Fluctuations and the Effective Moduli of an Isotropic, Random Aggregate of Identical, Frictionless Spheres

We consider a random aggregate of identical frictionless elastic spheres that has first been subjected to an isotropic compression and then sheared. We assume that the average strain provides a good description of how stress is built up in the initial isotropic compression. However, when calculating the increment in the displacement between a typical pair of contaction particles due to the shearing, we employ force equilibrium for the particles of the pair, assuming that the average strain provides a good approximation for their interactions with their neighbors. The incorporation of these additional degrees of freedom in the displacement of a typical pair relaxes the system, leading to a decrease in the effective moduli of the aggregate. The introduction of simple models for the statistics of the ordinary and conditional averages contributes an additional decrease in moduli. The resulting value of the shear modulus is in far better agreement with that measured in numerical simulations

Contact anisotropy and coordination number for a granular assembly:a comparison between DEM simulation and theory

We study an ideal granular aggregate consisting of elastic spherical particles, isotropic in stress and anisotropic in the contact network. Because of the contact anisotropy, a confining pressure applied at zero deviatoric stress, produces shear strain as well as volume strain. Our goal is to predict the coordination number k, the average number of contacts per particle, and the magnitude of the contact anisotropy ɛ, from knowledge of the elastic moduli of the aggregate. We do this through a theoretical model based upon the well known effective medium theory. However, rather than focusing on the moduli, we consider their ratios over the moduli of an equivalent isotropic state. We observe good agreement between numerical simulation and theory

Valproic acid protects against haemorrhagic shock-induced signalling changes via PPARγ activation in an in vitro model.

BACKGROUND AND PURPOSE: Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock-induced mortality in a range of in vivo models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β-Ser(9) phosphorylation. Here, we developed an in vitro model to investigate this protective effect of VPA and define a molecular mechanism. EXPERIMENTAL APPROACH: The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3β-Ser(9) phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA. KEY RESULTS: Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3β-Ser(9) phosphorylation shown in vivo during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β-catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA-related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPARγ blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPARγ using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock-like conditions. CONCLUSION AND IMPLICATIONS: Changes in GSK3β-Ser(9) phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPARγ activation in the protective role of VPA

Bedforms Produced on a Particle Bed by Vertical Oscillations of a Plate

We describe a new mechanism that produces bedforms and characterize the conditions under which it operates. The mechanism is associated with pressure gradients generated in a fluid saturated particle bed by a plate oscillating in the water above it. These vertical pressure gradients cause oscillatory bed failure. This facilitates particle displacement in its interior and transport at and near its surface that contribute to the formation of a heap under the plate. Flows over erodible beds generally cause shear stresses on the bed and these induce bed failure. Failure driven by pressure gradients is different from this. We report on bedforms in a bed of glass beads associated with such fluctuating pressure gradients. We measure the development of the profiles of heaps as a function of time and determine the tangential and normal motion of areas on the beds surface and estimate the depth of penetration of the tangential transport. The measurements compare favorably with a simple model that describes the onset of failure due to oscillations in pressure

Metabonomics-based analysis of Brachyspira pilosicoli's response to tiamulin reveals metabolic activity despite significant growth inhibition

Pathogenic anaerobes Brachyspira spp. are responsible for an increasing number of Intestinal Spirochaetosis (IS) cases in livestock against which few approved treatments are available. Tiamulin is used to treat swine dysentery caused by Brachyspira spp. and recently has been used to handle avian intestinal spirochaetosis (AIS). The therapeutic dose used in chickens requires further evaluation since cases of bacterial resistance to tiamulin have been reported. In this study, we evaluated the impact of tiamulin at varying concentrations on the metabolism of B. pilosicoli using a 1H-NMR-based metabonomics approach allowing the capture of the overall bacterial metabolic response to antibiotic treatment. Based on growth curve studies, tiamulin impacted bacterial growth even at very low concentration (0.008 μg/mL) although its metabolic activity was barely affected 72 h post exposure to antibiotic treatment. Only the highest dose of tiamulin tested (0.250 μg/mL) caused a major metabolic shift. Results showed that below this concentration, bacteria could maintain a normal metabolic trajectory despite significant growth inhibition by the antibiotic, which may contribute to disease reemergence post antibiotic treatment. Indeed, we confirmed that B. pilosicoli remained viable even after exposition to the highest antibiotic dose. This paper stresses the need to ensure new evaluation of bacterial viability post bacteriostatic exposure such as tiamulin to guarantee treatment efficacy and decrease antibiotic resistance development

Curing vector for IncI1 plasmids and its use to provide evidence for a metabolic burden of IncI1 CTX-M-1 plasmid pIFM3791 on Klebsiella pneumoniae

Using a sequence based approach we previously identified an IncI1 CTX-M-1 plasmid,pIFM3791, on a single pig farm in the UK that was harboured by K. pneumoniae,Escherichia coli and Salmonella enterica serotype 4,5,12,i:-. To test the hypothesis that the plasmid had spread rapidly into these differing host bacteria we wished to assess whether the plasmid conferred a fitness advantage. To do this an IncI1 curing vector was constructed and used to displace the IncI1 CTX-M-1 plasmids from K. pneumoniae strain B3791 and several other unrelated IncI1 harbouring strains indicating the potential wider application of the curing plasmid. The IncI1 CTX-M-1 plasmid was re-introduced by conjugation into the cured K. pneumoniae strain and also a naturally IncI1 plasmid free S. enterica serotype 4,5,12,i:-, S348/1. Original, cured and complemented strains were tested for metabolic competence using BiologTM technology and in competitive growth, association to mammalian cells and biofilm formation experiments. The plasmid-cured K. pneumoniae strain grew more rapidly than either the original plasmid-carrying strain or plasmid-complemented strains in competition experiments. Additionally, the plasmid-cured strain was significantly better at respiring with L-sorbose as a carbon source and putrescine, γ-amino-n-butyric acid,L-alanine, L-proline as a nitrogen sources. By contrast, no differences in phenotype were found when comparing plasmid harbouring and plasmid free S. enterica S348/11. In conclusion, the IncI1 curing vector successfully displaced multiple IncI plasmids. The IncI1 CTX-M1 plasmid conferred a growth disadvantage upon K. pneumoniae, possibly by imposing a metabolic burden the mechanism of which remains to be determined