A1  - Byerley, William
A1  - Coryell, William
A1  - Foroud, Tatiana
A1  - Guo, Yirin
A1  - Hipolito, Maria
A1  - Keating, Brendan
A1  - Lawson, William
A1  - Liu, Chunyu
A1  - Mahon, Pamela
A1  - McInnis, Melvin
A1  - Murray, Sarah
A1  - Nwulia, Evaristus
A1  - Potash, James
A1  - Rice, John
A1  - Scheftner, William
A1  - Zöllner, Sebastian
A1  - McMahon, Francis J.
A1  - Rietschel, Marcella
A1  - Schulze, Thomas G.
T1  - Detecting significant genotype–phenotype association rules in bipolar disorder: market research meets complex genetics
JF  - International Journal of Bipolar Disorders
N2  - Background
Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype–phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted.

Results
Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings.

Conclusion
Our approach detected novel specific genotype–phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype–phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
KW  - bipolar disorder
KW  - subphenotypes
KW  - rule discovery
KW  - data mining
KW  - genotype-phenotype patterns
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220509
VL  - 6
ER  - 
TY  - JOUR
A1  - Thomas, Sarah
A1  - Fiebig, Juliane E.
A1  - Kuhn, Eva-Maria
A1  - Mayer, Dominik S.
A1  - Filbeck, Sebastian
A1  - Schmitz, Werner
A1  - Krischke, Markus
A1  - Gropp, Roswitha
A1  - Mueller, Thomas D.
T1  - Design of glycoengineered IL-4 antagonists employing chemical and biosynthetic glycosylation
JF  - ACS Omega
N2  - Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.
KW  - Interleukin-4 (IL-4)
KW  - atopic diseases
KW  - IL-4 antagonists
KW  - glycoengineering
KW  - biosynthetic glycosylation
KW  - chemical glycosylation
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350278
SN  - 2470-1343
VL  - 8
IS  - 28
ER  - 
TY  - JOUR
A1  - Goeritzer, Madeleine
A1  - Kuentzel, Katharina B.
A1  - Beck, Sarah
A1  - Korbelius, Melanie
A1  - Rainer, Silvia
A1  - Bradić, Ivan
A1  - Kolb, Dagmar
A1  - Mussbacher, Marion
A1  - Schrottmaier, Waltraud C.
A1  - Assinger, Alice
A1  - Schlagenhauf, Axel
A1  - Rost, René
A1  - Gottschalk, Benjamin
A1  - Eichmann, Thomas O.
A1  - Züllig, Thomas
A1  - Graier, Wolfgang F.
A1  - Vujić, Nemanja
A1  - Kratky, Dagmar
T1  - Monoglyceride lipase deficiency is associated with altered thrombogenesis in mice
JF  - International Journal of Molecular Sciences
N2  - Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) to glycerol and one fatty acid. Among the various MG species, MGL also degrades 2-arachidonoylglycerol, the most abundant endocannabinoid and potent activator of the cannabinoid receptors 1 and 2. We investigated the consequences of MGL deficiency on platelet function using systemic (Mgl\(^{−/−}\)) and platelet-specific Mgl-deficient (platMgl\(^{−/−}\)) mice. Despite comparable platelet morphology, loss of MGL was associated with decreased platelet aggregation and reduced response to collagen activation. This was reflected by reduced thrombus formation in vitro, accompanied by a longer bleeding time and a higher blood volume loss. Occlusion time after FeCl\(_3\)-induced injury was markedly reduced in Mgl\(^{−/−}\) mice, which is consistent with contraction of large aggregates and fewer small aggregates in vitro. The absence of any functional changes in platelets from platMgl\(^{−/−}\) mice is in accordance with lipid degradation products or other molecules in the circulation, rather than platelet-specific effects, being responsible for the observed alterations in Mgl\(^{−/−}\) mice. We conclude that genetic deletion of MGL is associated with altered thrombogenesis.
KW  - platelets
KW  - MGL
KW  - in vitro and in vivo thrombus formation
KW  - platelet activation
KW  - platelet aggregation
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304052
SN  - 1422-0067
VL  - 24
IS  - 4
ER  - 
TY  - JOUR
A1  - Göbel, Kerstin
A1  - Pankratz, Susann
A1  - Asaridou, Chloi-Magdalini
A1  - Herrmann, Alexander M.
A1  - Bittner, Stefan
A1  - Merker, Monika
A1  - Ruck, Tobias
A1  - Glumm, Sarah
A1  - Langhauser, Friederike
A1  - Kraft, Peter
A1  - Krug, Thorsten F.
A1  - Breuer, Johanna
A1  - Herold, Martin
A1  - Gross, Catharina C.
A1  - Beckmann, Denise
A1  - Korb-Pap, Adelheid
A1  - Schuhmann, Michael K.
A1  - Kuerten, Stefanie
A1  - Mitroulis, Ioannis
A1  - Ruppert, Clemens
A1  - Nolte, Marc W.
A1  - Panousis, Con
A1  - Klotz, Luisa
A1  - Kehrel, Beate
A1  - Korn, Thomas
A1  - Langer, Harald F.
A1  - Pap, Thomas
A1  - Nieswandt, Bernhard
A1  - Wiendl, Heinz
A1  - Chavakis, Triantafyllos
A1  - Kleinschnitz, Christoph
A1  - Meuth, Sven G.
T1  - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
JF  - Nature Communications
N2  - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
KW  - blood coagulation
KW  - factor XII
KW  - neuroinflammation
KW  - dendric cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165503
VL  - 7
IS  - 11626
ER  - 
TY  - JOUR
A1  - Leopold, Karolina
A1  - Bauer, Michael
A1  - Bechdolf, Andreas
A1  - Correll, Christoph U.
A1  - Holtmann, Martin
A1  - Juckel, Georg
A1  - Lambert, Martin
A1  - Meyer, Thomas D.
A1  - Pfeiffer, Steffi
A1  - Kittel‐Schneider, Sarah
A1  - Reif, Andreas
A1  - Stamm, Thomas J.
A1  - Rottmann‐Wolf, Maren
A1  - Mathiebe, Josephine
A1  - Kellmann, Eva L.
A1  - Ritter, Philipp
A1  - Krüger‐Özgürdal, Seza
A1  - Karow, Anne
A1  - Sondergeld, Lene‐Marie
A1  - Roessner, Veit
A1  - Sauer, Cathrin
A1  - Pfennig, Andrea
T1  - Efficacy of cognitive‐behavioral group therapy in patients at risk for serious mental illness presenting with subthreshold bipolar symptoms: Results from a prespecified interim analysis of a multicenter, randomized, controlled study
JF  - Bipolar Disorders
N2  - Objective
Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at‐risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive‐behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms.

Method
In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15‐30 years were randomized to 14 weeks of at‐risk for BD‐specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At‐risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75% of the targeted sample.

Results
Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8%) vs unstructured group meetings (n = 37, completers = 78.4%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between‐group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop‐outs.

Conclusions
Results suggest that young patients at‐risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.
KW  - at‐risk
KW  - bipolar disorder
KW  - CBT
KW  - early intervention
KW  - group treatment
KW  - prodromal
KW  - serious mental illness
KW  - subthreshold bipolar
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215469
VL  - 22
IS  - 5
SP  - 517
EP  - 529
ER  - 
TY  - JOUR
A1  - Kaiser, Anna
A1  - Aggensteiner, Pascal-M.
A1  - Holtmann, Martin
A1  - Fallgatter, Andreas
A1  - Romanos, Marcel
A1  - Abenova, Karina
A1  - Alm, Barbara
A1  - Becker, Katja
A1  - Döpfner, Manfred
A1  - Ethofer, Thomas
A1  - Freitag, Christine M.
A1  - Geissler, Julia
A1  - Hebebrand, Johannes
A1  - Huss, Michael
A1  - Jans, Thomas
A1  - Jendreizik, Lea Teresa
A1  - Ketter, Johanna
A1  - Legenbauer, Tanja
A1  - Philipsen, Alexandra
A1  - Poustka, Luise
A1  - Renner, Tobias
A1  - Retz, Wolfgang
A1  - Rösler, Michael
A1  - Thome, Johannes
A1  - Uebel-von Sandersleben, Henrik
A1  - von Wirth, Elena
A1  - Zinnow, Toivo
A1  - Hohmann, Sarah
A1  - Millenet, Sabina
A1  - Holz, Nathalie E.
A1  - Banaschewski, Tobias
A1  - Brandeis, Daniel
T1  - EEG data quality: determinants and impact in a multicenter study of children, adolescents, and adults with attention-deficit/hyperactivity disorder (ADHD)
JF  - Brain Sciences
N2  - Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (n\(_{total}\) = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.
KW  - electroencephalography (EEG)
KW  - data quality
KW  - attention-deficit/hyperactivity disorder (ADHD)
KW  - artifacts
KW  - multicenter study
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228788
SN  - 2076-3425
VL  - 11
IS  - 2
ER  - 
TY  - JOUR
A1  - Sommerfeld, Andreas
A1  - Senf, Cornelius
A1  - Buma, Brian
A1  - D'Amato, Anthony W.
A1  - Després, Tiphaine
A1  - Díaz-Hormazábal, Ignacio
A1  - Fraver, Shawn
A1  - Frelich, Lee E.
A1  - Gutiérrez, Álvaro G.
A1  - Hart, Sarah J.
A1  - Harvey, Brian J.
A1  - He, Hong S.
A1  - Hlásny, Tomáš
A1  - Holz, Andrés
A1  - Kitzberger, Thomas
A1  - Kulakowski, Dominik
A1  - Lindenmayer, David
A1  - Mori, Akira S.
A1  - Müller, Jörg
A1  - Paritsis, Juan
A1  - Perry, George L. W.
A1  - Stephens, Scott L.
A1  - Svoboda, Miroslav
A1  - Turner, Monica G.
A1  - Veblen, Thomas T.
A1  - Seidl, Rupert
T1  - Patterns and drivers of recent disturbances across the temperate forest biome
JF  - Nature Communications
N2  - Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001–2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes.
KW  - forest ecology
KW  - forestry
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239157
VL  - 9
ER  - 
TY  - THES
A1  - Thomas, Sarah Katharina
T1  - Design of novel IL-4 antagonists employing site-specific chemical and biosynthetic glycosylation
T1  - Herstellung neuer IL-4 basierter Antagonisten durch zielgerichtete chemische und biosynthetische Glykosylierung
N2  - The cytokines interleukin 4 (IL-4) and IL-13 are important mediators in the humoral immune response and play a crucial role in the pathogenesis of chronic inflammatory diseases, such as asthma, allergies, and atopic dermatitis. Hence, IL-4 and IL-13 are key targets for treatment of such atopic diseases.
For cell signalling IL-4 can use two transmembrane receptor assemblies, the type I receptor consisting of receptors IL-4R and γc, and type II receptor consisting of receptors IL-4R and IL-13R1. The type II receptor is also the functional receptor of IL-13, receptor sharing being the molecular basis for the partially overlapping effects of IL-4 and IL-13. Since both cytokines require the IL-4R receptor for signal transduction, this allows the dual inhibition of both IL-4 and IL-13 by specifically blocking the receptor IL-4R.
This study describes the design and synthesis of novel antagonistic variants of human IL-4. Chemical modification was used to target positions localized in IL-4 binding sites for γc and IL-13R1 but outside of the binding epitope for IL-4R. In contrast to existing studies, which used synthetic chemical compounds like polyethylene glycol for modification of IL-4, we employed glycan molecules as a natural alternative. Since glycosylation can improve important pharmacological parameters of protein therapeutics, such as immunogenicity and serum half-life, the introduced glycan molecules thus would not only confer a steric hindrance based inhibitory effect but simultaneously might improve the pharmacokinetic profile of the IL-4 antagonist.
For chemical conjugation of glycan molecules, IL-4 variants containing additional cysteine residues were produced employing prokaryotic, as well as eukaryotic expression systems. The thiol-groups of the engineered cysteines thereby allow highly specific modification. Different strategies were developed enabling site-directed coupling of amine- or thiol- functionalized monosaccharides to introduced cysteine residues in IL-4. A linker-based coupling procedure and an approach requiring phenylselenyl bromide activation of IL-4 thiol-groups were hampered by several drawbacks, limiting their feasibility. Surprisingly, a third strategy, which involved refolding of IL-4 cysteine variants in the presence of thiol- glycans, readily allowed synthesis of IL-4 glycoconjugates in form of mixed disulphides in milligram amount. This approach, therefore, has the potential for large-scale synthesis of IL-4 antagonists with highly defined glycosylation. Obtaining a homogenous glycoconjugate with exactly defined glycan pattern would allow using the attached glycan structures for fine-tuning of pharmacokinetic properties of the IL-4 antagonist, such as absorption and metabolic stability.
The IL-4 glycoconjugates generated in this work proved to be highly effective antagonists inhibiting IL-4 and/or IL-13 dependent responses in cell-based experiments and in in vitro binding studies. Glycoengineered IL-4 antagonists thus present valuable alternatives to IL-4 inhibitors used for treatment of atopic diseases such as the neutralizing anti-IL-4R antibody Dupilumab.
N2  - Die Zytokine Interleukin-4 (IL-4) und IL-13 sind zentrale Mediatoren in der humoralen Immunantwort und sind wesentlich an der Entstehung chronisch inflammatorischer Erkrankungen, wie Asthma, Allergien und atopischer Dermatitis beteiligt. Daher werden IL- 4 und IL-13 als wichtige therapeutische Angriffspunkte für die Behandlung atopischer Erkrankungen betrachtet.
Zur Signaltransduktion aktiviert IL-4 zwei heterodimere Rezeptorkomplexe, den Typ I Rezeptor bestehend aus den Untereinheiten IL-4R und γc und den Typ II Rezeptor, der sich aus IL-4R und IL-13R1 zusammensetzt. Der Typ II Rezeptor wird auch von IL-13 zur Signalweiterleitung genutzt, wodurch sich die teilweise überschneidenden Funktionen der beiden Zytokine erklären lassen. Die überlappende Rezeptornutzung erlaubt es durch eine gezielte Blockade des IL-4R-Rezeptors sowohl IL-4, als auch IL-13 gleichzeitig zu inhibieren.
Ziel dieser Arbeit war die Herstellung neuartiger IL-4 basierter Antagonisten. Dazu wurden ausgewählte Positionen innerhalb der IL-4 Bindestelle für γc and IL-13R1, jedoch außerhalb des Bindeepitops für IL-4R gezielt chemisch modifiziert. Im Gegensatz zu bereits existierenden Studien, die synthetische Gruppen wie Polyethylenglykol (PEG) zur chemischen Modifizierung von IL-4 nutzten, wurden in dieser Arbeit Glykane als natürliche Alternative zu PEG an IL-4 gekoppelt. Da sich Glykosylierung auf wichtige pharmakologische Eigenschaften proteinbasierter Therapeutika, wie Immunogenität oder Serum Halbwertszeit, positiv auswirken kann, würde der Zucker in dieser Strategie nicht nur den auf sterischer Hinderung basierenden inhibitorischen Effekt vermitteln, sondern könnte gleichzeitig zu einer Optimierung der pharmakologischen Eigenschaften des IL-4 Inhibitors beitragen.
Zur chemischen Zucker-Kopplung wurden zusätzliche Cystein-Reste in IL-4 eingebracht, deren freie Thiol-gruppen eine hochspezifische Modifizierung der IL-4 Mutanten erlauben. Die IL-4 Cystein-Mutanten wurden rekombinant in prokaryotischen und eukaryotischen Expressionssystemen hergestellt. Anschließend wurden verschiedene Strategien entwickelt, die eine ortsspezifische Kopplung Amin- und Thiol-haltiger Zucker an die eingebrachten Cystein-Reste in IL-4 ermöglichen. Eine Linker-basierte Reaktion, sowie ein Kopplungsansatz, der eine Aktivierung der Thiol-Gruppe mittels Bromselenobenzol erforderte, wiesen einige Nachteile auf, die eine erhebliche Einschränkung ihrer technischen Durchführbarkeit zur Folge hatte. Eine dritte Strategie hingegen, die eine Rückfaltung derIL-4 Cystein-Mutanten in Anwesenheit von Thiol-Glykanen involvierte, erlaubte eine effiziente Herstellung von IL-4 Glykokonjugaten in Form gemischter Disulfide im Milligrammbereich. Dieser Ansatz könnte somit zur Produktion homogen glykosylierter IL-4 Antagonisten im Großmaßstab eingesetzt werden. Die Herstellung homogener Glykokonjugate mit klar definierten Glykosylierungsmuster würde es erlauben über die gekoppelten Glykanstrukturen die pharmakologischen Eigenschaften von IL-4, wie Absorption und metabolische Stabilität, gezielt zu modulieren.
Die hergestellten IL-4 Glykokonjugate erwiesen sich als hochwirksame Antagonisten, die die Aktivität von IL-4 und IL-13 in zellbasierten Experimenten inhibieren konnten. Glykosylierte IL-4 Antagonisten stellen somit eine vergleichbare Alternative zu gängigen IL-4 Inhibitoren dar, die zur Behandlung von atopischen Erkrankungen eingesetzt werden, wie beispielweise der neutralisierende anti-IL-4R Antikörper Dupilumab.
KW  - Glykosylierung
KW  - Modifizierung
KW  - Interleukin
KW  - Inhibitor
KW  - Entzündung
KW  - Glykomodifizierung
KW  - Interleukin-4 Antagonist
KW  - TH2 Immunantwort
KW  - Proteinmodifizierung
KW  - Rezeptorblocker
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175172
ER  - 
TY  - JOUR
A1  - Andreska, Thomas
A1  - Aufmkolk, Sarah
A1  - Sauer, Markus
A1  - Blum, Robert
T1  - High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons
JF  - Frontiers in Cellular Neuroscience
N2  - In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity.
KW  - hippocampal neurons
KW  - synapse structure
KW  - presynapse
KW  - synaptic localization
KW  - BDNF
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119793
SN  - 1662-5102
VL  - 8
IS  - 107
ER  - 
TY  - JOUR
A1  - Brunkhorst-Kanaan, Nathalie
A1  - Trautmann, Sandra
A1  - Schreiber, Yannick
A1  - Thomas, Dominique
A1  - Kittel-Schneider, Sarah
A1  - Gurke, Robert
A1  - Geisslinger, Gerd
A1  - Reif, Andreas
A1  - Tegeder, Irmgard
T1  - Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder
JF  - Biomedicines
N2  - Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
KW  - attention deficit hyperactivity disorder
KW  - endocannabinoids
KW  - ceramides
KW  - bipolar disorder
KW  - major depression
KW  - tandem mass spectrometry
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246080
SN  - 2227-9059
VL  - 9
IS  - 9
ER  - 
TY  - JOUR
A1  - Moll, Corinna
A1  - Reboredo, Jenny
A1  - Schwarz, Thomas
A1  - Appelt, Antje
A1  - Schürlein, Sebastian
A1  - Walles, Heike
A1  - Nietzer, Sarah
T1  - Tissue Engineering of a Human 3D in vitro Tumor Test System
JF  - Journal of Visualized Experiments
N2  - Cancer is one of the leading causes of death worldwide. Current therapeutic strategies are predominantly developed in 2D culture systems, which inadequately reflect physiological conditions in vivo. Biological 3D matrices provide cells an environment in which cells can self-organize, allowing the study of tissue organization and cell differentiation. Such scaffolds can be seeded with a mixture of different cell types to study direct 3D cell-cell-interactions. To mimic the 3D complexity of cancer tumors, our group has developed a 3D in vitro tumor test system.

Our 3D tissue test system models the in vivo situation of malignant peripheral nerve sheath tumors (MPNSTs), which we established with our decellularized porcine jejunal segment derived biological vascularized scaffold (BioVaSc). In our model, we reseeded a modified BioVaSc matrix with primary fibroblasts, microvascular endothelial cells (mvECs) and the S462 tumor cell line For static culture, the vascular structure of the BioVaSc is removed and the remaining scaffold is cut open on one side (Small Intestinal Submucosa SIS-Muc). The resulting matrix is then fixed between two metal rings (cell crowns).

Another option is to culture the cell-seeded SIS-Muc in a flow bioreactor system that exposes the cells to shear stress. Here, the bioreactor is connected to a peristaltic pump in a self-constructed incubator. A computer regulates the arterial oxygen and nutrient supply via parameters such as blood pressure, temperature, and flow rate. This setup allows for a dynamic culture with either pressure-regulated pulsatile or constant flow.

In this study, we could successfully establish both a static and dynamic 3D culture system for MPNSTs. The ability to model cancer tumors in a more natural 3D environment will enable the discovery, testing, and validation of future pharmaceuticals in a human-like model.
KW  - bioengineering
KW  - biomedical engineering
KW  - tissue engineering
KW  - biotechnology
KW  - cultured
KW  - tumor cells
KW  - cell culture
KW  - 3D in vitro models
KW  - bioreactor
KW  - dynamic culture conditions
KW  - tumor test system
KW  - primary cell isolation
KW  - BioVaSc
KW  - decellularization
KW  - equipment and supplies
KW  - cellular microenvironment
KW  - culture techniques
KW  - cell engineering
KW  - anatomy
KW  - physiology
KW  - molecular biology
KW  - cellular biology
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132277
UR  - http://www.jove.com/video/50460
VL  - 78
IS  - e50460
ER  - 
TY  - JOUR
A1  - Brehm, Klaus
A1  - Hemer, Sarah
A1  - Konrad, Christian
A1  - Spiliotis, Markus
A1  - Koziol, Uriel
A1  - Schaack, Dominik
A1  - Förster, Sabine
A1  - Gelmedin, Verena
A1  - Stadelmann, Britta
A1  - Dandekar, Thomas
A1  - Hemphill, Andrew
T1  - Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development
N2  - Background

The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host’s liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood.

Results

Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite’s glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin.

Conclusions

Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.
KW  - Cestode
KW  - Tapeworm
KW  - Echinococcus
KW  - Echinococcosis
KW  - Insulin
KW  - Receptor kinase
KW  - Kinase inhibitor
KW  - Host-parasite interaction
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110357
ER  - 
TY  - JOUR
A1  - Gordon, Sarah
A1  - Daneshian, Mardas
A1  - Bouwstra, Joke
A1  - Caloni, Francesca
A1  - Constant, Samuel
A1  - Davies, Donna E.
A1  - Dandekar, Gudrun
A1  - Guzman, Carlos A.
A1  - Fabian, Eric
A1  - Haltner, Eleonore
A1  - Hartung, Thomas
A1  - Hasiwa, Nina
A1  - Hayden, Patrick
A1  - Kandarova, Helena
A1  - Khare, Sangeeta
A1  - Krug, Harald F.
A1  - Kneuer, Carsten
A1  - Leist, Marcel
A1  - Lian, Guoping
A1  - Marx, Uwe
A1  - Metzger, Marco
A1  - Ott, Katharina
A1  - Prieto, Pilar
A1  - Roberts, Michael S.
A1  - Roggen, Erwin L.
A1  - Tralau, Tewes
A1  - van den Braak, Claudia
A1  - Walles, Heike
A1  - Lehr, Claus-Michael
T1  - Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology
JF  - ALTEX: Alternatives to Animal Experimentation
N2  - Models of the outer epithelia of the human body namely the skin, the intestine and the lung have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
KW  - on-a-chip
KW  - asthmatic bronchial epithelium
KW  - vesicle-based barrier
KW  - pulmonary drug-delivery
KW  - epithelial cell culture
KW  - cytotoxicity
KW  - transport studies
KW  - permeability
KW  - in vitro models
KW  - air-liquid interface
KW  - respiratory syncytial virus
KW  - reconstructed human epidermis
KW  - artificial membrane-permeability
KW  - embryonic stem cells
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144275
VL  - 32
IS  - 4
ER  - 
TY  - JOUR
A1  - Baur, Florentin
A1  - Nietzer, Sarah L.
A1  - Kunz, Meik
A1  - Saal, Fabian
A1  - Jeromin, Julian
A1  - Matschos, Stephanie
A1  - Linnebacher, Michael
A1  - Walles, Heike
A1  - Dandekar, Thomas
A1  - Dandekar, Gudrun
T1  - Connecting cancer pathways to tumor engines: a stratification tool for colorectal cancer combining human in vitro tissue models with boolean in silico models
JF  - Cancers
N2  - To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
KW  - in silico simulation
KW  - 3D tissue models
KW  - colorectal cancer
KW  - BRAF mutation
KW  - targeted therapy
KW  - stratification
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193798
SN  - 2072-6694
VL  - 12
IS  - 1
ER  - 
TY  - JOUR
A1  - Kopf, Juliane
A1  - Glöckner, Stefan
A1  - Althen, Heike
A1  - Cevada, Thais
A1  - Schecklmann, Martin
A1  - Dresler, Thomas
A1  - Kittel-Schneider, Sarah
A1  - Reif, Andreas
T1  - Neural responses to a working memory task in acute depressed and remitted phases in bipolar patients
JF  - Brain Sciences
N2  - (1) Cognitive impairments such as working memory (WM) deficits are amongst the most common dysfunctions characterizing bipolar disorder (BD) patients, severely contributing to functional impairment. We aimed to investigate WM performance and associated brain activation during the acute phase of BD and to observe changes in the same patients during remission. (2) Frontal brain activation was recorded using functional near-infrared spectroscopy (fNIRS) during n-back task conditions (one-back, two-back and three-back) in BD patients in their acute depressive (n = 32) and remitted (n = 15) phases as well as in healthy controls (n = 30). (3) Comparison of BD patients during their acute phase with controls showed a trend (p = 0.08) towards lower dorsolateral prefrontal cortex (dlPFC) activation. In the remitted phase, BD patients showed lower dlPFC and ventrolateral prefrontal cortex (vlPFC) activation (p = 0.02) compared to controls. No difference in dlPFC and vlPFC activation between BD patients’ phases was found. (4) Our results showed decreased working memory performance in BD patients during the working memory task in the acute phase of disease. Working memory performance improved in the remitted phase of the disease but was still particularly attenuated for the more demanding conditions.
KW  - verbal n-back
KW  - fNIRS
KW  - prefrontal cortex
KW  - cognitive deficits
KW  - bipolar disorder
KW  - remitted/acute phase
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313509
SN  - 2076-3425
VL  - 13
IS  - 5
ER  - 
TY  - JOUR
A1  - Englmeier, Jana
A1  - Mitesser, Oliver
A1  - Benbow, M. Eric
A1  - Hothorn, Torsten
A1  - von Hoermann, Christian
A1  - Benjamin, Caryl
A1  - Fricke, Ute
A1  - Ganuza, Cristina
A1  - Haensel, Maria
A1  - Redlich, Sarah
A1  - Riebl, Rebekka
A1  - Rojas Botero, Sandra
A1  - Rummler, Thomas
A1  - Steffan-Dewenter, Ingolf
A1  - Stengel, Elisa
A1  - Tobisch, Cynthia
A1  - Uhler, Johannes
A1  - Uphus, Lars
A1  - Zhang, Jie
A1  - Müller, Jörg
T1  - Diverse effects of climate, land use, and insects on dung and carrion decomposition
JF  - Ecosystems
N2  - Land-use intensification and climate change threaten ecosystem functions. A fundamental, yet often overlooked, function is decomposition of necromass. The direct and indirect anthropogenic effects on decomposition, however, are poorly understood. We measured decomposition of two contrasting types of necromass, rat carrion and bison dung, on 179 study sites in Central Europe across an elevational climate gradient of 168–1122 m a.s.l. and within both local and regional land uses. Local land-use types included forest, grassland, arable fields, and settlements and were embedded in three regional land-use types (near-natural, agricultural, and urban). The effects of insects on decomposition were quantified by experimental exclusion, while controlling for removal by vertebrates. We used generalized additive mixed models to evaluate dung weight loss and carrion decay rate along elevation and across regional and local land-use types. We observed a unimodal relationship of dung decomposition with elevation, where greatest weight loss occurred between 600 and 700 m, but no effects of local temperature, land use, or insects. In contrast to dung, carrion decomposition was continuously faster with both increasing elevation and local temperature. Carrion reached the final decomposition stage six days earlier when insect access was allowed, and this did not depend on land-use effect. Our experiment identified different major drivers of decomposition on each necromass form. The results show that dung and carrion decomposition are rather robust to local and regional land use, but future climate change and decline of insects could alter decomposition processes and the self-regulation of ecosystems.
KW  - decay
KW  - ecosystem function
KW  - global change
KW  - land-use intensification
KW  - necrobiome
KW  - urbanization
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325064
SN  - 1432-9840
VL  - 26
IS  - 2
ER  - 
TY  - JOUR
A1  - Nanda, Indrajit
A1  - Steinlein, Claus
A1  - Haaf, Thomas
A1  - Buhl, Eva M.
A1  - Grimm, Domink G.
A1  - Friedman, Scott L.
A1  - Meurer, Steffen K.
A1  - Schröder, Sarah K.
A1  - Weiskirchen, Ralf
T1  - Genetic characterization of rat hepatic stellate cell line HSC-T6 for in vitro cell line authentication
JF  - Cells
N2  - Immortalized hepatic stellate cells (HSCs) established from mouse, rat, and humans are valuable in vitro models for the biomedical investigation of liver biology. These cell lines are homogenous, thereby providing consistent and reproducible results. They grow more robustly than primary HSCs and provide an unlimited supply of proteins or nucleic acids for biochemical studies. Moreover, they can overcome ethical concerns associated with the use of animal and human tissue and allow for fostering of the 3R principle of replacement, reduction, and refinement proposed in 1959 by William M. S. Russell and Rex L. Burch. Nevertheless, working with continuous cell lines also has some disadvantages. In particular, there are ample examples in which genetic drift and cell misidentification has led to invalid data. Therefore, many journals and granting agencies now recommend proper cell line authentication. We herein describe the genetic characterization of the rat HSC line HSC-T6, which was introduced as a new in vitro model for the study of retinoid metabolism. The consensus chromosome markers, outlined primarily through multicolor spectral karyotyping (SKY), demonstrate that apart from the large derivative chromosome 1 (RNO1), at least two additional chromosomes (RNO4 and RNO7) are found to be in three copies in all metaphases. Additionally, we have defined a short tandem repeat (STR) profile for HSC-T6, including 31 species-specific markers. The typical features of these cells have been further determined by electron microscopy, Western blotting, and Rhodamine-Phalloidin staining. Finally, we have analyzed the transcriptome of HSC-T6 cells by mRNA sequencing (mRNA-Seq) using next generation sequencing (NGS).
KW  - liver
KW  - extracellular matrix
KW  - hepatic stellate cell
KW  - myofibroblast
KW  - fibrosis
KW  - in vitro model
KW  - SKY analysis
KW  - phalloidin stain
KW  - next generation sequencing
KW  - STR profile
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275178
SN  - 2073-4409
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Kunz, Meik
A1  - Göttlich, Claudia
A1  - Walles, Thorsten
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
A1  - Dandekar, Thomas
T1  - MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact
JF  - Tumor Biology
N2  - MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.
KW  - biomarker
KW  - microRNA–target interaction
KW  - microRNAs
KW  - lung cancer
KW  - therapeutic strategy
KW  - bioinformatics
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158399
VL  - 39
IS  - 7
ER  - 
TY  - JOUR
A1  - Peindl, Matthias
A1  - Göttlich, Claudia
A1  - Crouch, Samantha
A1  - Hoff, Niklas
A1  - Lüttgens, Tamara
A1  - Schmitt, Franziska
A1  - Pereira, Jesús Guillermo Nieves
A1  - May, Celina
A1  - Schliermann, Anna
A1  - Kronenthaler, Corinna
A1  - Cheufou, Danjouma
A1  - Reu-Hofer, Simone
A1  - Rosenwald, Andreas
A1  - Weigl, Elena
A1  - Walles, Thorsten
A1  - Schüler, Julia
A1  - Dandekar, Thomas
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
T1  - EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures
JF  - Cancers
N2  - Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
KW  - EMT
KW  - drug resistance
KW  - invasion
KW  - stemness
KW  - 3D lung tumor tissue models
KW  - KRAS biomarker signatures
KW  - boolean in silico models
KW  - targeted combination therapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270744
SN  - 2072-6694
VL  - 14
IS  - 9
ER  - 
TY  - JOUR
A1  - Janson, Patrick
A1  - Willeke, Kristina
A1  - Zaibert, Lisa
A1  - Budnick, Andrea
A1  - Berghöfer, Anne
A1  - Kittel-Schneider, Sarah
A1  - Heuschmann, Peter U.
A1  - Zapf, Andreas
A1  - Wildner, Manfred
A1  - Stupp, Carolin
A1  - Keil, Thomas
T1  - Mortality, morbidity and health-related outcomes in informal caregivers compared to non-caregivers: a systematic review
JF  - International Journal of Environmental Research and Public Health
N2  - A systematic overview of mental and physical disorders of informal caregivers based on population-based studies with good methodological quality is lacking. Therefore, our aim was to systematically summarize mortality, incidence, and prevalence estimates of chronic diseases in informal caregivers compared to non-caregivers. Following PRISMA recommendations, we searched major healthcare databases (CINAHL, MEDLINE and Web of Science) systematically for relevant studies published in the last 10 years (without language restrictions) (PROSPERO registration number: CRD42020200314). We included only observational cross-sectional and cohort studies with low risk of bias (risk scores 0–2 out of max 8) that reported the prevalence, incidence, odds ratio (OR), hazard ratio (HR), mean- or sum-scores for health-related outcomes in informal caregivers and non-caregivers. For a thorough methodological quality assessment, we used a validated checklist. The synthesis of the results was conducted by grouping outcomes. We included 22 studies, which came predominately from the USA and Europe. Informal caregivers had a significantly lower mortality than non-caregivers. Regarding chronic morbidity outcomes, the results from a large longitudinal German health-insurance evaluation showed increased and statistically significant incidences of severe stress, adjustment disorders, depression, diseases of the spine and pain conditions among informal caregivers compared to non-caregivers. In cross-sectional evaluations, informal caregiving seemed to be associated with a higher occurrence of depression and of anxiety (ranging from 4 to 51% and 2 to 38%, respectively), pain, hypertension, diabetes and reduced quality of life. Results from our systematic review suggest that informal caregiving may be associated with several mental and physical disorders. However, these results need to be interpreted with caution, as the cross-sectional studies cannot determine temporal relationships. The lower mortality rates compared to non-caregivers may be due to a healthy-carer bias in longitudinal observational studies; however, these and other potential benefits of informal caregiving deserve further attention by researchers.
KW  - cohort studies
KW  - longitudinal studies
KW  - cross-sectional studies
KW  - family caregivers
KW  - informal caregiving
KW  - mental health
KW  - physical health
KW  - population-based studies
KW  - systematic review
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275219
SN  - 1660-4601
VL  - 19
IS  - 10
ER  - 
TY  - JOUR
A1  - Andreska, Thomas
A1  - Lüningschrör, Patrick
A1  - Wolf, Daniel
A1  - McFleder, Rhonda L.
A1  - Ayon-Olivas, Maurilyn
A1  - Rattka, Marta
A1  - Drechsler, Christine
A1  - Perschin, Veronika
A1  - Blum, Robert
A1  - Aufmkolk, Sarah
A1  - Granado, Noelia
A1  - Moratalla, Rosario
A1  - Sauer, Markus
A1  - Monoranu, Camelia
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
A1  - Stigloher, Christian
A1  - Sendtner, Michael
T1  - DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons
JF  - Cell Reports
N2  - Highlights
• Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons
• Dopaminergic deficits cause TrkB accumulation and clustering in the ER
• TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons
• Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion

Summary
Disturbed motor control is a hallmark of Parkinson’s disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.
KW  - motor learning
KW  - cortico-striatal synapse
KW  - basal ganglia
KW  - direct pathway
KW  - DRD1
KW  - dSPN
KW  - BDNF
KW  - TrkB
KW  - synaptic plasticity
KW  - GPCR
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349932
VL  - 42
IS  - 6
ER  - 
TY  - JOUR
A1  - Biere, Silvia
A1  - Kranz, Thorsten M.
A1  - Matura, Silke
A1  - Petrova, Kristiyana
A1  - Streit, Fabian
A1  - Chiocchetti, Andreas G.
A1  - Grimm, Oliver
A1  - Brum, Murielle
A1  - Brunkhorst-Kanaan, Natalie
A1  - Oertel, Viola
A1  - Malyshau, Aliaksandr
A1  - Pfennig, Andrea
A1  - Bauer, Michael
A1  - Schulze, Thomas G.
A1  - Kittel-Schneider, Sarah
A1  - Reif, Andreas
T1  - Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults
JF  - Frontiers in Psychiatry
N2  - Objective: 
Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD.

Methods: 
A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes.

Results: 
We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls.

Conclusions: 
In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.
KW  - polygenic risk score
KW  - bipolar disorder
KW  - genetic phenotypes
KW  - depression
KW  - ADHD
KW  - early recognition
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214976
VL  - 11
ER  - 
TY  - JOUR
A1  - Fazeli, Gholamreza
A1  - Beer, Katharina B.
A1  - Geisenhof, Michaela
A1  - Tröger, Sarah
A1  - König, Julia
A1  - Müller-Reichert, Thomas
A1  - Wehman, Ann M.
T1  - Loss of the Major Phosphatidylserine or Phosphatidylethanolamine Flippases Differentially Affect Phagocytosis
JF  - Frontiers in Cell and Developmental Biology
N2  - The lipids phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEth) are normally asymmetrically localized to the cytosolic face of membrane bilayers, but can both be externalized during diverse biological processes, including cell division, cell fusion, and cell death. Externalized lipids in the plasma membrane are recognized by lipid-binding proteins to regulate the clearance of cell corpses and other cell debris. However, it is unclear whether PtdSer and PtdEth contribute in similar or distinct ways to these processes. We discovered that disruption of the lipid flippases that maintain PtdSer or PtdEth asymmetry in the plasma membrane have opposite effects on phagocytosis in Caenorhabditis elegans embryos. Constitutive PtdSer externalization caused by disruption of the major PtdSer flippase TAT-1 led to increased phagocytosis of cell debris, sometimes leading to two cells engulfing the same debris. In contrast, PtdEth externalization caused by depletion of the major PtdEth flippase TAT-5 or its activator PAD-1 disrupted phagocytosis. These data suggest that PtdSer and PtdEth externalization have opposite effects on phagocytosis. Furthermore, externalizing PtdEth is associated with increased extracellular vesicle release, and we present evidence that the extent of extracellular vesicle accumulation correlates with the extent of phagocytic defects. Thus, a general loss of lipid asymmetry can have opposing impacts through different lipid subtypes simultaneously exerting disparate effects.
KW  - phagocytosis
KW  - lipid asymmetry
KW  - flippase
KW  - phosphatidylserine
KW  - phosphatidylethanolamine
KW  - extracellular vesicle
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208771
SN  - 2296-634X
VL  - 8
ER  - 
TY  - JOUR
A1  - Nietzer, Sarah
A1  - Baur, Florentin
A1  - Sieber, Stefan
A1  - Hansmann, Jan
A1  - Schwarz, Thomas
A1  - Stoffer, Carolin
A1  - Häfner, Heide
A1  - Gasser, Martin
A1  - Waaga-Gasser, Ana Maria
A1  - Walles, Heike
A1  - Dandekar, Gudrun
T1  - Mimicking metastases including tumor stroma: a new technique to generate a three-dimensional colorectal cancer model based on a biological decellularized intestinal scaffold
JF  - Tissue Engineering Part C-Methods
N2  - Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of beta-catenin in a subset of cells. One central drawback of 2D cultures-especially in consideration of drug testing-is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue generation, a bioreactor was constructed for dynamic culture approaches. This induced a close tissue-like association of cultured tumor cells with fibroblasts reflecting tumor biopsies. Therapy with 5-fluorouracil (5-FU) was effective only in 3D coculture. In conclusion, our 3D tumor model reflects human tissue-related tumor characteristics, including lower tumor cell proliferation. It is now available for drug testing in metastatic context-especially for substances targeting tumor-stroma interactions.
KW  - Multicenter randomized-trial
KW  - Carcinoma cells
KW  - Tissue
KW  - Fluorouracil
KW  - Matrix
KW  - 1st-line treatment
KW  - Beta-catenin
KW  - Invasion
KW  - 5-Fluorouracil
KW  - Fibroblasts
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188202
VL  - 22
IS  - 7
ER  - 
TY  - JOUR
A1  - Groma, Michaela
A1  - Horst, Sarah A.
A1  - Das, Sudip
A1  - Huettel, Bruno
A1  - Klepsch, Maximilian
A1  - Rudel, Thomas
A1  - Medina, Eva
A1  - Fraunholz, Martin
T1  - Identification of a Novel LysR-Type Transcriptional Regulator in Staphylococcus aureus That Is Crucial for Secondary Tissue Colonization during Metastatic Bloodstream Infection
JF  - mbio
N2  - Staphylococcus aureus is a common cause of bacteremia that can lead to severe complications once the bacteria exit the bloodstream and establish infection in secondary organs. Despite its clinical relevance, little is known about the bacterial factors facilitating the development of these metastatic infections. Here, we used an S. aureus transposon mutant library coupled to transposon insertion sequencing (Tn-Seq) to identify genes that are critical for efficient bacterial colonization of secondary organs in a murine model of metastatic bloodstream infection. Our transposon screen identified a LysR-type transcriptional regulator (LTTR), which was required for efficient colonization of secondary organs such as the kidneys in infected mice. The critical role of LTTR in secondary organ colonization was confirmed using an isogenic mutant deficient in the expression of LTTR. To identify the set of genes controlled by LTTR, we used an S. aureus strain carrying the LTTR gene in an inducible expression plasmid. Gene expression analysis upon induction of LTTR showed increased transcription of genes involved in branched-chain amino acid biosynthesis, a methionine sulfoxide reductase, and a copper transporter as well as decreased transcription of genes coding for urease and components of pyrimidine nucleotides. Furthermore, we show that transcription of LTTR is repressed by glucose, is induced under microaerobic conditions, and required trace amounts of copper ions. Our data thus pinpoints LTTR as an important element that enables a rapid adaptation of S. aureus to the changing host microenvironment.

IMPORTANCE Staphylococcus aureus is an important pathogen that can disseminate via the bloodstream and establish metastatic infections in distant organs. To achieve a better understanding of the bacterial factors facilitating the development of these metastatic infections, we used in this study a Staphylococcus aureus transposon mutant library in a murine model of intravenous infection, where bacteria first colonize the liver as the primary infection site and subsequently progress to secondary sites such as the kidney and bones. We identified a novel LysR-type transcriptional regulator (LTTR), which was specifically required by S. aureus for efficient colonization of secondary organs. We also determined the transcriptional activation as well as the regulon of LTTR, which suggests that this regulator is involved in the metabolic adaptation of S. aureus to the host microenvironment found in secondary infection sites.
KW  - Staphylococcus aureus
KW  - metabolic adaptation
KW  - secondary site infection
KW  - transcriptional regulation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230473
VL  - 11
IS  - 4
ER  - 
TY  - JOUR
A1  - Uhler, Johannes
A1  - Redlich, Sarah
A1  - Zhang, Jie
A1  - Hothorn, Torsten
A1  - Tobisch, Cynthia
A1  - Ewald, Jörg
A1  - Thorn, Simon
A1  - Seibold, Sebastian
A1  - Mitesser, Oliver
A1  - Morinère, Jérôme
A1  - Bozicevic, Vedran
A1  - Benjamin, Caryl S.
A1  - Englmeier, Jana
A1  - Fricke, Ute
A1  - Ganuza, Cristina
A1  - Haensel, Maria
A1  - Riebl, Rebekka
A1  - Rojas-Botero, Sandra
A1  - Rummler, Thomas
A1  - Uphus, Lars
A1  - Schmidt, Stefan
A1  - Steffan-Dewenter, Ingolf
A1  - Müller, Jörg
T1  - Relationships of insect biomass and richness with land use along a climate gradient
JF  - Nature Communications
N2  - Recently reported insect declines have raised both political and social concern. Although the declines have been attributed to land use and climate change, supporting evidence suffers from low taxonomic resolution, short time series, a focus on local scales, and the collinearity of the identified drivers. In this study, we conducted a systematic assessment of insect populations in southern Germany, which showed that differences in insect biomass and richness are highly context dependent. We found the largest difference in biomass between semi-natural and urban environments (-42%), whereas differences in total richness (-29%) and the richness of threatened species (-56%) were largest from semi-natural to agricultural environments. These results point to urbanization and agriculture as major drivers of decline. We also found that richness and biomass increase monotonously with increasing temperature, independent of habitat. The contrasting patterns of insect biomass and richness question the use of these indicators as mutual surrogates. Our study provides support for the implementation of more comprehensive measures aimed at habitat restoration in order to halt insect declines.
KW  - biodiversity
KW  - ecology
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265058
VL  - 12
IS  - 1
ER  - 
TY  - JOUR
A1  - Hautmann, Christopher
A1  - Döpfner, Manfred
A1  - Katzmann, Josepha
A1  - Schürmann, Stephanie
A1  - Wolff Metternich-Kaizman, Tanja
A1  - Jaite, Charlotte
A1  - Kappel, Viola
A1  - Geissler, Julia
A1  - Warnke, Andreas
A1  - Jacob, Christian
A1  - Hennighausen, Klaus
A1  - Haack-Dees, Barbara
A1  - Schneider-Momm, Katja
A1  - Philipsen, Alexandra
A1  - Matthies, Swantje
A1  - Rösler, Michael
A1  - Retz, Wolfgang
A1  - Gontard, Alexander von
A1  - Sobanski, Esther
A1  - Alm, Barbara
A1  - Hohmann, Sarah
A1  - Häge, Alexander
A1  - Poustka, Luise
A1  - Colla, Michael
A1  - Gentschow, Laura
A1  - Freitag, Christine M.
A1  - Becker, Katja
A1  - Jans, Thomas
T1  - Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial
JF  - BMC Psychiatry
N2  - Background
The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment.

Methods
The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher).

Results
Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2).

Conclusions
Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand.

Trial registration
ISRCTN registry ISRCTN73911400. Registered 29 March 2007.
KW  - mothers
KW  - children
KW  - adult treatment
KW  - parent training
KW  - efficacy
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227930
VL  - 18
ER  - 
TY  - JOUR
A1  - Nanda, Indrajit
A1  - Schröder, Sarah K.
A1  - Steinlein, Claus
A1  - Haaf, Thomas
A1  - Buhl, Eva M.
A1  - Grimm, Domink G.
A1  - Weiskirchen, Ralf
T1  - Rat hepatic stellate cell line CFSC-2G: genetic markers and short tandem repeat profile useful for cell line authentication
JF  - Cells
N2  - Hepatic stellate cells (HSCs) are also known as lipocytes, fat-storing cells, perisinusoidal cells, or Ito cells. These liver-specific mesenchymal cells represent about 5% to 8% of all liver cells, playing a key role in maintaining the microenvironment of the hepatic sinusoid. Upon chronic liver injury or in primary culture, these cells become activated and transdifferentiate into a contractile phenotype, i.e., the myofibroblast, capable of producing and secreting large quantities of extracellular matrix compounds. Based on their central role in the initiation and progression of chronic liver diseases, cultured HSCs are valuable in vitro tools to study molecular and cellular aspects of liver diseases. However, the isolation of these cells requires special equipment, trained personnel, and in some cases needs approval from respective authorities. To overcome these limitations, several immortalized HSC lines were established. One of these cell lines is CFSC, which was originally established from cirrhotic rat livers induced by carbon tetrachloride. First introduced in 1991, this cell line and derivatives thereof (i.e., CFSC-2G, CFSC-3H, CFSC-5H, and CFSC-8B) are now used in many laboratories as an established in vitro HSC model. We here describe molecular features that are suitable for cell authentication. Importantly, chromosome banding and multicolor spectral karyotyping (SKY) analysis demonstrate that the CFSC-2G genome has accumulated extensive chromosome rearrangements and most chromosomes exist in multiple copies producing a pseudo-triploid karyotype. Furthermore, our study documents a defined short tandem repeat (STR) profile including 31 species-specific markers, and a list of genes expressed in CFSC-2G established by bulk mRNA next-generation sequencing (NGS).
KW  - liver
KW  - extracellular matrix
KW  - hepatic stellate cell
KW  - myofibroblast
KW  - fibrosis
KW  - stress fibers
KW  - spectral karyotyping
KW  - rhodamine–phalloidin stain
KW  - next-generation sequencing
KW  - STR profile
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288067
SN  - 2073-4409
VL  - 11
IS  - 18
ER  - 
TY  - JOUR
A1  - Schümann, Franziska Lea
A1  - Groß, Elisabeth
A1  - Bauer, Marcus
A1  - Rohde, Christian
A1  - Sandmann, Sarah
A1  - Terziev, Denis
A1  - Müller, Lutz P.
A1  - Posern, Guido
A1  - Wienke, Andreas
A1  - Fend, Falko
A1  - Hansmann, Martin-Leo
A1  - Klapper, Wolfram
A1  - Rosenwald, Andreas
A1  - Stein, Harald
A1  - Dugas, Martin
A1  - Müller-Tidow, Carsten
A1  - Wickenhauser, Claudia
A1  - Binder, Mascha
A1  - Weber, Thomas
T1  - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas
JF  - Biomedicines
N2  - T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.
KW  - T-cell non-Hodgkin's lymphomas
KW  - PTCL
KW  - epigenetics
KW  - EZH1
KW  - EZH2
KW  - H3K27me3
KW  - immunohistochemistry
KW  - next generation sequencing
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155
SN  - 2227-9059
VL  - 9
IS  - 12
ER  - 
TY  - JOUR
A1  - Hornick, Thomas
A1  - Richter, Anett
A1  - Harpole, William Stanley
A1  - Bastl, Maximilian
A1  - Bohlmann, Stephanie
A1  - Bonn, Aletta
A1  - Bumberger, Jan
A1  - Dietrich, Peter
A1  - Gemeinholzer, Birgit
A1  - Grote, Rüdiger
A1  - Heinold, Bernd
A1  - Keller, Alexander
A1  - Luttkus, Marie L.
A1  - Mäder, Patrick
A1  - Motivans Švara, Elena
A1  - Passonneau, Sarah
A1  - Punyasena, Surangi W.
A1  - Rakosy, Demetra
A1  - Richter, Ronny
A1  - Sickel, Wiebke
A1  - Steffan‐Dewenter, Ingolf
A1  - Theodorou, Panagiotis
A1  - Treudler, Regina
A1  - Werchan, Barbora
A1  - Werchan, Matthias
A1  - Wolke, Ralf
A1  - Dunker, Susanne
T1  - An integrative environmental pollen diversity assessment and its importance for the Sustainable Development Goals
JF  - Plants, People, Planet
N2  - Societal Impact Statement
Pollen relates to many aspects of human and environmental health, which protection and improvement are endorsed by the United Nations Sustainable Development Goals. By highlighting these connections in the frame of current challenges in monitoring and research, we discuss the need of more integrative and multidisciplinary pollen research related to societal needs, improving health of humans and our ecosystems for a sustainable future.
Summary
Pollen is at once intimately part of the reproductive cycle of seed plants and simultaneously highly relevant for the environment (pollinators, vector for nutrients, or organisms), people (food safety and health), and climate (cloud condensation nuclei and climate reconstruction). We provide an interdisciplinary perspective on the many and connected roles of pollen to foster a better integration of the currently disparate fields of pollen research, which would benefit from the sharing of general knowledge, technical advancements, or data processing solutions. We propose a more interdisciplinary and holistic research approach that encompasses total environmental pollen diversity (ePD) (wind and animal and occasionally water distributed pollen) at multiple levels of diversity (genotypic, phenotypic, physiological, chemical, and functional) across space and time. This interdisciplinary approach holds the potential to contribute to pressing human issues, including addressing United Nations Sustainable Development Goals, fostering social and political awareness of these tiny yet important and fascinating particles.
KW  - aerobiology
KW  - allergy
KW  - diversity
KW  - environmental monitoring
KW  - food safety
KW  - paleoecology
KW  - palynology
KW  - pollination
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276487
VL  - 4
IS  - 2
SP  - 110
EP  - 121
ER  - 
TY  - JOUR
A1  - Alnusaire, Taghreed S.
A1  - Sayed, Ahmed M.
A1  - Elmaidomy, Abeer H.
A1  - Al-Sanea, Mohammad M.
A1  - Albogami, Sarah
A1  - Albqmi, Mha
A1  - Alowaiesh, Bassam F.
A1  - Mostafa, Ehab M.
A1  - Musa, Arafa
A1  - Youssif, Khayrya A.
A1  - Refaat, Hesham
A1  - Othman, Eman M.
A1  - Dandekar, Thomas
A1  - Alaaeldin, Eman
A1  - Ghoneim, Mohammed M.
A1  - Abdelmohsen, Usama Ramadan
T1  - An in vitro and in silico study of the enhanced antiproliferative and pro-oxidant potential of Olea europaea L. cv. Arbosana leaf extract via elastic nanovesicles (spanlastics)
JF  - Antioxidants
N2  - The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC\(_{50}\) values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC\(_{50}\) 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC\(_{50}\) 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.
KW  - olive
KW  - metabolomic profiling
KW  - antiproliferative
KW  - pro-oxidant
KW  - encapsulation
KW  - spanlastic
KW  - nanocarrier
KW  - docking
KW  - molecular dynamics simulation
KW  - Olea
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250064
SN  - 2076-3921
VL  - 10
IS  - 12
ER  - 
TY  - JOUR
A1  - Kühnemundt, Johanna
A1  - Leifeld, Heidi
A1  - Scherg, Florian
A1  - Schmitt, Matthias
A1  - Nelke, Lena C.
A1  - Schmitt, Tina
A1  - Bauer, Florentin
A1  - Göttlich, Claudia
A1  - Fuchs, Maximilian
A1  - Kunz, Meik
A1  - Peindl, Matthias
A1  - Brähler, Caroline
A1  - Kronenthaler, Corinna
A1  - Wischhusen, Jörg
A1  - Prelog, Martina
A1  - Walles, Heike
A1  - Dandekar, Thomas
A1  - Dandekar, Gudrun
A1  - Nietzer, Sarah L.
T1  - Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing
JF  - ALTEX
N2  - High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.
KW  - modular tumor tissue models
KW  - invasiveness
KW  - bioreactor culture
KW  - combinatorial drug predictions
KW  - immunotherapies
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231465
VL  - 38
ER  - 
TY  - JOUR
A1  - Englmeier, Jana
A1  - von Hoermann, Christian
A1  - Rieker, Daniel
A1  - Benbow, Marc Eric
A1  - Benjamin, Caryl
A1  - Fricke, Ute
A1  - Ganuza, Cristina
A1  - Haensel, Maria
A1  - Lackner, Tomáš
A1  - Mitesser, Oliver
A1  - Redlich, Sarah
A1  - Riebl, Rebekka
A1  - Rojas-Botero, Sandra
A1  - Rummler, Thomas
A1  - Salamon, Jörg-Alfred
A1  - Sommer, David
A1  - Steffan-Dewenter, Ingolf
A1  - Tobisch, Cynthia
A1  - Uhler, Johannes
A1  - Uphus, Lars
A1  - Zhang, Jie
A1  - Müller, Jörg
T1  - Dung-visiting beetle diversity is mainly affected by land use, while community specialization is driven by climate
JF  - Ecology and Evolution
N2  - Dung beetles are important actors in the self-regulation of ecosystems by driving nutrient cycling, bioturbation, and pest suppression. Urbanization and the sprawl of agricultural areas, however, destroy natural habitats and may threaten dung beetle diversity. In addition, climate change may cause shifts in geographical distribution and community composition. We used a space-for-time approach to test the effects of land use and climate on α-diversity, local community specialization (H\(_2\)′) on dung resources, and γ-diversity of dung-visiting beetles. For this, we used pitfall traps baited with four different dung types at 115 study sites, distributed over a spatial extent of 300 km × 300 km and 1000 m in elevation. Study sites were established in four local land-use types: forests, grasslands, arable sites, and settlements, embedded in near-natural, agricultural, or urban landscapes. Our results show that abundance and species density of dung-visiting beetles were negatively affected by agricultural land use at both spatial scales, whereas γ-diversity at the local scale was negatively affected by settlements and on a landscape scale equally by agricultural and urban land use. Increasing precipitation diminished dung-visiting beetle abundance, and higher temperatures reduced community specialization on dung types and γ-diversity. These results indicate that intensive land use and high temperatures may cause a loss in dung-visiting beetle diversity and alter community networks. A decrease in dung-visiting beetle diversity may disturb decomposition processes at both local and landscape scales and alter ecosystem functioning, which may lead to drastic ecological and economic damage.
KW  - coleoptera
KW  - coprophagous beetles
KW  - decomposition
KW  - global change
KW  - hill numbers
KW  - network analysis
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312846
SN  - 2045-7758
VL  - 12
IS  - 10
ER  - 
TY  - JOUR
A1  - Otto, Christoph
A1  - Kastner, Carolin
A1  - Schmidt, Stefanie
A1  - Uttinger, Konstantin
A1  - Baluapuri, Apoorva
A1  - Denk, Sarah
A1  - Rosenfeldt, Mathias T.
A1  - Rosenwald, Andreas
A1  - Roehrig, Florian
A1  - Ade, Carsten P.
A1  - Schuelein-Voelk, Christina
A1  - Diefenbacher, Markus E.
A1  - Germer, Christoph-Thomas
A1  - Wolf, Elmar
A1  - Eilers, Martin
A1  - Wiegering, Armin
T1  - RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells
JF  - Molecular Oncology
N2  - Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.
KW  - CRC
KW  - CX5461
KW  - MIZ1
KW  - MYC
KW  - ribosome
KW  - RNAPOL1
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312806
VL  - 16
IS  - 15
ER  - 
TY  - JOUR
A1  - Ullmann, Tobias
A1  - Banks, Sarah N.
A1  - Schmitt, Andreas
A1  - Jagdhuber, Thomas
T1  - Scattering characteristics of X-, C- and L-Band PolSAR data examined for the tundra environment of the Tuktoyaktuk Peninsula, Canada
JF  - Applied Sciences
N2  - In this study, polarimetric Synthetic Aperture Radar (PolSAR) data at X-, C- and L-Bands, acquired by the satellites: TerraSAR-X (2011), Radarsat-2 (2011), ALOS (2010) and ALOS-2 (2016), were used to characterize the tundra land cover of a test site located close to the town of Tuktoyaktuk, NWT, Canada. Using available in situ ground data collected in 2010 and 2012, we investigate PolSAR scattering characteristics of common tundra land cover classes at X-, C- and L-Bands. Several decomposition features of quad-, co-, and cross-polarized data were compared, the correlation between them was investigated, and the class separability offered by their different feature spaces was analyzed. Certain PolSAR features at each wavelength were sensitive to the land cover and exhibited distinct scattering characteristics. Use of shorter wavelength imagery (X and C) was beneficial for the characterization of wetland and tundra vegetation, while L-Band data highlighted differences of the bare ground classes better. The Kennaugh Matrix decomposition applied in this study provided a unified framework to store, process, and analyze all data consistently, and the matrix offered a favorable feature space for class separation. Of all elements of the quad-polarized Kennaugh Matrix, the intensity based elements K0, K1, K2, K3 and K4 were found to be most valuable for class discrimination. These elements contributed to better class separation as indicated by an increase of the separability metrics squared Jefferys Matusita Distance and Transformed Divergence. The increase in separability was up to 57% for Radarsat-2 and up to 18% for ALOS-2 data.
KW  - decomposition
KW  - arctic
KW  - PolSAR
KW  - dual polarimetry
KW  - quad polarimetry
KW  - TerraSAR-X
KW  - Radarsat-2
KW  - ALOS
KW  - ALOS-2
KW  - tundra
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158362
VL  - 7
IS  - 6
ER  -