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One Pass to Bind Them: The First Single-Pass SYCL Compiler with Unified Code Representation Across Backends

Abstract

Not specified

Authors: Aksel Alpay, Vincent Heuveline

Date Published: 18th Apr 2023

Publication Type: Journal

Collagen breaks at weak sacrificial bonds taming its mechanoradicals

Abstract (Expand)

Collagen is a force-bearing, hierarchical structural protein important to all connective tissue. In tendon collagen, high load even below macroscopic failure level creates mechanoradicals by homolytic … bond scission, similar to polymers. The location and type of initial rupture sites critically decide on both the mechanical and chemical impact of these micro-ruptures on the tissue, but are yet to be explored. We here use scale-bridging simulations supported by gel electrophoresis and mass spectrometry to determine breakage points in collagen. We find collagen crosslinks, as opposed to the backbone, to harbor the weakest bonds, with one particular bond in trivalent crosslinks as the most dominant rupture site. We identify this bond as sacrificial, rupturing prior to other bonds while maintaining the material’s integrity. Also, collagen’s weak bonds funnel ruptures such that the potentially harmful mechanoradicals are readily stabilized. Our results suggest this unique failure mode of collagen to be tailored towards combatting an early onset of macroscopic failure and material ageing.

Authors: Benedikt Rennekamp, Christoph Karfusehr, Markus Kurth, Aysecan Ünal, Kai Riedmiller, Ganna Gryn’ova, David M. Hudson, Frauke Gräter

Date Published: 12th Apr 2023

Publication Type: Journal

Disulfide Bond Reduction and Exchange in von-Willebrand-Factor’s C4-Domain Undermines Platelet Binding

Abstract

Not specified

Authors: Fabian Kutzki, Diego Butera, Angelina J. Lay, Denis Maag, Joyce Chiu, Heng-Giap Woon, Tomáš Kubař, Marcus Elstner, Camilo Aponte-Santamaría, Philip J. Hogg, Frauke Gräter

Date Published: 12th Apr 2023

Publication Type: Journal

Scaling Protein–Water Interactions in the Martini 3 Coarse-Grained Force Field to Simulate Transmembrane Helix Dimers in Different Lipid Environments

Abstract

Not specified

Authors: Ainara Claveras Cabezudo, Christina Athanasiou, Alexandros Tsengenes, Rebecca C. Wade

Date Published: 11th Apr 2023

Publication Type: Journal

Mechano-Redox Control of Macrophage-1 Antigen De-Adhesion From ICAM-1 (Intercellular Adhesion Molecule 1) by Protein Disulfide Isomerase Promotes Directional Movement Under Flow

Abstract (Expand)

BACKGROUND: Neutrophil migration is critical to the initiation and resolution of inflammation. Macrophage-1 antigen (Mac-1; CD11b/CD18, αMβ2) is a leukocyte integrin essential for firm adhesion to …firm adhesion to endothelial ICAM-1 (intercellular adhesion molecule 1) and migration of neutrophils in the shear forces of the circulation. PDI (protein disulfide isomerase) has been reported to influence neutrophil adhesion and migration. We aimed to elucidate the molecular mechanism of PDI control of Mac-1 affinity for ICAM-1 during neutrophil migration under fluid shear. METHODS: Neutrophils isolated from whole blood were perfused over microfluidic chips coated with ICAM-1. Colocalization of Mac-1 and PDI on neutrophils was visualized by fluorescently labeled antibodies and confocal microscopy. The redox state of Mac-1 disulfide bonds was mapped by differential cysteine alkylation and mass spectrometry. Wild-type or disulfide mutant Mac-1 was expressed recombinantly in Baby Hamster Kidney cells to measure ligand affinity. Mac-1 conformations were measured by conformation-specific antibodies and molecular dynamics simulations. Neutrophils crawling on immobilized ICAM-1 were measured in presence of oxidized or reduced PDI, and the effect of PDI inhibition using isoquercetin on neutrophil crawling on inflamed endothelial cells was examined. Migration indices in the X- and Y-direction were determined and the crawling speed was calculated. RESULTS: PDI colocalized with high-affinity Mac-1 at the trailing edge of stimulated neutrophils when crawling on ICAM-1 under fluid shear. PDI cleaved 2 allosteric disulfide bonds, C169-C176 and C224-C264, in the βI domain of the β2 subunit, and cleavage of the C224-C264 disulfide bond selectively controls Mac-1 disengagement from ICAM-1 under fluid shear. Molecular dynamics simulations and conformation-specific antibodies reveal that cleavage of the C224-C264 bond induces conformational change and mechanical stress in the βI domain. This allosterically alters the exposure of an αI domain epitope associated with a shift of Mac-1 to a lower-affinity state. These molecular events promote neutrophil motility in the direction of flow at high shear stress. Inhibition of PDI by isoquercetin reduces neutrophil migration in the direction of flow on endothelial cells during inflammation. CONCLUSIONS: Shear-dependent PDI cleavage of the 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, Elinor Hortle, Stefan H. Oehlers, Frauke Gräter, Philip J. Hogg, Freda H. Passam, Joyce Chiu

Date Published: 6th Apr 2023

Publication Type: Journal

Experimental and Computational Study on the Effects of High Pressure on the Crystal Structure of Boron Nitrilotriacetate

Abstract (Expand)

Herein, we report the structural changes occurring to the molecule of boron nitrilotriacetate and its interactions when the crystal is under compression. A special focus is on the intermolecular … interactions involving the carbonyl groups. In fact, these short-range contacts may anticipate cooperative addition reactions that could eventually lead to a polymer. However, X-ray diffraction experiments do not evidence any polymerization at least up to 16 GPa, due to competing interactions. In this work, we use and illustrate several theoretical tools to investigate the variable nature of the intermolecular interactions and their changes upon compression.

Authors: Fabio Montisci, Michelle Ernst, Piero Macchi

Date Published: 5th Apr 2023

Publication Type: Journal

ACSEG: AUTOMATED 3D CYTOPLASM SEGMENTATION IN SOFT X-RAY TOMOGRAPHY

Abstract (Expand)

The structure of cells is a key to understanding cellular function, diagnosis of pathological conditions, and development of new treatments. Soft X-ray tomography (SXT) is a unique tool to image cellular … structure without fixation or labeling at high spatial resolution and throughput. Ongoing improvements in faster acquisition times increase demand for accelerated image analysis. Currently, the automatic segmentation of cellular structures is a major bottleneck in the SXT data analysis pipeline. In this paper, we introduce an automated 3D cytoplasm segmentation model - ACSeg - by use of semi-automatically segmented labels and 3D U-Net, implemented in the online platform Biomedisa. The segmentation model is trained on semi-automatically labeled datasets and shows rapid convergence to high-accuracy segmentation, therefore reducing time and labor. ACSeg trained on 43 SXT tomograms of human immune T cells, the model successfully segmented unseen SXT tomograms of human hepatocyte-derived carcinoma cells, mouse microglia, and embryonic fibroblast cells. Furthermore, we could diversify the model by adding only 6 specific SXT tomograms, showing the potential for the development of an optimal experimental design. The ACSeg is published on the open image segmentation platform Biomedisa, enabling high-throughput analysis of cell volume and structure of cytoplasm in diverse cell types. The approach can be expanded for automatic segmentation of other organelles visualized by SXT, providing means for structural analysis of cell remodeling under different pathogens at statistically significant sizes, therefore enabling the development of novel drug treatments.

Authors: Ayse Erozan, Philipp Lösel, Vincent Heuveline, Venera Weinhardt

Date Published: 5th Apr 2023

Publication Type: Journal

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