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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.