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

Searches and seizures of electronic devices in european criminal proceedings:a new pattern for independent review?

In the field of digital searches and seizures, there is not a comprehensive EU regulation. Accordingly, the Authors analyze the scope and the content of Article 8 ECHR in order to depict the minimum standards stemming thereof for what concerns the need for both a prior and an ex post facto independent oversight. Against this background, the Italian legal framework will serve as a benchmark in order to find to what extent the aforementioned guarantees are safeguarded, and which impact could the relevant ECtHR’s case-law have at the domestic level

Capturing of the internal mechanics of liquid-granular flows comprised of polydisperse spherical particles

This paper presents a series of flume experiments designed to examine the motion and arrest of concentrated granular-fluid flows, with a view to understanding the role of polydispersity in debris flows. A non-intrusive technique is used to investigate the internal behaviour of small scale experimental flows. Three different particle size distributions comprised of polydisperse spherical particles and one with the finer component made of angular particles were analysed. The choice of using spherical shaped particles was made to improve the visualization of the internal mechanics without reducing overmuch the complexity involved in the study of these flows. We examined and compared the internal velocities of the flows and their depositional spreads. While the optical performance of the non-intrusive technique was improved, some of the characteristics commonly seen in these types of granular flows were not observed. Velocity profiles obtained in the body of the flows were similar in shape but with differences in velocity magnitude depending on the amount of fines and the angularity of the particle in one case. Depositional runouts between flows were similar at low inclinations when little internal energy was supplemented to the system or when the viscous effects dominated the mechanics at steeper angles

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

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

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

Zinc oxide nanocrystals as nano-antibiotic and osteoinductive agents

The use of nanomaterials in the field of bone tissue engineering implants is continuously dealing with the development of innovative solutions to common problems, as infection by colonization with common microbial agents, antibiotic bacterial resistance, and the formation of new bone tissue. Among them, ZnO nanostructures are promising candidates thanks to their intrinsic antimicrobial activity and high biocompatibility. In this paper we aim to analyse the behaviour of ZnO nanocrystals (ZnO NCs), prepared with a new synthetic approach and not embedded in any composite matrix, for bone implants applications in-vitro. In particular, we have developed a novel, fast and reproducible microwave-assisted synthesis, obtaining highly-crystalline, round-shaped ZnO NCs of 20 nm in diameter as an extremely-stable colloidal solution in ethanol. Part of them were also chemically functionalized by anchoring amino-propyl groups to the ZnO surface (ZnO-NH2 NCs). Thus, the role of both ZnO NCs concentration and surface chemistry are tested in terms of biocompatibility towards pre-osteoblasts cells, promotion of cell proliferation and differentiation, and also in terms of antimicrobial activity against Gram positive and negative bacteria, such as Escherichia coli and Staphylococcus aureus, respectively. The results propose the ZnO-NH2 NCs as the most promising candidate to solve infections disease in bone implants and promote bone tissue proliferation at the same time, even at high concentrations. Whereas further investigations are needed for example to clarify the mechanism inhibiting biofilm formation and to investigate their role in in-vivo assays, we demonstrated that a fine and reproducible control over the chemical and structural parameters in ZnO nanomaterials can open new horizons in the use of functionalized ZnO NCs as a highly biocompatible and osteoinductive nanoantibiotic agent for bone tissue engineering

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

The Rosetta Stone Project – Integrating experimental results on debris flow mechanics across the scales: Next results

We present the combined efforts of a research network designed to address the many challenges in the experimental modelling of debris flow phenomena. The approach has been to use apparatuses of different functional arrangement and at different scale with identical and commonly sourced flow materials from the highly idealised (dry, coarse and uniform) to the highly complex (well graded, segregating, fluid saturated). Here we briefly present some key findings of the network and point to the research questions that are currently being addressed. This complementary view of experimental debris flows helps to constrain methodological artefacts/scale effects and to identify key processes responsible for the diverse appearance and often high mobility of debris flows

Mediators of lifestyle behaviour changes in obese pregnant women. Secondary analyses from the DALI lifestyle randomised controlled trial

A better understanding of what drives behaviour change in obese pregnant overweight women is needed to improve the effectiveness of lifestyle interventions in this group at risk for gestational diabetes (GDM). Therefore, we assessed which factors mediated behaviour change in the Vitamin D and Lifestyle Intervention for GDM Prevention (DALI) Lifestyle Study. A total of 436 women, with pre-pregnancy body mass index ≥29 kg/m 2 , ≤19 + 6 weeks of gestation and without GDM, were randomised for counselling based on motivational interviewing (MI) on healthy eating and physical activity, healthy eating alone, physical activity alone, or to a usual care group. Lifestyle was measured at baseline, and at 24–28 and 35–37 weeks of gestation. Outcome expectancy, risk perception, task self-efficacy and social support were measured at those same time points and considered as possible mediators of intervention effects on lifestyle. All three interventions resulted in increased positive outcome expectancy for GDM reduction, perceived risk to the baby and increased task self-efficacy. The latter mediated intervention effects on physical activity and reduced sugared drink consumption. In conclusion, our MI intervention was successful in increasing task self-efficacy, which was related to improved health behaviours