Fracture Mechanical Analysis of Cracks in Ice Shelves using the Finite Element Method and Configurational Forces

Ice shelves are important elements of the climate system and sensitive to climate changes. The disintegration of large Antarctic ice shelves is the focus of this fracture mechanical analysis. Ice is a complex material which, depending on the context, can be seen as a viscous fluid or as an elastic solid. A fracture event usually occurs on a rather short time scale, thus the elastic response is important and linear elastic fracture mechanics can be used. The investigation of the stress intensity factor as a measure of crack tip loading is based on a 2-dimensional analysis of a single crack with a mode-I type load and additional body loads. This investigation is performed using configurational forces. Depth dependent density and temperature profiles are considered. The relevant parameters are obtained by literature, remote sensing data analysis and modeling of the ice dynamics. The criticality of wet surface cracks is investigated

Finite Element Simulation of Frost Wedging in Ice Shelves

Break-up events in ice shelves have been studied extensively during the last years. One popular assumption links disintegration events to surface melting of the ice shelf in conjunction with growing melt-water ponds, leading to hydro-fracture. As this explanation only holds during warm seasons [1], the possibility of frost wedging as forcing mechanism for autumn and winter break-up events is considered. Frost wedging can only occur if a closed ice lid seals the water inside the crack. Hence, the present study of frost wedging in a single crack uses ice lid thicknesses to evaluate the additional pressure on the crack faces. The investigation of the resulting stress intensity factor as a measure of crack criticality follows consequently. The results show that freezing water inside a crack can result in unstable crack growth of an initially stable water filled crack

Analysis of Calving Events in Antarctic Ice Shelves Using Configurational Forces

Previous studies on the sensitivity of cracks in ice shelves with different boundary conditions, stress states and density profiles revealed the need for further analyses. As the transfer of boundary conditions from dynamic ice flow simulations to the linear elastic fracture analyses proved to be a critical point in previous studies, a new approach to relate viscous and elastic material behaviour is proposed. The numerical simulations are conducted using Finite Elements utilizing the concept of configurational forces. To show the applicability of the approach, a 2-dimensional plane stress geometry with volume loads due to the ice shelf flow is analyzed. The resulting crack path is compared to available crack paths from satellite images

Viscous and viscoelastic stress states at the calving front of Antarctic ice shelves

Calving mechanisms are still poorly understood and stress states in the vicinity of ice-shelf fronts are insufficiently known for the development of physically motivated calving laws that match observations. A calving model requires the knowledge of maximum tensile stresses. These stresses depend on different simulation approaches and material models. Therefore, this study compares results of a two-dimensional (2-D) continuum approach using finite elements with results of a one- dimensional (1-D) beam model elaborated in Reeh (1968). A purely viscous model, as well as a viscoelas- tic Maxwell model, is applied for the 2-D case. The maximum tensile stress usually appears at the top surface of an ice shelf. Its location and magnitude are predominantly influenced by the thickness of the ice shelf and the height of the freeboard, the traction-free part at the ice front. More precisely, doub- ling the thickness leads to twice the stress maximum, while doubling the freeboard, based on changes of the ice density, results in an increase of the stress maximum by 61%. Poisson’s ratio controls the evolu- tion of the maximum stress with time. The viscosity and Young’s modulus define the characteristic time of the Maxwell model and thus the time to reach the maximum principal stress

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C−/− mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C−/− mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C−/− C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C−/− mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3rd ventricle in JAM-C−/− C57BL/6 mice. Taken together, our study suggests that JAM-C−/− C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

The endothelial-enriched lncRNA LINC00607 mediates angiogenic function

Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis

Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

As revealed in a new model of cerebral cavernous malformations (CCM), the timing of ablation of Ccm genes determines whether or not CCM lesions arise in brain and retina venous beds

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11β-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1