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Hobe, Marc von ; Bekki, Slimane ; Borrmann, Stephan ; Cairo, Francesco ; D'Amato, Francesco ; Di Donfrancesco, Guido ; Dörnbrack, Andreas ; Ebersoldt, Andreas ; Ebert, Martin ; Emde, Claudia ; Engel, Ines ; Ern, Manfred ; Frey, Wiebke ; Genco, Silvia ; Griessbach, Sabine ; Grooß, Jens-Uwe ; Gulde, Thomas ; Günther, Gebhard ; Hösen, Elisabeth ; Hoffmann, Lars ; Homonnai, Viktoria ; Hoyle, Christopher Robert ; Isaksen, Ivar S.A. ; Jackson, David R. ; Jánosi, Imre M. ; Jones, Rod L. ; Kandler, Konrad ; Kalicinsky, Christoph ; Keil, Andrea ; Khaykin, Sergey M. ; Khosrawi, Farahnaz ; Kivi, Rigel ; Kuttippurath, Jayan ; Laube, Johannes Christian ; Lefèvre, Franck ; Lehmann, Ralph ; Ludmann, Sabrina ; Luo, Beiping P. ; Marchand, Marion ; Meyer, Jessica ; Mitev, Valentin ; Molleker, Sergej ; Müller, Rolf ; Oelhaf, Hermann ; Olschewski, Friedhelm ; Orsolini, Yvan ; Peter, Thomas ; Pfeilsticker, Klaus ; Piesch, Christof ; Pitts, Michael C. ; Poole, Lamont R. ; Pope, Francis D. ; Ravegnani, Fabrizio ; Rex, Markus ; Riese, Martin ; Röckmann, Thomas ; Rognerud, Bjørg ; Roiger, Anke ; Rolf, Christian ; Santee, Michelle L. ; Scheibe, Monika ; Schiller, Cornelius ; Schlager, Hans ; Siciliani de Cumis, Matteo ; Sitnikov, Nikolay ; Søvde, Ole Amund ; Spang, Reinhold ; Spelten, Nicole ; Stordal, Frode ; Sumińska-Ebersoldt, Olga ; Viciani, Silvia ; Volk, C.-Michael ; vom Scheidt, Marcel ; Ulanovski, Alexey ; Gathen, Peter von der ; Walker, Kaley A. ; Wegner, Tobias ; Weigel, Ralf ; Weinbruch, Stephan ; Wetzel, Gerald ; Wienhold, Franck G. ; Wohltmann, Ingo ; Woiwode, Wolfgang ; Young, Isla A. K. ; Yushkov, Vladimir ; Zobrist, Bernhard ; Stroh, Fred
The international research project RECONCILE has addressed central questions regarding polar ozone depletion, with the objective to quantify some of the most relevant yet still uncertain physical and chemical processes and thereby improve prognostic modelling capabilities to realistically predict the response of the ozone layer to climate change. This overview paper outlines the scope and the general approach of RECONCILE, and it provides a summary of observations and modelling in 2010 and 2011 that have generated an in many respects unprecedented dataset to study processes in the Arctic winter stratosphere. Principally, it summarises important outcomes of RECONCILE including (i) better constraints and enhanced consistency on the set of parameters governing catalytic ozone destruction cycles, (ii) a better understanding of the role of cold binary aerosols in heterogeneous chlorine activation, (iii) an improved scheme of polar stratospheric cloud (PSC) processes that includes heterogeneous nucleation of nitric acid trihydrate (NAT) and ice on non-volatile background aerosol leading to better model parameterisations with respect to denitrification, and (iv) long transient simulations with a chemistry-climate model (CCM) updated based on the results of RECONCILE that better reproduce past ozone trends in Antarctica and are deemed to produce more reliable predictions of future ozone trends. The process studies and the global simulations conducted in RECONCILE show that in the Arctic, ozone depletion uncertainties in the chemical and microphysical processes are now clearly smaller than the sensitivity to dynamic variability.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Hopfner, Franziska ; Müller, Stefanie H. ; Steppat, Dagmar ; Miller, Joanna ; Schmidt, Nele ; Wandinger, Klaus-Peter ; Leypoldt, Frank ; Berg, Daniela ; Franke, Andre ; Lieb, Wolfgang ; Tittmann, Lukas ; Balzer-Geldsetzer, Monika ; Baudrexel, Simon ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Kalbe, Elke ; Kassubek, Jan ; Klockgether, Thomas ; Liepelt-Scarfone, Inga ; Mollenhauer, Brit ; Neuser, Petra ; Reetz, Kathrin ; Riedel, Oliver ; Schulte, Claudia ; Schulz, Jörg B. ; Spottke, Annika ; Storch, Alexander ; Trenkwalder, Claudia ; Wittchen, Hans-Ulrich ; Witt, Karsten ; Wüllner, Ullrich ; Deuschl, Günther ; Kuhlenbäumer, Gregor
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Paulus, Frieder Michel ; Krach, Sören ; Blanke, Marius ; Roth, Christine ; Belke, Marcus ; Sommer, Jens ; Müller-Pinzler, Laura ; Menzler, Katja ; Jansen, Andreas ; Rosenow, Felix ; Bremmer, Frank ; Einhäuser, Wolfgang ; Knake, Susanne
Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.
Nambiar, Romi ; Kniest, Jorit F. ; Schmidt, Alexander ; Raddatz, Jacek ; Müller, Wolfgang ; Evans, David
Rationale: Potassium (K) is a major component of several silicate minerals and seawater, and, therefore, constraining past changes in the potassium cycle is a promising way of tracing large-scale geological processes on Earth. However, [K] measurement using inductively coupled plasma mass spectrometry (ICP-MS) is challenging due to an ArH+ interference, which may be of a similar magnitude to the K+ ion beam in samples with <0.1% m/m [K].
Methods: In this work, we investigated the effect of the ArH+ interference on K/Ca data quality by comparing results from laser-ablation (LA)-ICP-MS measured in medium and high mass resolution modes and validating our LA results via solution ICP-optical emission spectroscopy (OES) and solution ICP-MS measurements. To do so, we used a wide range of geological reference materials, with a particular focus on marine carbonates, which are potential archives of past changes in the K cycle but are typically characterised by [K] < 200 μg/g. In addition, we examine the degree to which trace-element data quality is driven by downhole fractionation during LA-ICP-MS measurements.
Results: Our results show that medium mass resolution (MR) mode is sufficiently capable of minimising the effect of the ArH+ interference on K+. However, the rate of downhole fractionation for Na and K varies between different samples as a result of their differing bulk composition, resulting in matrix-specific inaccuracy. We show how this can be accounted for via downhole fractionation corrections, resulting in an accuracy of better than 1% and a long-term reproducibility (intermediate precision) of <6% (relative standard deviation) in JCp-1NP using LA-ICP-MS in MR mode.
Conclusion: Our [K] measurement protocol is demonstrably precise and accurate and applicable to a wide range of materials. The measurement of K/Ca in relatively low-[K] marine carbonates is presented here as a key example of a new application opened up by these advances.
Non-matrix-matched calibration of laser ablation ICPMS (trace/major) element data is a common quantification strategy. However, LA sampling is associated with downhole elemental fractionation, potentially causing inaccuracies if the magnitude of fractionation between the sample and reference material (RM) differs. Here, we estimate fractionation factors (FFs) for different elements (El) in a range of RMs relative to NIST SRM610/612 (FFEl/Ca-NIST) and evaluate element-specific corrections for downhole fractionation using these measured FFEl/Ca-NIST. Significantly different mean El/Ca values were observed before and after correction, particularly for the alkali elements (all RMs), and B, Fe, and Zn (some RMs), notably improving accuracy, especially for the alkali elements. In cases where this methodology does not result in an accuracy improvement, this may help identify underlying issues in reported/reference values for RMs, given that this phenomenon should be accounted for. Overall, we recommend considering routine assessment of FFs and applying a FF correction to enhance data quality.
A low potential electron carrier ferredoxin (E0′ ≈ −500 mV) is used to fuel the only bioenergetic coupling site, a sodium-motive ferredoxin:NAD+ oxidoreductase (Rnf) in the acetogenic bacterium Acetobacterium woodii. Because ferredoxin reduction with physiological electron donors is highly endergonic, it must be coupled to an exergonic reaction. One candidate is NADH-dependent caffeyl-CoA reduction. We have purified a complex from A. woodii that contains a caffeyl-CoA reductase and an electron transfer flavoprotein. The enzyme contains three subunits encoded by the carCDE genes and is predicted to have, in addition to FAD, two [4Fe-4S] clusters as cofactor, which is consistent with the experimental determination of 4 mol of FAD, 9 mol of iron, and 9 mol of acid-labile sulfur. The enzyme complex catalyzed caffeyl-CoA-dependent oxidation of reduced methyl viologen. With NADH as donor, it catalyzed caffeyl-CoA reduction, but this reaction was highly stimulated by the addition of ferredoxin. Spectroscopic analyses revealed that ferredoxin and caffeyl-CoA were reduced simultaneously, and a stoichiometry of 1.3:1 was determined. Apparently, the caffeyl-CoA reductase-Etf complex of A. woodii uses the novel mechanism of flavin-dependent electron bifurcation to drive the endergonic ferredoxin reduction with NADH as reductant by coupling it to the exergonic NADH-dependent reduction of caffeyl-CoA.
Maurer, Gabriele D. ; Brucker, Daniel P. ; Bähr, Roy Oliver ; Harter, Patrick Nikolaus ; Hattingen, Elke ; Walenta, Stefan ; Müller-Klieser, Wolfgang ; Steinbach, Joachim Peter ; Rieger, Johannes
Background: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.
Thill, Marc ; Friedrich, Michael ; Kolberg-Liedtke, Cornelia ; Albert, Ute-Susann ; Banys-Paluchowski, Maggie ; Bauerfeind, Ingo ; Blohmer, Jens-Uwe ; Budach, Wilfried ; Dall, Peter ; Fallenberg, Eva Maria ; Fasching, Peter Andreas ; Fehm, Tanja ; Gerber, Bernd ; Gluz, Oleg ; Harbeck, Nadia ; Heil, Jörg ; Huober, Jens ; Jackisch, Christian ; Kreipe, Hans-H. ; Krug, David ; Kühn, Thorsten ; Kümmel, Sherko ; Loibl, Sibylle ; Lüftner, Diana ; Lux, Michael Patrick ; Maass, Nicolai ; Mundhenke, Christoph ; Nitz, Ulrike ; Park-Simon, Tjoung-Won ; Reimer, Toralf ; Rhiem, Kerstin ; Rody, Achim ; Schmidt, Marcus ; Schneeweiss, Andreas ; Schütz, Florian ; Sinn, Peter ; Solbach, Christine ; Solomayer, Erich-Franz ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Witzel, Isabell ; Wöckel, Achim ; Müller, Volkmar ; Janni, Wolfgang ; Ditsch, Nina
Peter, Antonia Sophia ; Roth, Edith ; Schulz, Sebastian R. ; Fraedrich, Kirsten ; Steinmetz, Tobit ; Damm, Dominik ; Hauke, Manuela ; Richel, Elie ; Müller-Schmucker, Sandra ; Habenicht, Katharina ; Eberlein, Valentina ; Issmail, Leila ; Uhlig, Nadja ; Dolles, Simon ; Grüner, Eva ; Peterhoff, David ; Ciesek, Sandra ; Hoffmann, Markus ; Pöhlmann, Stefan ; McKay, Paul F. ; Shattock, Robin J. ; Wölfel, Roman ; Socher, Eileen ; Wagner, Ralf ; Eichler, Jutta ; Sticht, Heinrich ; Schuh, Wolfgang ; Neipel, Frank ; Ensser, Armin ; Mielenz, Dirk Alexander ; Tenbusch, Matthias ; Winkler, Thomas H. ; Grunwald, Thomas ; Überla, Klaus Thomas ; Jäck, Hans-Martin
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.