TY  - JOUR
A1  - Dornelas, Maria
A1  - Antão, Laura H.
A1  - Moyes, Faye
A1  - Bates, Amanda E.
A1  - Magurran, Anne E.
A1  - Adam, Dušan
A1  - Akhmetzhanova, Asem A.
A1  - Appeltans, Ward
A1  - Arcos, José Manuel
A1  - Arnold, Haley
A1  - Ayyappan, Narayanan
A1  - Badihi, Gal
A1  - Baird, Andrew H.
A1  - Barbosa, Miguel
A1  - Barreto, Tiago Egydio
A1  - Bässler, Claus
A1  - Bellgrove, Alecia
A1  - Belmaker, Jonathan
A1  - Benedetti-Cecchi, Lisandro
A1  - Bett, Brian J.
A1  - Bjorkman, Anne D.
A1  - Błażewicz, Magdalena
A1  - Blowes, Shane A.
A1  - Bloch, Christopher P. Bloch
A1  - Bonebrake, Timothy C.
A1  - Boyd, Susan
A1  - Bradford, Matt
A1  - Brooks, Andrew J.
A1  - Brown, James H.
A1  - Bruelheide, Helge
A1  - Budy, Phaedra
A1  - Carvalho, Fernando
A1  - Castañeda-Moya, Edward
A1  - Chen, Chaolun Allen
A1  - Chamblee, John F.
A1  - Chase, Tory J.
A1  - Siegwart Collier, Laura
A1  - Collinge, Sharon K.
A1  - Condit, Richard
A1  - Cooper, Elisabeth J.
A1  - Cornelissen, J. Hans C.
A1  - Cotano, Unai
A1  - Crow, Shannan Kyle
A1  - Damasceno, Gabriella
A1  - Davies, Claire H.
A1  - Davis, Robert A.
A1  - Day, Frank P.
A1  - Degraer, Steven
A1  - Doherty, Tim S.
A1  - Dunn, Timothy E.
A1  - Durigan, Giselda
A1  - Duffy, J. Emmett
A1  - Edelist, Dor
A1  - Edgar, Graham J.
A1  - Elahi, Robin
A1  - Elmendorf, Sarah C.
A1  - Enemar, Anders
A1  - Ernest, S. K. Morgan
A1  - Escribano, Rubén
A1  - Estiarte, Marc
A1  - Evans, Brian S.
A1  - Fan, Tung-Yung
A1  - Turini Farah, Fabiano
A1  - Loureiro Fernandes, Luiz
A1  - Farneda, Fábio Z.
A1  - Fidelis, Alessandra
A1  - Fitt, Robert
A1  - Fosaa, Anna Maria
A1  - Franco, Geraldo Antonio Daher Correa
A1  - Frank, Grace E.
A1  - Fraser, William R.
A1  - García, Hernando
A1  - Cazzolla Gatti, Roberto
A1  - Givan, Or
A1  - Gorgone-Barbosa, Elizabeth
A1  - Gould, William A.
A1  - Gries, Corinna
A1  - Grossman, Gary D.
A1  - Gutierréz, Julio R.
A1  - Hale, Stephen
A1  - Harmon, Mark E.
A1  - Harte, John
A1  - Haskins, Gary
A1  - Henshaw, Donald L.
A1  - Hermanutz, Luise
A1  - Hidalgo, Pamela
A1  - Higuchi, Pedro
A1  - Hoey, Andrew
A1  - Van Hoey, Gert
A1  - Hofgaard, Annika
A1  - Holeck, Kristen
A1  - Hollister, Robert D.
A1  - Holmes, Richard
A1  - Hoogenboom, Mia
A1  - Hsieh, Chih-hao
A1  - Hubbell, Stephen P.
A1  - Huettmann, Falk
A1  - Huffard, Christine L.
A1  - Hurlbert, Allen H.
A1  - Ivanauskas, Natália Macedo
A1  - Janík, David
A1  - Jandt, Ute
A1  - Jażdżewska, Anna
A1  - Johannessen, Tore
A1  - Johnstone, Jill
A1  - Jones, Julia
A1  - Jones, Faith A. M.
A1  - Kang, Jungwon
A1  - Kartawijaya, Tasrif
A1  - Keeley, Erin C.
A1  - Kelt, Douglas A.
A1  - Kinnear, Rebecca
A1  - Klanderud, Kari
A1  - Knutsen, Halvor
A1  - Koenig, Christopher C.
A1  - Kortz, Alessandra R.
A1  - Král, Kamil
A1  - Kuhnz, Linda A.
A1  - Kuo, Chao-Yang
A1  - Kushner, David J.
A1  - Laguionie-Marchais, Claire
A1  - Lancaster, Lesley T.
A1  - Lee, Cheol Min
A1  - Lefcheck, Jonathan S.
A1  - Lévesque, Esther
A1  - Lightfoot, David
A1  - Lloret, Francisco
A1  - Lloyd, John D.
A1  - López-Baucells, Adrià
A1  - Louzao, Maite
A1  - Madin, Joshua S.
A1  - Magnússon, Borgþór
A1  - Malamud, Shahar
A1  - Matthews, Iain
A1  - McFarland, Kent P.
A1  - McGill, Brian
A1  - McKnight, Diane
A1  - McLarney, William O.
A1  - Meador, Jason
A1  - Meserve, Peter L.
A1  - Metcalfe, Daniel J.
A1  - Meyer, Christoph F. J.
A1  - Michelsen, Anders
A1  - Milchakova, Nataliya
A1  - Moens, Tom
A1  - Moland, Even
A1  - Moore, Jon
A1  - Moreira, Carolina Mathias
A1  - Müller, Jörg
A1  - Murphy, Grace
A1  - Myers-Smith, Isla H.
A1  - Myster, Randall W.
A1  - Naumov, Andrew
A1  - Neat, Francis
A1  - Nelson, James A.
A1  - Nelson, Michael Paul
A1  - Newton, Stephen F.
A1  - Norden, Natalia
A1  - Oliver, Jeffrey C.
A1  - Olsen, Esben M.
A1  - Onipchenko, Vladimir G.
A1  - Pabis, Krzysztof
A1  - Pabst, Robert J.
A1  - Paquette, Alain
A1  - Pardede, Sinta
A1  - Paterson, David M.
A1  - Pélissier, Raphaël
A1  - Peñuelas, Josep
A1  - Pérez-Matus, Alejandro
A1  - Pizarro, Oscar
A1  - Pomati, Francesco
A1  - Post, Eric
A1  - Prins, Herbert H. T.
A1  - Priscu, John C.
A1  - Provoost, Pieter
A1  - Prudic, Kathleen L.
A1  - Pulliainen, Erkki
A1  - Ramesh, B. R.
A1  - Ramos, Olivia Mendivil
A1  - Rassweiler, Andrew
A1  - Rebelo, Jose Eduardo
A1  - Reed, Daniel C.
A1  - Reich, Peter B.
A1  - Remillard, Suzanne M.
A1  - Richardson, Anthony J.
A1  - Richardson, J. Paul
A1  - van Rijn, Itai
A1  - Rocha, Ricardo
A1  - Rivera-Monroy, Victor H.
A1  - Rixen, Christian
A1  - Robinson, Kevin P.
A1  - Rodrigues, Ricardo Ribeiro
A1  - de Cerqueira Rossa-Feres, Denise
A1  - Rudstam, Lars
A1  - Ruhl, Henry
A1  - Ruz, Catalina S.
A1  - Sampaio, Erica M.
A1  - Rybicki, Nancy
A1  - Rypel, Andrew
A1  - Sal, Sofia
A1  - Salgado, Beatriz
A1  - Santos, Flavio A. M.
A1  - Savassi-Coutinho, Ana Paula
A1  - Scanga, Sara
A1  - Schmidt, Jochen
A1  - Schooley, Robert
A1  - Setiawan, Fakhrizal
A1  - Shao, Kwang-Tsao
A1  - Shaver, Gaius R.
A1  - Sherman, Sally
A1  - Sherry, Thomas W.
A1  - Siciński, Jacek
A1  - Sievers, Caya
A1  - da Silva, Ana Carolina
A1  - da Silva, Fernando Rodrigues
A1  - Silveira, Fabio L.
A1  - Slingsby, Jasper
A1  - Smart, Tracey
A1  - Snell, Sara J.
A1  - Soudzilovskaia, Nadejda A.
A1  - Souza, Gabriel B. G.
A1  - Souza, Flaviana Maluf
A1  - Souza, Vinícius Castro
A1  - Stallings, Christopher D.
A1  - Stanforth, Rowan
A1  - Stanley, Emily H.
A1  - Sterza, José Mauro
A1  - Stevens, Maarten
A1  - Stuart-Smith, Rick
A1  - Suarez, Yzel Rondon
A1  - Supp, Sarah
A1  - Tamashiro, Jorge Yoshio
A1  - Tarigan, Sukmaraharja
A1  - Thiede, Gary P.
A1  - Thorn, Simon
A1  - Tolvanen, Anne
A1  - Toniato, Maria Teresa Zugliani
A1  - Totland, Ørjan
A1  - Twilley, Robert R.
A1  - Vaitkus, Gediminas
A1  - Valdivia, Nelson
A1  - Vallejo, Martha Isabel
A1  - Valone, Thomas J.
A1  - Van Colen, Carl
A1  - Vanaverbeke, Jan
A1  - Venturoli, Fabio
A1  - Verheye, Hans M.
A1  - Vianna, Marcelo
A1  - Vieira, Rui P.
A1  - Vrška, Tomáš
A1  - Vu, Con Quang
A1  - Vu, Lien Van
A1  - Waide, Robert B.
A1  - Waldock, Conor
A1  - Watts, Dave
A1  - Webb, Sara
A1  - Wesołowski, Tomasz
A1  - White, Ethan P.
A1  - Widdicombe, Claire E.
A1  - Wilgers, Dustin
A1  - Williams, Richard
A1  - Williams, Stefan B.
A1  - Williamson, Mark
A1  - Willig, Michael R.
A1  - Willis, Trevor J.
A1  - Wipf, Sonja
A1  - Woods, Kerry D.
A1  - Woehler, Eric J.
A1  - Zawada, Kyle
A1  - Zettler, Michael L.
T1  - BioTIME: A database of biodiversity time series for the Anthropocene
JF  - Global Ecology and Biogeography
N2  - Motivation
The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.

Main types of variables included
The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.

Spatial location and grain
BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).

Time period and grain
BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.

Major taxa and level of measurement
BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.

Software format
.csv and .SQL.
KW  - biodiversity
KW  - global
KW  - spatial
KW  - species richness
KW  - temporal
KW  - turnover
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222846
VL  - 27
ER  - 
TY  - JOUR
A1  - Davis, Lea K.
A1  - Yu, Dongmei
A1  - Keenan, Clare L.
A1  - Gamazon, Eric R.
A1  - Konkashbaev, Anuar I.
A1  - Derks, Eske M.
A1  - Neale, Benjamin M.
A1  - Yang, Jian
A1  - Lee, S. Hong
A1  - Evans, Patrick
A1  - Barr, Cathy L.
A1  - Bellodi, Laura
A1  - Benarroch, Fortu
A1  - Berrio, Gabriel Bedoya
A1  - Bienvenu, Oscar J.
A1  - Bloch, Michael H.
A1  - Blom, Rianne M.
A1  - Bruun, Ruth D.
A1  - Budman, Cathy L.
A1  - Camarena, Beatriz
A1  - Campbell, Desmond
A1  - Cappi, Carolina
A1  - Cardona Silgado, Julio C.
A1  - Cath, Danielle C.
A1  - Cavallini, Maria C.
A1  - Chavira, Denise A.
A1  - Chouinard, Sylvian
A1  - Conti, David V.
A1  - Cook, Edwin H.
A1  - Coric, Vladimir
A1  - Cullen, Bernadette A.
A1  - Deforce, Dieter
A1  - Delorme, Richard
A1  - Dion, Yves
A1  - Edlund, Christopher K.
A1  - Egberts, Karin
A1  - Falkai, Peter
A1  - Fernandez, Thomas V.
A1  - Gallagher, Patience J.
A1  - Garrido, Helena
A1  - Geller, Daniel
A1  - Girard, Simon L.
A1  - Grabe, Hans J.
A1  - Grados, Marco A.
A1  - Greenberg, Benjamin D.
A1  - Gross-Tsur, Varda
A1  - Haddad, Stephen
A1  - Heiman, Gary A.
A1  - Hemmings, Sian M. J.
A1  - Hounie, Ana G.
A1  - Illmann, Cornelia
A1  - Jankovic, Joseph
A1  - Jenike, Micheal A.
A1  - Kennedy, James L.
A1  - King, Robert A.
A1  - Kremeyer, Barbara
A1  - Kurlan, Roger
A1  - Lanzagorta, Nuria
A1  - Leboyer, Marion
A1  - Leckman, James F.
A1  - Lennertz, Leonhard
A1  - Liu, Chunyu
A1  - Lochner, Christine
A1  - Lowe, Thomas L.
A1  - Macciardi, Fabio
A1  - McCracken, James T.
A1  - McGrath, Lauren M.
A1  - Restrepo, Sandra C. Mesa
A1  - Moessner, Rainald
A1  - Morgan, Jubel
A1  - Muller, Heike
A1  - Murphy, Dennis L.
A1  - Naarden, Allan L.
A1  - Ochoa, William Cornejo
A1  - Ophoff, Roel A.
A1  - Osiecki, Lisa
A1  - Pakstis, Andrew J.
A1  - Pato, Michele T.
A1  - Pato, Carlos N.
A1  - Piacentini, John
A1  - Pittenger, Christopher
A1  - Pollak, Yehunda
A1  - Rauch, Scott L.
A1  - Renner, Tobias J.
A1  - Reus, Victor I.
A1  - Richter, Margaret A.
A1  - Riddle, Mark A.
A1  - Robertson, Mary M.
A1  - Romero, Roxana
A1  - Rosàrio, Maria C.
A1  - Rosenberg, David
A1  - Rouleau, Guy A.
A1  - Ruhrmann, Stephan
A1  - Ruiz-Linares, Andreas
A1  - Sampaio, Aline S.
A1  - Samuels, Jack
A1  - Sandor, Paul
A1  - Sheppard, Broke
A1  - Singer, Harvey S.
A1  - Smit, Jan H.
A1  - Stein, Dan J.
A1  - Strengman, E.
A1  - Tischfield, Jay A.
A1  - Valencia Duarte, Ana V.
A1  - Vallada, Homero
A1  - Van Nieuwerburgh, Flip
A1  - Veenstra-VanderWeele, Jeremy
A1  - Walitza, Susanne
A1  - Wang, Ying
A1  - Wendland, Jens R.
A1  - Westenberg, Herman G. M.
A1  - Shugart, Yin Yao
A1  - Miguel, Euripedes C.
A1  - McMahon, William
A1  - Wagner, Michael
A1  - Nicolini, Humberto
A1  - Posthuma, Danielle
A1  - Hanna, Gregory L.
A1  - Heutink, Peter
A1  - Denys, Damiaan
A1  - Arnold, Paul D.
A1  - Oostra, Ben A.
A1  - Nestadt, Gerald
A1  - Freimer, Nelson B.
A1  - Pauls, David L.
A1  - Wray, Naomi R.
A1  - Stewart, S. Evelyn
A1  - Mathews, Carol A.
A1  - Knowles, James A.
A1  - Cox, Nancy J.
A1  - Scharf, Jeremiah M.
T1  - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture
JF  - PLoS Genetics
N2  - The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
KW  - TIC disorders
KW  - missing heritability
KW  - complex diseases
KW  - neuropsychiatric disorders
KW  - common SNPS
KW  - gilles
KW  - family
KW  - brain
KW  - expression
KW  - autism
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127377
SN  - 1553-7390
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Schilbach, Karin
A1  - Alkhaled, Mohammed
A1  - Welker, Christian
A1  - Eckert, Franziska
A1  - Blank, Gregor
A1  - Ziegler, Hendrik
A1  - Sterk, Marco
A1  - Müller, Friederike
A1  - Sonntag, Katja
A1  - Wieder, Thomas
A1  - Braumüller, Heidi
A1  - Schmitt, Julia
A1  - Eyrich, Matthias
A1  - Schleicher, Sabine
A1  - Seitz, Christian
A1  - Erbacher, Annika
A1  - Pichler, Bernd J.
A1  - Müller, Hartmut
A1  - Tighe, Robert
A1  - Lim, Annick
A1  - Gillies, Stephen D.
A1  - Strittmatter, Wolfgang
A1  - Röcken, Martin
A1  - Handgretinger, Rupert
T1  - Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation
JF  - OncoImmunology
N2  - Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.
KW  - TH17 cells
KW  - cancer-targeted IL-12
KW  - differentiation
KW  - humanized mice
KW  - immunocytokine
KW  - immunotherapy
KW  - M1/M2 macrophages
KW  - rhabdomyosarcoma
KW  - TH1-induced senescence
KW  - tumor-infiltrating lymphocytes
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154579
VL  - 4
IS  - 7
ER  - 
TY  - JOUR
A1  - Doll, Julia
A1  - Vona, Barbara
A1  - Schnapp, Linda
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Khan, Saadullah
A1  - Muhammad, Noor
A1  - Alam Khan, Sher
A1  - Nawaz, Hamed
A1  - Khan, Ajmal
A1  - Ahmad, Naseer
A1  - Kolb, Susanne M.
A1  - Kühlewein, Laura
A1  - Labonne, Jonathan D. J.
A1  - Layman, Lawrence C.
A1  - Hofrichter, Michaela A. H.
A1  - Röder, Tabea
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Graves, Tyler D.
A1  - Kong, Il-Keun
A1  - Nanda, Indrajit
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
T1  - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families
JF  - Genes
N2  - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
KW  - genetic diagnosis
KW  - consanguinity
KW  - genome-wide linkage analysis
KW  - hearing loss
KW  - Pakistan
KW  - exome sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293
SN  - 2073-4425
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Müller, Stefanie H.
A1  - Girard, Simon L.
A1  - Hopfner, Franziska
A1  - Merner, Nancy D.
A1  - Bourassa, Cynthia V.
A1  - Lorenz, Delia
A1  - Clark, Lorraine N.
A1  - Tittmann, Lukas
A1  - Soto-Ortolaza, Alexandra I.
A1  - Klebe, Stephan
A1  - Hallett, Mark
A1  - Schneider, Susanne A.
A1  - Hodgkinson, Colin A.
A1  - Lieb, Wolfgang
A1  - Wszolek, Zbigniew K.
A1  - Pendziwiat, Manuela
A1  - Lorenzo-Betancor, Oswaldo
A1  - Poewe, Werner
A1  - Ortega-Cubero, Sara
A1  - Seppi, Klaus
A1  - Rajput, Alex
A1  - Hussl, Anna
A1  - Rajput, Ali H.
A1  - Berg, Daniela
A1  - Dion, Patrick A.
A1  - Wurster, Isabel
A1  - Shulman, Joshua M.
A1  - Srulijes, Karin
A1  - Haubenberger, Dietrich
A1  - Pastor, Pau
A1  - Vilariño-Güell, Carles
A1  - Postuma, Ronald B.
A1  - Bernard, Geneviève
A1  - Ladwig, Karl-Heinz
A1  - Dupré, Nicolas
A1  - Jankovic, Joseph
A1  - Strauch, Konstantin
A1  - Panisset, Michel
A1  - Winkelmann, Juliane
A1  - Testa, Claudia M.
A1  - Reischl, Eva
A1  - Zeuner, Kirsten E.
A1  - Ross, Owen A.
A1  - Arzberger, Thomas
A1  - Chouinard, Sylvain
A1  - Deuschl, Günther
A1  - Louis, Elan D.
A1  - Kuhlenbäumer, Gregor
A1  - Rouleau, Guy A.
T1  - Genome-wide association study in essential tremor identifies three new loci
JF  - Brain
N2  - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
KW  - quality-control
KW  - disease
KW  - tool
KW  - movement disorders
KW  - genome-wide association study
KW  - tremor
KW  - genetics
KW  - essential tremor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541
VL  - 139
ER  - 
TY  - JOUR
A1  - Guhn, Anne
A1  - Dresler, Thomas
A1  - Andreatta, Marta
A1  - Müller, Laura D.
A1  - Hahn, Tim
A1  - Tupak, Sara V.
A1  - Polak, Thomas
A1  - Deckert, Jürgen
A1  - Herrmann, Martin J.
T1  - Medial prefrontal  cortex stimulation modulates the processing of conditioned fear
N2  - The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).
KW  - fear conditioning
KW  - memory consolidation and extinction
KW  - learning
KW  - transcranial magnetic stimulation (TMS)
KW  - medial prefrontal cortex (mPFC)
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111309
ER  - 
TY  - JOUR
A1  - Chopra, Martin
A1  - Biehl, Marlene
A1  - Steinfatt, Tim
A1  - Brandl, Andreas
A1  - Kums, Juliane
A1  - Amich, Jorge
A1  - Vaeth, Martin
A1  - Kuen, Janina
A1  - Holtappels, Rafaela
A1  - Podlech, Jürgen
A1  - Mottok, Anja
A1  - Kraus, Sabrina
A1  - Jordán-Garotte, Ana-Laura
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Ribechini, Eliana
A1  - Fick, Andrea
A1  - Seher, Axel
A1  - Polz, Johannes
A1  - Ottmueller, Katja J.
A1  - Baker, Jeannette
A1  - Nishikii, Hidekazu
A1  - Ritz, Miriam
A1  - Mattenheimer, Katharina
A1  - Schwinn, Stefanie
A1  - Winter, Thorsten
A1  - Schäfer, Viktoria
A1  - Krappmann, Sven
A1  - Einsele, Hermann
A1  - Müller, Thomas D.
A1  - Reddehase, Matthias J.
A1  - Lutz, Manfred B.
A1  - Männel, Daniela N.
A1  - Berberich-Siebelt, Friederike
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
JF  - Journal of Experimental Medicine
N2  - Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
KW  - Tumor-necrosis-factor
KW  - Regulatory-cells
KW  - Bone marrow transplantantation
KW  - Graft-versus-leukemia
KW  - Rheumatoid arthritis
KW  - Autoimmune diseases
KW  - Factor receptor
KW  - Alpha therapy
KW  - Expression
KW  - Suppression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640
VL  - 213
IS  - 9
ER  - 
TY  - JOUR
A1  - Klammert, Uwe
A1  - Müller, Thomas D.
A1  - Hellmann, Tina V.
A1  - Wuerzler, Kristian K.
A1  - Kotzsch, Alexander
A1  - Schliermann, Anna
A1  - Schmitz, Werner
A1  - Kuebler, Alexander C.
A1  - Sebald, Walter
A1  - Nickel, Joachim
T1  - GDF-5 can act as a context-dependent BMP-2 antagonist
JF  - BMC Biology
N2  - Background
Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a “BMP-2 mimic” with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor.

Results
Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites.

Conclusions
Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs.
KW  - growth and differentiation factor 5
KW  - ligand-receptor complex
KW  - crystal structure
KW  - antagonist
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125550
VL  - 13
IS  - 77
ER  - 
TY  - JOUR
A1  - Diestel, Uschi
A1  - Resch, Marcus
A1  - Meinhardt, Kathrin
A1  - Weiler, Sigrid
A1  - Hellmann, Tina V.
A1  - Mueller, Thomas D.
A1  - Nickel, Joachim
A1  - Eichler, Jutta
A1  - Muller, Yves A.
T1  - Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-\(\beta\)-Receptor-3 (TGFR-3)
JF  - PLoS ONE
N2  - The zona pellucida (ZP) domain is present in extracellular proteins such as the zona pellucida proteins and tectorins and participates in the formation of polymeric protein networks. However, the ZP domain also occurs in the cytokine signaling co-receptor transforming growth factor beta (TGF-\(\beta\)) receptor type 3 (TGFR-3, also known as betaglycan) where it contributes to cytokine ligand recognition. Currently it is unclear how the ZP domain architecture enables this dual functionality. Here, we identify a novel major TGF-beta-binding site in the FG loop of the C-terminal subdomain of the murine TGFR-3 ZP domain (ZP-C) using protein crystallography, limited proteolysis experiments, surface plasmon resonance measurements and synthetic peptides. In the murine 2.7 angstrom crystal structure that we are presenting here, the FG-loop is disordered, however, well-ordered in a recently reported homologous rat ZP-C structure. Surprisingly, the adjacent external hydrophobic patch (EHP) segment is registered differently in the rat and murine structures suggesting that this segment only loosely associates with the remaining ZP-C fold. Such a flexible and temporarily-modulated association of the EHP segment with the ZP domain has been proposed to control the polymerization of ZP domain-containing proteins. Our findings suggest that this flexibility also extends to the ZP domain of TGFR-3 and might facilitate co-receptor ligand interaction and presentation via the adjacent FG-loop. This hints that a similar C-terminal region of the ZP domain architecture possibly regulates both the polymerization of extracellular matrix proteins and cytokine ligand recognition of TGFR-3.
KW  - coreceptor
KW  - receptor type III
KW  - growth factor beta
KW  - ligand binding
KW  - betaglycan
KW  - proteins
KW  - mutagenesis
KW  - polymerization
KW  - glycoprotein
KW  - superfamily
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130904
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - van Dinther, Maarten
A1  - Zhang, Juan
A1  - Weidauer, Stella E.
A1  - Boschert, Verena
A1  - Muth, Eva-Maria
A1  - Knappik, Achim
A1  - de Gorter, David J. J.
A1  - van Kasteren, Puck B.
A1  - Frisch, Christian
A1  - Müller, Thomas D.
A1  - ten Dijke, Peter
T1  - Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling
JF  - PLoS ONE
N2  - Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with \([^{125} I]\) Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti-Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses.
KW  - gene
KW  - rat model
KW  - Dickkopf proteins
KW  - postmenopausal osteoporosis
KW  - increases bone-formation
KW  - WNT
KW  - LRP6
KW  - density
KW  - receptor
KW  - ligand
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130981
VL  - 8
IS  - 4
ER  -