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- Biodiversität und Klima Forschungszentrum (BiK-F) (2)
- Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES) (2)
Leong, Lou Sai ; Tassan-Got, Laurent ; Tarrío Vilas, Diego ; Audouin, Laurent ; Paradela Dobarro, Carlos ; Durán, Ignacio ; Le Naour, Claire ; Altstadt, Sebastian ; Andrzejewsky, Jozef ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Jenkins, David ; Jericha, Erwin ; Kadi, E. ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Korschinek, Gunther ; Kroll, Jiří ; Krtička, Milan ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Massimi, Cristian ; Martı́nez, Trinitario ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mengon, A. ; Mendoza Cembranos, Emilio ; Milazzo, Paolo Maria ; Mingrone, T. ; Mirea, Mihail ; Mondelaers, Willy ; Pavlik, Andreas ; Perkowski, Jarosław ; Pignatari, Marco ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifhart, R. ; Riego Pérez, Albert ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sarmento, Raul ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Taı́n Enríquez, Jose Luis ; Tagliente, Giuseppe ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, V. ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
Above 1 MeV of incident neutron energy the fission fragment angular distribution (FFAD) has generally a strong anisotropic behavior due to the combination of the incident orbital momentum and the intrinsic spin of the fissioning nucleus. This effect has to be taken into account for the efficiency estimation of devices used for fission cross section measurements. In addition it bears information on the spin deposition mechanism and on the structure of transitional states. We designed and constructed a detection device, based on Parallel Plate Avalanche Counters (PPAC), for measuring the fission fragment angular distributions of several isotopes, in particular 232Th. The measurement has been performed at n_TOF at CERN taking advantage of the very broad energy spectrum of the neutron beam. Fission events were recognized by back to back detection in coincidence in two position-sensitive detectors surrounding the targets. The detection efficiency, depending mostly on the stopping of fission fragments in backings and electrodes, has been computed with a Geant4 simulation and validated by the comparison to the measured case of 235U below 3 keV where the emission is isotropic. In the case of 232Th, the result is in good agreement with previous data below 10 MeV, with a good reproduction of the structures associated to vibrational states and the opening of second chance fission. In the 14 MeV region our data are much more accurate than previous ones which are broadly scattered.
Seiro, Silvia ; Jiao, Lin ; Kirchner, Stefan ; Hartmann, Stefanie ; Friedemann, Sven ; Krellner, Cornelius ; Geibel, Christoph ; Si, Qimiao ; Steglich, Frank ; Wirth, Steffen
Strong electron correlations can give rise to extraordinary properties of metals with renormalized Landau quasiparticles. Near a quantum critical point, these quasiparticles can be destroyed and non-Fermi liquid behavior ensues. YbRh2Si2 is a prototypical correlated metal exhibiting the formation of quasiparticle and Kondo lattice coherence, as well as quasiparticle destruction at a field-induced quantum critical point. Here we show how, upon lowering the temperature, Kondo lattice coherence develops at zero field and finally gives way to non-Fermi liquid electronic excitations. By measuring the single-particle excitations through scanning tunneling spectroscopy, we find the Kondo lattice peak displays a non-trivial temperature dependence with a strong increase around 3.3 K. At 0.3 K and with applied magnetic field, the width of this peak is minimized in the quantum critical regime. Our results demonstrate that the lattice Kondo correlations have to be sufficiently developed before quantum criticality can set in.
Gu, Wenyi ; Hortlik, Hannah ; Erasmus, Hans-Peter ; Schaaf, Louisa ; Zeleke, Yasmin ; Uschner, Frank Erhard ; Ferstl, Philip ; Schulz, Martin ; Peiffer, Kai-Henrik ; Queck, Alexander David Roger ; Sauerbruch, Tilman ; Brol, Maximilian ; Rohde, Gernot Gerhard Ulrich ; Sanchez, Cristina ; Moreau, Richard ; Arroyo, Vicente ; Zeuzem, Stefan ; Welsch, Christoph ; Trebicka, Jonel
Background: Cirrhosis is known to have a high prevalence and mortality worldwide. However, in Europe, the epidemiology of cirrhosis is possibly undergoing demographic changes, and etiologies may have changed due to improvements in standard of care. The aim of this population-based study was to analyze the trends and the course of liver cirrhosis and its complications in recent years in Germany.
Methods: We analyzed the data of all hospital admissions in Germany within diagnosis-related groups from 2005 to 2018. The diagnostic records of cirrhosis and other categories of diseases were based on ICD-10-GM codes. The primary outcome measurement was in-hospital mortality. Trends were analyzed through Poisson regression of annual number of admissions. The impact of cirrhosis on overall in-hospital mortality were assessed through the multivariate multilevel logistic regression model adjusted for age, sex, and comorbidities.
Findings: Of the 248,085,936 admissions recorded between 2005 and 2018, a total of 2,302,171(0•94%) were admitted with the diagnosis of cirrhosis, mainly as a comorbidity. Compared with other chronic diseases, patients admitted with cirrhosis were younger, mainly male and had the highest in-hospital mortality rate. Diagnosis of cirrhosis was an independent risk factor of in-hospital mortality with the highest odds ratio (OR:6•2[95%CI:6.1-6•3]) among all diagnoses. The prevalence of non-alcoholic fatty liver disease has increased four times from 2005 to 2018, while alcoholic cirrhosis is 20 times than other etiologies. Bleeding was found to be decreasing over time, but ascites remained the most common complication and was increasing.
Interpretation: This nationwide study demonstrates that cirrhosis represents a considerable healthcare burden, as shown by the increasing in-hospital mortality, also in combination with other chronic diseases. Alcohol-related cirrhosis and complications are on the rise. More resources and better management strategies are warranted.
Objective: To study the effect of total hip replacement (THR) on serum cartilage oligomeric matrix protein concentration (sCOMP) and its correlation with joint loading during gait in patients with unilateral hip osteoarthritis.
Design: In this prospective multimodal (clinical, biomechanical, biochemical) study blood samples from 15 patients were taken before and up to three times after THR (7 days, 3 months and 1 year), each after a resting period of at least 30 min, for analysis of sCOMP. Gait analysis was performed before and 1 year after THR to determine hip and knee joint moments.
Results: Seven days after THR, sCOMP decreased significantly compared to the preoperative measurement (p < 0.001). Three months and 1 year postoperatively, sCOMP reverted to concentrations in the range of the preoperative value. One year postoperatively, a linear correlation between sCOMP and the maximum hip flexion moment was indicated in the first half of the stance phase on the unaffected side (r = −0.736, p = 0.024). No further correlations could be determined.
Conclusions: Surprisingly, the removal of a joint affected by osteoarthritis did not have a sustained effect on sCOMP. Both before and after THR there was no scientifically substantiated correlation between sCOMP and joint moments from gait analysis. Consequently, the examination of sCOMP is not useful to detect altered joint loads that may influence degenerative changes of adjacent joints after THR.
The registration number in the German Registry of Clinical Trials is DRKS00015053.
Kron, Anna ; Alidousty, Christina ; Scheffler, Matthias ; Merkelbach-Bruse, Sabine ; Seidel, Danila ; Riedel, Richard ; Ihle, Michaela A. ; Michels, Sebastian Yves Friedrich ; Nogova, Lucia ; Fassunke, Jana ; Heydt, Carina ; Kron, Florian ; Ueckeroth, Frank ; Serke, Monika ; Krüger, Stefan ; Grohé, Christian ; Koschel, Dirk ; Benedikter, Josef ; Kaminsky, Britta ; Schaaf, Bernhard ; Braess, Jan ; Sebastian, Martin ; Kambartel, Karl-Otto ; Thomas, Roman ; Zander, Thomas ; Schultheis, Anne Maria ; Büttner, Reinhard ; Wolf, Jürgen
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Kleineberg, Nina Natascha ; Knauss, Samuel ; Gülke, Eileen ; Pinnschmidt, Hans O. ; Jakob, Carolin Ellen Marianne ; Lingor, Paul ; Hellwig, Kerstin ; Berthele, Achim ; Höglinger, Günter ; Fink, Gereon R. ; Endres, Matthias ; Gerloff, Christian ; Klein, Christine ; Stecher, Melanie ; Claßen, Annika ; Rieg, Siegbert ; Borgmann, Stefan ; Hanses, Frank ; Rüthrich, Maria Madeleine ; Hower, Martin ; Tometten, Lukas ; Haselberger, Martina Maria ; Piepel, Christiane ; Merle, Uta ; Dolff, Sebastian Conrad Johannes ; Degenhardt, Christian ; Jensen, Björn-Erik Ole ; Vehreschild, Maria J. G. T. ; Erber, Johanna ; Franke, Christiana ; Warnke, Clemens
Background and purpose: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. Methods: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. Results: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20–1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07–1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. Conclusion: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.
Waidmann, Oliver ; Pleli, Thomas ; Weigert, Andreas ; Imelmann, Esther ; Kakoschky, Bianca ; Schmithals, Jens Christian Johannes ; Döring, Claudia ; Frank, Matthias ; Longerich, Thomas ; Köberle, Verena ; Hansmann, Martin-Leo ; Brüne, Bernhard ; Zeuzem, Stefan ; Piiper, Albrecht ; Đikić, Ivan
The nuclear factor kappa beta (NFκB) signaling pathway plays an important role in liver homeostasis and cancer development. Tax1-binding protein 1 (Tax1BP1) is a regulator of the NFκB signaling pathway, but its role in the liver and hepatocellular carcinoma (HCC) is presently unknown. Here we investigated the role of Tax1BP1 in liver cells and murine models of HCC and liver fibrosis. We applied the diethylnitrosamine (DEN) model of experimental hepatocarcinogenesis in Tax1BP1+/+ and Tax1BP1−/− mice. The amount and subsets of non-parenchymal liver cells in in Tax1BP1+/+ and Tax1BP1−/− mice were determined and activation of NFκB and stress induced signaling pathways were assessed. Differential expression of mRNA and miRNA was determined. Tax1BP1−/− mice showed increased numbers of inflammatory cells in the liver. Furthermore, a sustained activation of the NFκB signaling pathway was found in hepatocytes as well as increased transcription of proinflammatory cytokines in isolated Kupffer cells from Tax1BP1−/− mice. Several differentially expressed mRNAs and miRNAs in livers of Tax1BP1−/− mice were found, which are regulators of inflammation or are involved in cancer development or progression. Furthermore, Tax1BP1−/− mice developed more HCCs than their Tax1BP1+/+ littermates. We conclude that Tax1BP1 protects from liver cancer development by limiting proinflammatory signaling.
Die Asiatische Keiljungfer (Gomphus flavipes) und die Grüne Flussjungfer (Ophiogomphus cecilia) sind Fließgewässer bewohnende Libellenarten mit hoher Naturschutzrelevanz. Beide Arten sind in ihrem Vorkommen sowohl in Sachsen-Anhalt als auch deutschlandweit gefährdet. Nach fast vollständigem Erlöschen der Populationen von G. flavipes in Mitteleuropa vor 70 Jahren wird in Sachsen-Anhalt seit Anfang der 1990er Jahre die Elbe von dieser Art wiederbesiedelt, vermutlich aufgrund der gestiegenen Wasserqualität. Bei O. cecilia liegen keine ausreichend belastbaren historischen Daten vor, wahrscheinlich ist die Situation bei dieser Art jedoch ähnlich. Es wird vermutet, dass beide Arten mittlerweile die Mittlere Elbe wieder weitgehend vollständig besiedeln. Das Elbegebiet besitzt daher europaweite Bedeutung als Reservoir für den Erhalt der beiden Arten.
Kozina, Andrijana ; Opresnik, Stefan ; Wong, Michael Sze Ka ; Hallström, Seth ; Graier, Wolfgang F. ; Malli, Roland ; Schröder, Katrin ; Schmidt, Kurt ; Frank, Saša
Previously we reported modulation of endothelial prostacyclin and interleukin-8 production, cyclooxygenase-2 expression and vasorelaxation by oleoyl-lysophosphatidylcholine (LPC 18:1). In the present study, we examined the impact of this LPC on nitric oxide (NO) bioavailability in vascular endothelial EA.hy926 cells. Basal NO formation in these cells was decreased by LPC 18:1. This was accompanied with a partial disruption of the active endothelial nitric oxide synthase (eNOS)-dimer, leading to eNOS uncoupling and increased formation of reactive oxygen species (ROS). The LPC 18:1-induced ROS formation was attenuated by the superoxide scavenger Tiron, as well as by the pharmacological inhibitors of eNOS, NADPH oxidases, flavin-containing enzymes and superoxide dismutase (SOD). Intracellular ROS-formation was most prominent in mitochondria, less pronounced in cytosol and undetectable in endoplasmic reticulum. Importantly, Tiron completely prevented the LPC 18:1-induced decrease in NO bioavailability in EA.hy926 cells. The importance of the discovered findings for more in vivo like situations was analyzed by organ bath experiments in mouse aortic rings. LPC 18:1 attenuated the acetylcholine-induced, endothelium dependent vasorelaxation and massively decreased NO bioavailability. We conclude that LPC 18:1 induces eNOS uncoupling and unspecific superoxide production. This results in NO scavenging by ROS, a limited endothelial NO bioavailability and impaired vascular function.
The soluble loop BC region guides, but not dictates, the assembly of the transmembrane cytochrome b6
(2017)
Studying folding and assembly of naturally occurring α-helical transmembrane proteins can inspire the design of membrane proteins with defined functions. Thus far, most studies have focused on the role of membrane-integrated protein regions. However, to fully understand folding pathways and stabilization of α–helical membrane proteins, it is vital to also include the role of soluble loops. We have analyzed the impact of interhelical loops on folding, assembly and stability of the heme-containing four-helix bundle transmembrane protein cytochrome b6 that is involved in charge transfer across biomembranes. Cytochrome b6 consists of two transmembrane helical hairpins that sandwich two heme molecules. Our analyses strongly suggest that the loop connecting the helical hairpins is not crucial for positioning the two protein “halves” for proper folding and assembly of the holo-protein. Furthermore, proteolytic removal of any of the remaining two loops, which connect the two transmembrane helices of a hairpin structure, appears to also not crucially effect folding and assembly. Overall, the transmembrane four-helix bundle appears to be mainly stabilized via interhelical interactions in the transmembrane regions, while the soluble loop regions guide assembly and stabilize the holo-protein. The results of this study might steer future strategies aiming at designing heme-binding four-helix bundle structures, involved in transmembrane charge transfer reactions.
Žugec, Petar ; Colonna, Nicola ; Bosnar, Damir ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lo Meo, Sergio ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The neutron sensitivity of the C6D6 detector setup used at n_TOF facility for capture measurements has been studied by means of detailed GEANT4 simulations. A realistic software replica of the entire n_TOF experimental hall, including the neutron beam line, sample, detector supports and the walls of the experimental area has been implemented in the simulations. The simulations have been analyzed in the same manner as experimental data, in particular by applying the Pulse Height Weighting Technique. The simulations have been validated against a measurement of the neutron background performed with a natC sample, showing an excellent agreement above 1 keV. At lower energies, an additional component in the measured natC yield has been discovered, which prevents the use of natC data for neutron background estimates at neutron energies below a few hundred eV. The origin and time structure of the neutron background have been derived from the simulations. Examples of the neutron background for two different samples are demonstrating the important role of accurate simulations of the neutron background in capture cross-section measurements.
Žugec, Petar ; Barbagallo, Massimo ; Colonna, Nicola ; Bosnar, Damir ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lo Meo, Sergio ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Pignatari, Marco ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riegov, A. ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The neutron capture cross section of 58Ni was measured at the neutron time of flight facility n_TOF at CERN, from 27 meV to 400 keV neutron energy. Special care has been taken to identify all the possible sources of background, with the so-called neutron background obtained for the first time using high-precision GEANT4 simulations. The energy range up to 122 keV was treated as the resolved resonance region, where 51 resonances were identified and analyzed by a multilevel R-matrix code SAMMY. Above 122 keV the code SESH was used in analyzing the unresolved resonance region of the capture yield. Maxwellian averaged cross sections were calculated in the temperature range of kT = 5 – 100 keV, and their astrophysical implications were investigated.
Stenner, Frank ; Liewen, Heike ; Göttig, Stephan ; Henschler, Reinhard ; Markuly, Norbert ; Kleber, Sascha ; Faust, Michael ; Mischo, Axel ; Bauer, Stefan ; Zweifel, Martin ; Knuth, Alexander ; Renner, Christoph ; Wadle, Andreas
RP1 (synonym: MAPRE2, EB2) is a member of the microtubule binding EB1 protein family, which interacts with APC, a key regulatory molecule in the Wnt signalling pathway. While the other EB1 proteins are well characterized the cellular function and regulation of RP1 remain speculative to date. However, recently RP1 has been implicated in pancreatic cancerogenesis. CK2 is a pleiotropic kinase involved in adhesion, proliferation and anti-apoptosis. Overexpression of protein kinase CK2 is a hallmark of many cancers and supports the malignant phenotype of tumor cells. In this study we investigate the interaction of protein kinase CK2 with RP1 and demonstrate that CK2 phosphorylates RP1 at Ser236 in vitro. Stable RP1 expression in cell lines leads to a significant cleavage and down-regulation of N-cadherin and impaired adhesion. Cells expressing a Phospho-mimicking point mutant RP1-ASP236 show a marked decrease of adhesion to endothelial cells under shear stress. Inversely, we found that the cells under shear stress downregulate endogenous RP1, most likely to improve cellular adhesion. Accordingly, when RP1 expression is suppressed by shRNA, cells lacking RP1 display significantly increased cell adherence to surfaces. In summary, RP1 phosphorylation at Ser236 by CK2 seems to play a significant role in cell adhesion and might initiate new insights in the CK2 and EB1 family protein association.
Mazzone, Annamaria ; Cristallo, Sergio ; Aberle, Oliver ; Alaerts, Gery ; Alcayne, Victor ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Babiano Suarez, Victor ; Bacak, Michael ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Bellia, Giorgio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam S. ; Busso, Maurizio ; Caamaño, Manuel ; Caballero Ontanaya, Luis ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Casanovas Hoste, Adrià ; Castelluccio, Donato Maurizio ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Clai, Giulia ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Diakaki, Maria ; Dietz, Mirco ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Gonçalves, Isabel Maria Ferro ; Finocchiaro, Paolo ; Furman, Valter ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Glodariu, Tudor ; Göbel, Kathrin ; González Romero, Enrique Miguel ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Kimura, Atsushi ; Kivel, Nikolay ; Kokkoris, Michael ; Kopatch, Yuri N. ; Kopecky, Stefan ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Ladarescu, Ion ; Lederer-Woods, Claudia ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah-Jane ; Macina, Daniela ; Manna, Alice ; Martínez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Maugeri, Emilio Andrea ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mucciola, Riccardo ; Musumarra, Agatino ; Negret, Alexandru ; Nolte, Ralf ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Piersanti, Luciano ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Radeck, Désirée ; Ramos Doval, Diego ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Talip, Zeynep ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; 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 ; Wynants, Ruud ; Wright, Tobias J. ; Žugec, Petar
The neutron capture cross section of 154Gd was measured from 1 eV to 300 keV in the experimental area located 185 m from the CERN n_TOF neutron spallation source, using a metallic sample of gadolinium, enriched to 67% in 154Gd. The capture measurement, performed with four C6D6 scintillation detectors, has been complemented by a transmission measurement performed at the GELINA time-of-flight facility (JRC-Geel), thus minimising the uncertainty related to sample composition. An accurate Maxwellian averaged capture cross section (MACS) was deduced over the temperature range of interest for s process nucleosynthesis modelling. We report a value of 880(50) mb for the MACS at kT = 30 keV, significantly lower compared to values available in literature. The new adopted 154Gd(n,γ) cross section reduces the discrepancy between observed and calculated solar s-only isotopic abundances predicted by s-process nucleosynthesis models.
Einleitung: Für angehende Ärztinnen und Ärzte sind gründliche biochemische Kenntnisse von großer Bedeutung für das Verständnis molekularer Mechanismen, physiologischer Abläufe und pathologischer Entwicklungen. Entsprechend nimmt die biochemische Lehre im vorklinischen Abschnitt des Medizinstudiums viel Zeit in Anspruch. Zugleich ist aber die Biochemie bei den Studienanfängern ein ungeliebtes Fach: Die Stofffülle, die Komplexität molekularer Prozesse, das geforderte hohe Abstraktionsniveau und die oft unzureichenden schulischen Vorkenntnisse führen bei vielen Erstsemestern zu tiefer Abneigung gegenüber der molekularen Medizin. Um diesem Problem zu begegnen, bieten wir den Medizinstudierenden der Johann Wolfgang Goethe-Universität als vorklinisches Wahlfach eine neuartige Lehrveranstaltung an, die multimedial-biografische Vorträge mit biochemischem Unterricht kombiniert.
Methodik: Das Institut für Biochemie am FB Medizin führt eine propädeutische Lehrveranstaltung durch, in der Biografien bekannter Persönlichkeiten ebenso wie die korrespondierenden Krankheiten vorgestellt werden. Konzipiert als Wahlpflichtfach bietet diese multimediale Lehrveranstaltung (Titel: "Leben und Leiden berühmter Persönlichkeiten. Eine Einführung in die molekulare Medizin") den 40 teilnehmenden Studierenden in zehn wöchentlichen Doppelsitzungen pro Studienjahr einen breitgefächerten Lernstoff mit drei Lernzielen:
1. Im ersten Teil (45 Min.) jeder Doppelsitzung werden Leben, Leiden und Werk berühmter Persöhnlichkeiten aus Literatur, Musik, Politik, Kunst, Sport und Wissenschaft vorgestellt, die an einer bekannten Krankheit litten bzw. leiden. Unterstützt wird dieser biografische Vortrag in der Regel durch multimediale Einspielungen kurzer Video-Clips oder Musikstücke.
2. Im zweiten Teil (75 Min.) werden die molekularmedizinischen Hintergründe dieser Erkrankungen in einem biochemischen Vortrag vermittelt.
3. Dieser Vortrag wird durch Kurzreferate (jeweils 5 min.) der Studierenden zu grundlegenden biochemischen Strukturen und Prozessen ergänzt.
Unter den regelmäßig angebotenen Doppel-Themen sind: der Rockmusiker Freddy Mercury (AIDS), der Schriftsteller Ernest Hemingway (Alkoholismus), der Rock ´n Roll-Sänger Elvis Presley (Diabetes), der Komponist Ludwig van Beethoven (Morbus Crohn), der Boxer Muhammad Ali (Morbus Parkinson), der Rockmusiker Frank Zappa (Krebs).
Ergebnisse: Die Vortragsreihe wurde seit 2005 zum vierten Mal durchgeführt. Die Evaluation durch die Teilnehmer mittels Fragebogen ergab durchweg eine gute bis sehr gute Gesamtbewertung. Der Lernerfolg für die biochemischen Grundlagen wurde hoch eingeschätzt. Die multimedial präsentierten Biografien wurden als sinnvolle Ergänzung zu den molekularmedizinischen Themen empfunden.
Schlussfolgerung: Das studentische Feed-back bestätigt die Vermutung, dass diese spezifische Kombination die Attraktivität und Akzeptanz von Biochemie und Molekularbiologie bei den Studienanfängern erheblich steigert.
Schierwagen, Robert ; Uschner, Frank Erhard ; Ortiz, Cristina ; Torres Núñez, Sandra ; Brol, Maximilian ; Tyc, Olaf ; Gu, Wenyi ; Grimm, Christian ; Zeuzem, Stefan ; Plamper, Andreas ; Pfeifer, Philipp ; Zimmer, Sebastian ; Welsch, Christoph ; Schäfer, Liliana ; Rheinwalt, Karl P. ; Clària, Joan ; Arroyo, Vicente ; Trebicka, Jonel ; Klein, Sabine
The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Le Clerc, Sigrid ; Lombardi, Laura ; Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Hou, Liping ; Clark, Scott R. ; Papiol, Sergi ; Cearns, Micah ; Heilbronner, Urs ; Degenhardt, Franziska ; Tekola-Ayele, Fasil ; Hsu, Yi-Hsiang ; Shekhtman, Tatyana ; Adli, Mazda ; Akula, Nirmala ; Akiyama, Kazufumi ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Bhattacharjee, Abesh Kumar ; Bellivier, Frank ; Benabarre, Antonio ; Bengesser, Susanne ; Biernacka, Joanna ; Birner, Armin ; Brichant-Petitjean, Clara ; Cervantes, Pablo ; Chen, Hsi-Chung ; Chillotti, Caterina ; Cichon, Sven ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dalkner, Nina ; Dayer, Alexandre ; Baune, Bernhard T. ; Del Zompo, Maria ; DePaulo, J. Raymond ; Étain, Bruno ; Jamain, Stephane ; Falkai, Peter ; Forstner, Andreas Josef ; Frisen, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grigoroiu-Serbanescu, Maria ; Grof, Paul ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kuo, Po-Hsiu ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Ferensztajn-Rochowiak, Ewa ; König, Barbara ; Kusumi, Ichiro ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leckband, Susan G. ; Tortorella, Alfonso ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan ; Colom, Francesc ; Millischer, Vincent ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; O'Donovan, Claire ; Ozaki, Norio ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Reif, Andreas ; Reininghaus, Eva ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schweizer, Barbara W. ; Severino, Giovanni ; Shilling, Paul D. ; Shimoda, Katzutaka ; Simhandl, Christian ; Slaney, Claire M. ; Pisanu, Claudia ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Maj, Mario ; Turecki, Gustavo ; Vieta, Eduard ; Veeh, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Mitchell, Philip B. ; Bauer, Michael ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas Gerd ; Spadoni, Jean-Louis ; Boukouaci, Wahid ; Richard, Jean-Romain ; Le Corvoisier, Philippe ; Barrau, Caroline ; Zagury, Jean-François ; Leboyer, Marion ; Tamouza, Ryad
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Altınçekiç, Nadide ; Korn, Sophie Marianne ; Qureshi, Nusrat Shahin ; Dujardin, Marie ; Ninot-Pedrosa, Martí ; Abele, Rupert ; Abi Saad, Marie Jose ; Alfano, Caterina ; Almeida, Fabio C. L. ; Alshamleh, Islam ; Amorim, Gisele Cardoso de ; Anderson, Thomas K. ; Anobom, Cristiane D. ; Anorma, Chelsea ; Bains, Jasleen Kaur ; Bax, Adriaan ; Blackledge, Martin ; Blechar, Julius ; Böckmann, Anja ; Brigandat, Louis ; Bula, Anna ; Bütikofer, Matthias ; Camacho-Zarco, Aldo R. ; Carlomagno, Teresa ; Caruso, Icaro Putinhon ; Ceylan, Betül ; Chaikuad, Apirat ; Chu, Feixia ; Cole, Laura ; Crosby, Marquise G. ; De Jesus, Vanessa ; Dhamotharan, Karthikeyan ; Felli, Isabella C. ; Ferner, Jan ; Fleischmann, Yanick ; Fogeron, Marie-Laure ; Fourkiotis, Nikolaos K. ; Fuks, Christin ; Fürtig, Boris ; Gallo, Angelo ; Gande, Santosh L. ; Gerez, Juan Atilio ; Ghosh, Dhiman ; Gomes-Neto, Francisco ; Gorbatyuk, Oksana ; Guseva, Serafima ; Hacker, Carolin ; Häfner, Sabine ; Hao, Bing ; Hargittay, Bruno ; Henzler-Wildman, Katherine ; Hoch, Jeffrey C. ; Hohmann, Katharina Felicitas ; Hutchison, Marie T. ; Jaudzems, Kristaps ; Jović, Katarina ; Kaderli, Janina ; Kalnins, Gints ; Kanepe, Iveta ; Kirchdoerfer, Robert N. ; Kirkpatrick, John ; Knapp, Stefan ; Krishnathas, Robin ; Kutz, Felicitas ; Zur Lage, Susanne ; Lambertz, Roderick ; Lang, Andras ; Laurents, Douglas ; Lecoq, Lauriane ; Linhard, Verena ; Löhr, Frank ; Malki, Anas ; Bessa, Luiza Mamigonian ; Martin, Rachel W. ; Matzel, Tobias ; Maurin, Damien ; McNutt, Seth W. ; Mebus-Antunes, Nathane Cunha ; Meier, Beat H. ; Meiser, Nathalie ; Mompeán, Miguel ; Monaca, Elisa ; Montserret, Roland ; Perez, Laura Mariño ; Moser, Celine ; Muhle-Goll, Claudia ; Neves-Martins, Thais Cristtina ; Ni, Xiamonin ; Norton-Baker, Brenna ; Pierattelli, Roberta ; Pontoriero, Letizia ; Pustovalova, Yulia ; Ohlenschläger, Oliver ; Orts, Julien ; Poian, Andrea T. da ; Pyper, Dennis Joshua ; Richter, Christian ; Riek, Roland ; Rienstra, Chad M. ; Robertson, Angus ; Pinheiro, Anderson S. ; Sabbatella, Raffaele ; Salvi, Nicola ; Saxena, Krishna ; Schulte, Linda ; Schiavina, Marco ; Schwalbe, Harald ; Silber, Mara ; Almeida, Marcius da Silva ; Sprague-Piercy, Marc A. ; Spyroulias, Georgios A. ; Sreeramulu, Sridhar ; Tants, Jan-Niklas ; Tars, Kaspars ; Torres, Felix ; Töws, Sabrina ; Trevino, Miguel A. ; Trucks, Sven ; Tsika, Aikaterini C. ; Varga, Krisztina ; Wang, Ying ; Weber, Marco E. ; Weigand, Julia E. ; Wiedemann, Christoph ; Wirmer-Bartoschek, Julia ; Wirtz Martin, Maria Alexandra ; Zehnder, Johannes ; Hengesbach, Martin ; Schlundt, Andreas
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.