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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.
Bacak, Michael ; Aïche, Mourad ; Bélier, Gilbert ; Berthoumieux, Eric ; Diakaki, Maria ; Dupont, Emmeric ; Gunsing, Frank ; Heyse, Jan ; Kopecky, Stefan ; Krtička, Milan ; Laurent, Benoit ; Leeb, Helmut ; Mathieu, Ludovic ; Schillebeeckx, Peter ; Serot, Olivier ; Taieb, Julien ; Valenta, Stanislav ; Vlachoudis, Vasilis ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Bečvář, František ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Gawlik, Aleksandra ; Gilardoni, Simone ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Harada, Hideo ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Kalamara, Antigoni ; Kavrigin, Pavel ; Kimura, Atsushi ; Kivel, Nikolay ; Knapová, Ingrid ; Kokkoris, Michael ; Kurtulgil, Cem Deniz ; Leal Cidoncha, Esther ; Lederer, Claudia ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Marganiec, Justyna ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Musumarra, Agatino ; Negret, Alexandru ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Radeck, Désirée ; Rauscher, Thomas ; Reifarth, René ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weiß, Christina ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
233U is the fissile nuclei in the Th-U fuel cycle with a particularily small neutron capture cross setion which is on average about one order of magnitude lower than its fission cross section. Hence, the measurement of the 233U(n, γ) cross section relies on a method to accurately distinguish between capture and fission γ-rays. A measurement of the 233U α-ratio has been performed at the n_TOF facility at CERN using a so-called fission tagging setup, coupling n_TOF 's Total Absorption Calorimeter with a novel fission chamber to tag the fission γ-rays. The experimental setup is described and essential parts of the analysis are discussed. Finally, a preliminary 233U α-ratio is presented.
Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.
Gliflozins are inhibitors of the renal proximal tubular sodium-glucose co-transporter-2 (SGLT-2), that inhibit reabsorption of urinary glucose and they are able to reduce hyperglycemia in patients with type 2 diabetes. A renoprotective function of gliflozins has been proven in diabetic nephropathy, but harmful side effects on the kidney have also been described. In the current project, primary highly purified human renal proximal tubular epithelial cells (PTCs) have been shown to express functional SGLT-2, and were used as an in vitro model to study possible cellular damage induced by two therapeutically used gliflozins: empagliflozin and dapagliflozin. Cell viability, proliferation, and cytotoxicity assays revealed that neither empagliflozin nor dapagliflozin induce effects in PTCs cultured in a hyperglycemic environment, or in co-medication with ramipril or hydro-chloro-thiazide. Oxidative stress was significantly lowered by dapagliflozin but not by empagliflozin. No effect of either inhibitor could be detected on mRNA and protein expression of the pro-inflammatory cytokine interleukin-6 and the renal injury markers KIM-1 and NGAL. In conclusion, empa- and dapagliflozin in therapeutic concentrations were shown to induce no direct cell injury in cultured primary renal PTCs in hyperglycemic conditions.
Baer, Patrick C. ; Sann, Julia ; Dücker, Ruth Pia ; Ullrich, Evelyn ; Geiger, Helmut ; Bader, Peter ; Zielen, Stefan ; Schubert, Ralf
Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Cell therapy using adipose-derived mesenchymal stromal/stem cells (ASCs) might be a promising approach for tissue regeneration. The aim of the present project was to investigate whether ASCs migrate into the injured lung parenchyma of Atm-deficient mice as an indication of incipient tissue damage during A-T. Therefore, ASCs isolated from luciferase transgenic mice (mASCs) were intravenously transplanted into Atm-deficient and wild-type mice. Retention kinetics of the cells were monitored using in vivo bioluminescence imaging (BLI) and completed by subsequent verification using quantitative real-time polymerase chain reaction (qRT-PCR). The in vivo imaging and the qPCR results demonstrated migration accompanied by a significantly longer retention time of transplanted mASCs in the lung parenchyma of Atm-deficient mice compared to wild type mice. In conclusion, our study suggests incipient damage in the lung parenchyma of Atm-deficient mice. In addition, our data further demonstrate that a combination of luciferase-based PCR together with BLI is a pivotal tool for tracking mASCs after transplantation in models of inflammatory lung diseases such as A-T.
Bajnai, David ; Guo, Weifu ; Spötl, Christoph ; Coplen, Tyler B. ; Methner, Katharina ; Löffler, Niklas ; Krsnik, Emilija ; Gischler, Eberhard ; Hansen, Maximilian ; Henkel, Daniela ; Price, Gregory D. ; Raddatz, Jacek ; Scholz, Denis ; Fiebig, Jens
Surface temperature is a fundamental parameter of Earth’s climate. Its evolution through time is commonly reconstructed using the oxygen isotope and the clumped isotope compositions of carbonate archives. However, reaction kinetics involved in the precipitation of carbonates can introduce inaccuracies in the derived temperatures. Here, we show that dual clumped isotope analyses, i.e., simultaneous ∆47 and ∆48 measurements on the single carbonate phase, can identify the origin and quantify the extent of these kinetic biases. Our results verify theoretical predictions and evidence that the isotopic disequilibrium commonly observed in speleothems and scleractinian coral skeletons is inherited from the dissolved inorganic carbon pool of their parent solutions. Further, we show that dual clumped isotope thermometry can achieve reliable palaeotemperature reconstructions, devoid of kinetic bias. Analysis of a belemnite rostrum implies that it precipitated near isotopic equilibrium and confirms the warmer-than-present temperatures during the Early Cretaceous at southern high latitudes.
Baldering, Tim N. ; Karathanasis, Christos ; Harwardt, Marie-Lena ; Freund, Petra ; Meurer, Matthias ; Rahm, Johanna Viola ; Knop, Michael ; Dietz, Marina ; Heilemann, Mike
Single-molecule localization microscopy (SMLM) reports on protein organization in cells with near-molecular resolution and in combination with stoichiometric labeling enables protein counting. Fluorescent proteins allow stoichiometric labeling of cellular proteins; however, most methods either lead to overexpression or are complex and time demanding. We introduce CRISPR/Cas12a for simple and efficient tagging of endogenous proteins with a photoactivatable protein for quantitative SMLM and single-particle tracking. We constructed a HEK293T cell line with the receptor tyrosine kinase MET tagged with mEos4b and demonstrate full functionality. We determine the oligomeric state of MET with quantitative SMLM and find a reorganization from monomeric to dimeric MET upon ligand stimulation. In addition, we measured the mobility of single MET receptors in vivo in resting and ligand-treated cells. The combination of CRISPR/Cas12a-assisted endogenous protein labeling and super-resolution microscopy represents a powerful tool for cell biological research with molecular resolution.
Die Kommunikation von Zellen mit ihrer Umgebung wird durch Rezeptorproteine arrangiert, die sich in der Plasmamembran befinden. Membranrezeptoren werden durch die Bindung von extrazellulären Liganden, Pathogenen oder Zell-Zell-Interaktionen aktiviert, wodurch die Bildung eines aktiven Zustands gefördert wird, der eine intrazelluläre Reaktion einleitet. Eine Beschreibung auf molekularer Ebene, wie sich Membranrezeptoren in Proteinanordnungen organisieren und wie diese Proteinanordnungen eine spezifische funktionelle Aufgabe ausführen, ist der Ausgangspunkt für das Verständnis der molekularen Mechanismen, die Gesundheit und Krankheit zugrunde liegen.
Die Fluoreszenzmikroskopie gibt Aufschluss über die Lage von Proteinen in Zellen, und mit der Einführung der höchstauflösenden Mikroskopie wurde der Nachweis einzelner Proteingruppierungen möglich. Eine Einschränkung der meisten Methoden der höchstauflösenden Mikroskopie ist, dass einzelne Komponenten einer Proteingruppierung optisch nicht aufgelöst werden können, was an der geringen Größe und dichten Packung der Bestandteile im Vergleich zur erreichbaren räumlichen Auflösung liegt. Eine Lösung, die für Einzelmolekül-Lokalisierungsmethoden gezeigt wurde, besteht darin, zusätzliche experimentelle Informationen in die Analyse zu implementieren, also „die Aufl sungsgrenze der höchstauflösenden Mikroskopie zu umgehen". Bei der Einzelmolekül-Bildgebung kann diese zusätzliche Information zum Beispiel die Kinetik von mehrfachen und wiederkehrenden
Emissionsereignissen sein, die bei einzelnen Fluorophoren beobachtet werden, was als "Blinken" bezeichnet wird. Das Ziel dieser Arbeit war die Entwicklung einer höchstauflösenden Fluoreszenzmikroskopiemethode zur Detektion von Proteinmonomeren und -dimeren in der Plasmamembran von Zellen durch die Verwendung der kinetischen Information.
Im ersten Teil dieser Arbeit wurden photoschaltbare fluoreszierende Proteine als Reporter verwendet, deren photoschaltbare Kinetik mit kinetischen Gleichungen analysiert wurden.
Synthetische, genetische und zelluläre Referenzproteine wurden konstruiert und dienten als Kalibrierungsreferenzen für monomere und dimere Proteine.
Im zweiten Teil dieser Arbeit wurde das kinetische Modell, das zur Annäherung des Häufigkeitshistogramms von Blinkereignissen einzelner Fluorophore verwendet wird, auf Oligomere höherer Ordnung erweitert. Ein Vergleich mit einem zuvor entwickelten Modell zeigte, dass das erweiterte Modell genauere Ergebnisse für Oligomere höherer Ordnung und Mischungen verschiedener Oligomere liefert. Zusätzlich wird die Anwesenheit von unerkannten Oligomeren berücksichtigt. Die erweiterte Theorie bietet somit die Grundlage, um größere Oligomere und Mischungen unterschiedlicher Stöchiometrie mit besserer Genauigkeit zu untersuchen.
Im dritten Teil dieser Arbeit wurde eine Methode zur stöchiometrischen endogenen Markierung von Proteinen verwendet, um zwei Rezeptortyrosinkinasen, MET und EGFR, mit einem photoschaltbaren fluoreszierenden Protein zu markieren. Das Vorkommen von monomerem und dimerem MET-Rezeptor wurde auf der Plasmamembran von HEK293T- Zellen mittels quantitativer höchstauflösender Mikroskopie bestimmt. Der Diffusionskoeffizient und der Diffusionsmodus des MET-Rezeptors in lebenden HEK293T-Zellen wurden mit
Einzelpartikelverfolgung gemessen. Dieser Teil der Arbeit zeigte, dass die Kombination von CRISPR/Cas12a-gestützter endogener Markierung und Einzelmolekül-Lokalisierungsmikroskopie ein leistungsfähiges Werkzeug zur Untersuchung der molekularen Organisation und Dynamik von Membranproteinen ist.
Im vierten Teil dieser Arbeit wurde die Einzelmoleküldatenanalyse durch ein Softwaretool beschleunigt, das eine automatisierte und unvoreingenommene Detektion von Einzelmolekül-Emissionsereignissen ermöglicht. Der Anteil von Monomeren und Dimeren von fluoreszierenden Reportern wurde durch die Implementierung eines neuronalen Netzwerks bestimmt (die Software wurde von Alon Saguy geschrieben; Gruppe von Prof. Yoav Shechtman, Technion, Israel). Der oligomere Zustand der monomeren und dimeren Referenzproteine CD86 und CTLA-4 wurde erfolgreich bestimmt. Die automatisierte Detektion einzelner Proteingruppierungen ermöglichte die Analyse von MET-mEos4b in einzelnen Zellen, wodurch die Heterogenität zwischen den Zellen bestimmt und das Expressionsniveau des Rezeptors mit der Dimerisierung korreliert werden konnte.
Zusammenfassend wurden in dieser Arbeit Ergebnisse zu elementaren Aspekten hin zu einer molekularen Quantifizierung von Proteinzahlen mittels Einzelmolekül-
Lokalisationsmikroskopie generiert, die fluoreszierende Reporter, stöchiometrische Markierung von zellulären Proteinen und Bildanalyse umfassen. Das Potential dieser
Entwicklungen wurde anhand der Beobachtung der Liganden-induzierten Verschiebung von monomeren zu dimeren MET-Rezeptoren in einzelnen HEK293T-Zellen gezeigt.
We determine the magnetic susceptibility of thermal QCD matter by means of first principles lattice simulations using staggered quarks with physical masses. A novel method is employed that only requires simulations at zero background field, thereby circumventing problems related to magnetic flux quantization. After a careful continuum limit extrapolation, diamagnetic behavior (negative susceptibility) is found at low temperatures and strong paramagnetism (positive susceptibility) at high temperatures. We revisit the decomposition of the magnetic susceptibility into spin- and orbital angular momentum- related contributions. The spin term — related to the normalization of the photon lightcone distribution amplitude at zero temperature — is calculated non-perturbatively and extrapolated to the continuum limit. Having access to both the full magnetic susceptibility and the spin term, we calculate the orbital angular momentum contribution for the first time. The results reveal the opposite of what might be expected based on a free fermion picture. We provide a simple parametrization of the temperature- and magnetic field-dependence of the QCD equation of state that can be used in phenomenological studies.
Ballo, Olivier ; Fleckenstein, Philine ; Eladly, Fagr ; Kreisel, Eva-Maria ; Stratmann, Jan Alexander ; Seifried, Erhard ; Müller, Markus Matthias ; Serve, Hubert ; Bug, Gesine ; Bönig, Halvard-Björn ; Brandts, Christian Hubertus ; Finkelmeier, Fabian
Background and Objectives: Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non‐inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes.
Materials and Methods: A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007–2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016–2018). Liberal transfusion triggers were never endorsed.
Results: A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C‐reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts.
Conclusion: From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.
Ballo, Olivier Karl Friedrich ; Kreisel, Eva-Maria ; Eladly, Fagr ; Brunnberg, Uta ; Stratmann, Jan Alexander ; Hunyady, Peter Marton ; Hogardt, Michael ; Wichelhaus, Thomas A. ; Kempf, Volkhard A. J. ; Steffen, Björn ; Vehreschild, Jörg Janne ; Vehreschild, Maria J. G. T. ; Finkelmeier, Fabian ; Serve, Hubert ; Brandts, Christian Hubertus
Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.
Ballweg, Stephanie ; Sezgin, Erdinc ; Doktorova, Milka ; Covino, Roberto ; Reinhard, John ; Wunnicke, Dorith ; Hänelt, Inga ; Levental, Ilya ; Hummer, Gerhard ; Ernst, Robert
Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. We have reconstituted the core machinery for regulating lipid saturation in baker’s yeast to study its molecular mechanism. By combining molecular dynamics simulations with experiments, we uncover a remarkable sensitivity of the transcriptional regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl chains, and provide insights into the molecular rules of membrane adaptation. Our data challenge the prevailing hypothesis that membrane fluidity serves as the measured variable for regulating lipid saturation. Rather, we show that Mga2 senses the molecular lipid-packing density in a defined region of the membrane. Our findings suggest that membrane property sensors have evolved remarkable sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the way toward the development of genetically encoded reporters for such properties in the future.
The way in which dendrites spread within neural tissue determines the resulting circuit connectivity and computation. However, a general theory describing the dynamics of this growth process does not exist. Here we obtain the first time-lapse reconstructions of neurons in living fly larvae over the entirety of their developmental stages. We show that these neurons expand in a remarkably regular stretching process that conserves their shape. Newly available space is filled optimally, a direct consequence of constraining the total amount of dendritic cable. We derive a mathematical model that predicts one time point from the previous and use this model to predict dendrite morphology of other cell types and species. In summary, we formulate a novel theory of dendrite growth based on detailed developmental experimental data that optimises wiring and space filling and serves as a basis to better understand aspects of coverage and connectivity for neural circuit formation.
The digital and information age has fundamentally transformed the way in which students learn and the study material they have at their disposal, especially in higher education. Students need to possess a number of higher-order cognitive and metacognitive skills, including effective information processing and critical reasoning to be able to navigate the Internet and use online sources, even those found outside of academically curated domains and in the depths of the Internet, and to solve (domain-specific) problems. Linking qualitative and quantitative research and connecting the humanities to empirical educational science studies, this article investigates the role of narratives and their impact on university students’ information seeking and their critical online reasoning (COR). This study focuses on the link between students’ online navigation skills, information seeking behavior and critical reasoning with regard to the specific domains: economics and medicine. For the empirical analysis in this article, we draw on a study that assesses the COR skills of undergraduate students of economics and medicine at two German universities. To measure COR skills, we used five tasks from the computer-based assessment “Critical Online Reasoning Assessment” (CORA), which assesses students’ skills in critically evaluating online sources and reasoning using evidence on contentious issues. The conceptual framework of this study is based on an existing methodology – narrative economics and medicine – and discusses its instructional potential and how it can be used to develop a new tool of “wise interventions” to enhance students’ COR in higher education. Based on qualitative content analyses of the students’ written responses, i.e., short essays, three distinct patterns of information seeking behavior among students have been identified. These three patterns – “Unambiguous Fact-Checking,” “Perspective-Taking Without Fact-Checking,” and “Web Credibility-Evaluating” – differ substantially in their potential connection to underlying narratives of information used by students to solve the CORA tasks. This analysis suggests that training university students in narrative analysis can strongly contribute to enhancing their critical online reasoning.
Die Extrakorporale Membranoxygenierung (ECMO) ist ein extrakorporales Organersatzverfahren, welches heutzutage insbesondere als Lungenersatzverfahren oder als kreislaufunterstützendes Verfahren zum Einsatz kommt. Seit dem ersten Einsatz 1971 im Rahmen eines posttraumatischen „Acute Respiratory Distress Syndrom“ (ARDS) ist die Zahl der ECMO-Behandlungen im kardiopulmonalen Bereich massiv gestiegen. Dennoch wird der Nutzen der ECMO kontrovers diskutiert. Die aktuellste randomisiert kontrollierte Studie aus dem Jahre 2018 konnte keinen signifikanten Nachweis erbringen, dass die Therapie des ARDS mittels einer ECMO einen Überlebensvorteil bringt. Randomisiert kontrollierte Studien bei Patienten mit kardiogenem Schock liegen zum gegenwärtigen Zeitpunkt nicht vor und für den Einsatz bei septischem Schock ist die Datenlage und Evidenz schwach. Angesichts der ungeklärten Evidenz und weil die ECMO ein komplexes, kostenintensives und mit Risiken verbundenes Verfahren ist, scheint eine sorgfältige Indikationsstellung unverzichtbar zu sein. Das Ziel unserer Studie war daher die Analyse der Mortalität bei Patienten mit Lungenversagen, kardiogenem Schock und septischem Schock. Darüber hinaus sollten mit der Mortalität assoziierte prognostische Variablen identifiziert werden. Des Weiteren sollte untersucht werden, ob sich mit steigender Fallzahl eine Lernkurve beobachten lässt.
Zu diesem Zwecke führten wir eine retrospektive Kohortenstudie an 131 Patienten durch, die zwischen April 2011 und Juli 2016 in der Asklepios Klinik Langen mit einer ECMO behandelt wurden. Die Patienten wurden hierbei in die drei oben genannten Gruppen kategorisiert. Mithilfe logistischer Regression erfolgte die Identifizierung prognostischer Variablen. Eine Lernkurve wurde anhand des „non-risk-adjusted cumulative observed minus expected failure graph“-Verfahrens erstellt.
Die Analyse der Daten ergab eine Gesamtmortalität von 56%. Die Mortalität bei Patienten mit Lungenversagen, kardiogenem Schock und septischem Schock betrug 54%, 59% bzw. 58%. Bei Patienten mit Lungenversagen waren das Alter, das Jahr und weniger als 20 Fälle pro Jahr signifikant mit der Mortalität assoziiert. Bei Patienten mit kardiogenem Schock waren mit der Mortalität assoziierte Variablen das Alter, der SAPS II-Score, der pH-Wert, der Serumlaktatwert prä-ECMO, der Basenüberschuss prä-ECMO sowie eine Hyperlipidämie. Bei Patienten mit septischem Schock konnten keine mit der Mortalität assoziierten Variablen identifiziert werden. In der multivariaten Regressionsanalyse nach Modellabbau zeigten sich in der gesamten Kohorte das Alter, das prä-ECMO Serumlaktat sowie weniger als 20 Fälle pro Jahr als signifikant mit der Mortalität assoziierte Variablen. Patienten, die vor 2014 behandelt wurden, also in einem Zeitraum mit weniger als 20 ECMO-Fällen pro Jahr, hatten eine signifikant höhere Mortalität als Patienten die im Intervall 2014-2016 behandelt wurden. Mit steigender Fallzahl konnte eine Lernkurve nachgewiesen werden, die einen Wendepunkt im Jahr 2014 zeigte. Der im Jahr 2014 beginnende Abwärtstrend signalisierte eine geringere Sterblichkeitsrate als erwartet.
Zusammenfassend ist die Mortalität in allen Indikationen weiter hoch. Die Fallzahl und damit auch die Erfahrung scheint eine wichtige Rolle in Bezug auf die Mortalität zu spielen. Des Weiteren unterstützen unsere Ergebnisse frühere Studien, die einen Einfluss des Alters und des prä-ECMO Laktat-Wertes auf die Mortalität zeigen konnten.
Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterised by a proliferation of fibroblasts in the tumour microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancerassociated fibroblasts (CAF). However, to date a deep molecular understanding of these fibroblasts is lacking. Aim of the present study therefore was a comprehensive
characterisation of these fibroblasts. Moreover, only a few studies describe the interplay of HRS cells and CAF. The paracrine communication and direct interaction of these two
cellular fractions have been investigated within this study. Finally, the influence of a few HRS cells within a lymph node orchestrate the mere alteration of its architecture and
morphology. Gene expression and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic - inflammatory phenotype characterised by MYOCD, CNN1 and IL-6 expression. TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. Treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble
factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin(BV) induced cell death. However, HRS cells adherent to fibroblasts were protected from BV-induced injury. The cHL specific interaction of both cell fractions reveals an initiation of inflammatory key regulators such as IL13 and IL4. Among important adhesion molecules known from literature the blocking of integrin beta 1 solely interrupted the adhesion of HRS cells to CAF. In summary, this study proves the stable reprograming of CAF phenotype and expression derived from NS cHL. It presents a suitable in vitro model for studying the interaction of HRS cells and CAF by paracrine factors and adherence. Most importantly the observations confirm the importance of fibroblasts for HRS cells´ inflammatory niche and cell survival associated with TIMP3 which probably acts as a major factor to the typical accumulation of fibrosis observed in NS cHL.
The ongoing biodiversity crisis becomes evident in the widely observed decline in abundance and diversity of species, profound changes in community structure, and shifts in species’ phenology. Insects are among the most affected groups, with documented decreases in abundance up to 76% in the last 25–30 years in some terrestrial ecosystems. Identifying the underlying drivers is a major obstacle as most ecosystems are affected by multiple stressors simultaneously and in situ measurements of environmental variables are often missing. In our study, we investigated a headwater stream belonging to the most common stream type in Germany located in a nature reserve with no major anthropogenic impacts except climate change. We used the most comprehensive quantitative long‐term data set on aquatic insects available, which includes weekly measurements of species‐level insect abundance, daily water temperature and stream discharge as well as measurements of additional physicochemical variables for a 42‐year period (1969–2010). Overall, water temperature increased by 1.88 °C and discharge patterns changed significantly. These changes were accompanied by an 81.6% decline in insect abundance, but an increase in richness (+8.5%), Shannon diversity (+22.7%), evenness (+22.4%), and interannual turnover (+34%). Moreover, the community's trophic structure and phenology changed: the duration of emergence increased by 15.2 days, whereas the peak of emergence moved 13.4 days earlier. Additionally, we observed short‐term fluctuations (<5 years) in almost all metrics as well as complex and nonlinear responses of the community toward climate change that would have been missed by simply using snapshot data or shorter time series. Our results indicate that climate change has already altered biotic communities severely even in protected areas, where no other interacting stressors (pollution, habitat fragmentation, etc.) are present. This is a striking example of the scientific value of comprehensive long‐term data in capturing the complex responses of communities toward climate change.
Barbagallo, Massimo ; Aberle, Oliver ; Alcayne, Victor ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Babiano Suarez, Victor ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Bosnar, Damir ; Brown, Adam S. ; Busso, Maurizio ; Caamaño, Manuel ; Caballero Ontanaya, Luis ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Casanovas Hoste, Adrià ; 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 ; Domingo-Pardo, César ; Dressler, Rugard ; Ducasse, Quentin ; 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 ; Göbel, Kathrin ; González Romero, Enrique Miguel ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Jiri, U. ; Junghans, Arnd Rudolf ; Kadi, Yacine ; Käppeler, Franz ; Kimura, Atsushi ; Knapová, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Ladarescu, Ion ; Lederer-Woods, Claudia ; Lerendegui-Marco, Jorge ; Lonsdale, Sarah-Jane ; Macina, Daniela ; Manna, Alice ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Millán Callado, María de los Ángeles ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Petrone, Cristina ; Piersanti, Luciano ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté- Gilarte, M. ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Thomas, Benedikt ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; 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 J. ; Žugec, Petar
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Barbarossa, Maria Vittoria ; Fuhrmann, Jan ; Heidecke, Julian ; Vinod Varma, Hridya ; Castelletti, Noemi ; Meinke, Jan H. ; Krieg, Stefan F. ; Lippert, Thomas
The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe, with about 571,700 confirmed cases and about 26,500 deaths as of March 28th, 2020. We present here the preliminary results of a mathematical study directed at informing on the possible application or lifting of control measures in Germany. The developed mathematical models allow to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions.
Barbarossa, Maria Vittoria ; Fuhrmann, Jan ; Meinke, Jan H. ; Krieg, Stefan F. ; Vinod Varma, Hridya ; Castelletti, Noemi ; Lippert, Thomas
The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe with about 2.2 million confirmed cases and more than 150,000 deaths as of April 17, 2020 [37]. In view of most recent information on testing activity [32], we present here an update of our initial work [4]. In this work, mathematical models have been developed to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions. Systems of differential equations of SEIR type are extended here to account for undetected infections, as well as for stages of infections and age groups. The models are calibrated on data until April 5, data from April 6 to 14 are used for model validation. We simulate different possible strategies for the mitigation of the current outbreak, slowing down the spread of the virus and thus reducing the peak in daily diagnosed cases, the demand for hospitalization or intensive care units admissions, and eventually the number of fatalities. Our results suggest that a partial (and gradual) lifting of introduced control measures could soon be possible if accompanied by further increased testing activity, strict isolation of detected cases and reduced contact to risk groups.
Die Goethe-Universität gibt Impulse an die Menschen in der Stadt. Die Bürgerinnen und Bürger wiederum besuchen die Universität. Diese Idee der Bürgeruniversität eines Dialogs zwischen Universität und Stadt ist in Pandemiezeiten schwer umzusetzen. Dennoch: Nach einer Pause gibt es wieder ein – überwiegend digitales – Programm.
(Un)glaubwürdig grün? : Wie Anleger im boomenden Markt für Grüne Anleihen nach Orientierung suchen
(2020)
Der Klimaschutz ist in der Finanzwelt angekommen. Diesen Eindruck erweckt zumindest das wachsende Angebot an »grünen« Anleihen. Diese Wertpapiere beschaffen Kapital für explizit klimafreundliche Industrien und Projekte. Doch können Anleger sicher sein, dass sie ihr Geld in einen klimafreundlichen CO2-Fußabdruck investieren und nicht doch beim »Greenwashing« eines rasant ressourcenabbauenden Unternehmens Beihilfe leisten? Die Wirtschaftswissenschaftlerin Julia Kapraun hat sich mit der Glaubwürdigkeit Grüner Anleihen befasst.
Ionenstrahlen werden in der Grundlagenforschung, in der Industrie und der Medizin verwendet. Um die Teilchen für die jeweiligen Anforderungen nutzbar zu machen, werden sie mit Ionenbeschleunigern je nach Anwendung auf eine bestimmte Energie beschleunigt. Eine Beschleunigeranlage besteht dabei aus einer Reihe von unterschiedlichen Elementen: Ionenquellen, Linearbeschleuniger, Kreisbeschleuniger, Fokussierelemente, Diagnosesysteme usw. In jeder dieser Kategorien gibt es wiederum verschiedene Realisierungsmöglichkeiten, je nach Anforderung des jeweiligen Abschnitts und der gesamten Anlage. Im Bereich der Linearbeschleuniger ist als Bindeglied zwischen Ionenquelle/Niederenergiebereich und Nachfolgebeschleuniger der Radiofrequenzquadrupol (RFQ) weit verbreitet. Dieser kann den aus der Quelle kommenden Gleichstromstrahl in Teilchenpakete (Bunche) formen und diese gleichzeitig auf die nächste Beschleunigerstufe angepasst vorbeschleunigen. Desweiteren wird der Teilchenstrahl innerhalb des RFQ kontinuierlich fokussiert, wodurch insbesondere bei diesen niedrigen Energien Strahlverluste minimiert werden. Bei hohem Masse-zu-Ladungs-Verhältnis wird für schwere Ionen eine niedrige Resonanzfrequenz von deutlich unter 100 MHz benötigt. Dies führt zu längeren Beschleunigungszellen entlang der Elektroden, womit durch eine bessere Fokussierung auch höhere Strahlströme beschleunigt werden können. Im Allgemeinen bedeutet eine niedrigere Resonanzfrequenz aber auch einen größeren Querschnitt der Resonanzstruktur sowie einen längeren Beschleuniger. Gegenstand dieser Arbeit ist die Untersuchung unterschiedlicher RFQ-Strukturen für niedrige Frequenzen, wie sie beispielsweise im Linearbeschleunigerbereich der Gesellschaft für Schwerionenforschung (GSI) in Darmstadt Anwendung finden. Zunächst wird die Beschleunigeranlage des GSI Helmholtzzentrums für Schwerionenforschung in Darmstadt und dessen zur Zeit im Bau befindliche Erweiterung FAIR (Facility for Antiproton and Ion Research) kurz vorgestellt. Teil dieser Anlage ist der Hochstrominjektor genannte Anfangsbeschleuniger, der wiederum aus einem RFQ und zwei nachfolgenden Driftröhrenbeschleunigern besteht. Dieser Hochstrominjektor dient als Referenz für die vorliegende Arbeit. In Kapitel 3 wird kurz auf Linearbeschleuniger im Allgemeinen und auf das Grundprinzip und die Eigenschaften eines RFQ näher eingegangen. Anschließend werden verschiedene RFQ-Strukturkonzepte vorgestellt und die Strahldynamik in einem RFQ sowie charakteristische Resonatorgrößen beschrieben. Ausgangspunkt ist der aktuelle RFQ des Hochstrominjektors (Kapitel 4). Dieser IH-RFQ mit einer Betriebsfrequenz von 36 MHz ist seit vielen Jahren in Betrieb und soll für eine verbesserte Effizienz und Betriebssicherheit ein Upgrade erfahren. Dazu wurden Simulationen sowohl der bestehenden Struktur als auch mit Modifikationen durchgeführt und diese miteinander verglichen. Zur Entwicklung eines kompakten Resonators werden in Kapitel 5 verschiedene Splitring-RFQ-Modelle als Alternative zur IH-Struktur mittels Simulationen untersucht. Diese wurden für eine niedrigere Frequenz von 27 MHz entworfen, was der Frequenz des ursprünglichen Wideröe-Beschleunigers (Vorgänger des Hochstrominjektors HSI) entspricht und ebenso wie die 36 MHz des IH-RFQ eine Subharmonische der 108 MHz des Folgebeschleunigers ist. Abschließend wurde noch eine neue RFQ-Struktur, der Splitframe-RFQ, entworfen und untersucht. Auch dieser wurde für eine Frequenz von 27 MHz ausgelegt. Die Ergebnisse dieser Entwicklung, die eine Mischung aus einem Splitring- und einem klassischen 4-Rod-RFQ darstellt, befinden sich in Kapitel 6. Alle Feldsimulationen wurden mit dem Programm Microwave Studio von CST durchgeführt. Zusammenfassend werden die verschiedenen Konzepte anhand der charakteristischen Resonatorgrößen verglichen und ein Ausblick auf weiterführende Arbeiten gegeben.
Autophagy, together with the ubiquitin-proteasome system, is the main quality control pathway responsible for maintaining cell homeostasis. There are several types of autophagy distinguished by cargo selectivity and means of induction. This thesis focuses on macroautophagy, hereafter autophagy, where a double-layered membrane is formed originating from the endoplasmatic reticulum (ER) engulfing cargo selectively or unselectively. Subsequently, a vesicle forms around the cargo, an autophagosome, and eventually fuses with the lysosome leading to degradation of the vesicle content and release of the cargo “building blocks”. Basal autophagy continuously occurs, unselectively engulfing a portion of the cytoplasm. However, autophagy can also be induced by stress such as starvation, protein aggregation, damaged organelles, intracellular pathogens etc. In this case, the cargo is selectively targeted, and the fate of the autophagosome is the same as in basal autophagy. In recent years, interest in identifying mechanisms of autophagy regulation has risen due to its importance in neurodegenerative diseases and cancer. Given the complexity of the process, its execution is tightly regulated from initiation, autophagosome formation, expansion, closure, and finally fusion with the lysosome. Each of the steps involves different protein complexes, whose timely activity is orchestrated by post-translational modifications. One of them is ubiquitination. Ubiquitin is a small, 76-amino acid protein conjugated in a 3-step reaction to other proteins, in a reversible manner, meaning undone by deubiquitinases. Originally described as a degradation signal targeting proteins to the proteasome, today it is known it has various additional non-proteolytic functions, such as regulating a protein’s activity, localization, or interaction partners. The role of ubiquitin in autophagy has already been shown. However, given the reversibility and fine-tuning of the ubiquitin signal, many expected regulators remain unidentified. This work aimed to identify novel deubiquitinating enzymes that regulate autophagy. We identified ubiquitin-specific protease 11 (USP11) as a novel, negative regulator of autophagy. Loss of USP11 leads to an increase in autophagic flux, whereas overexpression of USP11 attenuates it. Moreover, this observation was reproducible in model organism Caenorhabditis elegans, emphasizing the importance of USP11 in autophagy regulation. To identify the mechanism of USP11-dependent autophagy regulation, we performed a USP11 interactome screen after 4 hour Torin1 treatment and identified a plethora of autophagy-related proteins. Following the most prominent hits, we have investigated versatile ways in which USP11 regulates autophagy. USP11 interacts with the PI3KC3 complex, the role of which is phosphorylating lipids of the ER, thereby initiating the formation of the autophagosomal membrane. Phosphorylated lipids serve as a recruitment signal for downstream effector proteins necessary for the membrane expansion. The core components of the complex are VPS34, the lipid kinase, ATG14, the protein responsible for targeting the complex to the ER, VPS15, a pseudokinase with a scaffolding role, Beclin1, a regulatory subunit, and NRBF2, the dimer-inducing subunit. We have found USP11 interacts with the complex and, based on its activity, USP11 influences post-translational status of all the aforementioned subunits, except for ATG14. Moreover, we have found that loss of USP11 leads to an increase in NRBF2 levels, whereas it does not change the levels of the other proteins. Given that the dimerization of the complex leads to an increase in complex activity, we investigated if the complex is more tightly formed in the absence of USP11, and if it is more active. We have found both to be the case. Although the exact mechanism of USP11-dependent PI3KC3 complex regulation remains to be identified, we found that loss of USP11 stimulates the complex formation and activity, likely contributing to the general effect of USP11 on autophagy flux. Additionally, we found that USP11 modulates levels of mTOR, the most upstream kinase in autophagy initiation steps and general multifaceted metabolism regulator. Loss of USP11 led to downregulation of mTOR levels, suggesting USP11 may rescue mTOR from proteasome-mediated degradation. Furthermore, we found mTOR to be differentially modified depending on the activity of USP11. However, it remains to be shown if USP11-dependent mTOR regulation contributes to the observed autophagy phenotype. Taken together, USP11 is a novel, versatile, negative regulator of autophagy, and an important addition to our knowledge on the regulation of autophagy by the ubiquitin system.
Bast, Nico ; Mason, Luke ; Freitag, Christine M. ; Smith, Tim ; Portugal, Ana Maria ; Poustka, Luise ; Banaschewski, Tobias ; Johnson, Mark
Background: Visual exploration in autism spectrum disorder (ASD) is characterized by attenuated social attention. The underlying oculomotor function during visual exploration is understudied, whereas oculomotor function during restricted viewing suggested saccade dysmetria in ASD by altered pontocerebellar motor modulation. Methods: Oculomotor function was recorded using remote eye tracking in 142 ASD participants and 142 matched neurotypical controls during free viewing of naturalistic videos with and without human content. The sample was heterogenous concerning age (6–30 years), cognitive ability (60–140 IQ), and male/female ratio (3:1). Oculomotor function was defined as saccade, fixation, and pupil-dilation features that were compared between groups in linear mixed models. Oculomotor function was investigated as ASD classifier and features were correlated with clinical measures. Results: We observed decreased saccade duration (∆M = −0.50, CI [−0.21, −0.78]) and amplitude (∆M = −0.42, CI [−0.12, −0.72]), which was independent of human video content. We observed null findings concerning fixation and pupil-dilation features (POWER = .81). Oculomotor function is a valid ASD classifier comparable to social attention concerning discriminative power. Within ASD, saccade features correlated with measures of restricted and repetitive behavior. Conclusions: We conclude saccade dysmetria as ASD oculomotor phenotype relevant to visual exploration. Decreased saccade amplitude and duration indicate spatially clustered fixations that attenuate visual exploration and emphasize endogenous over exogenous attention. We propose altered pontocerebellar motor modulation as underlying mechanism that contributes to atypical (oculo-)motor coordination and attention function in ASD.
O presente objeto de pesquisa busca proceder ao estudo e identificação dos traços essenciais envolvidos na abordagem teórica das relações sociais e políticas trazidas na obra O Direito da Liberdade do filósofo alemão Axel Honneth. Faz-se uma análise da influência hegeliana sobre o conceito de liberdade, assim como dos fatores relacionados com o suprimento das carências subjetivas, mediadas pelas diferentes “esferas” sociais. Honneth, assim, procura trazer à tona a compreensão de um novo modelo de liberdade advindo da Filosofia do Direito de Hegel, o qual se distingue substancialmente dos modelos tradicionais. O autor busca evidenciar a limitação das teorias da justiça de tradição liberal, invocando a necessidade de uma visão integrada das relações sociais experimentadas nas esferas referidas por Hegel, concebendo-se uma experiência concreta de liberdade social. Nesse sentido, evidencia-se o caráter interdisciplinar e emancipatório do método de reconstrução normativa como base teórica para a justificação pública nas sociedades modernas.
Batarfi, AbdulAziz ; Alenezi, Haitham ; Alshehri, Abdulrahman ; Balelah, Saud ; Kazim, Hameedullah ; Algthami, Mohammed ; Hussain, Mariam M. ; Alshehri, Nada ; Alsharif, Rahaf ; Ashour, Hadeel ; Althobaiti, Mutaz ; Alotaibi, Shomokh ; Steinmetz, Helmuth ; Förch, Christian
Fasting Ramadan is known to influence patients’ medication adherence. Data on patients’ behavior to oral anticoagulant (OAC) drug intake during Ramadan is missing. We aimed to determine patient-guided modifications of OAC medication regimen during Ramadan and to evaluate its consequences. A multicenter cross-sectional study conducted in Saudi Arabia. Data were collected shortly after Ramadan 2019. Participants were patients who fasted Ramadan and who were on long-term anticoagulation. Patient-guided medication changes during Ramadan in comparison to the regular intake schedule before Ramadan were recorded. Modification behavior was compared between twice daily (BID) and once daily (QD) treatment regimens. Rates of hospital admission during Ramadan were determined. We included 808 patients. During Ramadan, 53.1% modified their intake schedule (31.1% adjusted intake time, 13.2% skipped intakes, 2.2% took double dosing). A higher frequency of patient-guided modification was observed in patients on BID regimen compared to QD regimen. During Ramadan, 11.3% of patients were admitted to hospital. Patient-guided modification was a strong predictor for hospital admission. Patient-guided modification of OAC intake during Ramadan is common, particularly in patients on BID regimen. It increases the risk of hospital admission during Ramadan. Planning of OAC intake during Ramadan and patient education on the risk of low adherence are advisable.
Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics
(2020)
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal, development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
Bauer, Jan ; Brüggmann, Dörthe ; Klingelhöfer, Doris ; Maier, Werner Albert ; Schwettmann, Lars ; Maier, Werner Albert ; Schwettmann, Lars ; Weiss, Daniel J. ; Groneberg, Jan David Alexander
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Bauer, Jan ; Klingelhöfer, Doris ; Maier, Werner Albert ; Schwettmann, Lars ; Groneberg, Jan David Alexander
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
Bauer, Jan ; Klingelhöfer, Doris ; Maier, Werner Albert ; Schwettmann, Lars ; Groneberg, Jan David Alexander
Background: The adequate allocation of inpatient care resources requires assumptions about the need for health care and how this need will be met. However, in current practice, these assumptions are often based on outdated methods (e.g. Hill-Burton Formula). This study evaluated floating catchment area (FCA) methods, which have been applied as measures of spatial accessibility, focusing on their ability to predict the need for health care in the inpatient sector in Germany.
Methods: We tested three FCA methods (enhanced (E2SFCA), modified (M2SFCA) and integrated (iFCA)) for their accuracy in predicting hospital visits regarding six medical diagnoses (atrial flutter/fibrillation, heart failure, femoral fracture, gonarthrosis, stroke, and epilepsy) on national level in Germany. We further used the closest provider approach for benchmark purposes. The predicted visits were compared with the actual visits for all six diagnoses using a correlation analysis and a maximum error from the actual visits of ± 5%, ± 10% and ± 15%.
Results: The analysis of 229 million distances between hospitals and population locations revealed a high and significant correlation of predicted with actual visits for all three FCA methods across all six diagnoses up to ρ = 0.79 (p < 0.001). Overall, all FCA methods showed a substantially higher correlation with actual hospital visits compared to the closest provider approach (up to ρ = 0.51; p < 0.001). Allowing a 5% error of the absolute values, the analysis revealed up to 13.4% correctly predicted hospital visits using the FCA methods (15% error: up to 32.5% correctly predicted hospital). Finally, the potential of the FCA methods could be revealed by using the actual hospital visits as the measure of hospital attractiveness, which returned very strong correlations with the actual hospital visits up to ρ = 0.99 (p < 0.001).
Conclusion: We were able to demonstrate the impact of FCA measures regarding the prediction of hospital visits in non-emergency settings, and their superiority over commonly used methods (i.e. closest provider). However, hospital beds were inadequate as the measure of hospital attractiveness resulting in low accuracy of predicted hospital visits. More reliable measures must be integrated within the proposed methods. Still, this study strengthens the possibilities of FCA methods in health care planning beyond their original application in measuring spatial accessibility.
Bauer, Jochen ; Hechtel, Michael ; Konrad, Christoph ; Holzwarth, Martin ; Mayr, Andreas ; Schneider, Sven ; Franke, Jörg ; Hoffmann, Hilko ; Zinnikus, Ingo ; Feld, Thomas ; Runge, Mathias ; Hinz, Oliver
In the upcoming years, the internet of things (IoT)will enrich daily life. The combination of artificial intelligence(AI) and highly interoperable systems will bring context-sensitive multi-domain services to reality. This paper describesa concept for an AI-based smart living platform with open-HAB, a smart home middleware, and Web of Things (WoT) askey components of our approach. The platform concept con-siders different stakeholders, i.e. the housing industry, serviceproviders, and tenants. These activities are part of the Fore-Sight project, an AI-driven, context-sensitive smart living plat-form.
Using a novel experimental design, I test how the exposure to information about a group’s relative performance causally affects the members’ level of identification and thereby their propensity to harm affiliates of comparison groups. I find that both, being informed about a high and poor relative performance of the ingroup similarly fosters identification. Stronger ingroup identification creates increased hostility against the group of comparison. In cases where participants learn about poor relative performance, there appears to be a direct level effect additionally elevating hostile discrimination. My findings shed light on a specific channel through which social media may contribute to intergroup fragmentation and polarization.
Using experimental data from a comprehensive field study, we explore the causal effects of algorithmic discrimination on economic efficiency and social welfare. We harness economic, game-theoretic, and state-of-the-art machine learning concepts allowing us to overcome the central challenge of missing counterfactuals, which generally impedes assessing economic downstream consequences of algorithmic discrimination. This way, we are able to precisely quantify downstream efficiency and welfare ramifications, which provides us a unique opportunity to assess whether the introduction of an AI system is actually desirable. Our results highlight that AI systems’ capabilities in enhancing welfare critically depends on the degree of inherent algorithmic biases. While an unbiased system in our setting outperforms humans and creates substantial welfare gains, the positive impact steadily decreases and ultimately reverses the more biased an AI system becomes. We show that this relation is particularly concerning in selective-labels environments, i.e., settings where outcomes are only observed if decision-makers take a particular action so that the data is selectively labeled, because commonly used technical performance metrics like the precision measure are prone to be deceptive. Finally, our results depict that continued learning, by creating feedback loops, can remedy algorithmic discrimination and associated negative effects over time.
Bauer, Tobias ; Ernst, Leon ; David, Bastian ; Becker, Albert J. ; Wagner, Jan ; Witt, Juri-Alexander ; Helmstaedter, Christoph ; Weber, Bernd ; Hattingen, Elke ; Elger, Christian Erich ; Surges, Rainer ; Rüber, Theodor
Limbic encephalitis (LE) is an autoimmune syndrome often associated with temporal lobe epilepsy. Recent research suggests that particular structural changes in LE depend on the type of the associated antibody and occur in both mesiotemporal gray matter and white matter regions. However, it remains questionable to what degree conventional diffusion tensor imaging (DTI)-methods reflect alterations in white matter microstructure, since these methods do not account for crossing fibers. To address this methodological shortcoming, we applied fixel-based analysis as a novel technique modeling distinct fiber populations. For our study, 19 patients with LE associated with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE, mean age = 35.9 years, 11 females), 4 patients with LE associated with autoantibodies against leucine-rich glioma-inactivated 1 (LGI1-LE, mean age = 63.3 years, 2 females), 5 patients with LE associated with contactin-associated protein-like 2 (CASPR2, mean age = 57.4, 0 females), 20 age- and gender-matched control patients with hippocampal sclerosis (19 GAD-LE control patients: mean age = 35.1 years, 11 females; 4 LGI1-LE control patients: mean age = 52.6 years, 2 females; 5 CASPR2-LE control patients: mean age = 42.7 years, 0 females; 10 patients are included in more than one group) and 33 age- and gender-matched healthy control subjects (19 GAD-LE healthy controls: mean age = 34.6 years, 11 females; 8 LGI1-LE healthy controls: mean age = 57.0 years, 4 females, 10 CASPR2-LE healthy controls: mean age = 57.2 years, 0 females; 4 subjects are included in more than one group) underwent structural imaging and DTI at 3 T and neuropsychological testing. Patient images were oriented according to lateralization in EEG resulting in an affected and unaffected hemisphere. Fixel-based metrics fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC = FD · FC) were calculated to retrieve information about white matter integrity both on the micro- and the macroscale. As compared to healthy controls, patients with GAD-LE showed significantly (family-wise error-corrected, p < 0.05) lower FDC in the superior longitudinal fascicle bilaterally and in the isthmus of the corpus callosum. In CASPR2-LE, lower FDC in the superior longitudinal fascicle was only present in the affected hemisphere. In LGI1-LE, we did not find any white matter alteration of the superior longitudinal fascicle. In an explorative tract-based correlation analysis within the GAD-LE group, only a correlation between the left/right ratio of FC values of the superior longitudinal fascicle and verbal memory performance (R = 0.64, Holm-Bonferroni corrected p < 0.048) remained significant after correcting for multiple comparisons. Our results underscore the concept of LE as a disease comprising a broad and heterogeneous group of entities and contribute novel aspects to the pathomechanistic understanding of this disease that may strengthen the role of MRI in the diagnosis of LE.
Cancer‐associated venous thromboembolism (VTE) is a frequent, potentially life‐threatening event that complicates cancer management. Anticoagulants are the cornerstone of therapy for the treatment and prevention of cancer‐associated thrombosis (CAT); factor Xa–inhibiting direct oral anticoagulants (DOACs; apixaban, edoxaban, and rivaroxaban), which have long been recommended for the treatment of VTE in patients without cancer, have been investigated in this setting. The first randomized comparisons of DOACs against low‐molecular‐weight heparin for the treatment of CAT indicated that DOACs are efficacious in this setting, with findings reflected in recent updates to published guidance on CAT treatment. However, the higher risk of bleeding events (particularly in the gastrointestinal tract) with DOACs highlights the need for appropriate patient selection. Further insights will be gained from additional studies that are ongoing or awaiting publication. The efficacy and safety of DOAC thromboprophylaxis in ambulatory patients with cancer at a high risk of VTE have also been assessed in placebo‐controlled randomized controlled trials of apixaban and rivaroxaban. Both studies showed efficacy benefits with DOACs, but both studies also showed a nonsignificant increase in major bleeding events while on treatment. This review summarizes the evidence base for rivaroxaban use in CAT, the patient profile potentially most suited to DOAC use, and ongoing controversies under investigation. We also describe ongoing studies from the CALLISTO (Cancer Associated thrombosis—expLoring soLutions for patients through Treatment and Prevention with RivarOxaban) program, which comprises several randomized clinical trials and real‐world evidence studies, including investigator‐initiated research.
Bauersachs, Rupert ; Wu, Olivia ; Briere, Jean-Baptiste ; Bowrin, Kevin ; Borkowska, Katarzyna ; Jakubowska, Anna ; Taieb, Vanessa ; Toumi, Mondher ; Huelsebeck, Maria
Aims: Acetylsalicylic acid (ASA) is widely used for the prevention of atherothrombotic events in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD), but the risk of vascular events remains high. We aimed at identifying randomised controlled trials (RCTs) on antithrombotic treatments in patients with chronic CAD or PAD.
Methods: Searches were conducted on MEDLINE, EMBASE, and CENTRAL on March 1st, 2018. This systematic review (SR) uses a narrative synthesis to summarize the evidence for the efficacy and safety of antiplatelet and anticoagulant therapies in the population of both chronic CAD or PAD patients.
Results: Four RCTs from 27 publications were included. Study groups included 15,603 to 27,395 patients. ASA alone was the most extensively studied (n = 3); other studies included rivaroxaban with or without ASA (n = 1), vorapaxar alone (n = 1), and clopidogrel with (n = 1) or without ASA (n = 1). Clopidogrel alone and clopidogrel plus ASA compared to ASA presented similar efficacy with comparable safety profile. Rivaroxaban plus ASA significantly reduced the risk of the composite of cardiovascular death, myocardial infarction, and stroke compared to ASA alone, although major bleeding with rivaroxaban plus ASA increased.
Conclusion: There is limited and heterogeneous evidence on the prevention of atherothrombotic events in patients with chronic CAD or PAD. Clopidogrel alone and clopidogrel plus ASA did not demonstrate superiority over ASA alone. A combination of rivaroxaban plus ASA may offer significant additional benefit in reducing cardiovascular outcomes, yet it may increase the risk of bleeding, compared to ASA alone.
Diese Bachelorarbeit befasst sich mit der Themenklassifikation von unstrukturiertem Text. Aufgrund der stetig steigenden Menge von textbasierten Daten werden automatisierte Klassifikationsmethoden in vielen Disziplinen benötigt und erforscht. Aufbauend auf dem text2ddc-Klassifikator, der am Text Technology Lab der Goethe-Universität Frankfurt am Main entwickelt wurde, werden die Auswirkungen der Vergrößerung des Trainingskorpus mittels unterschiedlicher Methoden untersucht. text2ddc nutzt die Dewey Decimal Classification (DDC) als Zielklassifikation und wird trainiert auf Artikeln der Wikipedia. Nach einer Einführung, in der Grundlagen beschrieben werden, wird das Klassifikationsmodell von text2ddc vorgestellt, sowie die Probleme und daraus resultierenden Aufgaben betrachtet. Danach wird die Aktualisierung der bisherigen Daten beschrieben, gefolgt von der Vorstellung der verschiedenen Methoden, das Trainingskorpus zu erweitern. Mit insgesamt elf Sprachen wird experimentiert. Die Evaluation zeigt abschließend die Verbesserungen der Qualität der Klassifikation mit text2ddc auf, diskutiert die problematischen Fälle und gibt Anregungen für weitere zukünftige Arbeiten.
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.
Baumgarten, Nina ; Schmidt, Florian ; Wegner, Martin ; Hebel, Marie ; Kaulich, Manuel ; Schulz, Marcel Holger
Genome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.
In Offenbach am Main wurde im Herbst 2018 eine Fahrradstraßen-Teststrecke eröffnet, die Teil des Vorhabens ist, die Stadt fahrradfreundlicher zu gestalten. Um herauszufinden, inwiefern das Design dieser Teststrecke einen Einfluss darauf ausübt, wie die Fahrradstraße von den Verkehrsteilnehmenden wahrgenommen und genutzt wird, wurden im Rahmen dieser Forschungsarbeit im Mai 2019 zwei Fokusgruppengespräche mit Nutzer*innen durchgeführt. In den Fokusgruppen wurden unter der Betrachtung der Fragestellung unterschiedliche Konzeptvorschläge der Offenbacher Hochschule für Gestaltung (HfG) thematisiert. In der Forschungsarbeit wird herausgearbeitet, wieso es sinnvoll ist, das Design der gebauten Umwelt näher zu betrachten und vor allem es gezielt zu verändern, wenn es darum geht, mehr Stadtbewohner*innen zum Fahrradfahren und hiermit zu einem umweltfreundlicheren Fortbewegen zu motivieren. Basierend auf den Ausführungen von JENSEN (2014, 2016) zum Mobilitätsdesign und unter Verwendung seines staging mobilities frameworks konnten die Erfahrungen der Teilnehmenden der Fokusgruppen ausgewertet und erste Aussagen über den Einfluss des Designs auf die Wahrnehmung und Nutzung der Teststrecke getroffen werden.
This research examines the impact of online display advertising and paid search advertising relative to offline advertising on firm performance and firm value. Using proprietary data on annualized advertising expenditures for 1651 firms spanning seven years, we document that both display advertising and paid search advertising exhibit positive effects on firm performance (measured by sales) and firm value (measured by Tobin's q). Paid search advertising has a more positive effect on sales than offline advertising, consistent with paid search being closest to the actual purchase decision and having enhanced targeting abilities. Display advertising exhibits a relatively more positive effect on Tobin's q than offline advertising, consistent with its long-term effects. The findings suggest heterogeneous economic benefits across different types of advertising, with direct implications for managers in analyzing advertising effectiveness and external stakeholders in assessing firm performance.
The most frequently used boundary-layer turbulence parameterization in numerical weather prediction (NWP) models are turbulence kinetic energy (TKE) based-based schemes. However, these parameterizations suffer from a potential weakness, namely the strong dependence on an ad-hoc quantity, the so-called turbulence length scale. The physical interpretation of the turbulence length scale is difficult and hence it cannot be directly related to measurements or large eddy simulation (LES) data. Consequently, formulations for the turbulence length scale in basically all TKE schemes are based on simplified assumptions and are model-dependent. A good reference for the independent evaluation of the turbulence length scale expression for NWP modeling is missing. Here we propose a new turbulence length scale diagnostic which can be used in the gray zone of turbulence without modifying the underlying TKE turbulence scheme. The new diagnostic is based on the TKE budget: The core idea is to encapsulate the sum of the molecular dissipation and the cross-scale TKE transfer into an effective dissipation, and associate it with the new turbulence length scale. This effective dissipation can then be calculated as a residuum in the TKE budget equation (for horizontal sub-domains of different sizes) using LES data. Estimation of the scale dependence of the diagnosed turbulence length scale using this novel method is presented for several idealized cases.
Die extrem hohen Interaktionsraten, die mit dem CBM Experiment verfügbar sein werden, erlauben die Messung von einigen der herausfordensten Observablen im Feld der Schwerionenphysik. Im besonderen die Messung von Dileptonen im mittleren Massenbereich ist nahezu unmöglich für eine Vielzahl anderer Experimente, da die extrem kleinen Wirkungsquerschnitte der Produktionskanäle das Auftreten eines messbaren Ereignisses so selten machen, so dass es nicht möglich ist eine ausreichende Anzahl dieser Ereignisse zu messen. Hinzu kommt, dass speziell im Energiebereich des CBM Experiments bisher absolut keine Messdaten verfügbar sind, obwohl es zahlreiche Hinweise von theoretischer Seite und von Messungen bei größeren Kollisionsenergien darauf gibt, dass wir im Energiebereich des CBM Experiments bedeutende Entdeckungen machen k¨onnten. Eine solche Messung dieser Observable könnte einen direkten Zugang zu Informationen bezüglich eines potentiellen Phasenubergangs von hadronischer Materie (bzw. im Hadronengas) in den Zustand eines Quark-Gluonen Plasmas liefern. Zusätzlich bieten Dileptonen noch die Möglichkeit Indikatoren für eine Wiederherstellung der chiralen Symmetrie zu messen...
The Specialised Information Service Performing Arts (SIS PA) is part of a funding programme by the German Research Foundation that enables libraries to develop tailor-made services for individual disciplines in order to provide researchers direct access to relevant materials and resources from their field. For the field of performing arts, the SIS PA is aggregating metadata about theater and dance resources from currently, mostly, German-speaking cultural heritage institutions in a VuFind-based search portal.
In this article, we focus on metadata quality and its impact on the aggregation workflow by describing the different, possibly data provider-specific, process stages of improving data quality in order to achieve a searchable, interlinked knowledge base. We also describe lessons learned and limitations of the process.
Becker, Jeremias M. ; Ganatra, Akbar A. ; Kandie, Faith Jebiwot ; Mühlbauer, Lina ; Ahlheim, Jörg ; Brack, Werner ; Torto, Baldwyn ; Agola, Eric L. ; McOdimba, Francis ; Hollert, Henner ; Fillinger, Ulrike ; Liess, Matthias
Schistosomiasis is a severe neglected tropical disease caused by trematodes and transmitted by freshwater snails. Snails are known to be highly tolerant to agricultural pesticides. However, little attention has been paid to the ecological consequences of pesticide pollution in areas endemic for schistosomiasis, where people live in close contact with non-sanitized freshwaters. In complementary laboratory and field studies on Kenyan inland areas along Lake Victoria, we show that pesticide pollution is a major driver in increasing the occurrence of host snails and thus the risk of schistosomiasis transmission. In the laboratory, snails showed higher insecticide tolerance to commonly found pesticides than associated invertebrates, in particular to the neonicotinoid Imidacloprid and the organophosphate Diazinon. In the field, we demonstrated at 48 sites that snails were present exclusively in habitats characterized by pesticide pollution and eutrophication. Our analysis revealed that insensitive snails dominated over their less tolerant competitors. The study shows for the first time that in the field, pesticide concentrations considered “safe” in environmental risk assessment have indirect effects on human health. Thus we conclude there is a need for rethinking the environmental risk of low pesticide concentrations and of integrating agricultural mitigation measures in the control of schistosomiasis.
Becker, Yvonne ; Roth, Sina ; Scheurer, Maximilian ; Jakob, Andreas ; Gacek, Daniel A. ; Walla, Peter Jomo ; Dreuw, Andreas ; Wachtveitl, Josef ; Heckel, Alexander
We developed three bathochromic, green-light activatable, photolabile protecting groups based on a nitrodibenzofuran (NDBF) core with D-π-A push–pull structures. Variation of donor substituents (D) at the favored ring position enabled us to observe their impact on the photolysis quantum yields. Comparing our new azetidinyl-NDBF (Az-NDBF) photolabile protecting group with our earlier published DMA-NDBF, we obtained insight into its excitation-specific photochemistry. While the “two-photon-only” cage DMA-NDBF was inert against one-photon excitation (1PE) in the visible spectral range, we were able to efficiently release glutamic acid from azetidinyl-NDBF with irradiation at 420 and 530 nm. Thus, a minimal change (a cyclization adding only one carbon atom) resulted in a drastically changed photochemical behavior, which enables photolysis in the green part of the spectrum.
Animals extract behaviorally relevant signals from “noisy” environments. To investigate signal extraction, echolocating provides a rich system testbed. For orientation, bats broadcast calls and assign each echo to the corresponding call. When orienting in acoustically enriched environments or when approaching targets, bats change their spectro-temporal call design. Thus, to assess call adjustments that are exclusively meant to facilitate signal extraction in “noisy” environments, it is necessary to control for distance-dependent call changes. By swinging bats in a pendulum, we tested the influence of acoustic playback on the echolocation behavior of Carollia perspicillata. This paradigm evokes reproducible orientation behavior and allows a precise definition of the influence of the acoustic context. Our results show that bats dynamically switch between different adaptations to cope with sound-based navigation in acoustically contaminated environments. These dynamics of echolocation behavior may explain the large variety of adaptations that have been reported in the bat literature.
In recent decades, the assessment of instructional quality has grown into a popular and well-funded arm of educational research. The present study contributes to this field by exploring first impressions of untrained raters as an innovative approach of assessment. We apply the thin slice procedure to obtain ratings of instructional quality along the dimensions of cognitive activation, classroom management, and constructive support based on only 30 s of classroom observations. Ratings were compared to the longitudinal data of students taught in the videos to investigate the connections between the brief glimpses into instructional quality and student learning. In addition, we included samples of raters with different backgrounds (university students, middle school students and educational research experts) to understand the differences in thin slice ratings with respect to their predictive power regarding student learning. Results suggest that each group provides reliable ratings, as measured by a high degree of agreement between raters, as well predictive ratings with respect to students’ learning. Furthermore, we find experts’ and middle school students’ ratings of classroom management and constructive support, respectively, explain unique components of variance in student test scores. This incremental validity can be explained with the amount of implicit knowledge (experts) and an attunement to assess specific cues that is attributable to an emotional involvement (students).
Behmanesh, Bedjan ; Geßler, Florian ; Quick-Weller, Johanna ; Dubinski, Daniel ; Konczalla, Jürgen ; Seifert, Volker ; Setzer, Matthias ; Weise, Lutz
Objective: Spinal epidural abscess (SEA) is a severe and life-threatening disease. Although commonly performed, the effect of timing in surgical treatment on patient outcome is still unclear. With this study, we aim to provide evidence for early surgical treatment in patients with SEA.
Methods: Patients treated for SEA in the authors' department between 2007 and 2016 were included for analysis and retrospectively analyzed for basic clinical parameters and outcome. Pre- and postoperative neurological status were assessed using the American Spinal Injury Association Impairment Scale (AIS). The self-reported quality of life (QOL) based on the Short-Form Health Survey 36 (SF-36) was assessed prospectively. Surgery was defined as "early", when performed within 12 hours after admission and "late" when performed thereafter. Conservative therapy was preferred and recommend in patients without neurological deficits and in patients denying surgical intervention.
Results: One hundred and twenty-three patients were included in this study. Forty-nine patients (39.8%) underwent early, 47 patients (38.2%) delayed surgery and 27 (21.9%) conservative therapy. No significant differences were observed regarding mean age, sex, diabetes, prior history of spinal infection, and bony destruction. Patients undergoing early surgery revealed a significant better clinical outcome before discharge than patients undergoing late surgery (p=0.001) and conservative therapy. QOL based on SF-36 were significantly better in the early surgery cohort in two of four physical items (physical functioning and bodily pain) and in one of four psychological items (role limitation) after a mean follow-up period of 58 months. Readmission to the hospital and failure of conservative therapy were observed more often in patients undergoing conservative therapy.
Conclusion: Our data on both clinical outcome and QOL provide evidence for early surgery within 12 hours after admission in patients with SEA.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma with a preserved B‐cell phenotype and follicular T helper (TFH) cells rosetting around the tumor cells, the lymphocyte‐predominant (LP) cells. As we recently described reactivity of the B‐cell receptors of LP cells of some NLPHL cases with Moraxella spp. proteins, we hypothesized that LP cells could present peptides to rosetting T cells in a major histocompatibility complex class II (MHCII)‐bound manner. Rosetting PD1+ T cells were present in the majority of NLPHL cases, both in typical (17/20) and variant patterns (16/19). In most cases, T‐cell rosettes were CD69+ (typical NLPHL, 17/20; NLPHL variant, 14/19). Furthermore, both MHCII alpha and beta chains were expressed in the LP cells in 23/39 NLPHL. Proximity ligation assay and confocal laser imaging demonstrated interaction of the MHCII beta chain expressed by the LP cells and the T‐cell receptor alpha chain expressed by rosetting T cells. We thus conclude that rosetting T cells in NLPHL express markers that are encountered after antigenic exposure, that MHCII is expressed by the LP cells, and that LP cells interact with rosetting T cells in an immunological synapse in a subset of cases. As they likely receive growth stimulatory signals in this way, blockade of this interaction, for example, by PD1‐directed checkpoint inhibitors, could be a treatment option in a subset of cases in the future.
We show that High Frequency Traders (HFTs) are not beneficial to the stock market during flash crashes. They actually consume liquidity when it is most needed, even when they are rewarded by the exchange to provide immediacy. The behavior of HFTs exacerbate the transient price impact, unrelated to fundamentals, typically observed during a flash crash. Slow traders provide liquidity instead of HFTs, taking advantage of the discounted price. We thus uncover a trade-o↵ between the greater liquidity and efficiency provided by HFTs in normal times, and the disruptive consequences of their trading activity during distressed times.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physicochemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein–protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low-complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS-LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model. For a scaling factor α = 0.65, we recover experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS-LCD condenses. In the region of phase separation, we simulate FUS-LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS-LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01–0.4 mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02 Pa s for the FUS-LCD droplets with scaling factors α in the range of 0.625–0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Our primary objective is to construct a plausible, unified model of inflation, dark energy and dark matter from a fundamental Lagrangian action first principle, wherein all fundamental ingredients are systematically dynamically generated starting from a very simple model of modified gravity interacting with a single scalar field employing the formalism of non-Riemannian spacetime volume-elements. The non-Riemannian volume element in the initial scalar field action leads to a hidden, nonlinear Noether symmetry which produces an energy-momentum tensor identified as the sum of a dynamically generated cosmological constant and dust-like dark matter. The non-Riemannian volume-element in the initial Einstein–Hilbert action upon passage to the physical Einstein-frame creates, dynamically, a second scalar field with a non-trivial inflationary potential and with an additional interaction with the dynamically generated dark matter. The resulting Einstein-frame action describes a fully dynamically generated inflationary model coupled to dark matter. Numerical results for observables such as the scalar power spectral index and the tensor-to-scalar ratio conform to the latest 2018 PLANCK data.
First, we propose a scale-invariant modified gravity interacting with a neutral scalar inflaton and a Higgs-like SU(2)×U(1) iso-doublet scalar field based on the formalism of non-Riemannian (metric-independent) spacetime volume-elements. This model describes, in the physical Einstein frame, a quintessential inflationary scenario driven by the “inflaton” together with the gravity-“inflaton” assisted dynamical spontaneous SU(2)×U(1) symmetry breaking in the post-inflationary universe, whereas the SU(2)×U(1) symmetry remains intact in the inflationary epoch. Next, we find the explicit representation of the latter quintessential inflationary model with a dynamical Higgs effect as an Eddington-type purely affine gravity.
Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis
(2020)
Benz, Fabian ; Bogen, Andreas ; Praktiknjo, Michael ; Jansen, Christian ; Meyer, Carsten ; Wree, Alexander ; Demir, Münevver ; Loosen, Sven ; Vucur, Mihael ; Schierwagen, Robert ; Tacke, Frank ; Trebicka, Jonel ; Roderburg, Christoph
Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.
Human protein kinases play essential roles in cellular signaling pathways and - if deregulated - are linked to a large diversity of diseases such as cancer and inflammation or to metabolic diseases. Because of their key role in disease development or progression, kinases have developed into major drug targets resulting in the approval of 52 kinase inhibitors by the Food and Drug Administration (FDA) so far.
Within the drug discovery process, the affinity of the inhibitors is the parameter that is used most often to predict the later efficacy in humans. However, the kinetics of binding have recently emerged as an important but largely neglected factor of kinase inhibitor efficacy. To efficiently suppress a signaling pathway, the targeted kinase needs to be continuously inhibited. Thus, it has been hypothesized that fast binding on-rates and slow off-rates would be the preferred property of an efficacious inhibitor. Despite optimizing the potency of kinase inhibitors, in the past decade optimization of kinetic selectivity has therefore gained interest as a molecule cannot be active unless it is bound, as Paul Ehrlich once stated. There is increasing evidence of correlations between prolonged drug-target residence time and increased drug efficacy, and that inhibitor selectivity in cellular contexts can be modulated by altered residence times. In order to contribute to the understanding of the effect of long residence times on cellular targets we initiated two projects.
The first of these projects is related to the STE20 kinase Serine/threonine kinase 10 (STK10) and its close relative STE20 like kinase (SLK) which have been reported to be frequent off-targets for kinase inhibitors used in the clinics. Also, an inhibition of STK10 and SLK has been linked to a common side-effect of severe skin rash developed upon treatment with the EGFR inhibitor erlotinib, but not gefitinib and the severity of this rash correlated with the treatment outcome, which fits the known biology of STK10 and SLK to be regulators of lymphocyte migration and PLK kinases. However, there are yet no explanations why these two proteins show such high hit-rates across the kinome among the kinase inhibitors. Using structural analysis, we identified the flexibility of STK10 to be the main reason for this hit-rate. The observed strong in vitro potencies did however not translate to the cellular system which is why we investigated the inhibitors residence time on STK10. We found the same flexibility to be the main reason for slow residence times among several inhibitors. We observed large rearrangements in the hydrophobic backpocket of STK10 including the αC, the P-loop enclosing the inhibitor like a lid and strong π-π-stackings to be the main reasons for prolonged residence times on STK10. Interestingly, we observed an increased residence time for erlotinib, which showed skin-related side-effects, giving rise whether the binding kinetics should be investigated for weak cellular off-target effects in future drug discovery efforts.
In the second project we initiated, we illuminate a structural mechanism that allows kinetic selection between two closely related kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). Using an inhibitor series designed to probe the mechanism, residence times measured in vitro and in cells showed a strong correlation. Crystal structures and mutagenesis identified hydrophobic interactions with L567, adjacent to the DFG-motif, as being crucial to kinetic selectivity of FAK over PYK2. This specific interaction was observed only when the DFG-motif was stabilized into a helical conformation upon ligand binding to FAK. The interplay between the protein structural mobility and ligand-induced effect was found to be the key regulator of kinetic inhibitor selectivity for FAK over PYK2.
These two projects showed that the parameter residence time should be considered for different problems among the drug discovery process. First, in an open in vivo system not only the potency of a drug alone, but as well its residence time might be of importance. Here we showed that the weak cellular potency translated to prolonged residence times for several inhibitors in cells and established a link between the phenotypic outcome of skin rash after erlotinib treatment and the residence time of this inhibitor on STK10 in cells. On the other hand, medicinal chemistry efforts should consider structure kinetic relationships (SKR) in the optimization process and aim to understand the molecular basis for prolonged target residence times. Here, we showed that a hydrophobic interaction that is enforced upon inhibitor binding is crucial for an unusual helical DFG conformation which arrests the inhibitor and prolongs its residence time providing the molecular basis for understanding the kinetic selectivity of two closely related protein kinases. Establishing the SKRs will help medicinal chemists to kinetically optimize their drug candidates to select a suitable molecule to proceed into further optimization programs. Hence, the projects showed that the target residence time parameter needs to be considered both as a molecular optimization parameter to improve compound potency and binding behavior as well as a parameter to be understood for proceeding to the open system of in vivo models to later modulate the in vivo efficacy of protein kinase targeting drugs.
Das PCOS ist die häufigste Endokrinopathie fertiler Frauen, die mit Infertilität und Metabolischem Syndrom ernst zu nehmende und belastende Konsequenzen haben kann. Vor dem Hintergrund einer bis heute teilweise unklaren Ätiopathogenese hat das PCOS umfassende Auswirkungen auf den Metabolismus und die Reproduktion. Aufgrund der phänotypischen Variabilität ist die Festlegung einheitlicher diagnostischer Kriterien ständiges Thema in der PCOS-Forschung. Die Rotterdam-Kriterien gelten aktuell als angemessenste Definition. Die Einführung einer aktuali- sierten Nomenklatur zur Optimierung der Diagnosefindung wird diskutiert. Die Therapie beläuft sich bisher auf symptomatische Ansätze.
Ziel dieser Arbeit war es, erstmals eine Analyse der weltweiten Forschung zum PCOS mittels szientometrischer Parameter durchzuführen. Die Erfassung der Daten aus dem WoS belief sich auf die Jahre 1900 – 2015 und ergab 6.262 Artikel zum Thema PCOS.
Die meisten Publikationen kamen aus den USA an erster, Großbritannien an zweiter und Italien an dritter Stelle. Diese drei Länder erhielten in gleicher Platzierung die meisten Zitierungen und erreichten die höchsten modifizierten h-Indizes. Bei Betrachtung der Zr standen jedoch die Niederlande aufgrund der dort veröffentlichten Rotterdam-Kriterien an erster Stelle. Im Verhältnis zur Einwohnerzahl publizierte Griechenland die meisten Artikel, gefolgt von Finnland und Slowenien. Bei Erstellung eines Quotienten aus Artikelanzahl und BIP lag Serbien vor Griechenland und Slowenien. Bezüglich der Artikel pro BIP p.c. fiel China auf den ersten Rang, danach die Türkei und die USA.
Bei den Fachzeitschriften rangierte das Journal of Clinical Endocrinology & Metabolism bezüglich des IF, der Zr und der Anzahl der Zitierungen an erster Stelle. Fertility & Sterility publizierte über die Zeit die meisten Artikel zum Thema PCOS und erlangte die zweithöchste Zahl an Zitierungen.
Die chronologische Analyse zeigt eine Abnahme der Zuteilung von Artikeln zum Fachgebiet Obstetrics & Gynecology und eine Zunahme von Reproductive Biology, während Endocrinology & Metabolism einen gleichbleibenden Anteil hat. Der Anteil kleinerer Fächer wie Research & Experimental, Nutrition & Dietetics und Pharmacy nimmt über die letzten zehn Jahre zu.
Bezüglich der Anzahl an Institutionen liegen die Türkei und Großbritannien auf Platz zwei und drei hinter den USA. Die produktivsten Forschungseinrichtungen sind die University of London, die Pennsylvania State University und die University of Athens. In der italienischen Forschungsgemeinde finden sich die meisten interinstitutionellen Kooperationen.
Die meisten Artikel, auch in Erst- und Koautorenschaft, hat R.S.Legro publiziert. S. Franks führt die Liste der Seniorautoren an. A. Dunaif erreicht bei Zitierungen, Zitationsrate und modifiziertem h-Index herausragende Werte. Wie schon bei den Institutionen liegen italienische Autoren bei der Kooperationsanalyse vorne. Unter den zehn produktionsstärksten Institutions- kooperationen finden sich mit einer griechischen und einer US-amerikanischen Liaison nur zwei nicht italienischen Ursprungs. Zum Zitierverhalten ist zu sagen, dass fast 50 % der Zitierungen Selbstzitierungen sind.
Generell dominieren Männer noch die Welt der Wissenschaft. Dies ist, in Bezug auf die PCOS-Forschung, zu jedem Zeitpunkt so gewesen und spiegelt sich bis heute in den Analysen wider. Seit 2008 ist allerdings eine Annäherung der Werte zu beobachten.
Es kristallisiert sich die Notwendigkeit einer klaren Definition und aktualisierter Nomenklatur des PCOS heraus, um die leicht stagnierende Forschung des komplexen Krankheitsbildes, dessen Ätiopathogenese nicht zur Gänze erklärt ist, anzustoßen. Überraschenderweise treten Nationen wie die Türkei, Griechenland und der Iran bei den Analysen hervor und reichen mit Produktivität und Resonanz an Staaten wie die USA und Großbritannien heran, übertreffen sie mitunter. Dies ist möglicherweise nationalen Besonderheiten, wie erhöhter Prävalenz des Syndroms bzw. erhöhtem sozialen Druck durch das Kardinalsymptom der Infertilität in diesen Ländern, geschuldet. Eine Dominanz an weiblichen Forscherinnen zeigt sich überdies im Iran und ist sonst in nur wenigen Ländern, darunter die USA, zu finden. Männliche Vorherrschaft ist also weniger an bestimmte Regionen, als vielmehr an nationale Strukturen gebunden.
Kognitive Beeinträchtigungen (KB) sind ein häufiges Symptom bei Patienten mit Multipler Sklerose (MS). Diese führen im Alltags- und Berufsleben oft zu Einschränkungen. In der Standarddiagnostik der Multiplen Sklerose fehlt es aktuell an validierten, zeitsparenden, kostengünstigen sowie sprach- und bildungsunabhängigen Screening-Verfahren von KB. Ziel des Screenings ist es zu diskriminieren, welche Patienten einer ausführlichen neuropsychologischen Diagnostik unterzogen werden sollten. Als mögliche neue Screening-Verfahren wurden erstens die Sound-induced Flash Illusion (SiFI) als Paradigma multisensorischer Integration und zweitens das visuelle Suchverhalten anhand von Bildern natürlicher Umgebungen mit Hilfe der Technik des Eyetrackings (ET) verwendet.
Mittels SiFI wurden 39 Patienten mit schubförmiger (relapsing-remitting) MS (RRMS) und 16 primär- bzw. sekundär-progrediente (progressive) MS-Patienten (PMS) versus 40 gesunde Kontrollen (healthy controls, HC) auf eine verlängerte Perzeption der Illusion getestet. Im ET Versuch wurden 36 RRMS- und 12 PMS-Patienten versus 39 HC auf abweichende Fixationszeiten und Genauigkeiten untersucht. Um Zusammenhänge zwischen den Testleistungen der SiFI bzw. des ET und kognitiven Beeinträchtigungen herstellen zu können, wurde eine ausführliche neuropsychologische Testung durchgeführt.
Insgesamt nahmen MS-Patienten die Illusion der SiFI häufiger wahr als HC. Insbesondere PMS-Patienten erfuhren die Illusion bei großen Interstimulus-Intervallen signifikant öfter als HC. Zusätzlich ist bei MS-Patienten eine erhöhte Prädisposition, die Illusion der SiFI wahrzunehmen mit einem unterdurchschnittlichen Abschneiden in der neuropsychologischen Testung assoziiert. Des Weiteren ist die SiFI sprach- und bildungsunabhängig, kostengünstig und unterliegt bei Mehrfachtestung keiner Lerneffekte.
Beim ET zeigten MS-Patienten im Vergleich zu HC signifikant veränderte Fixationszeiten und reduzierte Genauigkeiten bei der Betrachtung von Bildern natürlicher Umgebungen. Beeinträchtigtes visuelles Suchverhalten war ein Prädiktor für eine verlangsamte Informationsverarbeitungsgeschwindigkeit in der neuropsychologischen Testung. Zudem konnte anhand der ET-Daten zwischen RRMS- und PMS-Patienten diskriminiert werden.
Zusammenfassend bestätigte die Studie, dass durch die SiFI erfasste multisensorische Integration und durch ET analysiertes visuelles Suchverhalten geeignet sind, um KB bei MS-Patienten zu screenen. Insbesondere lieferte die Testleistung der SiFI einen robusten Bezug zum Abschneiden in der neuropsychologischen Testung. Gleichzeitig war durch die Analyse von visuellem Suchverhalten eine Vorhersage über den Krankheitsprogress möglich. Diese Forschungsergebnisse liefern Evidenz, um beide Methoden nach ergänzender Forschungsarbeit potentiell in den klinischen Alltag integrieren zu können. Eine frühe Detektion von KB bei MS-Patienten ist von hoher Relevanz, um lange eine hohe Lebensqualität zu gewährleisten. Daher können Erkenntnisse dieser Studie genutzt werden, um den Krankheitsverlauf langfristig positiv zu beeinflussen.
Bergmann, Lothar ; Grünwald, Viktor ; Maute, Luise ; Grimm, Marc-Oliver ; Weikert, Steffen ; Schleicher, Jan ; Klotz, Theodor ; Greiner, Jochen ; Flörcken, Anne ; Hartmann, Arndt ; Gauler, Thomas
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
Heute sterben zehn- bis hundertmal mehr Arten aus, als dies ohne die massiven Einflüsse des Menschen auf das System »Erde«der Fall wäre. Der Artenforscher Matthias Schleuning untersucht, wie Pflanzen und Tiere in komplexen Ökosystemen voneinander abhängen. Damit kann er voraussagen, wer zu den Gewinnern und den Verlierern von Klimawandel und stärkerer Landnutzung werden wird.
Bernatz, Simon ; Ackermann, Jörg ; Mandel, Philipp ; Kaltenbach, Benjamin ; Zhdanovich, Yauheniya ; Harter, Patrick Nikolaus ; Döring, Claudia ; Hammerstingl, Renate Maria ; Bodelle, Boris ; Smith, Kevin ; Bucher, Andreas ; Albrecht, Moritz Hans Ernst ; Rosbach, Nicolas ; Basten, Lajos Maximilian ; Yel, Ibrahim ; Wenzel, Mike ; Bankov, Katrin ; Koch, Ina ; Chun, Felix ; Köllermann, Jens ; Wild, Peter Johannes ; Vogl, Thomas J.
Objectives: To analyze the performance of radiological assessment categories and quantitative computational analysis of apparent diffusion coefficient (ADC) maps using variant machine learning algorithms to differentiate clinically significant versus insignificant prostate cancer (PCa). Methods: Retrospectively, 73 patients were included in the study. The patients (mean age, 66.3 ± 7.6 years) were examined with multiparametric MRI (mpMRI) prior to radical prostatectomy (n = 33) or targeted biopsy (n = 40). The index lesion was annotated in MRI ADC and the equivalent histologic slides according to the highest Gleason Grade Group (GrG). Volumes of interest (VOIs) were determined for each lesion and normal-appearing peripheral zone. VOIs were processed by radiomic analysis. For the classification of lesions according to their clinical significance (GrG ≥ 3), principal component (PC) analysis, univariate analysis (UA) with consecutive support vector machines, neural networks, and random forest analysis were performed. Results: PC analysis discriminated between benign and malignant prostate tissue. PC evaluation yielded no stratification of PCa lesions according to their clinical significance, but UA revealed differences in clinical assessment categories and radiomic features. We trained three classification models with fifteen feature subsets. We identified a subset of shape features which improved the diagnostic accuracy of the clinical assessment categories (maximum increase in diagnostic accuracy ΔAUC = + 0.05, p < 0.001) while also identifying combinations of features and models which reduced overall accuracy. Conclusions: The impact of radiomic features to differentiate PCa lesions according to their clinical significance remains controversial. It depends on feature selection and the employed machine learning algorithms. It can result in improvement or reduction of diagnostic performance.
he Pauli Exclusion Principle (PEP) is one of the most basic concepts in physics, but also the most difficult to implement in many-fermion systems, which are common in nuclear physics. To investigate the consequences of ignoring the PEP, we discuss several algebraic models in nuclear structure physics, in particular cluster models. Sometimes they tend to ignore the Pauli Exclusion Principle for practical reasons, leading to flawed interpretations. Though at first sight there seems to be an agreement to experiment, often it is due to the limited number of states known experimentally. We discuss several models which include or not the PEP, illustrating through their differences the importance of the PEP. This contribution is also a review of recently published results.
Ausgehend von spezifischen Anforderungen inklusiver Settings wird in diesem Beitrag ein Ansatz zur Weiterentwicklung des Modells der professionellen Handlungskompetenz von Lehrkräften für inklusiven (Mathematik-)Unterricht vorgestellt. Inklusion wird dabei verstanden als fachliches Lernen und gemeinsame Teilhabe aller Schülerinnen und Schüler. Für die Weiterentwicklung werden zunächst Anforderungen durch inklusive Bildung betrachtet, einerseits abgeleitet aus verschiedenen Aufgaben- und Kompetenzkatalogen, andererseits basierend auf Kernbeständen für den Umgang mit Heterogenität im (Mathematik-)Unterricht im Allgemeinen und für inklusiven (Mathematik-)Unterricht im Speziellen. Anschließend wird daraus Wissen zur Bewältigung dieser Anforderungen abgeleitet und unter Rückgriff auf die verschiedenen Bereiche des Professionswissens (Fachwissen, pädagogisches Wissen, fachdidaktisches Wissen, Organisationswissen und Beratungswissen) weiter ausgeführt, wobei der Fokus auf das fachdidaktische Wissen im inklusiven Mathematikunterricht gelegt wird. Die affektiven und motivationalen Merkmale (Überzeugungen, Selbstregulation und Motivation) der professionellen Handlungkompetenz werden ebenfalls in die Weiterentwicklung des Modells einbezogen. Insgesamt erfolgt die Weiterentwicklung des Modells somit im Rahmen einer Erweiterung der einzelnen bestehenden Kompetenzbereiche um Aspekte, die unter Inklusionsgesichtspunkten besondere Bedeutung erfahren. Mit der Identifizierung von Kompetenzbereichen bei Lehrkräften zu Beginn einer Fortbildung zu inklusivem Mathematikunterricht wird ein Beispiel präsentiert, wie das weiterentwickelte Modell angewendet werden kann. In diesem Zusammenhang konnten in den Äußerungen der Lehrkräfte – abgesehen vom Fachwissen – alle Kompetenzbereiche identifiziert werden. Abschließend werden Möglichkeiten vorgestellt, wie das Modell im Kontext der Lehrerprofessionalisierungsforschung weiterhin eingesetzt werden kann.
Volatility clustering and fat tails are prominently observed in financial markets. Here, we analyze the underlying mechanisms of three agent-based models explaining these stylized facts in terms of market instabilities and compare them on empirical grounds. To this end, we first develop a general framework for detecting tail events in stock markets. In particular, we introduce Hawkes processes to automatically identify and date onsets of market turmoils which result in increased volatility. Second, we introduce three different indicators to predict those onsets. Each of the three indicators is derived from and tailored to one of the models, namely quantifying information content, critical slowing down or market risk perception. Finally, we apply our indicators to simulated and real market data. We find that all indicators reliably predict market events on simulated data and clearly distinguish the different models. In contrast, a systematic comparison on the stocks of the Forbes 500 companies shows a markedly lower performance. Overall, predicting the onset of market turmoils appears difficult, yet, over very short time horizons high or rising volatility exhibits some predictive power.
Most living organisms possess varying degrees of regenerative capabilities but how these regenerative processes are controlled is still poorly understood. Naturally occurring bioelectric voltages (like Vmem) are thought to be playing instructive role in tissue regeneration, as well as embryonic development. The different distribution of ions on the either side of the cell membrane results in intra- and extra-cellular voltage differences, known as membrane potential or Vmem. The relationship between Vmem and cell physiology is conserved in a wide range of cell types and suggests that Vmem regulation is a fundamental control mechanism for regeneration related processes e.g., proliferation and differentiation. In the present study we measured Vmem in three different cell types (human osteogenic sarcoma cell line (OSC), rat bone marrow derived mesenchymal stem cells (BM-MSC), and rat dermal fibroblasts) and characterized the relationship between their Vmem and proliferation. In order to find out if Vmem controls proliferation, or visa-versa, we blocked and then unblocked Na+/K+-exchanging ATPase using ouabain and measured the proliferation. Our results demonstrate that Vmem can be pharmacologically manipulated to control proliferation in certain cell types like BM-MSC. Taken together, it is clear that control of bioelectrical properties in non-excitable cells could prove to be potentially a useful tool in regenerative medicine efforts.
This paper documents that resource reallocation across firms is an important mechanism through which creditor rights affect real outcomes. I exploit the staggered adoption of an international convention that provides globally consistent strong creditor protection for aircraft finance. After this reform, country-level productivity in the aviation sector increases by 12%, driven mostly by across-firm reallocation. Productive airlines borrow more, expand, and adopt new technology at the expense of unproductive ones. Such reallocation is facilitated by (i) easier and quicker asset redeployment; and (ii) the influx of foreign financiers offering innovative financial products to improve credit allocative efficiency. I further document an increase in competition and an improvement in the breadth and the quality of products available to consumers.
Biederstädt, Alexander ; Hassan, Zonera ; Schneeweis, Christian ; Schick, Markus ; Schneider, Lara ; Muckenhuber, Alexander ; Hong, Yingfen ; Siegers, Gerrit ; Nilsson, Lisa ; Wirth, Matthias ; Dantes, Zahra ; Steiger, Katja ; Schunck, Kathrin ; Langston, Steve ; Lenhof, Hans-Peter ; Coluccio, Andrea ; Orben, Felix ; Slawska, Jolanta ; Scherger, Anna ; Saur, Dieter ; Müller, Stefan ; Rad, Roland ; Weichert, Wilko ; Nilsson, Jonas ; Reichert, Maximilian ; Schneider, Günter ; Keller, Ulrich
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Bieler, Patrick ; Bister, Milena D. ; Hauer, Janine ; Klausner, Martina ; Niewöhner, Jörg ; Schmid, Christine ; Peter, Sebastian von
In ethnographic research and analysis, reflexivity is vital to achieving constant coordination between field and concept work. However, it has been conceptualized predominantly as an ethnographer’s individual mental capacity. In this article, we draw on ten years of experience in conducting research together with partners from social psychiatry and mental health care across different research projects. We unfold three modes of achieving reflexivity co-laboratively: contrasting and discussing disciplinary concepts in interdisciplinary working groups and feedback workshops; joint data interpretation and writing; and participating in political agenda setting. Engaging these modes reveals reflexivity as a distributed process able to strengthen the ethnographer’s interpretative authority, and also able to constantly push the conceptual boundaries of the participating disciplines and professions.
Risk stratification for bipolar disorder using polygenic risk scores among young high-risk adults
(2020)
Biere, Silvia ; Kranz, Thorsten Manfred ; Matura, Silke ; Petrova, Kristiyana ; Streit, Fabian ; Geburtig-Chiocchetti, Andreas ; Grimm, Oliver ; Brum, Murielle ; Brunkhorst-Kanaan, Nathalie ; Oertel, Viola ; Malyshau, Aliaksandr ; Pfennig, Andrea ; Bauer, Michael ; Schulze, Thomas Gerd ; Kittel-Schneider, Sarah ; Reif, Andreas
Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD.
Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes.
Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls.
Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.
We present novel evidence on the value of cross-border political access. We analyze data on meetings of US multinational enterprises (MNEs) with European Commission (EC) policymakers. Meetings with Commissioners are associated with positive abnormal equity returns. We study channels of value creation through political access in the areas of regulation and taxation. US enterprises with EC meetings are more likely to receive favorable outcomes in their European merger decisions and have lower effective tax rates on foreign income than their peers without meetings. Our results suggest that access to foreign policymakers is of substantial value for MNEs.
Bijanzadeh, Anne ; Hermanns, Ingo ; Ellegast, Rolf Peter ; Fräulin, Laura ; Holzgreve, Fabian Christian ; Mache, Stefanie ; Groneberg, Jan David Alexander ; Ohlendorf, Daniela Maren
Background: The aim of this pilot study was to analyze postures during the work of neurologists with respect to their occupational activities.
Methods: A total data material of 64.8 h (3885.74 min) of nine (three m/six f) neurologists (assistant physicians) was collected. Kinematic data were collected using the CUELA system (electro-goniometry). In addition, the occupational tasks performed on-site were subject to a detailed objective activity analysis. All activities were assigned to the categories "Office activities" (I), "Measures on patients" (II) and "Other activities" (III). The angle values of each body region (evaluation parameters) were evaluated according to ergonomic ISO standards.
Results: Only 3.4% of the working hours were spent with (II), while 50.8% of time was spent with (I) and 45.8% with (III). All tasks of category (II) revealed an increased ergonomic risk to the head, neck, trunk and back areas. During category (I) especially neck and back movements in the sagittal plane showed higher ergonomic risk levels.
Conclusion: Despite frequently performed awkward body positions in (II), the ergonomic risk is considered as rather low, since the percentage time share totaled only 3.4%. As a result, "Office activities" have been detected as high predictor to cause stress load on the musculoskeletal system in the daily work of neurologists.
We analyze the ESG rating criteria used by prominent agencies and show that there is a lack of a commonality in the definition of ESG (i) characteristics, (ii) attributes and (iii) standards in defining E, S and G components. We provide evidence that heterogeneity in rating criteria can lead agencies to have opposite opinions on the same evaluated companies and that agreement across those providers is substantially low. Those alternative definitions of ESG also a↵ect sustainable investments leading to the identification of di↵erent investment universes and consequently to the creation of di↵erent benchmarks. This implies that in the asset management industry it is extremely dicult to measure the ability of a fund manager if financial performances are strongly conditioned by the chosen ESG benchmark. Finally, we find that the disagreement in the scores provided by the rating agencies disperses the e↵ect of preferences of ESG investors on asset prices, to the point that even when there is agreement, it has no impact on financial performances.
In der vorgelegten kumulativen Arbeit wurden strukturelle und funktionale Untersuchungen an Nukleinsäuren durchgeführt, hauptsächlich, aber nicht ausschließlich unter Verwendung von NMR-Spektroskopie (Kernspin Resonanzspektroskopie) als Analysemethode. Die untersuchten Biomoleküle umfassten kleinere und größere biologisch relevante RNAs sowie einen artifiziellen DNA G-Quadruplex. Hierbei konnten Ergebnisse im Bereich der Bestimmung der molekularen Struktur, der Aufklärung der biologischen Funktion und der Wirkstoffentwicklung gewonnen werden, die in sechs verschiedenen Publikationen dargelegt sind, an deren Erstellung der Autor maßgeblich oder hauptverantwortlich beteiligt war. Des Weiteren wird in einem mehrgliedrigen Einleitungssegment auf den Stand der aktuellen Forschung in den jeweiligen Teilgebieten eingegangen.
We present the rapid biophysical characterization of six previously reported putative G‐quadruplex‐forming RNAs from the 5′‐untranslated region (5′‐UTR) of silvestrol‐sensitive transcripts for investigation of their secondary structures. By NMR and CD spectroscopic analysis, we found that only a single sequence—[AGG]2[CGG]2C—folds into a single well‐defined G‐quadruplex structure. Sequences with longer poly‐G strands form unspecific aggregates, whereas CGG‐repeat‐containing sequences exhibit a temperature‐dependent equilibrium between a hairpin and a G‐quadruplex structure. The applied experimental strategy is fast and provides robust readout for G‐quadruplex‐forming capacities of RNA oligomers.
Binas, Oliver ; Jesus, Vanessa de ; Landgraf, Tom ; Völklein, Albrecht Eduard ; Martins, Jason ; Hymon, Daniel ; Bains, Jasleen Kaur ; Berg, Hannes ; Biedenbänder, Thomas ; Fürtig, Boris ; Gande, Santosh Lakshmi ; Niesteruk, Anna ; Oxenfarth, Andreas ; Qureshi, Nusrat ; Schamber, Tatjana ; Schnieders, Robbin ; Tröster, Alix Friederike ; Wacker, Anna ; Wirmer-Bartoschek, Julia ; Wirtz Martin, Maria Alexandra ; Stirnal, Elke ; Azzaoui, Kamal ; Richter, Christian ; Sreeramulu, Sridhar ; Blommers, Marcel Jules José ; Schwalbe, Harald
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
Inspired by the physiology of neuronal systems in the brain, artificial neural networks have become an invaluable tool for machine learning applications. However, their biological realism and theoretical tractability are limited, resulting in poorly understood parameters. We have recently shown that biological neuronal firing rates in response to distributed inputs are largely independent of size, meaning that neurons are typically responsive to the proportion, not the absolute number, of their inputs that are active. Here we introduce such a normalisation, where the strength of a neuron’s afferents is divided by their number, to various sparsely-connected artificial networks. The learning performance is dramatically increased, providing an improvement over other widely-used normalisations in sparse networks. The resulting machine learning tools are universally applicable and biologically inspired, rendering them better understood and more stable in our tests.
The identification of unknown bodies is the fulfilment of a moral obligation towards the deceased, serves to maintain legal security within a society, and gives families the certainty they need to mourn. Taking into account respective local conditions, the aim should always be to achieve a secure and quick identification. To achieve this goal, a functioning cooperation between investigating authorities and forensic sciences is essential. The main objective of this study was to clarify the potential role of tattoos in the identification process of unknown deceased persons in the state of Jalisco, Mexico. Post-mortem data of 2045 bodies from the Instituto Jaliscience de Ciencias Forenses in Guadalajara were evaluated. Of the deceased 46% were tattooed (male: 47%, female: 39%), with 29% of all bodies (male: 29%, female: 26%) showing tattoos at body locations usually visible in everyday life (i.e. head and neck, forearms and hands). The male bodies were most frequently tattooed on the shoulders and upper arms, followed by the forearms and hands and the torso. Female bodies mostly showed tattoos on the forearms and hands, followed by the torso and legs. Taking local tattooing habits into account, the authors developed a classification for tattoo motives. With decreasing frequency, the following keywords could be assigned to the motives: letters and/or numbers, human, symbol (other), plant, symbol (religious), animal, object, tribal/ornament/geometry, fantasy/demon/comic, other. Results of the study indicate the great importance of tattoos as a possible mean of identification in Jalisco, Mexico – either as a stand-alone identification method, as a complementary tool or for planning and prioritizing subsequent investigations.
Accounting for financial stability: Bank disclosure and loss recognition in the financial crisis
(2020)
This paper examines banks’ disclosures and loss recognition in the financial crisis and identifies several core issues for the link between accounting and financial stability. Our analysis suggests that, going into the financial crisis, banks’ disclosures about relevant risk exposures were relatively sparse. Such disclosures came later after major concerns about banks’ exposures had arisen in markets. Similarly, the recognition of loan losses was relatively slow and delayed relative to prevailing market expectations. Among the possible explanations for this evidence, our analysis suggests that banks’ reporting incentives played a key role, which has important implications for bank supervision and the new expected loss model for loan accounting. We also provide evidence that shielding regulatory capital from accounting losses through prudential filters can dampen banks’ incentives for corrective actions. Overall, our analysis reveals several important challenges if accounting and financial reporting are to contribute to financial stability.
Bittner, Vera A. ; Szarek, Michael ; Aylward, Philip E. ; Bhatt, Deepak L. ; Diaz, Rafael ; Edelberg, Jay M. ; Fras, Zlatko ; Goodman, Shaun G. ; Halvorsen, Sigrun ; Hanotin, Corinne ; Harrington, Robert A. ; Jukema, J. Wouter ; Loizeau, Virginie ; Moriarty, Patrick M. ; Moryusef, Angèle ; Pordy, Robert ; Roe, Matthew T. ; Sinnaeve, Peter ; Tsimikas, Sotirios ; Vogel, Robert ; White, Harvey D. ; Zahger, Doron ; Zeiher, Andreas M. ; Schwartz, Gregory G.
Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).
Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).
Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.
Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).
Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
Blank, Martina ; Flug, Matthias ; Hussein, Jason ; Jovanović, Teodora ; Arfaoui, Rafik ; Bianco, Rosella ; Ortiz Cobo, Mónica ; Taccolini Pannagio, Annie ; Gonzalez Benson, Odessa ; Robinson, Daniel B. ; Robinson, Ingrid M. ; Currie, Vanessa ; Hall, Nathan
Blankenbach, Kira Vanessa ; Claas, Ralf Frederik ; Aster, Natalie Judith ; Spohner, Anna Katharina ; Trautmann, Sandra ; Ferreirós Bouzas, Nerea ; Black, Justin L. ; Tesmer, John J. G. ; Offermanns, Stefan ; Wieland, Thomas ; Meyer zu Heringdorf, Dagmar
Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.
The small photoreceptor Photoactive Yellow Protein (PYP) enters a reversible photocycle after excitation with blue light. The intermediate states are formed on timescales ranging from femtoseconds to seconds including chromophore isomerization and protonation as well as large structural rearrangements. To obtain local dynamic information the vibrational label thiocyanate (SCN) can be inserted site-specifically at any desired position in the protein by cysteine mutation and cyanylation. The label's CN stretch vibration is highly sensitive to polarity, hydrogen bonding interactions and electric fields and is spectrally well separated from the overlapping protein absorptions. During the course of this thesis it was impressively demonstrated that the successful incorporation of the SCN label at selected positions in PYP provides a powerful tool to study structure changes and dynamics during the photocycle and enhance the local information that are obtained by infrared (IR) spectroscopic methods. Hence the SCN-labeled protein mutants were studied under equilibrium (steady-state) and non-equilibrium conditions.
Examination of the SCN absorption by FTIR spectroscopy showed the influence of various local environments on the label for different locations in the dark state. The response of the label under illumination with blue light reveals information about structural changes in the signaling state. Additional information for both states were obtained by the vibrational lifetime of the CN vibration measured via ultrafast IR-pump-IR-probe experiments. This observable is particularly sensitive for solvent exposure of the label. Time-resolved IR spectroscopy proved to be an excellent method to follow the protein dynamics throughout most part of the photocycle on a hundreds of femtoseconds to milliseconds timescale. By close inspection of protein and chromophore dynamics in wildtype-PYP over nine decades in time, new insights into the changes leading to the proposed photocycle intermediates were obtained. The investigation of the SCN label allowed to follow the different transient structure changes with high local resolution. Depending on its position within the protein the response of the label provided additional information on the photocycle transitions.
The insights that are obtained by the different observables in the steady-state and by the reaction of the SCN label to formation of the different intermediate states during the photocycle contribute to an improved understanding of local, light-induced structure changes in the photoreceptor PYP. This comprehensive study demonstrated the potential provided by the application of SCN as IR label for investigation of protein dynamics.
Blessing, Recha ; Ahoopai, Majid ; Geyer, Martin ; Brandt, Moritz ; Zeiher, Andreas M. ; Münzel, Thomas ; Wenzel, Philip ; Gori, Tommaso ; Dimitriadis, Zisis
We sought to determine the effects of the use of a Bioengineered Combo Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent (Combo® DTS) in patients with chronic total occlusion (CTO) by evaluating clinical outcomes and by performing an optical coherence tomography (OCT) analysis. We retrospectively analyzed data from 39 patients who had successfully undergone OCT-guided revascularization of a CTO being treated with a Combo® DTS. Clinical assessment, angiography (with quantitative coronary angiography analysis) and OCT examination were performed at baseline and at follow-up. The median follow-up period was 189 days, ranging from 157 to 615 days. At follow-up, revascularization was required due to angiographic restenosis in 40% (14 of 35) of patients. OCT analysis detected neointima proliferation in 23 (76.6%) patients. Neointima formation was often associated with microvessels in 18 patients (60%). Neoatheroslcerosis was observed in 2 (6.6%) patients. Malapposition was found in 4 patients (13.3%), and stent fractures were found in 11 patients (36.6%). Rate of strut coverage was 96.3% at follow-up. In conclusion, the implantation of a Combo® DTS after successful CTO recanalization was associated with a restenosis rate of 40% despite good stent implantation at baseline, proven by OCT. Neointima formation was found as a main contributor to restenosis. Nevertheless, we observed a low rate of major cardiovascular events in our follow-up.
Mit dem Ziel, Erkenntnisse zum individuellen Mobilitätsverhalten im Zusammenhang mit der Gestaltung des umgebenden Verkehrssystems zu gewinnen, wurde im Rahmen des vom Land Hessen geförderten LOEWE-Schwerpunkts „Infrastruktur – Design – Gesellschaft“ im März und April 2019 eine schriftliche Haushaltsbefragung in einem innerstädtischen Gebiet der Großstadt Offenbach am Main durchgeführt (n=701). Der vorliegende Bericht beschreibt die methodische Vorgehensweise bei der Umsetzung und Datenerfassung dieser Erhebung. Dabei wird auf die vorbereitenden Maßnahmen mit Hinblick auf die Erstellung des Fragebogens und weiterer Befragungsmaterialen sowie die Durchführung des Pretests und der eigentlichen Hauptbefragung eingegangen. Um die Bereitschaft einer Teilnahme zu erhöhen, wurden die Haushalte mittels Vorankündigungsschreiben, Pressemitteilung und Erinnerungsrundgang mehrfach kontaktiert. Außerdem wurde ein Teil der Rücksendeumschläge mit Sonderbriefmarken versehen. Abschließend befasst sich der Bericht mit dem Erhebungsrücklauf, der Dateneingabe und -aufbereitung sowie dem ermittelten Antwortverhalten und der Repräsentativität der Stichprobe.