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Ex Luna, Scientia: The Lunar Occultation eXplorer (LOX) and the Future of MeV \ensuremathγ-Ray Astrophysics

Abstract

Not specified

Authors: Richard Miller, Marco Ajello, Katie Auchettl, John Beacom, Peter Bloser, Adam Burrows, Anna Frebel, Chris Fryer, Dieter Hartmann, Peter Hoeflich, Aimee Hungerford, Mark Leising, Laura Lopez, Peter Milne, Patrick Peplowski, Friedrich Roepke, Daniel Scolnic, Ivo Seitenzahl, Lih-Sin The, C. Alex Young, LOX Team

Date Published: 1st Apr 2022

Publication Type: InProceedings

Core-Count Independent Reproducible Reduce

Abstract (Expand)

ecause of rounding errors, parallel floating-point summation can produce different results on different core-counts. For some algorithms like hill climbing, RAxML-NG [7] or greedy algorithms, this … implies that results may be irreproducible with different core-counts. We present the Binary Tree Reduction algorithm, which follows a distributed binary tree scheme that keeps the calculation order fixed and independent of the core-count 푝. A naive implementation requires up to (푝 − 1) ∗ (log2 ( 푁 −1 푝 ) + 1) messages to sum 푁 floating-point numbers. To reduce the message count, we introduce a message buffer and optimize data distribution across the cores, the latter results in a runtime decrease of 18 %. We find that for 푝 = 256, Binary Tree Reduction has a slowdown of less than 2 compared to a naive, irreproducible solution. It is able to compute the sum of 푁 ≈ 21 ∗ 106 summands on 푝 = 256 cores in about 248 μs.

Authors: Christoph Stelz, Lukas Hübner, Alexandros Stamatakis

Date Published: 1st Apr 2022

Publication Type: Bachelor's Thesis

Mechano-redox control of Mac-1 de-adhesion from ICAM-1 by protein disulfide isomerase promotes directional movement of neutrophils under flow

Abstract (Expand)

Macrophage-1 antigen or Mac-1 (CD11b/CD18, αMβ2) is a leukocyte integrin essential for firm adhesion of neutrophils, lymphocytes and monocytes against flow when recruited to the endothelium. To migrate … to the site of inflammation, leukocytes require coordinated adhesion and de-adhesion for directional movement. The vascular thiol isomerase, protein disulfide isomerase (PDI), was found by fluorescence microscopy to colocalize with high affinity Mac-1 at the trailing edge of stimulated neutrophils when adhered to ICAM-1 under fluid shear. From differential cysteine alkylation and mass spectrometry studies, PDI cleaves two allosteric disulfide bonds, C169-C176 and C224-C264, in the βI domain of the β2 subunit, and in mutagenesis and cell transfection studies, cleavage of the C224-C264 disulfide bond was shown to selectively control Mac-1 dis-engagement from ICAM-1 under fluid shear. Molecular dynamics simulations and binding of conformation-specific antibodies reveal that cleavage of the C224-C264 bond induces conformational change and mechanical stress in the βI domain that allosterically alters exposure of an αI domain epitope and shifts Mac-1 to a lower affinity state. From studies of neutrophil adherence to ICAM-1 under fluid shear, these molecular events promote neutrophil motility in the direction of flow at high shear stress. In summary, shear-dependent PDI cleavage of neutrophil Mac-1 C224-C264 disulfide bond triggers Mac-1 de-adherence from ICAM-1 at the trailing edge of the cell and enables directional movement of neutrophils during inflammation.

Authors: Alexander Dupuy, Camilo Aponte-Santamaría, Adva Yeheskel, Frauke Gräter, Philip J. Hogg, Freda H. Passam, Joyce Chiu

Date Published: 30th Mar 2022

Publication Type: Journal

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

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