Uncertainty quantification of dynamic earthquake rupture simulations

© 2021 The Authors. We present a tutorial demonstration using a surrogate-model based uncertainty quantification (UQ) approach to study dynamic earthquake rupture on a rough fault surface. The UQ approach performs model calibration where we choose simulation points, fit and validate an approximate surrogate model or emulator, and then examine the input space to see which inputs can be ruled out from the data. Our approach relies on the mogp_emulator package to perform model calibration, and the FabSim3 component from the VECMA toolkit to streamline the workflow, enabling users to manage the workflow using the command line to curate reproducible simulations on local and remote resources. The tools in this tutorial provide an example template that allows domain researchers that are not necessarily experts in the underlying methods to apply them to complex problems. We illustrate the use of the package by applying the methods to dynamic earthquake rupture, which solves the elastic wave equation for the size of an earthquake and the resulting ground shaking based on the stress tensor in the Earth. We show through the tutorial results that the method is able to rule out large portions of the input parameter space, which could lead to new ways to constrain the stress tensor in the Earth based on earthquake observations. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.EPSRC grant no. EP/N510129/1HA to the Alan Turing Institute; European Union Horizon 2020 research and innovation programme under grant agreement no. 800925 (VECMA) and 824115 (HiDALGO)

STK35L1 Associates with Nuclear Actin and Regulates Cell Cycle and Migration of Endothelial Cells

BACKGROUND: Migration and proliferation of vascular endothelial cells are essential for repair of injured endothelium and angiogenesis. Cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors play an important role in vascular tissue injury and wound healing. Previous studies suggest a link between the cell cycle and cell migration: cells present in the G(1) phase have the highest potential to migrate. The molecular mechanism linking these two processes is not understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we explored the function of STK35L1, a novel Ser/Thr kinase, localized in the nucleus and nucleolus of endothelial cells. Molecular biological analysis identified a bipartite nuclear localization signal, and nucleolar localization sequences in the N-terminal part of STK35L1. Nuclear actin was identified as a novel binding partner of STK35L1. A class III PDZ binding domains motif was identified in STK35L1 that mediated its interaction with actin. Depletion of STK35L1 by siRNA lead to an accelerated G(1) to S phase transition after serum-stimulation of endothelial cells indicating an inhibitory role of the kinase in G(1) to S phase progression. Cell cycle specific genes array analysis revealed that one gene was prominently downregulated (8.8 fold) in STK35L1 silenced cells: CDKN2A alpha transcript, which codes for p16(INK4a) leading to G(1) arrest by inhibition of CDK4/6. Moreover in endothelial cells seeded on Matrigel, STK35L1 expression was rapidly upregulated, and silencing of STK35L1 drastically inhibited endothelial sprouting that is required for angiogenesis. Furthermore, STK35L1 depletion profoundly impaired endothelial cell migration in two wound healing assays. CONCLUSION/SIGNIFICANCE: The results indicate that by regulating CDKN2A and inhibiting G1- to S-phase transition STK35L1 may act as a central kinase linking the cell cycle and migration of endothelial cells. The interaction of STK35L1 with nuclear actin might be critical in the regulation of these fundamental endothelial functions

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations

PTMs in Conversation: Activity and Function of Deubiquitinating Enzymes Regulated via Post-Translational Modifications

Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoylation, acetylation, and phosphorylation as characterized and putative regulative factors of DUB function. Although this aspect of DUB functionality has not been yet thoroughly studied, PTMs represent a versatile and reversible method of controlling the role of DUBs in biological processes. In several cases PTMs might constitute a feedback mechanism insuring proper functioning of the ubiquitin proteasome system and other DUB-related pathways

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Nature of low-lying electric dipole resonance excitations in Ge 74

Isospin properties of dipole excitations in 74 Ge are investigated using the (α , α ′ γ ) reaction and compared to (γ , γ ′ ) data. The results indicate that the dipole excitations in the energy region of 6 to 9 MeV adhere to the scenario of the recently found splitting of the region of dipole excitations into two separated parts: one at low energy, being populated by both isoscalar and isovector probes, and the other at high energy, excited only by the electromagnetic probe. Relativistic quasiparticle time blocking approximation (RQTBA) calculations show a reduction in the isoscalar E1 strength with an increase in excitation energy, which is consistent with the measurement