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We compiled an NMR data set consisting of exact nuclear Overhauser enhancement (eNOE) distance limits, residual dipolar couplings (RDCs) and scalar (J) couplings for GB3, which forms one of the largest and most diverse data set for structural characterization of a protein to date. All data have small experimental errors, which are carefully estimated. We use the data in the research article Vogeli et al., 2015, Complementarity and congruence between exact NOEs and traditional NMR probes for spatial decoding of protein dynamics, J. Struct. Biol., 191, 3, 306–317, doi:10.1016/j.jsb.2015.07.008 [1] for cross-validation in multiple-state structural ensemble calculation. We advocate this set to be an ideal test case for molecular dynamics simulations and structure calculations.
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.
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.
Bernatz, Simon ; Zhdanovich, Yauheniya ; Ackermann, Jörg ; Koch, Ina ; Wild, Peter Johannes ; Pinto dos Santos, Daniel ; Vogl, Thomas J. ; Kaltenbach, Benjamin ; Rosbach, Nicolas
Our purpose was to analyze the robustness and reproducibility of magnetic resonance imaging (MRI) radiomic features. We constructed a multi-object fruit phantom to perform MRI acquisition as scan-rescan using a 3 Tesla MRI scanner. We applied T2-weighted (T2w) half-Fourier acquisition single-shot turbo spin-echo (HASTE), T2w turbo spin-echo (TSE), T2w fluid-attenuated inversion recovery (FLAIR), T2 map and T1-weighted (T1w) TSE. Images were resampled to isotropic voxels. Fruits were segmented. The workflow was repeated by a second reader and the first reader after a pause of one month. We applied PyRadiomics to extract 107 radiomic features per fruit and sequence from seven feature classes. We calculated concordance correlation coefficients (CCC) and dynamic range (DR) to obtain measurements of feature robustness. Intraclass correlation coefficient (ICC) was calculated to assess intra- and inter-observer reproducibility. We calculated Gini scores to test the pairwise discriminative power specific for the features and MRI sequences. We depict Bland Altmann plots of features with top discriminative power (Mann–Whitney U test). Shape features were the most robust feature class. T2 map was the most robust imaging technique (robust features (rf), n = 84). HASTE sequence led to the least amount of rf (n = 20). Intra-observer ICC was excellent (≥ 0.75) for nearly all features (max–min; 99.1–97.2%). Deterioration of ICC values was seen in the inter-observer analyses (max–min; 88.7–81.1%). Complete robustness across all sequences was found for 8 features. Shape features and T2 map yielded the highest pairwise discriminative performance. Radiomics validity depends on the MRI sequence and feature class. T2 map seems to be the most promising imaging technique with the highest feature robustness, high intra-/inter-observer reproducibility and most promising discriminative power.
Lorenz, Matthias ; Gao, Lu ; Ziegelbauer, Kathrin ; Norata, Giuseppe Danilo ; Empana, Jean Philippe ; Schmidtmann, Irene ; Lin, Hung-Ju ; McLachlan, Stela ; Bokemark, Lena ; Ronkainen, Kimmo ; Amato, Mauro ; Schminke, Ulf ; Srinivasan, Sathanur R. ; Lind, Lars ; Okazaki, Shuhei ; Stehouwer, Coen D. A. ; Willeit, Peter ; Polak, Joseph F. ; Steinmetz, Helmuth ; Sander, Dirk ; Poppert, Holger ; Desvarieux, Moise ; Ikram, M. Arfan ; Johnsen, Stein Harald ; Staub, Daniel ; Sirtori, Cesare R. ; Iglseder, Bernhard ; Beloqui, Oscar ; Engström, Gunnar ; Friera, Alfonso ; Rozza, Francesco ; Xie, Wuxiang ; Parraga, Grace ; Grigore, Liliana ; Plichart, Matthieu ; Blankenberg, Stefan ; Su, Ta-Chen ; Schmidt, Caroline ; Tuomainen, Tomi-Pekka ; Veglia, Fabrizio ; Völzke, Henry ; Nijpels, Giel ; Willeit, Johann ; Sacco, Ralph L. ; Franco, Oscar H. ; Uthoff, Heiko ; Hedblad, Bo ; Suarez, Carmen ; Izzo, Raffaele ; Zhao, Dong ; Wannarong, Thapat ; Catapano, Alberico ; Ducimetiere, Pierre ; Espinola-Klein, Christine ; Chien, Kuo-Liong ; Price, Jackie F. ; Bergström, Göran ; Kauhanen, Jussi ; Tremoli, Elena ; Dörr, Marcus ; Berenson, Gerald ; Kitagawa, Kazuo ; Dekker, Jacqueline M. ; Kiechl, Stefan ; Sitzer, Matthias ; Bickel, Horst ; Rundek, Tatjana ; Hofman, Albert ; Mathiesen, Ellisiv B. ; Castelnuovo, Samuela ; Landecho, Manuel F. ; Rosvall, Maria ; Gabriel, Rafael ; De Luca, Nicola ; Liu, Jing ; Baldassarre, Damiano ; Kavousi, Maryam ; De Groot, Eric ; Bots, Michiel L. ; Yanez, David N. ; Thompson, Simon G.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Bahls, Martin ; Lorenz, Matthias W. ; Dörr, Marcus ; Gao, Lu ; Kitagawa, Kazuo ; Tuomainen, Tomi-Pekka ; Agewall, Stefan ; Berenson, Gerald ; Catapano, Alberico L. ; Norata, Giuseppe D. ; Bots, Michiel L. ; Gilst, Wiek van ; Asselbergs, Folkert W. ; Brouwers, Frank P. ; Uthoff, Heiko ; Sander, Dirk ; Poppert, Holger ; Hecht Olsen, Michael ; Empana, Jean Philippe ; Schminke, Ulf ; Baldassarre, Damiano ; Veglia, Fabrizio ; Franco, Oscar H. ; Kavousi, Maryam ; Groot, Eric de ; Mathiesen, Ellisiv B. ; Grigore, Liliana ; Polak, Joseph F. ; Rundek, Tatjana ; Stehouwer, Coen D. A. ; Skilton, Michael R. ; Hatzitolios, Apostolos I. ; Savopoulos, Christos ; Ntaios, George ; Plichart, Matthieu ; McLachlan, Stela ; Lind, Lars ; Willeit, Peter ; Steinmetz, Helmuth ; Desvarieux, Moise ; Ikram, M. Arfan ; Johnsen, Stein Harald ; Schmidt, Caroline ; Willeit, Johann ; Ducimetiere, Pierre ; Price, Jackie F. ; Bergström, Göran ; Kauhanen, Jussi ; Kiechl, Stefan ; Sitzer, Matthias ; Bickel, Horst ; Sacco, Ralph L. ; Hofman, Albert ; Völzke, Henry ; Thompson, Simon G.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
Göbel, Kathrin ; Adrich, Przemysław ; Altstadt, Sebastian ; Altstadt, Sebastian ; Alvarez-Pol, Héctor ; Aksouh, Farouk ; Aumann, Thomas ; Babilon, Mari ; Behr, Karl-Heinz ; Berg, Thomas ; Böhmer, Michael ; Boretzky, Konstanze ; Brünle, Adolf ; Beyer, R. ; Casarejos Ruiz, Enrique ; Chartier, Marielle ; Cortina Gil, Dolores ; Chatillon, Audrey ; Datta Pramanik, Ushasi ; Deveaux, L. ; Elvers, Michael ; Elze, Thomas W. ; Emling, Hans ; Erhard, Martin Andreas ; Ershova, Olga ; Fernández Domínguez, Beatriz ; Geissel, Hans ; Górska, Magdalena ; Heftrich, Tanja ; Heil, Michael ; Hellstroem, M. ; Ickert, Günter ; Johansson, Håkan T. ; Junghans, Arnd Rudolf ; Käppeler, Franz ; Kiselev, Oleg A. ; Klimkiewicz, Adam ; Kratz, Jens-Volker ; Kratz, Jens-Volker ; Kulessa, Reinhard ; Kurz, Nikolaus ; Labiche, Marc ; Langer, Christoph ; Le Bleis, Tudi ; Lemmon, Roy Crawford ; Lindenberg, Kai ; Litvinov, Yuri A. ; Maierbeck, Peter ; Movsesyan, Alina ; Müller, S. ; Nilsson, Thomas ; Nociforo, Chiara ; Paar, Nils ; Palit, Rudrayoti ; Paschalis, Stefanos ; Plag, Ralf ; Prokopowicz, Wawrzyniec ; Reifarth, René ; Rossi, Dominic M. ; Schnorrenberger, Linda ; Simon, Haik ; Sonnabend, Kerstin ; Sümmerer, Klaus ; Surówka, Grzegorz ; Vretenar, Dario ; Wagner, Andreas ; Walter, S. ; Waluś, Władysław ; Wamers, Felix ; Weick, Helmut ; Weigand, Mario ; Winckler, Nicolas ; Winkler, Martin ; Zilges, Andreas
The Coulomb Dissociation (CD) cross sections of the stable isotopes 92,94,100Mo and of the unstable isotope 93Mo were measured at the LAND/R3B setup at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. Experimental data on these isotopes may help to explain the problem of the underproduction of 92,94Mo and 96,98Ru in the models of p-process nucleosynthesis. The CD cross sections obtained for the stable Mo isotopes are in good agreement with experiments performed with real photons, thus validating the method of Coulomb Dissociation. The result for the reaction 93Mo(γ,n) is especially important since the corresponding cross section has not been measured before. A preliminary integral Coulomb Dissociation cross section of the 94Mo(γ,n) reaction is presented. Further analysis will complete the experimental database for the (γ,n) production chain of the p-isotopes of molybdenum.
Leistenschneider, Armin ; Aumann, Thomas ; Boretzky, Konstanze ; Canto, Luiz Felipe ; Carlson, Brett Vern ; Cortina, Dolores ; Datta Pramanik, Ushasi ; Elze, Thomas W. ; Emling, Hans ; Geissel, Hans ; Grünschloss, Alexander ; Helariutta, Kerttuli ; Hellström, Margareta ; Hussein, Mahir S. ; Ilievski, Stamenko ; Kratz, Jens-Volker ; Kulessa, Reinhard ; Khiem, Le Hong ; Lubkiewicz, Edvard ; Münzenberg, Gottfried ; Palit, Rudrayoti ; Reiter, Peter ; Scheidenberger, Christoph ; Schmidt, Karl-Heinz ; Simon, Haik ; Sümmerer, Klaus ; Wajda, Eugeniusz ; Walús, Wladek
Abrasion-ablation models and the empirical EPAX parametrization of projectile fragmentation are described. Their cross section predictions are compared to recent data of the fragmentation of secondary beams of neutron-rich, unstable 19,20,21O isotopes at beam energies near 600 MeV/nucleon as well as data for stable 17,18O beams.