Downstream Profiles Research Articles

Simulating longitudinal ventilation flows in long tunnels: Comparison of full CFD and multi-scale modelling approaches in FDS6

The accurate computational modelling of airflows in transport tunnels is needed for regulations compliance, pollution and fire safety studies but remains a challenge for long domains because the computational time increases dramatically. We simulate air flows using the open-source code FDS 6.1.1 developed by NIST, USA. This work contains two parts. First we validate FDS6’s capability for predicting the flow conditions in the tunnel by comparing the predictions against on-site measurements in the Dartford Tunnel, London, UK, which is 1200m long and 8.5m in diameter. The comparison includes the average velocity and the profile downstream of an active jet fan up to 120m. Secondly, we study the performance of the multi-scale modelling approach by splitting the tunnel into CFD domain and a one-dimensional domain using the FDS HVAC (Heating, Ventilation and Air Conditioning) feature. The work shows the average velocity predicted by FDS6 using both the full CFD and multi-scale approaches is within the experimental uncertainty of the measurements. Although the results showed the prediction of the downstream velocity profile near the jet fan falls outside the on-site measurements, the predictions at 80m and beyond are accurate. Our results also show multi-scale modelling in FDS6 is as accurate as full CFD but up to 2.2 times faster and that computational savings increase with the length of the tunnel. This work sets the foundation for the next step in complexity with fire dynamics introduced to the tunnel.

Abstract 274: Carvedilol Stimulated Gαi-β-Arrestin Biased β1 Adrenergic Receptor Signaling

The β1 and β2 adrenergic receptors (βARs) are the predominant G-protein-coupled receptors (GPCRs) subtypes expressed in the heart. It is now appreciated that ligands can induce multiple distinct “active” receptor conformations with unique downstream functional signaling profiles or efficacies. Our current understanding of GPCR signaling is that ligands can be biased toward activating either a G protein or a β-arrestin-signaling pathway, a concept known as biased ligand signaling. To identify novel biased signaling pathways mediated by β1- and β2ARs, we performed a proteomic interactome study of β1AR and β2AR using stable isotope labeling by amino acids in cell culture (SILAC). We identified several hundred proteins that distinctly bind to the β1AR or β2AR following stimulation with the unbiased full agonist, isoproterenol, or the β-arrestin-biased ligand carvedilol. We found that stimulation by the β-arrestin-biased agonist carvedilol of only β1ARs resulted in the recruitment of Gαi. No of the other ligand tested promoted Gαi recruitment, suggesting that carvedilol may be unique in its ability to activate Gαi-biased signaling. The Gαi inhibitor pertussis toxin blocked β-arrestin-dependent extracellular signal-regulated kinase (ERK) activation and epidermal growth factor receptor (EGFR) transactivation stimulated by carvedilol, suggesting the involvement of Gαi in carvedilol-induced β-arrestin biased signaling of β1ARs. Using β1AR/β2AR chimeric receptors we show that the C-terminal tail of the β1AR is required for carvedilol stimulated Gαi recruitment, but is unable to rescue the lack of Gαi recruitment by the β2AR. Since our current conceptual framework for biased signaling is based on the “bar code hypothesis”, ongoing phosphoproteomic experiments are testing whether recruitment of Gαi by carvedilol induces a distinct phosphorylation pattern on the c-tail of the β1AR. Our study shows that activation of β-arrestin-biased signaling requires G proteins for signaling and provides a new mechanistic understanding of how biased β-blockers can activate signaling.

Comparative analyses of downstream signal transduction targets modulated after activation of the AT1 receptor by two β-arrestin-biased agonists.

G protein-coupled receptors (GPCRs) are involved in essentially all physiological processes in mammals. The classical GPCR signal transduction mechanism occurs by coupling to G protein, but it has recently been demonstrated that interaction with β-arrestins leads to activation of pathways that are independent of the G protein pathway. Also, it has been reported that some ligands can preferentially activate one of these signaling pathways; being therefore called biased agonists for G protein or β-arrestin pathways. The angiotensin II (AngII) AT1 receptor is a prototype GPCR in the study of biased agonism due to the existence of well-known β-arrestin-biased agonists, such as [Sar1, Ile4, Ile8]-AngII (SII), and [Sar1, D-Ala8]-AngII (TRV027). The aim of this study was to comparatively analyze the two above mentioned β-arrestin-biased agonists on downstream phosphorylation events and gene expression profiles. Our data reveal that activation of AT1 receptor by each ligand led to a diversity of activation profiles that is far broader than that expected from a simple dichotomy between “G protein-dependent” and “β-arrestin-dependent” signaling. We observed clusters of activation profiles common to AngII, SII, and TRV027, as well as downstream effector activation that are unique to AngII, SII, or TRV027. Analyses of β-arrestin conformational changes after AT1 receptor stimulation with SII or TRV027 suggests that the observed differences could account, at least partially, for the diversity of modulated targets observed. Our data reveal that, although the categorization “G protein-dependent” vs. “β-arrestin-dependent” signaling can be of pharmacological relevance, broader analyses of signaling pathways and downstream targets are necessary to generate an accurate activation profile for a given ligand. This may bring relevant information for drug development, as it may allow more refined comparison of drugs with similar mechanism of action and effects, but with distinct side effects.

Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region

Binding of transforming growth factor α (TGF-α) to the epidermal growth factor receptor (EGFR) extracellular domain is encoded through the formation of a unique antiparallel coiled coil within the juxtamembrane segment. This new coiled coil is an "inside-out" version of the coiled coil formed in the presence of epidermal growth factor (EGF). A third, intermediary coiled-coil interface is formed in the juxtamembrane region when EGFR is stimulated with betacellulin. The seven growth factors that activate EGFR in mammalian systems (EGF, TGF-α, epigen, epiregulin, betacellulin, heparin-binding EGF, and amphiregulin) fall into distinct categories in which the structure of the coiled coil induced within the juxtamembrane region correlates with cell state. The observation that coiled-coil state tracks with the downstream signaling profiles for each ligand provides evidence for growth factor functional selectivity by EGFR. Encoding growth factor identity in alternative coiled-coil rotamers provides a simple and elegant method for communicating chemical information across the plasma membrane.

Effect of a mesh on boundary layer transitions induced by free-stream turbulence and an isolated roughness element

Streamwise streaks, their lift-up and streak instability are integral to the bypass transition process. An experimental study has been carried out to find the effect of a mesh placed normal to the flow and at different wall-normal locations in the late stages of two transitional flows induced by free-stream turbulence (FST) and an isolated roughness element. The mesh causes an approximately 30 % reduction in the free-stream velocity, and mild acceleration, irrespective of its wall-normal location. Interestingly, when located near the wall, the mesh suppresses several transitional events leading to transition delay over a large downstream distance. The transition delay is found to be mainly caused by suppression of the lift-up of the high-shear layer and its distortion, along with modification of the spanwise streaky structure to an orderly one. However, with the mesh well away from the wall, the lifted-up shear layer remains largely unaffected, and the downstream boundary layer velocity profile develops an overshoot which is found to follow a plane mixing layer type profile up to the free stream. Reynolds stresses, and the size and strength of vortices increase in this mixing layer region. This high-intensity disturbance can possibly enhance transition of the accelerated flow far downstream, although a reduction in streamwise turbulence intensity occurs over a short distance downstream of the mesh. However, the shape of the large-scale streamwise structure in the wall-normal plane is found to be more or less the same as that without the mesh.

The effect of a curved bed on the discharge equation in a spillway with a breast wall

The flow through a breast wall spillway is greatly affected by the centripetal force due to a downstream curved profile. Therefore, the mean vertical pressure distribution at the outlet section is not consistent with the hydrostatic pressure law. This distribution in turn affects the discharge capacity of the breast wall spillway. This paper experimentally studies the effect of a convex downstream profile on the mean pressure variation and the discharge of a breast wall spillway without gates. It is indicated that the effect of the curvilinear streamline on the mean vertical pressure variation is significant. The regression analysis method is used to determine the water head effect Zo of the orifice opening through the mean pressure variation. A discharge prediction formula of the breast wall spillway is obtained under the limited conditions of a laboratory flume. The predicted discharge is compared to the measured discharge. A good agreement is evidenced for the free orifice flow with errors within ±5%, while a big error (20% or even more) is obtained if the hydrostatic pressure law is used for the determination of Zo.

On the simulation of flow around discrete coniferous trees

The present study is to establish a numerical model capable of predicting flow past discrete coniferous trees, so as to provide a handy tool for pedestrian wind analysis during the preliminary design stage for local wind environments. In the study, a tree factor was proposed to reflect the effect due to the existence of the trees. Besides the applications of numerical computations in flow analysis, wind tunnel measurements were also performed to guide and confirm the numerical simulations. By comparing the velocity profiles at certain downstream cross-sections of tree panels, the variation of the tree factor was calibrated and the result can be readily used to predict the flow around discrete coniferous trees. Results also showed that the proposed tree factor generally increased with increases in the volume ratio and horizontal thickness of the tree body. Based on the calibrated relationship of the tree factor, finally, additional numerical computations were performed to simulate flow past an isolated tree and dual trees in a tandem and a side-by-side arrangement. The predicted downstream wind velocity profiles appeared in good agreement with the measurement results.

Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR) and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKC and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and Isignaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1) SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2) CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3) elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs), is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

Streamwise bars in fish-friendly angled trashracks

Experimental results for fish-friendly trashracks placed in an open-water channel are presented. Eighteen angled trashracks were used to test different bar spacings, bar shapes and rack angles. Each model trashrack comprised two horizontal supports with regularly spaced slots adjusted to compensate for the trashrack angle, i.e. maintain the vertical bars “streamwise” (parallel to flow). Water depths and velocity profiles were acquired upstream and downstream of each rack configuration. The results reveal that the head-loss coefficient for angled racks with streamwise bars does not depend on the rack angle and can be calculated with equations for racks perpendicular to the channel. Upstream velocity profiles along the rack are not significantly affected by the rack angle and downstream transverse profiles are nearly uniform. A comparison with conventional angled trashracks with bars set perpendicular to the rack revealed the many advantages of streamwise bars.

APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Measurement of the airflow velocity upstream and downstream a wire mesh using constant temperature anemometry

Measurement of velocity upstream and downstream a special wire mesh was performed to ascertain the effect of the mesh on the flow. The mesh consisted of two components, a basic rectangular mesh with mesh width 1.22 mm and wire diameter 0.2 mm, and a top steel wool with random position of wires and wire diameter 0.05 mm. The velocity was measured by Constant Temperature Anemometry using single wire probe in a Plexiglas channel of rectangular cross-section. As a first step, measurement of one horizontal and one vertical measuring line was performed 10 mm upstream and 6 mm downstream the wire mesh. A spatial velocity profile upstream of the wire mesh was smooth, while the downstream velocity profile was highly disturbed. However, velocity fluctuations expressed in terms of turbulence intensity downstream of the wire mesh were attenuated down to 1%. Further measurements of the area downstream the wire mesh will be performed to describe the development of the flow.

Damping Tollmien–Schlichting waves in a boundary layer using plasma actuators

The response of a zero pressure gradient boundary layer modified by flow-wise oriented momentum injection similar to that of a plasma actuator is calculated using a two-dimensional (bi-global) stability analysis. It is found that the addition of momentum into the boundary layer has a significant impact on Tollmien–Schlichting waves, which may be damped by up to two orders of magnitude. Changes to the exponential growth rate of the perturbations are also measured. These stabilizing effects are largely due to the momentum addition modifying the downstream boundary layer profiles, but localized stabilization effects are also noted. The relative stabilization of the TS wave appears to be a linear function with respect to the ratio of the plasma-induced wall jet velocity under quiescent conditions and the free-stream velocity for lower levels of plasma actuation (i.e. velocity ratios less than 0.1). For higher levels of plasma actuation, the relative stabilization of the TS wave appears to be exponential with respect to the total momentum addition to the boundary layer by the plasma actuator.

Abstract C245: Discovery and characterization of a new Wnt/β-catenin pathway inhibitor targeting tankyrase.

Abstract Background: Wnt/β-catenin pathway controls many biological processes including cell proliferation and tissue development. In Wnt pathway, β-catenin is a key downstream factor which interacts with transcription factor T-cell factor (TCF) in the nucleus and induces expression of TCF responsive genes. β-catenin degradation is promoted by a cytoplasmic complex of APC, Axin and Gsk3β. In many cancers, constitutive activation of Wnt/β-catenin pathway is observed due to mutations of the related genes and overexpression of Wnt ligands and receptors. For example, truncating mutation of the tumor suppressor APC are the most prevalent in colon cancer. APC deficiency leads to accumulation of nuclear β-catenin and promotes the transcription of downstream target genes. Hence, Wnt/β-catenin pathway inhibitor can be an attractive therapeutic agent for cancer patients. Results: To screen for Wnt/β-catenin pathway inhibitor, a reporter-based screen using a colon cancer cell line harboring APC mutation was performed. We identified a Wnt/β-catenin pathway inhibitor K-756 with an IC50 of 110 nM, which is a distinct chemical structure from previously reported Wnt/β-catenin pathway inhibitors. The WNT/β-catenin downstream gene expression profile of K-756 treated cells was highly similar to that of β-catenin siRNA treated cells. K-756 upregulated Axin 1 and 2 protein levels, suggesting that K-756 inhibited Wnt/β-catenin pathway by stabilization of Axin 1 and 2, which led to degradation of active β-catenin. Axin protein levels are suppressed by tankyrase-mediated poly(ADP-ribosyl)ation. To examine whether K-756 inhibits tankyrase, tankyrase enzyme activity assay was performed. K-756 inhibited tankyrase 1 with an IC50 of 31 nM and tankyrase 2 with an IC50 of 36 nM, but did not inhibit other poly-ADP-ribose polymerase family members even at 10 μM, suggesting that K-756 is a selective TNKS1/2 inhibitor. Co-crystal structure of K-756 with TNKS1 was analyzed to reveal the binding site. K-756 bound to ADP-ribose binding pocket, which was different from that of XAV939, a known TNKS1/2 inhibitor. Using β-catenin siRNA, we have identified several colon cancer cell lines as Wnt pathway dependent cell lines. K-756 inhibited Wnt pathway signal and cell growth in the cell lines. Oral dosing of K-756 resulted in inhibition of the reporter activity and Wnt downstream genes in a colon cancer xenograft mouse model. Conclusions: We have screened Wnt/β-catenin pathway inhibitor by reporter assay and downstream gene profile analysis. The target of K-756 was revealed as TNKS1/2 and the binding state was identified. K-756 inhibited colon cancer cell growth via Wnt/β-catenin pathway inhibition. Moreover, K-756 exhibited Wnt/β-catenin signal inhibition in vivo. Taken together, K-756 represents a new TNKS inhibitor and has a potential to be an important lead for further development of antitumor agents targeting the Wnt/β-catenin pathway regulation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C245. Citation Format: Ryoko Okada, Yuichi Takahashi, Yasuo Watanabe, Hiroshi Ishida, Junichi Saito, Ryuichiro Nakai. Discovery and characterization of a new Wnt/β-catenin pathway inhibitor targeting tankyrase. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C245.

Inhibition of silent information regulator-1 in hepatocytes induces lipid metabolism disorders and enhances hepatitis C virus replication

To investigate the role of the host-encoded silent information regulator 1 (SIRT1) on hepatocytes' lipid metabolism under conditions of hepatitis C virus (HCV) infection and assess its potential effects on virus replication in vitro. The Huh-7.5 human hepatocyte cell line was used as the control group and Huh-7.5 cells stably expressing the HCV replicon (Huh7.5-HCV) were used as the experimental group. Effects of interferon (IFN) treatment and activation of SIRT1 by resveratrol were also observed. The mRNA and protein expression levels of SIRT1 were detected by real time (q)PCR and western blotting. Effects on SIRT1 protein activity were tested by measuring the levels of reactive oxygen species (ROS) and the nicotinamide adenine dinucleotide (NAD+)/beta-nicotinamide adenine dinucleotide, reduced (NADH) by flow cytometry and chromatometry, and the levels of triacylglycerol (TG), total cholesterol (TC), and fatty acid beta oxidation rate by enzymatic analysis and liquid scintillation counting. Effects on mRNA expression of SIRT1 downstream lipid-metabolism genes were measured by qPCR. The Huh7.5-HCV cells had a significantly higher level of ROS (3.8+/-0.5 vs. Huh-7.5: 1.0+/-0.2; t = 12.736, P less than 0.01) but significantly lower levels of NAD+/NADH (0.03+/-0.01 vs. 0.12+/-0.03; t = 6.971, P less than 0.01), SIRT1 activity (0.3+/-0.1 vs. 1.0+/-0.2, 0.9+/-0.2, F = 6.766, P less than 0.01), SIRT1 mRNA (0.4+/-0.1 vs. 1.0+/-0.3, 0.9+/-0.2, F = 5.864, P less than 0.01), and SIRT1 protein (0.3+/-0.1 vs. 0.8+/-0.2, 0.9+/-0.2, F = 5.419, P less than 0.01). The lower levels of SIRT1 in Huh7.5-HCV cells accompanied decreased phosphorylation of the forkhead box O1 (FoxO1), which not only up-regulated the downstream genes of SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS (which increased fatty acid synthesis) but also down-regulated the downstream genes of PPAR and CPT1A genes (which decreased fatty acid beta oxidation). IFN treatment restored all of the aforementioned changes. Resveratrol-induced SIRT activation improved the perturbations in lipid metabolism pathways, as evidenced by an increase in fatty acid beta oxidation and a decrease in TG and TC synthesis, as well as inhibited HCV replication. HCV may decrease the NAD+/NADH ratio in hepatocytes, leading to a down-regulation of SIRT1 activity and expression and perturbing the downstream expression profile of lipid metabolism-related factors, ultimately causing lipid metabolism disorders and establishing a permissive intracellular environment for HCV replication.

Configuring Maximum Entropy Deconvolution for the Identification of Residence Time Distributions in Solute Transport Applications

The advection-dispersion equation (ADE) or aggregated dead zone (ADZ) models and their derivatives are frequently used to describe mixing processes within rivers, channels, pipes, and urban drainage structures. The residence time distribution (RTD) provides a nonparametric model that may describe mixing effects in complex mixing contexts more completely. Identifying an RTD from laboratory data requires deconvolution. Previous studies have successfully applied maximum entropy deconvolution to solute transport data, with RTD subsampling used for computational simplification. However, this requires a number of configuration settings which have to date not been rigorously investigated. Four settings are investigated here: the number and distribution of sample points, the constraint function, and the maximum number of iterations. Configuration options for each setting have been systematically assessed with reference to representative solute transport data by comparing the goodness-of-fit of recorded and predicted downstream profiles using the Nash-Sutcliffe efficiency index, evaluating RTD smoothness with a measure of entropy, and through consideration of the mass-balance of the RTD. New methods for defining sample point distribution are proposed. The results indicate that goodness-of-fit is most sensitive to constraint function and that smoothness is most sensitive to the number and distribution of sample points. A set of configuration options that includes a new sample point distribution is shown to perform robustly for a representative range of laboratory solute transport data.

Flow through concertina-shape screens

An insect-proof screen acts as a mechanical barrier, preventing insects from reaching the plants in a greenhouse and thus reducing pesticide application requirements. However, the exclusion of very small insects requires fine-mesh screens which impede ventilation and thus increase temperature and humidity within the greenhouse. To minimise the effect on ventilation the screen resistance to airflow should be as low as possible. Experiments and computational fluid dynamics (CFD) simulations were used to compare the airflow resistance of flat vs. concertina-shape screens. The CFD results were validated against experimental data and then further simulations were done to explore additional concertina-screen configurations. Folding a fine-mesh screen into a concertina shape reduced airflow resistance: for upstream air velocities of 0.42–0.85 m s−1 a screen with a typical 60° fold allowed, on average, about 23–32% higher airflow than a flat screen with similar through-screen pressure drops. The simulation results allowed a detailed examination of the through-screen and downstream flow patterns, and showed that the downstream velocity profile close to a concertina screen was different to that of a near flat screen. Velocities downstream from the concave parts of the concertina screen were lower than those downstream from the convex parts, resulting in a form of ‘sinusoidal’ velocity distribution rather than the uniform velocity distribution downstream from a flat screen. The CFD results further suggest that for a given pressure drop the airflow may increase with decreasing fold angle; this depends on the pre-folding screen resistance to airflow.

Lipid mediator serum profiles in asthmatics significantly shift following dietary supplementation with omega‐3 fatty acids

In contrast to well-characterized PUFA levels in serum, little is known regarding their downstream metabolic products. However, many of these compounds are lipid mediators with prominent roles during pro- and antiinflammatory processes. In this double blind crossover study on asthmatics, shifts in serum levels of ω-3 and ω-6 PUFA-derived oxidized fatty acids (e.g. eicosanoids, oxylipins) were quantified following dietary fish oil supplementation. Serum was obtained from subjects following fasting at three occasions; (i) prior to supplementation, (ii) following a 3-week supplement intake of either placebo or fish oil, and (iii) following a 3-week washout period with a subsequent 3-week period of either fish oil or placebo supplement. A total of 87 oxylipins representing cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS. The primary alterations observed were in CYP- and 15-LOX-derived EPA- and CYP-derived DHA oxylipins. The results indicate that intake of an ω-3 rich diet alters not only the PUFA ratio, but also the ratio of downstream oxylipins. These data further support that dietary manipulation with ω-3 PUFAs affects not only PUFA levels, but importantly also the downstream metabolic profile.

Velocity profile variations in granular flows with changing boundary conditions: insights from experiments

We present results of detailed velocity profile measurements in a large series of granular flow experiments in a dam-break setup. The inclination angle, bead size, and roughness of the running surface were varied. In all experiments, the downstream velocity profiles changed continuously from the head to the tail of the avalanches. On rough running surfaces, an inflection point developed in the velocity profiles. These velocity profiles cannot be modeled by the large class of constitutive laws which relate the shear stress to a power law of the strain rate. The velocity profile shape factor increased from the head to the tail of the avalanches. Its maximum value grew with increasing roughness of the running surface. We conclude that flow features such as velocity profiles are strongly influenced by the boundary condition at the running surface, which depends on the ratio of bead size to the typical roughness length of the surface. Furthermore, we show that varying velocity profile shape factors inside gravitationally driven finite-mass flows give rise to an additional term in the depth-averaged momentum equation, which is normally solved in the simulation software of hazardous geophysical flows. We therefore encourage time dependent velocity profile measurements inside hazardous geophysical flows, to learn about the importance of this “new” term in the mathematical modeling of these flows.

Transcriptional profiling and pathway analysis of CSF-1 and IL-34 effects on human monocyte differentiation

CSF-1 is the well-known ligand for CSF-1R, which plays a vital role in monocyte–macrophage generation, survival, and function. IL-34 is a newly discovered cytokine that also signals through CSF-1R. Although there are limited data for downstream signaling and pathway activation for CSF-1, none are published, to date, for expression profiles of IL-34. The objective of this study was to characterize and compare the signaling pathways downstream of the CSF-1R receptor, based on these two ligands. This was accomplished through transcriptional profiling and pathway analysis of CD14+ human monocytes differentiated with each ligand. Additionally, cells were treated with a CSF-1R inhibitor GW2580 to establish that observations associated with each ligand were CSF-1R mediated. Gene expression profiles were generated for each condition using Agilent 4x44K Whole Human Genome Microarrays. Overall profiles generated by each cytokine were similar (∼75% of genes) with a dampened effect noted on some pathways (∼25% of genes) with IL-34. One key difference observed, between the two cytokines was in the repression of CCR2 message. A similar divergence in protein level was established by FACS analysis. The differential effect on CCR2 expression has major implications for monocyte/macrophage biology including homeostasis and function. Further study of IL-34 effects on monocyte/macrophage biology will shed light on the specific role each ligand plays and the context in which these roles are important. To our knowledge, this study is the first to illustrate downstream transcriptional profiles and pathways of IL-34 in comparison with CSF-1 and identify notable differences in CCR2 expression.

Chemo-damage modeling and cracking analysis of AAR-affected concrete dams

A chemo-damage model for cracking analysis of concrete dams affected by alkali-aggregate reaction (AAR) is proposed, which combines the plastic-damage model for concrete with the AAR kinetics law. The chemo-damage model is first verified by a stress-free AAR expansion test. The expansion deformation obtained from the simulation is in good agreement with the measurement, demonstrating that the proposed model has a sufficient accuracy to predict the expansion of AAR-affected concrete. Subsequently, the expansion deformation and cracking process of the AAR-affected Fontana gravity dam is analyzed. It shows that permanent displacements in the upstream direction and the vertical direction are gradually increased during the long-term operation period, and that their maximal values reach 1.6 and 3.6 cm, respectively. A crack is observed on the wall in the foundation drainage gallery, and extends towards the downstream face of the dam. With the further development of AAR, another crack forms on the downstream face, and then intersects with the gallery crack to penetrate the downstream side profile of the dam. The third crack occurs in the upstream side wall of the gallery and propagates a short distance towards the upstream face of the dam. The simulated cracking pattern in the dam due to AAR is similar to the in situ observation.