The impact of endotrophin on the progression of chronic liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease.Subject terms: Metabolic syndrome, Biological techniques     

Phase behavior and the partitioning of caveolin-1 scaffolding domain peptides in model lipid bilayers

The membrane binding and model lipid raft interaction of synthetic peptides derived from the caveolin scaffolding domain (CSD) of the protein caveolin-1 have been investigated. CSD peptides bind preferentially to liquid-disordered domains in model lipid bilayers composed of cholesterol and an equimolar ratio of dioleoylphosphatidylcholine (DOPC) and brain sphingomyelin. Three caveolin-1 peptides were studied: the scaffolding domain (residues 83-101), a water-insoluble construct containing residues 89-101, and a water-soluble construct containing residues 89-101. Confocal and fluorescence microscopy investigation shows that the caveolin-1 peptides bind to the more fluid cholesterol-poor phase. The binding of the water-soluble peptide to lipid bilayers was measured using fluorescence correlation spectroscopy (FCS). We measured molar partition coefficients of 10(4) M(-1) between the soluble peptide and phase-separated lipid bilayers and 10(3) M(-1) between the soluble peptide and bilayers with a single liquid phase. Partial phase diagrams for our phase-separating lipid mixture with added caveolin-1 peptides were measured using fluorescence microscopy. The water-soluble peptide did not change the phase morphology or the miscibility transition in giant unilamellar vesicles (GUVs); however, the water-insoluble and full-length CSD peptides lowered the liquid-liquid melting temperature.     

Chemical force titrations of functionalized Si(111) surfaces

Chemical force titrations-plots of the adhesive force between an atomic force microscope tip and sample as a function of pH-were acquired on alkyl monolayer-derivatized Si(111) surfaces. Gold-coated AFM tips modified with thioalkanoic acid self-assembled monolayers (SAM) were employed. Alkyl monolayer-derivatized Si(111) surfaces terminated with methyl, carboxyl, and amine groups were produced via hydrosilylation reactions between 1-alkene reagents and H-terminated silicon. The functionalized surfaces were characterized using standard surface science techniques (AFM, FTIR, and XPS). Titration of the methyl-terminated surface using the modified (carboxyl-terminated) atomic force microscope tip resulted in a small pH-independent hydrophobic interaction. Titration of the amine-terminated surface using the same tip resulted in the determination of a surface pKa of 5.8 for the amine from the pH value from the maximum in the force titration curve. A pK(1/2) of 4.3 was determined for the carboxyl-terminated Si(111) in a similar way. These results will be discussed in relation to the modified Si(111) surface chemistry and organic layer structure, as well as with respect to existing results on Au surfaces modified with SAMs bearing the same functional groups.     

Micellar kinetics in aqueous acetonitrile. Part A. Sodium-hydrogen ion-exchange constant for 1-dodecanesulfonate surfactant. Part B. Substrate structural effects for micellar catalysis by perfluorooctanoic acid as reactive counterion surfactant

The sodium-hydrogen ion exchange constant for the system sodium 1-dodecanesulfonate-hydrochloric acid in aqueous acetonitrile has been determined from the pseudo-phase ion exchange model for surfactant catalytic effects. The results indicate that the micellar system behaves similarly for the aqueous and the aqueous acetonitrile (2.106 M) solvent systems. The influence of substrate molecular structure on micellar catalysis by perfluorooctanoic acid of the hydrolysis of hydroxamic acids (R—CO—NHOH) in aqueous acetonitrile has been explored. Data for substrate structures of fifteen compounds with R=alkyl, aralkyl, alicyclylalkyl, phenylalkyl, alkyl-substituted phenylalkyl, and with chain branching at the α, β, and γ positions are compared. Relative binding constant values indicate that substrates with aromatic groups are less well solubilized in the perfluoro micellar environment than are substrates with saturated groups. There is now evidence for specific micellar effects on the reaction rate as well as general micellar catalysis. © 1997 John Wiley & Sons, Inc.     

Laminar flow in the entrance region of a porous-wall channel

Summary The effect of fluid injection at the walls of a two-dimensional channel on the development of flow in the entrance region of the channel has been investigated. The integral forms of the boundary layer equations for flow in the channel were set up for an injection velocity uniformly distributed along the channel walls.With an assumed polynomial of the n-th degree for the one-parameter velocity profile a solution of the above boundary layer equations was obtained by an iteration method. A closed form solution was also obtained for the case when a similar velocity profile was assumed. The agreement between the entrance region velocity profiles of the present analysis for an impermeable-walled channel and of Schlichting¹) and Bodoia and Osterle²) is found to be very good.The results of the analysis show that fluid injection at the channel walls increases the rate of the growth of the boundary layer thickness, and hence reduces considerably the entrance length required for a fully developed flow.Nomenclature h half channel thickness - L entrance length with wall-injection - L ₀ entrance length without wall-injection - p static pressure - p=p/U ₀ ² dimensionless pressure - Re=U ₀ h/ Reynolds number at inlet cross-section - u velocity in the x direction at any point in the channel - =u/U ₀ dimensionless velocity in the x direction at any point in the channel - U _av average velocity at a channel cross-section - U _c center line velocity - U ₀ inlet cross-section velocity - _c =U _c /U ₀ dimensionless center line velocity - v velocity in the y direction at any point in the channel - v ₀ constant injection velocity of fluid at the wall - v=v/v ₀ dimensionless velocity in the y direction at any point in the channel - x distance along the channel wall measured from the inlet cross-section - x=x/hRe dimensionless distance in the x direction - y distance perpendicular to the channel wall - y=y/h dimensionless distance in the y direction - thickness of the boundary layer - =/h dimensionless boundary layer thickness - =/ dimensionless distance within the boundary layer region - =v ₀ h/ injection parameter or injection Reynolds number - kinematic viscosity - 1+ie - mass density of the fluid - parameter defined in (14)     

de Broglie's Pilot-Wave Theory for the Klein–Gordon Equation and Its Space-Time Pathologies

We illustrate, using a simple model, that in the usual formulation the time-component of the Klein–Gordon current is not generally positive definite even if one restricts allowed solutions to those with positive frequencies. Since in de Broglie's theory of particle trajectories the particle follows the current this leads to difficulties of interpretation, with the appearance of trajectories which are closed loops in space-time and velocities not limited from above. We show that at least this pathology can be avoided if one adapts in a covariant form the formulation of relativistic point particle dynamics proposed by Gitman and Tyutin.     

Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin

Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B(12)) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin-colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine-cobalamin bioconjugate exhibits nanomolar LC(50) values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Heat,Water, and Solution Transfer in Unsaturated Porous Media: I -- Theory Development and Transport Coefficient Evaluation

A detailed theory describing the simultaneous transfer of heat, water, and solute in unsaturated porous mediais developed. The theory includes three fully-coupledpartial differential equations. Heat, water, andsolute move in the presence of temperature, T; matricpressure head, _m ; solution osmotic pressure head _o ; and solute concentration C gradients. Thetheory can be applied to describe the mass and energyin radioactive waste repositories, food processing,underground energy storage sites, buried electriccables positions, waste disposal sites, and inagricultural soil. Several transport coefficients forheat, water, and solute are included in the theory. The coefficients are evaluated for a silty clay loamsoil to clarify their dependence on water content (),T, and C. The thermal vapor diffusivity D _Tv first increased as increased to0.22 m³/m³ then decreased with furtherincreases in . D _Tv was 3 orders of magnitudegreater than either isothermal vapor D _mv orosmotic vapor D _ov , diffusivities at of0.20~m³/m³, T of 50°C, and C of 0.001mol/kg. All of the liquid and vapor water transport coefficients increased with increasing T. D _Tv decreased with increasing C to a greater extent thanD _mv and D _ov . The effective thermalconductivity decreased slightly with increasing C. Thesolute diffusion coefficient D _d was 6 to 7orders of magnitude greater than the thermal soluteand salt sieving diffusion coefficients at of0.20~m³/m³, T of 50°C, and C of 0.001 mol/kg.