Materials Solutions for Hydrogen Delivery in Pipelines

The main objective of the study is as follows: Identify steel compositions/microstructures suitable for construction of new pipeline infrastructure and evaluate the potential use of the existing steel pipeline infrastructure in high pressure gaseous hydrogen applications. The microstructures of four pipeline steels were characterized and tensile testing was conducted in gaseous hydrogen and helium at pressures of 5.5 MPa (800 psi), 11 MPa (1600 psi) and 20.7 MPa (3000 psi). Based on reduction of area, two of the four steels that performed the best across the pressure range were selected for evaluation of fracture and fatigue performance in gaseous hydrogen at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi). The basic format for this phase of the study is as follows: Microstructural characterization of volume fraction of phases in each alloy; Tensile testing of all four alloys in He and H{sub 2} at 5.5 MPa (800 psi), 11 MPa (1600 psi), and 20.7 MPa (3000 psi). RA performance was used to choose the two best performers for further mechanical property evaluation; Fracture testing (ASTM E1820) of two best tensile test performers in H{sub 2} at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi); Fatigue testing (ASTM E647) of two best tensile test performers in H2 at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi) with frequency =1.0 Hz and R-ratio=0.5 and 0.1

Discovery of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug

Renal Involvement in Leptospirosis: The Effect of Glycolipoprotein on Renal Water Absorption

on vasopressin (Vp) action in the guinea pig inner medullary collecting duct (IMCD). Copenhageni, GLPc, n = 5); Group II, IMCD from normal guinea-pigs in the presence of GLPc (GLPc group, n = 54); Group III, IMCD from injected animals with GLPc ip (n = 8). (GLPp, non pathogenic, 250 µg) did not alter Vp action. In Group III, GLPc (250 µg) injected intraperitoneally produced a decrease of about 20% in IMCD Aquaporin 2 expression.The IMCD Pf decrease caused by GLP is evidence, at least in part, towards explaining the urinary concentrating incapacity observed in infected guinea-pigs

Conditions for the occurrence of acicular ferrite transformation in HSLA steels

For the class of steels collectively known as high strength low alloy (HSLA), an acicular ferrite (AF) microstructure produces an excellent combination of strength and toughness. The conditions for the occurrence of the AF transformation are, however, still unclear, especially the effects of austenite deformation and continuous cooling. In this research, a commercial HSLA steel was used and subjected to deformation via plane strain compression with strains ranging from 0 to 0.5 and continuous cooling at rates between 5 and 50 °C s −1 . Based on the results obtained from optical microscopy, scanning electron microscopy and electron backscattering diffraction mapping, the introduction of intragranular nucleation sites and the suppression of bainitic ferrite (BF) laths lengthening were identified as the two key requirements for the occurrence of AF transformation. Austenite deformation is critical to meet these two conditions as it introduces a high density of dislocations that act as intragranular nucleation sites and deformation substructures, which suppress the lengthening of BF laths through the mechanism of mechanical stabilisation of austenite. However, the suppression effect of austenite deformation is only observed under relatively slow cooling rates or high transformation temperatures, i.e., conditions where the driving force for advancing the transformation interface is not sufficient to overcome the austenite deformation substructures

Materials Solutions for Hydrogen Delivery in Pipelines

The main objective of the study is as follows: Identify steel compositions/microstructures suitable for construction of new pipeline infrastructure and evaluate the potential use of the existing steel pipeline infrastructure in high pressure gaseous hydrogen applications. The microstructures of four pipeline steels were characterized and tensile testing was conducted in gaseous hydrogen and helium at pressures of 5.5 MPa (800 psi), 11 MPa (1600 psi) and 20.7 MPa (3000 psi). Based on reduction of area, two of the four steels that performed the best across the pressure range were selected for evaluation of fracture and fatigue performance in gaseous hydrogen at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi). The basic format for this phase of the study is as follows: Microstructural characterization of volume fraction of phases in each alloy; Tensile testing of all four alloys in He and H{sub 2} at 5.5 MPa (800 psi), 11 MPa (1600 psi), and 20.7 MPa (3000 psi). RA performance was used to choose the two best performers for further mechanical property evaluation; Fracture testing (ASTM E1820) of two best tensile test performers in H{sub 2} at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi); Fatigue testing (ASTM E647) of two best tensile test performers in H2 at 5.5 MPa (800 psi) and 20.7 MPa (3000 psi) with frequency =1.0 Hz and R-ratio=0.5 and 0.1

CCM1 and CCM2 protein interactions in cell signaling: Implications for cerebral cavernous malformations pathogenesis

Cerebral cavernous malformations (CCMs) are sporadically acquired or inherited vascular lesions of the central nervous system consisting of clusters of dilated thin-walled blood vessels that predispose individuals to seizures and stroke. Familial CCM is caused by mutations in KRIT1 (CCM1) or in malcavernin (CCM2), the murine ortholog of which was concurrently characterized as osmosensing scaffold for MEKK3 (OSM). The roles of the CCM proteins in the pathogenesis of the disorder remain largely unknown. Here, we use co-immunoprecipitation, fluorescence resonance energy transfer and subcellular localization strategies to show that the CCM1 gene product, KRIT1, interacts with the CCM2 gene product, malcavernin/OSM. Analogous to the established interactions of CCM1 and β1 integrin with ICAP1, the CCM1/CCM2 association is dependent upon the phosphotyrosine binding (PTB) domain of CCM2. A familial CCM2 missense mutation abrogates the CCM1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. CCM2 and ICAP1 bound to CCM1 via their respective PTB domains differentially influence the subcellular localization of CCM1. Furthermore, we expand upon the established involvement of CCM2 in the p38 mitogen-activated protein kinase signaling module by demonstrating that CCM1 associates with CCM2 and MEKK3 in a ternary complex. These data indicate that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex. © The Author 2005. Published by Oxford University Press. All rights reserved