Visualization of dominant stress-transfer mechanisms in experimental debris flows of different particle-size distribution

Physical modelling of debris flow in a small-scale flume has been carried out to investigate the internal stress-transfer mechanisms within unsteady, saturated, and segregating granular free-surface flows. Measurements of the internal velocity fields within model flows were obtained via planar laser–induced fluorescence and particle image velocimetry. Normalized velocity profiles taken at a section over the flow duration were found to essentially collapse onto a single curve, the shape of which was dependent on the particle-size distribution. While all flows exhibited internal basal slip and shear, for tests on well-graded materials that are most representative of debris flows, the shear rate was found to reduce towards the surface to near-zero, exhibiting near plug-flow. Dimensional analysis shows that particles of different size within these flows experienced different dominant stress-transfer mechanisms — frictional, collisional or viscous. Rapid grain-size segregation therefore is both due to and results in different modes of stress transfer within a single flow. This means that in a segregating and hence, stratified system, different flow regimes will act concurrently at microscale and mesoscale. Results highlight the complexity of debris flows, so that it may be undesirable to ascribe a single microscale constitutive behaviour throughout, and further calls into question the concept of flow regimes for debris flows based on bulk measurements

Experimental investigation on the impact dynamics of saturated granular flows on rigid barriers

Debris flows involve the high-speed downslope motion of rocks, soil, and water. Their high flow velocity and high potential for impact loading make them one of the most hazardous types of gravitational mass flows. This study focused on the roles of particle size grading and degree of fluid saturation on impact behavior of fluid-saturated granular flows on a model rigid barrier in a small-scale flume. The use of a transparent debris-flow model and plane laser-induced fluorescence allowed the motion of particles and fluid within the medium to be examined and tracked using image processing. In this study, experiments were conducted on flows consisting of two uniform and one well-graded particle size gradings at three different fluid contents. The evolution of the velocity profiles, impact load, bed normal pressure, and fluid pore pressure for the different flows were measured and analyzed in order to gain a quantitative comparison of their behavior before, during, and after impact

A New Class of Small Molecule Inhibitor of BMP Signaling

Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development

Using PIV to measure granular temperature in saturated unsteady polydisperse granular flows

The motion of debris flows, gravity-driven fast moving mixtures of rock, soil and water can be interpreted using the theories developed to describe the shearing motion of highly concentrated granular fluid flows. Frictional, collisional and viscous stress transfer between particles and fluid characterizes the mechanics of debris flows. To quantify the influence of collisional stress transfer, kinetic models have been proposed. Collisions among particles result in random fluctuations in their velocity that can be represented by their granular temperature, T. In this paper particle image velocimetry, PIV, is used to measure the instantaneous velocity field found internally to a physical model of an unsteady debris flow created by using “transparent soil”—i.e. a mixture of graded glass particles and a refractively matched fluid. The ensemble possesses bulk properties similar to that of real soil-pore fluid mixtures, but has the advantage of giving optical access to the interior of the flow by use of plane laser induced fluorescence, PLIF. The relationship between PIV patch size and particle size distribution for the front and tail of the flows is examined in order to assess their influences on the measured granular temperature of the system. We find that while PIV can be used to ascertain values of granular temperature in dense granular flows, due to increasing spatial correlation with widening gradation, a technique proposed to infer the true granular temperature may be limited to flows of relatively uniform particle size or large bulk

Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants

There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG

Internal imaging of saturated granular free-surface flows

This paper presents a novel method to investigate the internal behaviour of saturated granular free-surface flows in the context of high-speed movement. Such an approach aims to study the motion of the solids and fluid within the flow in small-scale model flume tests with a view to better understanding debris flows mechanics. Through the employment of a particular solid, liquid and fluorescent dye and the application of an optical technique that relies on precise matching of refractive indices, the arrangement and re-arrangement of the grains within the fluid can be determined by way of planar laser-induced fluorescence. The adopted methodologies, together with the physical and optical properties of the selected fluid and solid phases, are described. The results of a series of experiments performed in a small laboratory flume are presented. The results show the effectiveness of this technique and the reliability of an artificial glass–oil mixture in reproducing the key features of flows composed of natural materials

Deep learning assisted particle identification of photoelastic images of granular flows

The transmission of forces within high speed granular flows may be straightforwardly viewed in two-dimensional photoelastic experiments, but precise measurements have remained elusive due to difficulties in differentiating between particles and forces with sufficient accuracy at reasonable processing speeds. This paper presents a novel approach to detect the positions of disks embedded in this complex situation, which is a crucial step in applying the methodologies necessary for the analysis of the photoelastic response of individual disks. We have developed a Deep Learning based solution to perform the segmentation of experimental photoelastic images, disentangling with high fidelity the disk outlines from the rest of each image. The accuracy and the reliability of the proposed methodology are discussed in detail, demonstrating that this approach can be effectively adopted for the problem under investigation, improving the quality of the photoelastic analysis and dramatically accelerating the data processing procedure

Particle-scale observation of seepage flow in granular soils using PIV and CFD

Seepage-induced instabilities pose a challenge in many geotechnical applications. Particle-scale mechanisms govern the initiation of instability. However, current understanding is based on a macro-scale perspective that draws on continuum mechanics. Recent developments in imaging and numerical analysis can provide the particle-scale fundamental perspective needed to develop a comprehensive insight. This contribution demonstrates the value of combining particle-scale experimental and numerical studies. The experiments consider transparent soil samples created using refractive image matching and monitored by particle image velocimetry (PIV). Three-dimensional pore topology is extracted from a series of 2D images and imported into computational fluid dynamics (CFD)simulations. Permeability is estimated by three distinct approaches: using flow rate, PIV-and CFD-generated data. The flow fields obtained from PIV and CFD are in good agreement considering both flow rate contour plots and flow rate distributions; this demonstrates the successful reconstruction of three-dimensional pore structure and flow-field analysis. The comparison also reveals that the side boundary effects in CFD simulations are constrained within a limited region. The multi-plane results characterize the variance of flow velocity with the three-dimensional pore topology. Finally, the fluid-particle interactions obtained from CFD results show a larger variance in the angular particle packings

Investigation of Kinase Activation in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease resulting in episodic but progressive extraskeletal bone formation. FOP is caused by missense mutations in the cytoplasmic domain of the type I bone morphogenetic protein (BMP) receptor ACVR1, leading to dysregulated activation. Currently there are no available drug treatments and the structural mechanism of mutant activation is still poorly characterised. To address this, a number of BMP and TGFβ receptors, including FOP mutants of ACVR1 were cloned, expressed and purified for both structural and biophysical experiments. The arginine at the site of most recurrent FOP mutation, R206H, is common across all type I receptors except BMPR1A and BMPR1B which have a lysine at this site. The novel structure of BMPR1B differed to wild-type ACVR1 showing some of the conformational changes expected of the active conformation. However, a variety of disease related ACVR1 mutant structures, including ACVR1 R206H, revealed a surprisingly persistent inactive conformation in the kinase domain. Some conformational changes suggestive of activation were observed in the mutant Q207D affecting the ATP pocket, the β4–β5 hairpin and the activation loop. Additionally, the structure of the Q207E mutant showed a slight release of the regulatory glycine-serine rich domain from its inhibitory position. These subtle changes suggest that the mutant inactive conformation is destabilised and potentially more dynamic. In agreement, all of the ACVR1 mutants showed reduced binding to the inhibitory protein FKBP12. However, mutant phosphorylation of the substrate Smad1 was not constitutive, but dependent on the co-expression of the partner ACVR2, consistent with recent evidence from transgenic knock-out mice. A novel 2-aminopyridine inhibitor scaffold with favourable specificity for ACVR1 was identified using a fluorescence-based thermal shift assay. Further derivatives were characterised with improved potency and selectivity. The crystal structures of ACVR1 bound to these inhibitors showed exquisite shape complementarity, contributing to their favourable specificity. This work has increased the understanding of FOP-associated mutant activation and provided a novel starting scaffold for potential drug development.This thesis is not currently available on ORA