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1579 Publications visible to you, out of a total of 1579
Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity

Abstract (Expand)

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, …high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer’s Disease (AD) progression. However, its low bioavailability and its blood–brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer’s Disease, selectively targeting TrkA-mediated pro-survival signals.

Authors: Thanasis Rogdakis, Despoina Charou, Alessia Latorrata, Eleni Papadimitriou, Alexandros Tsengenes, Christina Athanasiou, Marianna Papadopoulou, Constantina Chalikiopoulou, Theodora Katsila, Isbaal Ramos, Kyriakos C. Prousis, Rebecca C. Wade, Kyriaki Sidiropoulou, Theodora Calogeropoulou, Achille Gravanis, Ioannis Charalampopoulos

Date Published: 1st Mar 2022

Publication Type: Journal

Dynamics in a stellar convective layer and at its boundary: Comparison of five 3D hydrodynamics codes

Abstract

Not specified

Authors: R. Andrassy, J. Higl, H. Mao, M. Mocák, D. G. Vlaykov, W. D. Arnett, I. Baraffe, S. W. Campbell, T. Constantino, P. V. F. Edelmann, T. Goffrey, T. Guillet, F. Herwig, R. Hirschi, L. Horst, G. Leidi, C. Meakin, J. Pratt, F. Rizzuti, F. K. Röpke, P. Woodward

Date Published: 1st Mar 2022

Publication Type: Journal

Models of pulsationally assisted gravitationally confined detonations with different ignition conditions

Abstract

Not specified

Authors: F. Lach, F. P. Callan, S. A. Sim, F. K. Röpke

Date Published: 1st Mar 2022

Publication Type: Journal

The Non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase GapN Is a Potential New Drug Target in Streptococcus pyogenes

Abstract (Expand)

The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or …to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes . GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro . As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.

Authors: Philip Eisenberg, Leon Albert, Jonathan Teuffel, Eric Zitzow, Claudia Michaelis, Jane Jarick, Clemens Sehlke, Lisa Große, Nicole Bader, Ariane Nunes-Alves, Bernd Kreikemeyer, Hermann Schindelin, Rebecca C. Wade, Tomas Fiedler

Date Published: 15th Feb 2022

Publication Type: Journal

Publication Policy of the National Research Data Infrastructure for Personal Health Data (NFDI4Health) and the NFDI4Health Task Force COVID-19

Abstract

Not specified

Authors: Birte Lindstädt, Aliaksandra Shutsko, Martin Golebiewski, Dennis-Kenji Kipker, Vanessa Lettieri, Sophie Klopfenstein, Carina Vorisek, Matthias Löbe, Carsten Oliver Schmidt

Date Published: 11th Feb 2022

Publication Type: Manual

Accurate Free Energies for Complex Condensed-Phase Reactions Using an Artificial Neural Network Corrected DFTB/MM Methodology.

Abstract (Expand)

Semiempirical methods like density functional tight-binding (DFTB) allow extensive phase space sampling, making it possible to generate free energy surfaces of complex reactions in condensed-phase … environments. Such a high efficiency often comes at the cost of reduced accuracy, which may be improved by developing a specific reaction parametrization (SRP) for the particular molecular system. Thiol-disulfide exchange is a nucleophilic substitution reaction that occurs in a large class of proteins. Its proper description requires a high-level ab initio method, while DFT-GAA and hybrid functionals were shown to be inadequate, and so is DFTB due to its DFT-GGA descent. We develop an SRP for thiol-disulfide exchange based on an artificial neural network (ANN) implementation in the DFTB+ software and compare its performance to that of a standard SRP approach applied to DFTB. As an application, we use both new DFTB-SRP as components of a QM/MM scheme to investigate thiol-disulfide exchange in two molecular complexes: a solvated model system and a blood protein. Demonstrating the strengths of the methodology, highly accurate free energy surfaces are generated at a low cost, as the augmentation of DFTB with an ANN only adds a small computational overhead.

Authors: Claudia L Gómez-Flores, Denis Maag, Mayukh Kansari, Van-Quan Vuong, Stephan Irle, Frauke Gräter, Tomáš Kubař, Marcus Elstner

Date Published: 8th Feb 2022

Publication Type: Journal

White Paper: Towards in silico approaches for personalised medicine – Recommendations for verifying and validating predictive computational models in EU collaborative research

Abstract (Expand)

Harmonization of data integration is the key to standardization efforts in personalised medicine, which would also facilitate cross-European studies. Standardization of the models themselves is less … essential within a research context, where new models are created and tested in line with research progress, harmonization and/or standardization of input data is both feasible and necessary. We argue that model validation should receive more attention, and other measures should be implemented such that validation of models within personalised medicine becomes easier, also across borders. While this is an evident necessity within the context of models implemented as medical devices or decision tools, which are regulated by the European Medicines Agency and national competent authorities, we argue that model validation should be a higher priority at research level also, facilitating assessment by peers and by medical doctors – who themselves should receive better training in assessment of research using in silico models. This will also ease the implementation of translational research results in the clinic. Acceptance by doctors and the relevant medical specialties is a key hurdle for in silico models in personalised medicine. Any medical product - device, algorithm or drug - has to prove itself safe and effective to be licensed for use by regulators; however, it has also to be accepted by medical experts as being a good choice, and be recommended within clinical specialties. EU-STANDS4PM joined forces to examine to what extent existing standards or standards under development for both format and semantics can be used to link clinical and health as well as research data to computational models relevant for personalised medicine. As all requirements should be equally understood and fulfilled by users it is important to define them uniformly in an international context. To achieve this the conclusion of our work shall be also discussed in international standardization and technical committees, especially in the case of standards that are still being drawn up, and new standardization projects shall be initiated where necessary. We present a White Paper featuring recommendations for standardization of data integration as well as recommendations for standardization of model validation within a collaborative research context, such that health-related data can be optimally used for translational research and personalised medicine across Europe. As such the White Paper showcases the approach that takes big data in health through harmonized data integration to the most relevant predictive computational models for personalised medicine. As they are refined and validated these models can provide guidance not just how to use data, but also how to best cope with disease and preserve wellbeing in the daily lives of patients.

Authors: Kirstine Belling, Marina Caldara, Catherine Bjerre Collin, Tom Gebhardt, Martin Golebiewski, Tugce Karaderi, Faiz M. Khan, Marc Kirschner, Sylvia Krobitsch, Lars Küpfer, Heike Moser, Flora Musuamba Tschinanu, Mariam Nassar, Tito Poli, Philip Rosenstiel, Dagmar Waltemath, Olaf Wolkehnauer, EU-STANDS4PM consortium

Date Published: 7th Feb 2022

Publication Type: Misc

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