Geohazards analysis of Pisa tunnel in a fractured incompetent rocks in Zagros Mountains, Iran.

The Pisa 2 tunnel with 740 m in length and 20° N trend is located along the Kazerun fault zone in Simply Folded Belt of Zagros, Iran. This tunnel has been excavated in the fractured incompetent marl layers with high expansive pressure of up to 2 kg/cm2. In this study, the geological hazards along the tunnel have been recognized and categorized. This study revealed that, in the long-term usage of the tunnel, the lining did not endure against the loading and the secondary leakages. It is mainly attributed due to the non-efficiencies of drainage and isolation systems in the tunnel site. Therefore, it caused asphalt damage, drainage damage, and wall distortion. FLAC3D software has been used in this research. We conducted various analyses for pre-excavation stress states, syn-excavation, and post-excavation strain states. The results showed no indication of instability and critical deformations during the excavation time. It also revealed that due to the non-efficiencies of drainage and isolation systems against secondary leakages and consequently marl expansion, the volumetric and shear strains (i.e., expansions and displacements) have exceeded from the critical states of strain along the tunnel. For various remedy purpose, this paper attempted several measures that can be taken in order to modify the drainage and isolation systems along the tunnel area. The reconstruction of drainage systems with suitable reinforced concrete and adequate slope has been proposed. The width of channel and isolation of backside of lining and implementation of multi-order outlets (i.e., backside of lining) for draining of groundwater into where the main drainage systems are located in the tunnel gallery were suggested

Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

Abstract Background Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. Methods We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Results Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. Conclusions BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

Background Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. Results Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol\u27s effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b,Gria1, Sncb and Nell2. Conclusions The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids

The definitive version is available at www.blackwell-synergy.comAIMS: To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. METHODS: M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70–500 µm) using three microsomal samples. RESULTS: Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean ± SD) was 4.8-fold greater than M6G Vmax (555 ± 110 vs. 115 ± 19 nmol mg1 protein h1; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg1 protein h1). Km values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 mm; P = 0.89, 0.02; − 0.29, 0.32 mm). M3G and M6G formation was inhibited (P < 0.01) with a significant increase in the M3G/M6G ratio (P < 0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320 ± 42 µm and 192 ± 12 µm for M3G and M6G, respectively, and (S)-methadone Ki of 226 ± 30 µm and 152 ± 20 µm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P = 0.017, 128; 55, 202 µm) and (S)-methadone (P = 0.026, 75; 22, 128 µm). CONCLUSIONS: Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G.Glynn A. Morrish, David J. R. Foster and Andrew A. Somogy

Physical characterization methods for supplementary cementitious materials

The main supplementary cementitious materials (SCMs) that are used today are industrial by-products. In most cases the quality of these materials cannot be controlled during their production, resulting in materials with varied characteristics. The adequate physical characterization of SCMs is important to better predict their performance and optimize their use in concretes production. There are standardized methods used to determine the particle characteristics for Portland cements that are usually adopted to characterize SCMs; however, these methods may not be as accurate when applied to SCMs. This paper is an overview of the techniques that are currently used for the determination of the density, particle size distribution, surface area and shape of SCMs. The main principles of each method are presented. The limitations that occur for the SCMs measurements are also discussed. This paper is an output from the work of the RILEM Technical Committee on Hydration and Microstructure of Concrete with Supplementary Cementitious Materials (TC-238-SCM)