Side Chain Structure Determines Unique Physiologic and Therapeutic Properties of norUrsodeoxycholic Acid in Mdr2(-/-) Mice

24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2-/- mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr-/- mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO3- -output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO3- -dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO 3- -output also in Cftr-/- mice. In Mdr2-/- mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA. Conclusion:The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO3- -rich hypercholeresis that protects the liver from cholestatic injury.

1- and 2-Chloromorphine. Halogenation of Morphine meta to the Free Phenolic Hydroxyl Group

Treatment of morphine in aqueous HCl at 70° with KIO3 yields a monochloromorphine, identified as 1-chloromorphine by spectroscopic means and by the fact that it, and its methyl ether 1-chlorocodeine, are different from 2-chloromorphine and 2-chlorocodeine prepared from 2-aminomorphine of unequivocally established structure. Formation of 1-chloromorphine and the previously known 1-bromomorphine involves entry of the halogen into the position meta to the free phenolic hydroxyl. Possible mechanistic interpretations of this unusual orientation are discussed.

From the {Cu(μ2-S)N}4 butterfly architecture to the {Cu(μ3-S)N}12 double wheel

Copper(I) complexes with {Cu(μ2-S)N}4 and {Cu(μ3-S)N}12 core portions of butterfly-shaped or double wheel architectures have been isolated in the reaction of Cu(I) with the Schiff base ligand C6H4(CHNC6H4S)2, aiso-abtâ, under different conditions. View the MathML source containing the tetranuclear electroneutral complex View the MathML source is formed by the reaction of CuI in acetonitrilic solution and recrystallization from DMF, whereas View the MathML source containing dodecanuclear View the MathML source wheels is accessible starting from CuBF4. Complexes 2 and 4 represent the first examples of cyclic complexes with the same overall stoichiometry but different ring sizes. The ligand induces two different coordination environments around copper(I) by switching between μ2- and μ3-sulfur bridging modes.

Enhancement of workability in AZ31 alloy-processing maps: Part I,castmaterial

Processing maps developed on the basis of the Dynamic Materials Model provide valuable information that might help the metal working industry in solving problems related to workability and microstructural control in commercial alloys. In this research, the processing maps for an as-cast AZ31 magnesium alloy are presented. The results are validated via microstructural observations, clearly delineating safe and unsafe regimes for further process design of this alloy.

Influence of cross-correlation between dipolar and chemical shift anisotropy relaxation mechanisms upon the transverse relaxation rates of 15N in macromolecules

Heteronuclear multiple-quantum coherence relaxation rate are calculated for the individual transitions of the S spin in an AIS nuclear spin system assuming that the heteronucleus (S spin) has relaxation contributions from both intramolecular dipole-dipole and chemical shift anisotropy relaxation. The individual multiplet components of the heteronuclear zero- and double-quantum coherences are shown to have different transverse relaxation rates. The cross-correlation between the two relaxation mechanisms is shown to be the dominant cause of the calculated differential line broadening. Experimental data are presented using as an example a uniformly 15N labelled sample of human epidermal growth factor.

Three Dimensional Line-Clipping by Systematic Enumeration

Three dimensional clipping is a critical component of the 3D graphics pipeline. A new 3D clipping algorithm is presented in this paper. An efficient 2D clipping routine reported earlier has been used as a submodule. This algorithm uses a new classification scheme for lines of all possible orientations with respect to a rectangular parallelopiped view volume. The performance of this algorithm has been evaluated using exact arithmetic operation counts. It is shown that our algorithm requires less arithmetic operations than the Cyrus-Beck 3D clipping algorithm in all cases. It is also shown that for lines that intersect the clipping volume, our algorithm performs better than the Liang-Barsky 3D clipping algorithm.

Non-conservatively loaded stochastic columns

A new finite element method is developed to analyse non-conservative structures with more than one parameter behaving in a stochastic manner. As a generalization, this paper treats the subsequent non-self-adjoint random eigenvalue problem that arises when the material property values of the non-conservative structural system have stochastic fluctuations resulting from manufacturing and measurement errors. The free vibration problems of stochastic Beck's column and stochastic Leipholz column whose Young's modulus and mass density are distributed stochastically are considered. The stochastic finite element method that is developed, is implemented to arrive at a random non-self-adjoint algebraic eigenvalue problem. The stochastic characteristics of eigensolutions are derived in terms of the stochastic material property variations. Numerical examples are given. It is demonstrated that, through this formulation, the finite element discretization need not be dependent on the characteristics of stochastic processes of the fluctuations in material property value.

Stability analysis of stochastically parametered nonconservative columns

Nonconservatively loaded columns. which have stochastically distributed material property values and stochastic loadings in space are considered. Young's modulus and mass density are treated to constitute random fields. The support stiffness coefficient and tip follower load are considered to be random variables. The fluctuations of external and distributed loadings are considered to constitute a random field. The variational formulation is adopted to get the differential equation and boundary conditions. The non self-adjoint operators are used at the boundary of the regularity domain. The statistics of vibration frequencies and modes are obtained using the standard perturbation method, by treating the fluctuations to be stochastic perturbations. Linear dependence of vibration and stability parameters over property value fluctuations and loading fluctuations are assumed. Bounds for the statistics of vibration frequencies are obtained. The critical load is first evaluated for the averaged problem and the corresponding eigenvalue statistics are sought. Then, the frequency equation is employed to transform the eigenvalue statistics to critical load statistics. Specialization of the general procedure to Beck, Leipholz and Pfluger columns is carried out. For Pfluger column, nonlinear transformations are avoided by directly expressing the critical load statistics in terms of input variable statistics.

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve `health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.

Iodo( trisyl) sulfane: Reactivity of a Stable Alkanesulfenyl Iodide towards Antithyroid Drugs

Iodination of tris(trimethylsilyl)methanethiol (trisylthiol, TsiSH) in tetrahydrofuran provides the new thermally stable alkanesulfenyl iodide iodo(trisyl)sulfane, TsiSI] as a violet solid. Iodo(trisyl)sulfane exhibits iodine-iodine contacts between pairs of TsiSI molecules in the solid state. Properties of TsiSI were studied by vibrational spectroscopy and with the help of density functional calculations. TsiSI reacts in the presence of triethylamine with the antithyroid drugs 6-n-propyl- and 6-methylthiouracil (PTU, MTU) and with N-methylmethimazole (MMI) to form unsymmetric disulfides that were investigated by means of X-ray crystallography. In the solid state, the PTU and MTU derivatives exist as hydrogen-bonded centrosymmetric dimers, whereas the MMI-derived disulfide is an unsymmetric monomer.

Markov chain splitting methods in structural reliability integral estimation

Monte Carlo simulation methods involving splitting of Markov chains have been used in evaluation of multi-fold integrals in different application areas. We examine in this paper the performance of these methods in the context of evaluation of reliability integrals from the point of view of characterizing the sampling fluctuations. The methods discussed include the Au-Beck subset simulation, Holmes-Diaconis-Ross method, and generalized splitting algorithm. A few improvisations based on first order reliability method are suggested to select algorithmic parameters of the latter two methods. The bias and sampling variance of the alternative estimators are discussed. Also, an approximation to the sampling distribution of some of these estimators is obtained. Illustrative examples involving component and series system reliability analyses are presented with a view to bring out the relative merits of alternative methods. (C) 2015 Elsevier Ltd. All rights reserved.

Cytotoxicity of Ultrasmall Gold Nanoparticles on Planktonic and Biofilm Encapsulated Gram-Positive Staphylococci

The emergence of multidrug resistant bacteria, especially biofilm-associated Staphylococci, urgently requires novel antimicrobial agents. The antibacterial activity of ultrasmall gold nanoparticles (AuNPs) is tested against two gram positive: S. aureus and S. epidermidis and two gram negative: Escherichia coli and Pseudomonas aeruginosa strains. Ultrasmall AuNPs with core diameters of 0.8 and 1.4 nm and a triphenylphosphine-monosulfonate shell (Au0.8MS and Au1.4MS) both have minimum inhibitory concentration (MIC) and minimum bactericidal concentration of 25 x 10(-6)m Au]. Disc agar diffusion test demonstrates greater bactericidal activity of the Au0.8MS nanoparticles over Au1.4MS. In contrast, thiol-stabilized AuNPs with a diameter of 1.9 nm (AuroVist) cause no significant toxicity in any of the bacterial strains. Ultrasmall AuNPs cause a near 5 log bacterial growth reduction in the first 5 h of exposure, and incomplete recovery after 21 h. Bacteria show marked membrane blebbing and lysis in biofilm-associated bacteria treated with ultrasmall AuNP. Importantly, a twofold MIC dosage of Au0.8MS and Au1.4MS each cause around 80%-90% reduction in the viability of Staphylococci enveloped in biofilms. Altogether, this study demonstrates potential therapeutic activity of ultrasmall AuNPs as an effective treatment option against staphylococcal infections.