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1699 Publications visible to you, out of a total of 1699
ATP allosterically stabilizes integrin-linked kinase for efficient force generation

Abstract (Expand)

Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic … and intrinsic forces, but how the essential adhesion component intergrin-linked kinase (ILK) dynamically responds to mechanical force and what role ATP bound to this pseudokinase plays remains elusive. Here, we apply force-probe molecular dynamics simulations of human ILK:α-parvin coupled to traction force microscopy to explore ILK mechanotransducing functions. We identify two key saltbridge-forming arginines within the allosteric, ATP-dependent force-propagation network of ILK. Disrupting this network by mutation impedes parvin binding, focal adhesion stabilization, force generation, and thus migration. Under tension, ATP shifts the balance from rupture of the complex to protein unfolding, indicating that ATP increases the force threshold required for focal adhesion disassembly. Our study proposes a new role of ATP as an obligatory binding partner for structural and mechanical integrity of the pseudokinase ILK, ensuring efficient cellular force generation and migration.

Authors: Isabel Martin, Michele Nava, Sara Wickström, Frauke Gräter

Date Published: 8th Mar 2022

Publication Type: Journal

An Absolute Calibration of the Near-infrared Period–Luminosity Relations of Type II Cepheids in the Milky Way and in the Large Magellanic Cloud

Abstract (Expand)

Abstract We present time-series photometry of 21 nearby type II Cepheids in the near-infrared J , H , and K s passbands. We use this photometry, together with the Third Gaia Early Data Release parallaxes, … K s passbands. We use this photometry, together with the Third Gaia Early Data Release parallaxes, to determine for the first time period–luminosity relations (PLRs) for type II Cepheids from field representatives of these old pulsating stars in the near-infrared regime. We found PLRs to be very narrow for BL Herculis stars, which makes them candidates for precision distance indicators. We then use archival photometry and the most accurate distance obtained from eclipsing binaries to recalibrate PLRs for type II Cepheids in the Large Magellanic Cloud (LMC). Slopes of our PLRs in the Milky Way and in the LMC differ by slightly more than 2 σ and are in a good agreement with previous studies of the LMC, Galactic bulge, and Galactic globular cluster type II Cepheids samples. We use PLRs of Milky Way type II Cepheids to measure the distance to the LMC, and we obtain a distance modulus of 18.540 ± 0.026(stat.) ± 0.034(syst.) mag in the W JK Wesenheit index. We also investigate the metallicity effect within our Milky Way sample, and we find a rather significant value of about −0.2 mag dex −1 in each band meaning that more metal-rich type II Cepheids are intrinsically brighter than their more metal-poor counterparts, in agreement with the value obtained from type II Cepheids in Galactic globular clusters. The main source of systematic error on our Milky Way PLRs calibration, and the LMC distance, is the current uncertainty of the Gaia parallax zero-point.

Authors: Piotr Wielgórski, Grzegorz Pietrzyński, Bogumił Pilecki, Wolfgang Gieren, Bartłomiej Zgirski, Marek Górski, Gergely Hajdu, Weronika Narloch, Paulina Karczmarek, Radosław Smolec, Pierre Kervella, Jesper Storm, Alexandre Gallenne, Louise Breuval, Megan Lewis, Mikołaj Kałuszyński, Dariusz Graczyk, Wojciech Pych, Ksenia Suchomska, Mónica Taormina, Gonzalo Rojas Garcia, Aleksandra Kotek, Rolf Chini, Francisco Pozo Nũnez, Sadegh Noroozi, Catalina Sobrino Figaredo, Martin Haas, Klaus Hodapp, Przemysław Mikołajczyk, Krzysztof Kotysz, Dawid Moździerski, Piotr Kołaczek-Szymański

Date Published: 8th Mar 2022

Publication Type: Journal

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

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