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Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Ackermann, K. H. ; Adams, N. ; Adler, Clemens ; Ahammed, Zubayer ; Ahmad, Shakeel ; Allgower, Chris ; Amsbaugh, J. ; Anderson, Mike ; Anderssen, E. ; Arnesen, H. ; Arnold, L. ; Averichev, Georgy S. ; Baldwin, A. ; Balewski, Jan ; Barannikova, Olga ; Barnby, Lee Stuart ; Baudot, Jérome ; Beddo, M. ; Bekele, Selemon ; Belaga, Victoria Vladimirovna ; Bellwied, Rene ; Bennett, Samuel ; Bercovitz, J. ; Berger, Jens ; Betts, W. ; Bichsel, Hans ; Bieser, F. ; Bland, Leslie C. ; Bloomer, Matthew A. ; Blyth, Charles O. ; Boehm, J. ; Bonner, Billy E. ; Bonnet, D. ; Bossingham, R. ; Botlo, M. ; Boucham, Abdelkrim ; Bouillo, N. ; Bouvier, S. ; Bradley, K. ; Brady, Franklin Paul ; Braithwaite, E. S. ; Braithwaite, Wilfred J. ; Brandin, Andrei V. ; Brown, R. L. ; Brugalette, G. ; Byrd, C. ; Caines, Helen Louise ; Calderón de la Barca Sánchez, Manuel ; Cardenas, Andrés ; Carr, Lincoln D. ; Carroll, J. ; Castillo Castellanos, Javier Ernesto ; Caylor, B. ; Cebra, Daniel A. ; Chatopadhyay, S. ; Chen, M. L. ; Chen, W. ; Chen, Y. ; Chernenko, Sergey P. ; Cherney, Michael Gerard ; Chikanian, Alexei ; Choi, B. ; Chrin, J. ; Christie, William ; Coffin, Jean Pierre ; Conin, L. ; Consiglio, C. ; Cormier, Thomas Michael ; Cramer, John G. ; Crawford, Henry J. ; Danilov, V. I. ; Dayton, D. ; DeMello, M. ; Deng, W. S. ; Derevschikov, Anatoly A. ; Dialinas, M. ; Diaz, H. ; DeYoung, P. A. ; Didenko, Lidia ; Dimassimo, D. ; Dioguardi, J. ; Dominik, W. ; Drancourt, C. ; Draper, James E. ; Dunin, V. B. ; Dunlop, James C. ; Eckardt, Volker ; Edwards, W. R. ; Efimov, Leonid G. ; Eggert, T. ; Emelianov, V. ; Engelage, Jon M. ; Eppley, Geary Wareham ; Erazmus, Barbara Ewa ; Etkin, A. ; Fachini, Patricia ; Feliciano, C. ; Ferenc, D. ; Ferguson, M. I. ; Fessler, H. ; Finch, Evan ; Fine, Valeri ; Fisyak, Yuri V. ; Flierl, Dominik Bernhard ; Flores, I. ; Foley, Kenneth John ; Fritz, D. ; Gagunashvili, N. ; Gans, J. ; Gaździcki, Marek ; Germain, Marie ; Geurts, Frank ; Ghazikhanian, Vahe ; Gojak, C. ; Grabski, J. ; Grachov, Oleg A. ; Grau, M. ; Greiner, D. ; Greiner, Leo Clifford ; Grigoriev, Vladislav A. ; Grosnick, David P. ; Gross, J. ; Guilloux, G. ; Gushin, E. ; Hall, J. ; Hallman, Timothy J. ; Hardtke, David H. ; Harper, G. ; Harris, John W. ; He, P. ; Heffner, M. ; Heppelmann, S. ; Herston, T. ; Hill, D. ; Hippolyte, Boris ; Hirsch, Andrew S. ; Hjort, Eric ; Hoffmann, Gerald W. ; Horsley, M. ; Howe, Mark A. ; Huang, Huan Zhong ; Humanic, Thomas J. ; Hümmler, H. ; Hunt, W. ; Hunter, J. ; Igo, George J. ; Ishihara, A. ; Ivanshin, Yu. I. ; Jacobs, P. ; Jacobs, William W. ; Jacobson, S. ; Jared, R. ; Jensen, P. ; Johnson, I. ; Jones, Peter Graham ; Judd, Eleanor G. ; Kaneta, Kaneta ; Kaplan, Morton ; Keane, Declan ; Kenney, V. P. ; Khodinov, A. ; Klay, Jennifer Lynn ; Klein, Spencer Robert ; Klyachko, A. ; Koehler, G. ; Konstantinov, A. S. ; Kormilitsyne, V. ; Kotchenda, L. ; Kotov, I. ; Kovalenko, A. D. ; Kramer, M. ; Kravtsov, Peter ; Krueger, Keith William ; Krupien, T. ; Kuczewski, P. ; Kuhn, Christian Claude ; Kunde, Gerd J. ; Kunz, Christopher Lee ; Kutuev, R. Kh. ; Kuznetsov, A. A. ; Lakehal-Ayat, L. ; Lamas-Valverde, Jose ; Lamont, Matthew A. C. ; Landgraf, Jeffery M. ; Lange, S. ; Lansdell, Curtis Patrick Leon ; Lasiuk, Brian ; Laue, Frank ; Lebedev, Alexei ; LeCompte, T. ; Leonhardt, W. J. ; Leontiev, V. M. ; Leszczynski, P. ; LeVine, Micheal J. ; Li, Q. ; Li, Q. ; Li, Z. ; Liaw, C.-J. ; Lin, J. ; Lindenbaum, Sam J. ; Lindenstruth, Volker ; Lindstrom, P. J. ; Lisa, Michael A. ; Liu, H. ; Ljubicic, Tonko A. ; Llope, William Joseph ; LoCurto, G. ; Long, H. ; Longacre, Ronald S. ; Lopez-Noriega, M. ; Lopiano, D. ; Love, William A. ; Lutz, J. R. ; Lynn, David ; Madansky, L. ; Maier, R. ; Majka, Richard Daniel ; Maliszewski, A. ; Margetis, Spyridon ; Marks, K. ; Marstaller, R. ; Martin, L. ; Marx, Jay N. ; Matis, Howard S. ; Matulenko, Yuri A. ; Matyushevski, E. A. ; McParland, C. ; McShane, Tom S. ; Meier, J. ; Melnick, Yu. ; Meščanin, Aleksei P. ; Middlekamp, P. ; Mikhalin, N. ; Miller, B. ; Milosevich, Z. ; Minaev, Nikolai G. ; Minor, B. ; Mitchell, J. ; Mogavero, E. ; Moiseenko, V. A. ; Moltz, D. ; Moore, C. F. ; Morozov, V. ; Morse, R. ; de Moura, M. M. ; Munhoz, Marcelo Gameiro ; Mutchler, G. S. ; Nelson, John M. ; Nevski, P. ; Ngo, T. ; Nguyen, M. ; Nguyen, T. ; Nikitin, Vladimir A. ; Nogach, Larisa V. ; Noggle, T. ; Norman, B. ; Nurušev, Sandibek B. ; Nussbaum, T. ; Nystrand, Joakim Ingemar ; Odyniec, Grazyna Janina ; Ogawa, Akio ; Ogilvie, C. A. ; Olchanski, K. ; Oldenburg, Markus D. ; Olson, Douglas L. ; Ososkov, G. A. ; Ott, G. ; Padrazo, D. ; Paic, Guy ; Pandey, S. U. ; Panebratsev, Yuri ; Panitkin, Sergei Yurievich ; Pavlinov, Alexei I. ; Pawlak, Tomasz Jan ; Pentia, M. ; Perevotchikov, V. ; Peryt, Wiktor Stanislaw ; Petrov, V. A ; Pinganaud, W. ; Pirogov, S. ; Platner, E. ; Pluta, Jan Marian ; Polk, I. ; Porile, Norbert T. ; Porter, Jeffrey Brent ; Poskanzer, Arthur M. ; Potrebenikova, E. ; Prindle, Duncan J. ; Pruneau, Claude A. ; Puskar-Pasewicz, J. ; Rai, Gulshan ; Rasson, J. ; Ravel, Olivier ; Ray, Robert L. ; Razin, Sergej V. ; Reichhold, Dennis Michael ; Reid, J. ; Renfordt, Rainer Arno Ernst ; Retiere, Fabrice ; Ridiger, Alexey ; Riso, J. ; Ritter, Hans Georg ; Roberts, Jabus B. ; Röhrich, Dieter ; Rogachevski, O. V. ; Romero, Juan L. ; Roy, Christelle Sophie ; Russ, D. ; Rykov, Vladimir L. ; Sakrejda, Iwona ; Sanchez, R. ; Sandler, Z. ; Sandweiss, Jack H. ; Sappenfield, P. ; Saulys, A. C. ; Savin, Igor A. ; Schambach, Joachim ; Scharenberg, Rolf Paul ; Scheblien, J. ; Scheetz, R. ; Schlueter, R. ; Schmitz, Norbert ; Schroeder, Lee S. ; Schulz, M. ; Schüttauf, Andreas ; Sedlmeir, J. ; Seger, Janet Elizabeth ; Seliverstov, D. ; Seyboth, J. ; Seyboth, Peter ; Seymour, R. ; Shakaliev, E. I. ; Shestermanov, Konstantin E. ; Shi, Y. ; Šimanskij, Stepan S. ; Shuman, D. ; Shvetcov, V. S. ; Skoro, Goran P. ; Smirnov, N. ; Smykov, L. P. ; Snellings, Raimond ; Solberg, K. ; Sowinski, James ; Spinka, Harold. M. ; Srivastava, B. ; Stephenson, Edward J. ; Stock, Reinhard ; Stolpovsky, Alexander ; Stone, N. ; Stone, R. ; Strichanov, Michail Nikolaevič ; Stringfellow, Blair ; Stroebele, H. ; Struck, Christof ; Suaide, Alexandre Alarcon do Passo ; Sugarbaker, Evan R. ; Suire, Christophe Pierre ; Symons, Timothy James MacNeil ; Takahashi, Jun ; Tang, Aihong ; Tarchini, A. ; Tarzian, J. ; Thomas, James H. ; Tikhomirov, V. ; Toledo, Alejandro Szanto de ; Tonse, S. ; Trainor, Thomas A. ; Trentalange, Stephen ; Tokarev, Mikhail V. ; Tonjes, Marguerite Belt ; Trofimov, V. ; Tsai, Oleg D. ; Turner, K. ; Ullrich, Thomas ; Underwood, David G. ; Vakula, I. ; Van Buren, Gene ; VanderMolen, A. M. ; Vanyashin, A. ; Vasilevski, I. M. ; Vasiliev, Alexander Nikolaevich ; Vigdor, Steven E. ; Visser, G. ; Voloshin, Sergei ; Vu, C. ; Wang, F. ; Ward, H. ; Weerasundara, Dhammika D. ; Weidenbach, R. ; Wells, R. ; Wells, R. ; Wenaus, T. ; Westfall, Gary D. ; Whitfield, J. P. ; Whitten, Charles A. ; Wieman, Howard ; Willson, Robert ; Wilson, K. ; Wirth, Joana ; Wisdom, J. ; Wissink, Scott W. ; Witt, Richard ; Wolf, J. ; Wood, L. ; Xu, N. ; Xu, Z. ; Yakutin, A. E. ; Yamamoto, E. ; Yang, J. ; Yepes, Pablo P. ; Yokosawa, A. ; Yurevich, Vladimir Yurevich ; Zanevski, Y. V. ; Zhang, J. ; Zhang, W. M. ; Zhu, Jianhui ; Zimmerman, D. ; Zoulkarneev, R. ; Zubarev, A. N.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt(s_NN)=130 GeV using the STAR TPC at RHIC. The elliptic flow signal, v_2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Winter, Nils R. ; Blanke, Julian ; Leenings, Ramona ; Ernsting, Jan ; Fisch, Lukas ; Sarink, Kelvin ; Barkhau, Carlotta ; Thiel, Katharina ; Flinkenflügel, Kira ; Winter, Alexandra ; Goltermann, Janik ; Meinert, Susanne ; Dohm, Katharina ; Repple, Jonathan ; Gruber, Marius ; Leehr, Elisabeth Johanna ; Opel, Nils ; Grotegerd, Dominik ; Redlich, Ronny ; Nitsch, Robert ; Bauer, Jochen ; Heindel, Walter ; Groß, Joachim ; Andlauer, Till ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella ; Hofmann, Stefan G. ; Pfarr, Julia-Katharina ; Teutenberg, Lea ; Usemann, Paula ; Thomas-Odenthal, Florian ; Wroblewski, Adrian ; Brosch, Katharina ; Stein, Frederike ; Jansen, Andreas ; Jamalabadi, Hamidreza ; Alexander, Nina ; Straube, Benjamin ; Nenadić, Igor ; Kircher, Tilo ; Dannlowski, Udo ; Hahn, Tim
Background: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, Major Depressive Disorder (MDD), patients only marginally differ from healthy individuals on the group-level. Whether Precision Psychiatry can solve this discrepancy and provide specific, reliable biomarkers remains unclear as current Machine Learning (ML) studies suffer from shortcomings pertaining to methods and data, which lead to substantial over-as well as underestimation of true model accuracy.
Methods: Addressing these issues, we quantify classification accuracy on a single-subject level in N=1,801 patients with MDD and healthy controls employing an extensive multivariate approach across a comprehensive range of neuroimaging modalities in a well-curated cohort, including structural and functional Magnetic Resonance Imaging, Diffusion Tensor Imaging as well as a polygenic risk score for depression.
Findings Training and testing a total of 2.4 million ML models, we find accuracies for diagnostic classification between 48.1% and 62.0%. Multimodal data integration of all neuroimaging modalities does not improve model performance. Similarly, training ML models on individuals stratified based on age, sex, or remission status does not lead to better classification. Even under simulated conditions of perfect reliability, performance does not substantially improve. Importantly, model error analysis identifies symptom severity as one potential target for MDD subgroup identification.
Interpretation: Although multivariate neuroimaging markers increase predictive power compared to univariate analyses, single-subject classification – even under conditions of extensive, best-practice Machine Learning optimization in a large, harmonized sample of patients diagnosed using state-of-the-art clinical assessments – does not reach clinically relevant performance. Based on this evidence, we sketch a course of action for Precision Psychiatry and future MDD biomarker research.
Baumeister, Sarah ; Mößnang, Carolin Ulrike ; Bast, Nico ; Hohmann, Sarah ; Tillmann, Julian ; Goyard, David ; Charman, Tony ; Ambrosino, Sara ; Baron-Cohen, Simon ; Beckmann, Christian F. ; Bölte, Sven ; Bourgeron, Thomas ; Rausch, Annika ; Crawley, Daisy ; Dell'Acqua, Flavio ; Dumas, Guillaume ; Durston, Sarah ; Ecker, Christine ; Floris, Dorothea L. ; Frouin, Vincent ; Hayward, Hannah ; Holt, Rosemary ; Johnson, Mark H. ; Jones, Emily J. H. ; Lai, Meng-Chuan ; Lombardo, Michael V. ; Mason, Luke ; Oldehinkel, Marianne ; Persico, Tony ; San José Cáceres, Antonia ; Wolfers, Thomas ; Spooren, Willibrordus Philippus Johannes Maria ; Loth, Eva ; Murphy, Declan G. M. ; Buitelaar, Jan K. ; Tost, Heike ; Meyer-Lindenberg, Andreas ; Banaschewski, Tobias ; Brandeis, Daniel
Background Reward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Methods Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).
Results Across social and monetary reward anticipation, whole-brain analyses (p<0.05, family-wise error-corrected) showed hypoactivation of the right ventral striatum (VS) in ASD. Further, region of interest (ROI) analysis across both reward types yielded hypoactivation in ASD in both the left and right VS. Across delivery of social and monetary reward, hyperactivation of the VS in individuals with ASD did not survive correction for multiple comparisons. Reward type by diagnostic group interactions, and a dimensional analysis of autism trait scores were not significant during anticipation or delivery. Levels of attention-deficit/hyperactivity disorder (ADHD) symptoms did not affect reward processing in ASD.
Conclusions Our results do not support current theories linking atypical social interaction in ASD to specific alterations in processing of social rewards. Instead, they point towards a generalized hypoactivity of VS in ASD during anticipation of both social and monetary rewards. We suggest that this indicates attenuated subjective reward value in ASD independent of social content and ADHD symptoms.
Babiano Suarez, Victor ; Lerendegui-Marco, Jorge ; Balibrea Correa, Javier ; Caballero Ontanaya, Luis ; Calvo, David ; Ladarescu, Ion ; Domingo-Pardo, César ; Calviño Tavares, Francisco ; Casanovas Hoste, Adrià ; Tarifeño-Saldivia, Ariel ; Alcayne, Victor ; Guerrero Sánchez, Carlos ; Millán Callado, María de los Ángeles ; Rodrı́guez-González, María Teresa ; Barbagallo, Massimo ; Aberle, Oliver ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Busso, Maurizio ; Caamaño, Manuel ; Calviani, Marco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Cristallo, Sergio ; Damone, Lucia Anna ; Davies, Paul John ; Diakaki, Maria ; Dietz, Mirco ; Dressler, Rugard ; Ducasse, Quentin ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Gunsing, Frank ; Harada, Hideo ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Junghans, Arnd Rudolf ; Käppeler, Franz ; Kadi, Yacine ; Kimura, Atsushi ; Knapova, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Lederer-Woods, Claudia ; Leeb, Helmut ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Martinez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Piersanti, Luciano ; Petrone, Cristina ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Rauscher, Thomas ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tassan-Got, Laurent ; Thomas, Th. ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; Ulrich, Jiri ; Urlaß, Sebastian ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n,γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim both 197Au(n,γ) and 56Fe(n,γ) reactions were measured at CERN n\_TOF using an i-TED demonstrator based on only three position-sensitive detectors. Two \cds detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼3 higher detection sensitivity than state-of-the-art \cds detectors in the ∼10~keV neutron energy range of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques.
Waldvogel, Ann-Marie ; Wieser, Andreas ; Schell, Tilman ; Patel, Simit ; Schmidt, Hanno ; Hankeln, Thomas ; Feldmeyer, Barbara ; Pfenninger, Markus
The gradual heterogeneity of climatic factors pose varying selection pressures across geographic distances that leave signatures of clinal variation in the genome. Separating signatures of clinal adaptation from signatures of other evolutionary forces, such as demographic processes, genetic drift, and adaptation to non-clinal conditions of the immediate local environment is a major challenge. Here, we examine climate adaptation in five natural populations of the harlequin fly Chironomus riparius sampled along a climatic gradient across Europe. Our study integrates experimental data, individual genome resequencing, Pool-Seq data, and population genetic modelling. Common-garden experiments revealed a positive correlation of population growth rates corresponding to the population origin along the climate gradient, suggesting thermal adaptation on the phenotypic level. Based on a population genomic analysis, we derived empirical estimates of historical demography and migration. We used an FST outlier approach to infer positive selection across the climate gradient, in combination with an environmental association analysis. In total we identified 162 candidate genes as genomic basis of climate adaptation. Enriched functions among these candidate genes involved the apoptotic process and molecular response to heat, as well as functions identified in other studies of climate adaptation in other insects. Our results show that local climate conditions impose strong selection pressures and lead to genomic adaptation despite strong gene flow. Moreover, these results imply that selection to different climatic conditions seems to converge on a functional level, at least between different insect species.
Improved integration of single cell transcriptome data demonstrated on heart failure in mice and men
(2023)
Ruz Jurado, Mariano ; Tombor, Lukas ; Arsalan, Mani ; Holubec, Tomas ; Emrich, Fabian Christoph ; Walther, Thomas ; Zeiher, Andreas M. ; Schulz, Marcel Holger ; Dimmeler, Stefanie ; John, David
Biomedical research frequently uses murine models to study disease mechanisms. However, the translation of these findings to human disease remains a significant challenge. In order to improve the comparability of mouse and human data, we present a cross-species integration pipeline for single-cell transcriptomic assays.
The pipeline merges expression matrices and assigns clear orthologous relationships. Starting from Ensembl ortholog assignments, we allocated 82% of mouse genes to unique orthologs by using additional publicly available resources such as Uniprot, and NCBI databases. For genes with multiple matches, we employed the Needleman-Wunsch global alignment based on either amino acid or nucleotide sequence to identify the ortholog with the highest degree of similarity.
The workflow was tested for its functionality and efficiency by integrating scRNA-seq datasets from heart failure patients with the corresponding mouse model. We were able to assign unique human orthologs to up to 80% of the mouse genes, utilizing the known 17,492 orthologous pairs. Curiously, the integration process enabled the identification of both common and unique regulatory pathways between species in heart failure.
In conclusion, our pipeline streamlines the integration process, enhances gene nomenclature alignment and simplifies the translation of mouse models to human disease. We have made the OrthoIntegrate R-package accessible on GitHub (https://github.com/MarianoRuzJurado/OrthoIntegrate), which includes the assignment of ortholog definitions for human and mouse, as well as the pipeline for integrating single cells.
Kennedy, Eamonn ; Vadlamani, Shashank ; Lindsey, Hannah M. ; Lei, Pui-Wa ; Jo-Pugh, Mary ; Adamson, Maheen ; Alda, Martin ; Alonso-Lana, Silvia ; Ambrogi, Sonia ; Anderson, Tim J. ; Arango, Celso ; Asarnow, Robert F. ; Avram, Mihai ; Ayesa-Arriola, Rosa ; Babikian, Talin ; Banaj, Nerisa ; Bird, Laura J. ; Borgwardt, Stefan ; Brodtmann, Amy ; Brosch, Katharina ; Caeyenberghs, Karen ; Calhoun, Vince D. ; Chiaravalloti, Nancy D. ; Cifu, David X. ; Crespo-Facorro, Benedicto ; Dalrymple-Alford, John C. ; Dams-O’Connor, Kristen ; Dannlowski, Udo ; Darby, David ; Davenport, Nicholas ; DeLuca, John ; Díaz-Caneja, Covadonga M. ; Disner, Seth G. ; Dobryakova, Ekaterina ; Ehrlich, Stefan ; Esopenko, Carrie ; Ferrarelli, Fabio ; Frank, Lea E. ; Franz, Carol ; Fuentes-Claramonte, Paola ; Genova, Helen ; Giza, Christopher C. ; Goltermann, Janik ; Grotegerd, Dominik ; Gruber, Marius ; Gutiérrez-Zotes, Alfonso ; Ha, Minji ; Haavik, Jan ; Hinkin, Charles ; Hoskinson, Kristen R. ; Hubl, Daniela ; Irimia, Andrei ; Jansen, Andreas ; Kaess, Michael ; Kang, Xiaojian ; Kenney, Kimbra ; Keřková, Barbora ; Khlif, Mohamed Salah ; Kim, Minah ; Kindler, Jochen ; Kircher, Tilo ; Knı́žková, Karolina ; Kolskår, Knut K. ; Krch, Denise ; Kremen, William S. ; Kuhn, Taylor ; Kumari, Veena ; Kwon, Jun Soo ; Langella, Roberto ; Laskowitz, Sarah ; Lee, Jungha ; Lengenfelder, Jean ; Liebel, Spencer W. ; Liou-Johnson, Victoria ; Lippa, Sara M. ; Løvstad, Marianne ; Lundervold, Astri ; Marotta, Cassandra ; Marquardt, Craig A. ; Mattos, Paulo ; Mayeli, Ahmad ; McDonald, Carrie R. ; Meinert, Susanne ; Melzer, Tracy R. ; Merchán Naranjo, Jessica ; Michel, Chantal ; Morey, Rajendra A. ; Mwangi, Benson ; Myall, Daniel J. ; Nenadić, Igor ; Newsome, Mary R. ; Nunes, Abraham ; O’Brien, Terence J. ; Oertel, Viola ; Ollinger, John ; Olsen, Alexander ; Ortiz Garcı́a de la Foz, Victor ; Ozmen, Mustafa ; Pardoe, Heath ; Parent, Marise ; Piras, Fabrizio ; Piras, Federica ; Pomarol-Clotet, Edith ; Repple, Jonathan ; Richard, Geneviève ; Rodriguez, Jonathan ; Rodriguez, Mabel ; Rootes-Murdy, Kelly ; Rowland, Jared ; Ryan, Nicholas P. ; Salvador, Raymond ; Sanders, Anne-Marthe ; Schmidt, André ; Soares, Jair C. ; Spalleta, Gianfranco ; Španiel, Filip ; Stasenko, Alena ; Stein, Frederike ; Straube, Benjamin ; Thames, April ; Thomas-Odenthal, Florian ; Thomopoulos, Sophia I. ; Tone, Erin ; Torres, Ivan ; Troyanskaya, Maya ; Turner, Jessica A. ; Ulrichsen, Kristine M. ; Umpierrez, Guillermo ; Vilella, Elisabet ; Vivash, Lucy ; Walker, William C. ; Werden, Emilio ; Westlye, Lars T. ; Wild, Krista ; Wroblewski, Adrian ; Wu, Mon-Ju ; Wylie, Glenn R. ; Yatham, Lakshmi N. ; Zunta-Soares, Giovana B. ; Thompson, Paul M. ; Tate, David F. ; Hillary, Frank G. ; Dennis, Emily L. ; Wilde, Elisabeth A.
Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences.
Wilhelm, Alexander ; Schoth, Jens ; Meinert-Berning, Christina ; Bastian, Daniel ; Ciesek, Sandra ; Teichgräber, Burkhard ; Wintgens, Thomas ; Weber, Frank-Andreas ; Widera, Marek
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
Tesch, Roberta ; Rak, Marcel ; Raab, Monika ; Berger, Lena Marie ; Kronenberger, Thales ; Jörger, Andreas C. ; Berger, Benedict-Tilman ; Abdi, Ismahan ; Hanke, Thomas ; Poso, Antti ; Strebhardt, Klaus ; Sanhaji, Mourad ; Knapp, Stefan
Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.