98 results on '"Heckmann D"'
Search Results
2. Unterbringungsrecht
- Author
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Heckmann, D., Leygraf, N., Kröber, Hans-Ludwig, editor, Dölling, Dieter, editor, Leygraf, Norbert, editor, and Sass, Henning, editor
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- 2009
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3. F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells
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Maier, P, Heckmann, D, Spier, I, Laufs, S, Zucknick, M, Allgayer, H, Fruehauf, S, Zeller, W J, and Wenz, F
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- 2012
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4. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways
- Author
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Keklikoglou, I, Koerner, C, Schmidt, C, Zhang, J D, Heckmann, D, Shavinskaya, A, Allgayer, H, Gückel, B, Fehm, T, Schneeweiss, A, Sahin, Ö, Wiemann, S, and Tschulena, U
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- 2012
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5. Manipulation of nitric oxide levels with a modified hydroxyethyl starch molecule
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Lupp, C, Baasner, S, Heckmann, D, Ince, C, Nocken, F, Schimmel, M, and Westphal, M
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- 2012
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6. Breaking the dogma of the metal-coordinating carboxylate group in integrin ligands: introducing hydroxamic acids to the MIDAS to tune potency and selectivity
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Heckmann D., Laufer B., Zahn G., Stragies R., Kessler H., MARINELLI, LUCIANA, LIMONGELLI, VITTORIO, NOVELLINO, ETTORE, Heckmann, D., Laufer, B., Marinelli, Luciana, Limongelli, Vittorio, Novellino, Ettore, Zahn, G., Stragies, R., and Kessler, H.
- Published
- 2009
7. UNEXPECTED NEW RESULTS IN THE RGD FIELD
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Kessler H, Heckmann D, Laufer B, Otto E, Zahn G, Stragies R., MARINELLI, LUCIANA, Kessler, H, Heckmann, D, Laufer, B, Otto, E, Marinelli, Luciana, Zahn, G, and Stragies, R.
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- 2009
8. Rational design of highly active and selective alpha 5 beta 1 integrin antagonists
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Laufer B., Heckmann D., Meyer A., Neubauer S., Zahn G., Stragies R., Kessler H., MARINELLI, LUCIANA, Laufer, B., Heckmann, D., Meyer, A., Marinelli, Luciana, Neubauer, S., Zahn, G., Stragies, R., and Kessler, H.
- Published
- 2008
9. CYCLIC PEPTIDES AS AFFINITY LIGANDS IN FACTOR VIII PURIFICATION
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Heckmann, D., Knoer, S., Marinelli, L., Saenko, E. L., Charlotte Hauser, Kessler, H., Heckmann, D., Knor, S., Marinelli, Luciana, Saenko, E. L., Hauser, C. A. E., and Kessler, H.
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- 2004
10. HUMAN INTEGRIN AVB5: HOMOLOGY MODELING AND LIGANDS
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MARINELLI, LUCIANA, NOVELLINO, ETTORE, GRIECO, PAOLO, Meyer A., Heckmann D., K.e.s.s.l.e.r. H., Marinelli, Luciana, Grieco, Paolo, Meyer, A., Heckmann, D., Novellino, Ettore, and K. e. s. s. l. e. r., H.
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- 2004
11. Adaptation step-by-step : challenges for real-time spatial personalization
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Hage, van, W.R., Stash, N., Wang, Y., Aroyo, L.M., Berkovsky, S., Bohnert, F., Carmagnola, F, Cheng, D., Heckmann, D., Kuflik, T., Nurmi, P., Partridge, K., Information Systems WSK&I, and Process Science
- Abstract
In this paper we outline challenges for user modeling and personalization with spatial information. To illustrate those challenges we use a use case with a real-time routing system that implements a mobile museum guide for providing personalized tours tailored to the user position inside the museum and her interests. In this scenario we combine on the one hand (1) interactive discovery of user's interests applied for semantic recommendations of artworks and art-related topics, and on the other hand (2) dynamic step-by-step adaptation of a user's route through a museum based on her current position and changing interests. For this, the existing CHIP mobile museum guide was extended with a routing mechanism based on the SWI-Prolog Space package.
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- 2010
12. User profile elicitation and conversion in a mashup environment
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Leonardi, E., Houben, G.J.P.M., Sluijs, van der, K.A.M., Hidders, A.J.H., Herder, E., Abel, F., Krause, D., Heckmann, D., Daniel, F., and Databases and Hypermedia
- Abstract
Many Web applications have offered personalization and adaptation as their features in order to provide personalized services to their users. The user profiles are gathered independently by these applications often through an explicit dialogue with the user. As a result, the users have to go through a similar elicitation process multiple times, that is, providing similar information that is used to build the user profiles to different applications. In the springtime of mashup applications, we observe the importance of considering user information in order to make the presented content more relevant to the user. For this purpose, it is necessary to have a platform/framework that enables components in the mashup to reuse and exchange user profiles. In this paper, we present the Morpho framework that elicits, enhances, and transforms a user profile from one application to another application in a mashup environment. It deals with semantic and syntactic heterogeneity of data and schema of the user profile. We present the architecture of Morpho and a case study to exemplify the approach followed in this current work.
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- 2009
13. Automatic generation of semantic metadata as basis for user modeling and adaptation
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Sluijs, van der, K.A.M., Houben, G.J.P.M., Kuflik, T., Berkovsky, S., Carmagnola, F., Heckmann, D., and Krüger, A.
- Subjects
Metadata ,World Wide Web ,Information retrieval ,Semantic grid ,business.industry ,Computer science ,User modeling ,Web application ,Semantic Web Stack ,Semantics ,business ,Semantic Web ,Ontology alignment - Abstract
With the help of the simple and world-wide accepted technique of tagging, users can help to collaboratively provide metadata over previously uncharted collections of multimedia documents. However, the semantics of tags are rather limited and not always as helpful in disclosing a dataset as a proper ontology can be. In this paper we introduce the Relco framework that applies syntactic, semantic and collaborative techniques to connect tags to ontological concepts, which helps to quickly get more semantics about a tag. We demonstrate the applicability of our techniques in two concrete Web applications: one in the educational domain and one in the cultural heritage domain. For the former we describe how students are better able to find the information in socially tagged videos and in the latter we also show how the used techniques allow building a faceted browser over the previously uncharted multimedia objects and we show which techniques could be applied to control the quality of user driven annotation.
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- 2009
14. A framework for flexible user profile mashups
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Abel, F., Heckmann, D., Herder, E., Hidders, A.J.H., Houben, G.J.P.M., Krause, D., Leonardi, E., Sluijs, van der, K.A.M., and Dattolo, A.
- Abstract
Exploiting the rich traces of users' Web interaction promises to enable cross-application user modeling techniques, which is in particular interesting for applications that have a small user population or that are used infrequently. In this paper we present a framework for the effective interchange of user profiles. In addition to derivation rules for user profile reasoning, the framework employs exible mash-ups of RSS-based user data streams for combining heterogeneous user data in a Web 2.0 environment.
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- 2009
15. User modeling for modular adaptive hypermedia
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Chepegin, V., Aroyo, L.M., De Bra, P.M.E., Heckmann, D., Aroyo, L., Tasso, C., and Databases and Hypermedia
- Abstract
More and more users work simultaneously with multiple applications, to perform various tasks. This situation puts high demands on the user adaptive systems (UAS), which traditionally support users’ work in a single isolated domain, and which now shift towards personalization in multi-task and crossapplication contexts. In their attempt to meet the increasing demands, UAS grow in complexity, but they do little about their compatibility and interoperability.We propose a Component-based Architecture for UAS: (CompAS). The key feature of CompAS is modularization of knowledge models and as a consequence allowing existing UAS to share their user models by means of a centralized user model service. As a proof of concept we show how two existing applications, AHA! [1] and UserModelService [2] can achieve interaction based on the extracted user model.
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- 2004
16. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways
- Author
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Keklikoglou, I, primary, Koerner, C, additional, Schmidt, C, additional, Zhang, J D, additional, Heckmann, D, additional, Shavinskaya, A, additional, Allgayer, H, additional, Gückel, B, additional, Fehm, T, additional, Schneeweiss, A, additional, Sahin, Ö, additional, Wiemann, S, additional, and Tschulena, U, additional
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- 2011
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17. Open Government - Retooling Democracy for the 21st Century
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Heckmann, D, primary
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- 2011
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18. 437 The role of the SDF1a/CXCR4 axis in invasion of colorectal cancer cells
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Heckmann, D., primary, Maier, P., additional, Zucknick, M., additional, Giordano, F.A., additional, Veldwijk, M.R., additional, Wenz, F., additional, Zeller, W.J., additional, Frühauf, S., additional, Laufs, S., additional, and Allgayer, H., additional
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- 2010
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19. Identification and Analysis of the Balhimycin Biosynthetic Gene Cluster and Its Use for Manipulating Glycopeptide Biosynthesis in Amycolatopsis mediterranei DSM5908
- Author
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Pelzer, S., primary, Süßmuth, R., additional, Heckmann, D., additional, Recktenwald, J., additional, Huber, P., additional, Jung, G., additional, and Wohlleben, W., additional
- Published
- 1999
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20. F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells.
- Author
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Maier, P, Heckmann, D, Spier, I, Laufs, S, Zucknick, M, Allgayer, H, Fruehauf, S, Zeller, W J, and Wenz, F
- Subjects
- *
TUMOR treatment , *CANCER chemotherapy , *ANTIVIRAL agents , *HEMATOPOIETIC stem cells , *TUMOR suppressor genes , *DRUG resistance in cancer cells , *O6-Methylguanine-DNA Methyltransferase , *DRUG efficacy - Abstract
Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMTP140K (an O6-benzylguanine-resistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMTP140K-F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMTP140K with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency. [ABSTRACT FROM AUTHOR]
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- 2012
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21. Rapid electromagnetic analysis of multilayer interconnects.
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Heckmann, D., Dvorak, S.L., and Cangellaris, A.C.
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- 1997
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22. Modal S-matrix method for the optimum design of inductively direct-coupled cavity filters.
- Author
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Arndt, F., Bornemann, J., Heckmann, D., Piontek, C., Semmerow, H., and Schueler, H.
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- 1986
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23. Stopband optimised E-plane filters with multiple metal inserts of variable number per coupling element.
- Author
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Arndt, F., Heckmann, D., Semmerow, H., Bornemann, J., and Vahldieck, R.
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- 1986
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24. Ligand Binding Analysis for Human α5β1 Integrin: Strategies for Designing New α5β1 Integrin Antagonists
- Author
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Marinelli, L., Meyer, A., Heckmann, D., Lavecchia, A., Novellino, E., and Kessler, H.
- Abstract
We report a three-dimensional model of the α5β1 integrin headgroup bound to the most potent and selective ligand (SJ749) known to date. The model was built using the comparative protein modeling method, and it is consistent with experimental data. From this study, we identified two potentially important regions in the α5β1 receptor that are peculiar to this integrin and might be worth considering for drug targeting.
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- 2005
25. Cloning and analysis of a peptide synthetase gene of the balhimycin producer Amycolatopsis mediterranei DSM5908 and development of a gene disruption/replacement system
- Author
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Pelzer, S., Reichert, W., Huppert, M., Heckmann, D., and Wohlleben, W.
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- 1997
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26. Predicting user experiences through cross-context reasoning
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Berkovsky, S., Kuflik, T., Lora Aroyo, Heckmann, D., Kröner, A., Ricci, F., J Houben, G., Business Web and Media, and Intelligent Information Systems
27. Mashing up user data in the grapple user modeling framework
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Abel, F., Heckmann, D., Herder, E., Jan Hidders, Houben, G. -J, Krause, D., Leonardi, E., Slujis, K., and Databases and Hypermedia
- Abstract
In this paper we demonstrate the Grapple User Modeling Framework (GUMF), which exploits Semantic Web technologies and Web 2.0 paradigms to model users across different applications and domains. It introduces novel features such as dataspaces, which logically bundle user data, and user pipes, which allow to mash up user data from different sources.
28. Rapid electromagnetic analysis of multilayer interconnects
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Heckmann, D., primary, Dvorak, S.L., additional, and Cangellaris, A.C., additional
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29. Synthesis of a Peptide with an Artificial Molecular Machine.
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LEWANDOWSKI, B., DE BO, G., WARD, J. W., PAPMEYER, M., KUSCHEL, S., ALDEGUNDE, M. J., GRAMLICH, P. M. E., HECKMANN, D., GOLDUP, S. M., D'SOUZA, D. M., FERNANDES, A. E., and LEIGH, D. A.
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- 2013
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30. Probing Integrin Selectivity: Rational Design of Highly Active and Selective Ligands for the α5β1 and αvβ3 Integrin Receptor
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Dominik Heckmann, Axel Meyer, Luciana Marinelli, Grit Zahn, Horst Kessler, Roland Stragies, Heckmann, D, Meyer, A, Marinelli, Luciana, Zahn, G, Stragies, R, and Kessler, H.
- Subjects
Integrins ,αvβ3 integrin ,biology ,Protein Conformation ,Chemistry ,Integrin ,Rational design ,General Chemistry ,Plasma protein binding ,Integrin alphaVbeta3 ,Ligands ,Catalysis ,Cell biology ,Protein structure ,Models, Chemical ,Drug Design ,biology.protein ,Peptides ,Receptor ,Selectivity ,Integrin alpha5beta1 ,Protein Binding - Abstract
A strategy for the rational design of α5β1 ligands for the purpose of lead generation and biochemical studies on integrin selectivity is based α5β1 homology modeling. Ligand 1 can bind α5β1 with activities in the subnanomolar range and high selectivity. Minor changes can result in a ligand with a high selectivity for the related αvβ3 receptor.
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- 2007
31. Reproductive toxicity in birds predicted by physiologically-based kinetics and bioenergetics modelling.
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Martin T, Bauer B, Baier V, Paini A, Schaller S, Hubbard P, Ebeling M, Heckmann D, and Gergs A
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- Animals, Quail, Energy Metabolism, Benzamides, Reproduction, Colinus
- Abstract
Effects on the growth and reproduction of birds are important endpoints in the environmental risk assessment (ERA) of pesticides. Toxicokinetic-toxicodynamic models based on dynamic energy budget theory (DEB) are promising tools to predict these effects mechanistically and make extrapolations relevant to ERA. However, before DEB-TKTD models are accepted as part of ERA for birds, ecotoxicological case studies are required so that stakeholders can assess their capabilities. We present such a case-study, modelling the effects of the fluopyram metabolite benzamide on the northern bobwhite quail (Colinus virginianus). We parametrised a DEB-TKTD model for the embryo stage on the basis of an egg injection study, designed to provide data for model development. We found that information on various endpoints, such as survival, growth, and yolk utilisation were needed to clearly distinguish between the performance of model variants with different TKTD assumptions. The calibration data were best explained when it was assumed that chemical uptake occurs via the yolk and that benzamide places stress on energy assimilation and mobilisation. To be able to bridge from the in vitro tests to real-life exposure, we developed a physiologically-based toxicokinetic (PBK) model for the quail and used it to predict benzamide exposure inside the eggs based on dietary exposure in a standard reproductive toxicity study. We then combined the standard DEB model with the TKTD module calibrated to the egg injection studies and used it to predict effects on hatchling and 14-day chick weight based on the exposure predicted by the PBK model. Observed weight reductions, relative to controls, were accurately predicted. Thus, we demonstrate that DEB-TKTD models, in combination with suitable experimental data and, if necessary, with an exposure model, can be used in bird ERA to predict chemical effects on reproduction., Competing Interests: Declaration of competing interest A. Gergs, M. Ebeling and D. Heckmann are employees of Bayer AG. The work of the other co-authors on the project was funded by Bayer AG. Bayer AG is a manufacturer of the active substance fluopyram investigated in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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32. Manipulation of Nitric Oxide Levels via a Modified Hydroxyethyl Starch Molecule.
- Author
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Aksu U, Ince C, Baasner S, Hermle J, Lupp C, Heckmann D, Nocken F, and Westphal M
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- Humans, Nitric Oxide, Heart Rate, Amylases, Starch pharmacology, Plasma Substitutes, Hydroxyethyl Starch Derivatives pharmacology, Hydroxyethyl Starch Derivatives therapeutic use, Hypotension
- Abstract
Introduction: Although the improving effect of nitric oxide (NO) donors has experimentally been demonstrated in shock, there are still no NO donor medications clinically available. Thiol-nitrosothiol-hydroxyethyl starch (S-NO-HES) is a novel molecule consisting of NO coupled to a thiolated derivative of hydroxyethyl starch (HES). It was aimed to assess the ability of S-NO-HES to serve as an NO donor under a variety of in vitro simulated physiologic conditions, which might be the first step to qualify this molecule as a novel type of NO donor-fluid., Methods: We studied the effect of temperature on NO-releasing properties of S-NO-HES in blood, at 34°C, 37°C, and 41°C. Ascorbic acid (Asc) and amylase were also tested in a medium environment. In addition, we evaluated the activity of S-NO-HES in the isolated aortic ring and Langendorff-perfused heart setup., Results: The NO release property of S-NO-HES was found at any temperature. Asc led to a significant increase in the production of NO compared to S-NO-HES incubation (P < 0.05). The addition of amylase together with Asc to the medium further increased the release of NO (P < 0.05). S-NO-HES exerted significant vasodilatory effects on phenylephrine precontracted aortic rings that were dose-dependent (P < 0.01). Furthermore, S-NO-HES significantly increased the heart rate and additionally reduced the duration of the cardiac action potential, as indicated by a reduction of QTc-B values (P < 0.01)., Conclusions: We demonstrated for the first time that the S-NO-HES molecule exhibited its NO-releasing effects. The effectiveness of this new NO donor to substitute NO deficiency under septic conditions or in other indications needs to be studied., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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33. A generic avian physiologically-based kinetic (PBK) model and its application in three bird species.
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Baier V, Paini A, Schaller S, Scanes CG, Bone AJ, Ebeling M, Preuss TG, Witt J, and Heckmann D
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- Animals, Computer Simulation, Ducks, Female, Kinetics, Male, Reproducibility of Results, Chickens, Models, Biological
- Abstract
Physiologically-based kinetic (PBK) models are effective tools for designing toxicological studies and conducting extrapolations to inform hazard characterization in risk assessment by filling data gaps and defining safe levels of chemicals. In the present work, a generic avian PBK model for male and female birds was developed using PK-Sim and MoBi from the Open Systems Pharmacology Suite (OSPS). The PBK model includes an ovulation model (egg development) to predict concentrations of chemicals in eggs from dietary exposure. The model was parametrized for chicken (Gallus gallus), bobwhite quail (Colinus virginianus) and mallard duck (Anas platyrhynchos) and was tested with nine chemicals for which in vivo studies were available. Time-concentration profiles of chemicals reaching tissues and egg compartment were simulated and compared to in vivo data. The overall accuracy of the PBK model predictions across the analyzed chemicals was good. Model simulations were found to be in the range of 22-79% within a 3-fold and 41-89% were within 10- fold deviation of the in vivo observed data. However, for some compounds scarcity of in-vivo data and inconsistencies between published studies allowed only a limited goodness of fit evaluation. The generic avian PBK model was developed following a "best practice" workflow describing how to build a PBK model for novel species. The credibility and reproducibility of the avian PBK models were scored by evaluation according to the available guidance documents from WHO (2010), and OECD (2021), to increase applicability, confidence and acceptance of these in silico models in chemical risk assessment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The project was conducted by Bayer Crop Science division. Some of the authors are employed at Bayer or were paid for their work by Bayer. Bayer produce and sell pharmaceuticals and agrochemicals. All the authors have the interest to get PBPK/PBK model accepted for regulatory purposes., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2022
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34. Energetic basis for bird ontogeny and egg-laying applied to the bobwhite quail.
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Marn N, Lika K, Augustine S, Goussen B, Ebeling M, Heckmann D, and Gergs A
- Abstract
Birds build up their reproductive system and undergo major tissue remodeling for each reproductive season. Energetic specifics of this process are still not completely clear, despite the increasing interest. We focused on the bobwhite quail - one of the most intensely studied species due to commercial and conservation interest - to elucidate the energy fluxes associated with reproduction, including the fate of the extra assimilates ingested prior to and during reproduction. We used the standard Dynamic Energy Budget model, which is a mechanistic process-based model capable of fully specifying and predicting the life cycle of the bobwhite quail: its growth, maturation and reproduction. We expanded the standard model with an explicit egg-laying module and formulated and tested two hypotheses for energy allocation of extra assimilates associated with reproduction: Hypothesis 1, that the energy and nutrients are used directly for egg production; and Hypothesis 2, that the energy is mostly spent fueling the increased metabolic costs incurred by building up and maintaining the reproductive system and, subsequently, by egg-laying itself. Our results suggest that Hypothesis 2 is the more likely energy pathway. Model predictions capture well the whole ontogeny of a generalized northern bobwhite quail and are able to reproduce most of the data variability via variability in (i) egg size, (ii) egg-laying rate and (iii) inter-individual physiological variability modeled via the zoom factor, i.e. assimilation potential. Reliable models with a capacity to predict physiological responses of individuals are relevant not only for experimental setups studying effects of various natural and anthropogenic pressures on the quail as a bird model organism, but also for wild quail management and conservation. The model is, with minor modifications, applicable to other species of interest, making it a most valuable tool in the emerging field of conservation physiology., (© The Author(s) 2022. Published by Oxford University Press and the Society for Experimental Biology.)
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- 2022
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35. Practices and Attitudes of Bavarian Stakeholders Regarding the Secondary Use of Health Data for Research Purposes During the COVID-19 Pandemic: Qualitative Interview Study.
- Author
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McLennan S, Rachut S, Lange J, Fiske A, Heckmann D, and Buyx A
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- Artificial Intelligence, Attitude, Ecosystem, Humans, Pandemics prevention & control, Qualitative Research, COVID-19 epidemiology, COVID-19 prevention & control
- Abstract
Background: The COVID-19 pandemic is a threat to global health and requires collaborative health research efforts across organizations and countries to address it. Although routinely collected digital health data are a valuable source of information for researchers, benefiting from these data requires accessing and sharing the data. Health care organizations focusing on individual risk minimization threaten to undermine COVID-19 research efforts, and it has been argued that there is an ethical obligation to use the European Union's General Data Protection Regulation (GDPR) scientific research exemption during the COVID-19 pandemic to support collaborative health research., Objective: This study aims to explore the practices and attitudes of stakeholders in the German federal state of Bavaria regarding the secondary use of health data for research purposes during the COVID-19 pandemic, with a specific focus on the GDPR scientific research exemption., Methods: Individual semistructured qualitative interviews were conducted between December 2020 and January 2021 with a purposive sample of 17 stakeholders from 3 different groups in Bavaria: researchers involved in COVID-19 research (n=5, 29%), data protection officers (n=6, 35%), and research ethics committee representatives (n=6, 35%). The transcripts were analyzed using conventional content analysis., Results: Participants identified systemic challenges in conducting collaborative secondary-use health data research in Bavaria; secondary health data research generally only happens when patient consent has been obtained, or the data have been fully anonymized. The GDPR research exemption has not played a significant role during the pandemic and is currently seldom and restrictively used. Participants identified 3 key groups of barriers that led to difficulties: the wider ecosystem at many Bavarian health care organizations, legal uncertainty that leads to risk-adverse approaches, and ethical positions that patient consent ought to be obtained whenever possible to respect patient autonomy. To improve health data research in Bavaria and across Germany, participants wanted greater legal certainty regarding the use of pseudonymized data for research purposes without the patient's consent., Conclusions: The current balance between enabling the positive goals of health data research and avoiding associated data protection risks is heavily skewed toward avoiding risks; so much so that it makes reaching the goals of health data research extremely difficult. This is important, as it is widely recognized that there is an ethical imperative to use health data to improve care. The current approach also creates a problematic conflict with the ambitions of Germany, and the federal state of Bavaria, to be a leader in artificial intelligence. A recent development in the field of German public administration known as norm screening (Normenscreening) could potentially provide a systematic approach to minimize legal barriers. This approach would likely be beneficial to other countries., (©Stuart McLennan, Sarah Rachut, Johannes Lange, Amelia Fiske, Dirk Heckmann, Alena Buyx. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 27.06.2022.)
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- 2022
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36. Quantitative Morphometric, Physiological, and Metabolic Characteristics of Chickens and Mallards for Physiologically Based Kinetic Model Development.
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Scanes CG, Witt J, Ebeling M, Schaller S, Baier V, Bone AJ, Preuss TG, and Heckmann D
- Abstract
Physiologically based kinetic (PBK) models are a promising tool for xenobiotic environmental risk assessment that could reduce animal testing by predicting in vivo exposure. PBK models for birds could further our understanding of species-specific sensitivities to xenobiotics, but would require species-specific parameterization. To this end, we summarize multiple major morphometric and physiological characteristics in chickens, particularly laying hens ( Gallus gallus ) and mallards ( Anas platyrhynchos ) in a meta-analysis of published data. Where such data did not exist, data are substituted from domesticated ducks ( Anas platyrhynchos ) and, in their absence, from chickens. The distribution of water between intracellular, extracellular, and plasma is similar in laying hens and mallards. Similarly, the lengths of the components of the small intestine (duodenum, jejunum, and ileum) are similar in chickens and mallards. Moreover, not only are the gastrointestinal absorptive areas similar in mallard and chickens but also they are similar to those in mammals when expressed on a log basis and compared to log body weight. In contrast, the following are much lower in laying hens than mallards: cardiac output (CO), hematocrit (Hct), and blood hemoglobin. There are shifts in ovary weight (increased), oviduct weight (increased), and plasma/serum concentrations of vitellogenin and triglyceride between laying hens and sexually immature females. In contrast, reproductive state does not affect the relative weights of the liver, kidneys, spleen, and gizzard., Competing Interests: JW, ME, AB, TP, and DH were employed by the company Bayer AG. SS and VB were employed by the company esqLABS GmbH. CS, his company Scanes Technology and Research and esqLABS GmbH received funding from Bayer AG., (Copyright © 2022 Scanes, Witt, Ebeling, Schaller, Baier, Bone, Preuss and Heckmann.)
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- 2022
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37. Quantitative Comparison of Avian and Mammalian Physiologies for Parameterization of Physiologically Based Kinetic Models.
- Author
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Scanes CG, Witt J, Ebeling M, Schaller S, Baier V, Bone AJ, Preuss TG, and Heckmann D
- Abstract
Physiologically based kinetic (PBK) models facilitate chemical risk assessment by predicting in vivo exposure while reducing the need for animal testing. PBK models for mammals have seen significant progress, which has yet to be achieved for avian systems. Here, we quantitatively compare physiological, metabolic and anatomical characteristics between birds and mammals, with the aim of facilitating bird PBK model development. For some characteristics, there is considerable complementarity between avian and mammalian species with identical values for the following: blood hemoglobin and hemoglobin concentrations per unit erythrocyte volume together with relative weights of the liver, heart, and lungs. There are also systematic differences for some major characteristics between avian and mammalian species including erythrocyte volume, plasma concentrations of albumin, total protein and triglyceride together with liver cell size and relative weights of the kidney, spleen, and ovary. There are also major differences between characteristics between sexually mature and sexually immature female birds. For example, the relative weights of the ovary and oviduct are greater in sexually mature females compared to immature birds as are the plasma concentrations of triglyceride and vitellogenin. Both these sets of differences reflect the genetic "blue print" inherited from ancestral archosaurs such as the production of large eggs with yolk filled oocytes surrounded by egg white proteins, membranes and a calciferous shell together with adaptions for flight in birds or ancestrally in flightless birds., Competing Interests: JW, ME, AB, TP, and DH were employed by the company Bayer AG. SS and VB were employed by the company esqLABS GmbH. CS declares that his company Scanes Technology and Research and esqLABS GmbH received funding from Bayer AG. The funder (in the person of the Bayer authors) had the following involvement with the study: contributed to conceiving the study, revising the manuscript, and critiquing the analysis., (Copyright © 2022 Scanes, Witt, Ebeling, Schaller, Baier, Bone, Preuss and Heckmann.)
- Published
- 2022
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38. Deep learning allows genome-scale prediction of Michaelis constants from structural features.
- Author
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Kroll A, Engqvist MKM, Heckmann D, and Lercher MJ
- Subjects
- Databases, Genetic, Enzymes metabolism, Kinetics, Metabolomics, Models, Biological, Neural Networks, Computer, Substrate Specificity, Deep Learning, Genome
- Abstract
The Michaelis constant KM describes the affinity of an enzyme for a specific substrate and is a central parameter in studies of enzyme kinetics and cellular physiology. As measurements of KM are often difficult and time-consuming, experimental estimates exist for only a minority of enzyme-substrate combinations even in model organisms. Here, we build and train an organism-independent model that successfully predicts KM values for natural enzyme-substrate combinations using machine and deep learning methods. Predictions are based on a task-specific molecular fingerprint of the substrate, generated using a graph neural network, and on a deep numerical representation of the enzyme's amino acid sequence. We provide genome-scale KM predictions for 47 model organisms, which can be used to approximately relate metabolite concentrations to cellular physiology and to aid in the parameterization of kinetic models of cellular metabolism., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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39. Modeling photosynthetic resource allocation connects physiology with evolutionary environments.
- Author
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Sundermann EM, Lercher MJ, and Heckmann D
- Abstract
The regulation of resource allocation in biological systems observed today is the cumulative result of natural selection in ancestral and recent environments. To what extent are observed resource allocation patterns in different photosynthetic types optimally adapted to current conditions, and to what extent do they reflect ancestral environments? Here, we explore these questions for C
3 , C4 , and C3 -C4 intermediate plants of the model genus Flaveria. We developed a detailed mathematical model of carbon fixation, which accounts for various environmental parameters and for energy and nitrogen partitioning across photosynthetic components. This allows us to assess environment-dependent plant physiology and performance as a function of resource allocation patterns. Models of C4 plants optimized for conditions experienced by evolutionary ancestors perform better than models accounting for experimental growth conditions, indicating low phenotypic plasticity. Supporting this interpretation, the model predicts that C4 species need to re-allocate more nitrogen between photosynthetic components than C3 species to adapt to new environments. We thus hypothesize that observed resource distribution patterns in C4 plants still reflect optimality in ancestral environments, allowing the quantitative inference of these environments from today's plants. Our work allows us to quantify environmental effects on photosynthetic resource allocation and performance in the light of evolutionary history., (© 2021. The Author(s).)- Published
- 2021
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40. Independent component analysis recovers consistent regulatory signals from disparate datasets.
- Author
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Sastry AV, Hu A, Heckmann D, Poudel S, Kavvas E, and Palsson BO
- Subjects
- Algorithms, Linear Models, Principal Component Analysis, RNA-Seq, Computational Biology methods, Databases, Genetic, Escherichia coli genetics, Gene Expression Profiling methods, Oligonucleotide Array Sequence Analysis methods, Transcriptome
- Abstract
The availability of bacterial transcriptomes has dramatically increased in recent years. This data deluge could result in detailed inference of underlying regulatory networks, but the diversity of experimental platforms and protocols introduces critical biases that could hinder scalable analysis of existing data. Here, we show that the underlying structure of the E. coli transcriptome, as determined by Independent Component Analysis (ICA), is conserved across multiple independent datasets, including both RNA-seq and microarray datasets. We subsequently combined five transcriptomics datasets into a large compendium containing over 800 expression profiles and discovered that its underlying ICA-based structure was still comparable to that of the individual datasets. With this understanding, we expanded our analysis to over 3,000 E. coli expression profiles and predicted three high-impact regulons that respond to oxidative stress, anaerobiosis, and antibiotic treatment. ICA thus enables deep analysis of disparate data to uncover new insights that were not visible in the individual datasets., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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41. The ERG-Regulated LINC00920 Promotes Prostate Cancer Cell Survival via the 14-3-3ε-FOXO Pathway.
- Author
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Angeles AK, Heckmann D, Flosdorf N, Duensing S, and Sültmann H
- Subjects
- 14-3-3 Proteins genetics, Cell Line, Tumor, Cell Survival physiology, Forkhead Box Protein O1 genetics, Humans, Male, PC-3 Cells, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Transcriptional Regulator ERG genetics, Transcriptional Regulator ERG metabolism, Up-Regulation, 14-3-3 Proteins metabolism, Forkhead Box Protein O1 metabolism, Prostatic Neoplasms metabolism
- Abstract
Numerous noncoding transcripts have been reported to correlate with cancer development and progression. Nevertheless, there remains a paucity of long noncoding RNAs (lncRNA) with well-elucidated functional roles. Here, we leverage the International Cancer Genome Consortium-Early Onset Prostate Cancer transcriptome and identify the previously uncharacterized lncRNA LINC00920 to be upregulated in prostate tumors. Phenotypic characterization of LINC00920 revealed its positive impact on cellular proliferation, colony formation, and migration. We demonstrate that LINC00920 transcription is directly activated by ERG, an oncogenic transcription factor overexpressed in 50% of prostate cancers. Chromatin isolation by RNA purification-mass spectrometry revealed the interaction of LINC00920 with the 14-3-3ε protein, leading to enhanced sequestration of tumor suppressive FOXO1. Altogether, our results provide a rationale on how ERG overexpression, partly by driving LINC00920 transcription, could confer survival advantage to prostate cancer cells and potentially prime PTEN-intact prostate cells for cellular transformation through FOXO inactivation. IMPLICATIONS: The study describes a novel lncRNA-mediated mechanism of regulating the FOXO signaling pathway and provides additional insight into the role of ERG in prostate cancer cells., (©2020 American Association for Cancer Research.)
- Published
- 2020
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42. Kinetic profiling of metabolic specialists demonstrates stability and consistency of in vivo enzyme turnover numbers.
- Author
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Heckmann D, Campeau A, Lloyd CJ, Phaneuf PV, Hefner Y, Carrillo-Terrazas M, Feist AM, Gonzalez DJ, and Palsson BO
- Subjects
- Escherichia coli genetics, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Gene Knockout Techniques methods, Genome genetics, Kinetics, Machine Learning, Models, Biological, Proteomics methods, Escherichia coli metabolism
- Abstract
Enzyme turnover numbers ( k
cat s) are essential for a quantitative understanding of cells. Because kcat s are traditionally measured in low-throughput assays, they can be inconsistent, labor-intensive to obtain, and can miss in vivo effects. We use a data-driven approach to estimate in vivo kcat s using metabolic specialist Escherichia coli strains that resulted from gene knockouts in central metabolism followed by metabolic optimization via laboratory evolution. By combining absolute proteomics with fluxomics data, we find that in vivo kcat s are robust against genetic perturbations, suggesting that metabolic adaptation to gene loss is mostly achieved through other mechanisms, like gene-regulatory changes. Combining machine learning and genome-scale metabolic models, we show that the obtained in vivo kcat s predict unseen proteomics data with much higher precision than in vitro kcat s. The results demonstrate that in vivo kcat s can solve the problem of inconsistent and low-coverage parameterizations of genome-scale cellular models., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)- Published
- 2020
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43. Causal mutations from adaptive laboratory evolution are outlined by multiple scales of genome annotations and condition-specificity.
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Phaneuf PV, Yurkovich JT, Heckmann D, Wu M, Sandberg TE, King ZA, Tan J, Palsson BO, and Feist AM
- Subjects
- Escherichia coli genetics, Genome, Mutation, Escherichia coli Proteins genetics, Laboratories
- Abstract
Background: Adaptive Laboratory Evolution (ALE) has emerged as an experimental approach to discover mutations that confer phenotypic functions of interest. However, the task of finding and understanding all beneficial mutations of an ALE experiment remains an open challenge for the field. To provide for better results than traditional methods of ALE mutation analysis, this work applied enrichment methods to mutations described by a multiscale annotation framework and a consolidated set of ALE experiment conditions. A total of 25,321 unique genome annotations from various sources were leveraged to describe multiple scales of mutated features in a set of 35 Escherichia coli based ALE experiments. These experiments totalled 208 independent evolutions and 2641 mutations. Additionally, mutated features were statistically associated across a total of 43 unique experimental conditions to aid in deconvoluting mutation selection pressures., Results: Identifying potentially beneficial, or key, mutations was enhanced by seeking coding and non-coding genome features significantly enriched by mutations across multiple ALE replicates and scales of genome annotations. The median proportion of ALE experiment key mutations increased from 62%, with only small coding and non-coding features, to 71% with larger aggregate features. Understanding key mutations was enhanced by considering the functions of broader annotation types and the significantly associated conditions for key mutated features. The approaches developed here were used to find and characterize novel key mutations in two ALE experiments: one previously unpublished with Escherichia coli grown on glycerol as a carbon source and one previously published with Escherichia coli tolerized to high concentrations of L-serine., Conclusions: The emergent adaptive strategies represented by sets of ALE mutations became more clear upon observing the aggregation of mutated features across small to large scale genome annotations. The clarification of mutation selection pressures among the many experimental conditions also helped bring these strategies to light. This work demonstrates how multiscale genome annotation frameworks and data-driven methods can help better characterize ALE mutations, and thus help elucidate the genotype-to-phenotype relationship of the studied organism.
- Published
- 2020
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44. A biochemically-interpretable machine learning classifier for microbial GWAS.
- Author
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Kavvas ES, Yang L, Monk JM, Heckmann D, and Palsson BO
- Subjects
- Aminosalicylic Acid pharmacology, Anti-Bacterial Agents pharmacology, Genome, Bacterial, Genome, Microbial, Isoniazid pharmacology, Pyrazinamide pharmacology, Reproducibility of Results, Drug Resistance, Bacterial drug effects, Drug Resistance, Bacterial genetics, Genome-Wide Association Study, Machine Learning, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis genetics
- Abstract
Current machine learning classifiers have successfully been applied to whole-genome sequencing data to identify genetic determinants of antimicrobial resistance (AMR), but they lack causal interpretation. Here we present a metabolic model-based machine learning classifier, named Metabolic Allele Classifier (MAC), that uses flux balance analysis to estimate the biochemical effects of alleles. We apply the MAC to a dataset of 1595 drug-tested Mycobacterium tuberculosis strains and show that MACs predict AMR phenotypes with accuracy on par with mechanism-agnostic machine learning models (isoniazid AUC = 0.93) while enabling a biochemical interpretation of the genotype-phenotype map. Interpretation of MACs for three antibiotics (pyrazinamide, para-aminosalicylic acid, and isoniazid) recapitulates known AMR mechanisms and suggest a biochemical basis for how the identified alleles cause AMR. Extending flux balance analysis to identify accurate sequence classifiers thus contributes mechanistic insights to GWAS, a field thus far dominated by mechanism-agnostic results.
- Published
- 2020
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45. Very High Dehydroepiandrosterone Sulfate (DHEAS) in Serum of an Overweight Female Adolescent Without a Tumor.
- Author
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Iliev DI, Braun R, Sánchez-Guijo A, Hartmann M, Wudy SA, Heckmann D, Bruchelt G, Rösner A, Grosser G, Geyer J, and Binder G
- Subjects
- Adolescent, Case-Control Studies, Female, Humans, Multidrug Resistance-Associated Protein 2, Pediatric Obesity blood, Pediatric Obesity genetics, Prognosis, Young Adult, Codon, Nonsense, Dehydroepiandrosterone Sulfate blood, Pediatric Obesity pathology, Steryl-Sulfatase genetics
- Abstract
Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids., (Copyright © 2020 Iliev, Braun, Sánchez-Guijo, Hartmann, Wudy, Heckmann, Bruchelt, Rösner, Grosser, Geyer and Binder.)
- Published
- 2020
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- View/download PDF
46. Adaptations of Escherichia coli strains to oxidative stress are reflected in properties of their structural proteomes.
- Author
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Mih N, Monk JM, Fang X, Catoiu E, Heckmann D, Yang L, and Palsson BO
- Subjects
- Antioxidants metabolism, Escherichia coli Proteins metabolism, Fimbriae, Bacterial metabolism, Models, Biological, Molybdenum metabolism, Operon genetics, Oxidation-Reduction, Periplasm metabolism, Phenotype, Reactive Oxygen Species metabolism, Adaptation, Physiological, Escherichia coli K12 physiology, Oxidative Stress, Proteome metabolism
- Abstract
Background: The reconstruction of metabolic networks and the three-dimensional coverage of protein structures have reached the genome-scale in the widely studied Escherichia coli K-12 MG1655 strain. The combination of the two leads to the formation of a structural systems biology framework, which we have used to analyze differences between the reactive oxygen species (ROS) sensitivity of the proteomes of sequenced strains of E. coli. As proteins are one of the main targets of oxidative damage, understanding how the genetic changes of different strains of a species relates to its oxidative environment can reveal hypotheses as to why these variations arise and suggest directions of future experimental work., Results: Creating a reference structural proteome for E. coli allows us to comprehensively map genetic changes in 1764 different strains to their locations on 4118 3D protein structures. We use metabolic modeling to predict basal ROS production levels (ROStype) for 695 of these strains, finding that strains with both higher and lower basal levels tend to enrich their proteomes with antioxidative properties, and speculate as to why that is. We computationally assess a strain's sensitivity to an oxidative environment, based on known chemical mechanisms of oxidative damage to protein groups, defined by their localization and functionality. Two general groups - metalloproteins and periplasmic proteins - show enrichment of their antioxidative properties between the 695 strains with a predicted ROStype as well as 116 strains with an assigned pathotype. Specifically, proteins that a) utilize a molybdenum ion as a cofactor and b) are involved in the biogenesis of fimbriae show intriguing protective properties to resist oxidative damage. Overall, these findings indicate that a strain's sensitivity to oxidative damage can be elucidated from the structural proteome, though future experimental work is needed to validate our model assumptions and findings., Conclusion: We thus demonstrate that structural systems biology enables a proteome-wide, computational assessment of changes to atomic-level physicochemical properties and of oxidative damage mechanisms for multiple strains in a species. This integrative approach opens new avenues to study adaptation to a particular environment based on physiological properties predicted from sequence alone.
- Published
- 2020
- Full Text
- View/download PDF
47. Molecular typing and in vitro resistance of Cryptococcus neoformans clinical isolates obtained in Germany between 2011 and 2017.
- Author
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Selb R, Fuchs V, Graf B, Hamprecht A, Hogardt M, Sedlacek L, Schwarz R, Idelevich EA, Becker SL, Held J, Küpper-Tetzel CP, McCormick-Smith I, Heckmann D, Gerkrath J, Han CO, Wilmes D, and Rickerts V
- Subjects
- Cryptococcosis epidemiology, Cryptococcus neoformans classification, DNA, Fungal genetics, Drug Resistance, Fungal genetics, Female, Fluconazole pharmacology, Flucytosine pharmacology, Fungal Proteins genetics, Genotype, Germany epidemiology, Humans, Male, Microbial Sensitivity Tests, Molecular Typing, Mutation, Mycological Typing Techniques, Antifungal Agents pharmacology, Cryptococcosis microbiology, Cryptococcus neoformans drug effects, Cryptococcus neoformans genetics
- Abstract
Cryptococcosis is a fungal infection of the central nervous system predominantly caused by Cryptococcus neoformans in immunocompromised patients. In several countries worldwide, up to 50% of isolates show in vitro resistance to clinically used antifungals including fluconazole. No prospective data on susceptibility to antifungal drugs are available for Germany. In this study, we characterised all C. neoformans isolates collected from individual patients' samples at the German reference laboratory for cryptococcosis 2011 and 2017 (n = 133) by multi-locus sequence typing and phenotypic drug susceptibility testing. We identified serotype A/genotype VNI isolates belonging to clonal complexes previously described from Europe, Africa, Asia and South America as the most prevalent agents of cryptococcosis in Germany. Overall, we observed minimal inhibitory concentrations (MICs) above the epidemiological cut-offs (ECVs) in 1.6% of isolates regarding fluconazole and 2.3% of isolates regarding 5-flucytosine. Here, two C. neoformans var. grubii isolates displayed decreased drug susceptibility to fluconazole, one of them additionally to 5-flucytosine. We also found 5-flucytosine MICs above the ECV for two C. neoformans var. neoformans isolates. We identified a novel mutation in the ERG11 gene which might be associated with the elevated fluconazole MIC in one of the isolates. The clinical importance of the detected in vitro resistance is documented by patient histories showing relapsed infection or primary fatal disease. Of note, sertraline demonstrated antifungal activity comparable to previous reports. Systematic collection of susceptibility data in combination with molecular typing of C. neoformans is important to comprehensively assess the spread of isolates and to understand their drug resistance patterns., (Copyright © 2019 Elsevier GmbH. All rights reserved.)
- Published
- 2019
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48. Cellular responses to reactive oxygen species are predicted from molecular mechanisms.
- Author
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Yang L, Mih N, Anand A, Park JH, Tan J, Yurkovich JT, Monk JM, Lloyd CJ, Sandberg TE, Seo SW, Kim D, Sastry AV, Phaneuf P, Gao Y, Broddrick JT, Chen K, Heckmann D, Szubin R, Hefner Y, Feist AM, and Palsson BO
- Subjects
- Catalysis, Cell Proliferation genetics, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression Regulation genetics, Hydrogen Peroxide metabolism, Operon genetics, Oxidative Stress genetics, Sulfur metabolism, Iron metabolism, Iron-Sulfur Proteins genetics, Metalloproteins genetics, Reactive Oxygen Species metabolism
- Abstract
Catalysis using iron-sulfur clusters and transition metals can be traced back to the last universal common ancestor. The damage to metalloproteins caused by reactive oxygen species (ROS) can prevent cell growth and survival when unmanaged, thus eliciting an essential stress response that is universal and fundamental in biology. Here we develop a computable multiscale description of the ROS stress response in Escherichia coli , called OxidizeME. We use OxidizeME to explain four key responses to oxidative stress: 1) ROS-induced auxotrophy for branched-chain, aromatic, and sulfurous amino acids; 2) nutrient-dependent sensitivity of growth rate to ROS; 3) ROS-specific differential gene expression separate from global growth-associated differential expression; and 4) coordinated expression of iron-sulfur cluster (ISC) and sulfur assimilation (SUF) systems for iron-sulfur cluster biosynthesis. These results show that we can now develop fundamental and quantitative genotype-phenotype relationships for stress responses on a genome-wide basis., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
- Full Text
- View/download PDF
49. Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex.
- Author
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Wong W, Huang R, Menant S, Hong C, Sandow JJ, Birkinshaw RW, Healer J, Hodder AN, Kanjee U, Tonkin CJ, Heckmann D, Soroka V, Søgaard TMM, Jørgensen T, Duraisingh MT, Czabotar PE, de Jongh WA, Tham WH, Webb AI, Yu Z, and Cowman AF
- Subjects
- Animals, Antigens, Protozoan chemistry, Antigens, Protozoan metabolism, Carrier Proteins chemistry, Carrier Proteins metabolism, Cell Line, Tumor, Drosophila, Erythrocyte Membrane metabolism, Erythrocyte Membrane parasitology, Humans, Models, Molecular, Multiprotein Complexes metabolism, Protein Binding, Protozoan Proteins chemistry, Protozoan Proteins metabolism, Antigens, Protozoan ultrastructure, Carrier Proteins ultrastructure, Cryoelectron Microscopy, Multiprotein Complexes chemistry, Multiprotein Complexes ultrastructure, Plasmodium falciparum chemistry, Plasmodium falciparum pathogenicity, Plasmodium falciparum ultrastructure, Protozoan Proteins ultrastructure
- Abstract
Plasmodium falciparum causes the severe form of malaria that has high levels of mortality in humans. Blood-stage merozoites of P. falciparum invade erythrocytes, and this requires interactions between multiple ligands from the parasite and receptors in hosts. These interactions include the binding of the Rh5-CyRPA-Ripr complex with the erythrocyte receptor basigin
1,2 , which is an essential step for entry into human erythrocytes. Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. We report a cryo-electron microscopy structure of the Rh5-CyRPA-Ripr complex at subnanometre resolution, which reveals the organization of this essential invasion complex and the mode of interactions between members of the complex, and shows that CyRPA is a critical mediator of complex assembly. Our structure identifies blades 4-6 of the β-propeller of CyRPA as contact sites for Rh5 and Ripr. The limited contacts between Rh5-CyRPA and CyRPA-Ripr are consistent with the dissociation of Rh5 and Ripr from CyRPA for membrane insertion. A comparision of the crystal structure of Rh5-basigin with the cryo-electron microscopy structure of Rh5-CyRPA-Ripr suggests that Rh5 and Ripr are positioned parallel to the erythrocyte membrane before membrane insertion. This provides information on the function of this complex, and thereby provides insights into invasion by P. falciparum.- Published
- 2019
- Full Text
- View/download PDF
50. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
- Author
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Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y, Heckmann D, Sidiropoulos N, Waszak SM, Hübschmann D, Urbanucci A, Girma EG, Kuryshev V, Klimczak LJ, Saini N, Stütz AM, Weichenhan D, Böttcher LM, Toth R, Hendriksen JD, Koop C, Lutsik P, Matzk S, Warnatz HJ, Amstislavskiy V, Feuerstein C, Raeder B, Bogatyrova O, Schmitz EM, Hube-Magg C, Kluth M, Huland H, Graefen M, Lawerenz C, Henry GH, Yamaguchi TN, Malewska A, Meiners J, Schilling D, Reisinger E, Eils R, Schlesner M, Strand DW, Bristow RG, Boutros PC, von Kalle C, Gordenin D, Sültmann H, Brors B, Sauter G, Plass C, Yaspo ML, Korbel JO, Schlomm T, and Weischenfeldt J
- Subjects
- Adult, Biomarkers, Tumor metabolism, Evolution, Molecular, Humans, Male, Middle Aged, Mutation, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Risk Factors, Whole Genome Sequencing methods, Biomarkers, Tumor genetics, DNA Methylation, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics, Transcriptome
- Abstract
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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