N-terminal Pro B-type Natriuretic Peptide and the Evaluation of Cardiac Dysfunction and Severity of Disease in Cirrhotic Patients

Purpose: Cardiac dysfunction and hyperdynamic systemic circulation may be present in patients with cirrhosis. The purpose of this study was to identify relations between plasma levels of N-terminal-proBNP (NT-proBNP), reflecting early ventricular dysfunction, and the severity of liver disease and cardiac dysfunction in cirrhotic patients. Materials and Methods: Sixty-three cirrhotic patients and 15 controls (group 1) were enrolled in this study. Plasma levels of NT-proBNP were determined in echocardiographically examined patients, which were allocated to 1 of 3 groups according to Child-Pugh classification or into 2 groups, i.e., a compensated group without ascites (group 2) and decompensated group with ascites (group 3). Results: Plasma NT-proBNP levels were significantly higher in cirrhotic patients (groups 2 and 3) than in age-matched controls (155.9 and 198.3 vs. 40.3 pg/mL

UBR2 of the N-End Rule Pathway Is Required for Chromosome Stability via Histone Ubiquitylation in Spermatocytes and Somatic Cells

The N-end rule pathway is a proteolytic system in which its recognition components (N-recognins) recognize destabilizing N-terminal residues of short-lived proteins as an essential element of specific degrons, called N-degrons. The RING E3 ligases UBR2 and UBR1 are major N-recognins that share size (200 kDa), conserved domains and substrate specificities to N-degrons. Despite the known function of the N-end rule pathway in degradation of cytosolic proteins, the major phenotype of UBR2-deficient male mice is infertility caused by arrest of spermatocytes at meiotic prophase I. UBR2-deficient spermatocytes are impaired in transcriptional silencing of sex chromosome-linked genes and ubiquitylation of histone H2A. In this study we show that the recruitment of UBR2 to meiotic chromosomes spatiotemporally correlates to the induction of chromatin-associated ubiquitylation, which is significantly impaired in UBR2-deficient spermatocytes. UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent ubiquitylation of H2A and H2B but not H3 and H4, through a mechanism distinct from typical polyubiquitylation. The E3 activity of UBR2 in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. Insufficient monoubiquitylation and polyubiquitylation on UBR2-deficient meiotic chromosomes correlate to defects in double strand break (DSB) repair and other meiotic processes, resulting in pachytene arrest at stage IV and apoptosis. Some of these functions of UBR2 are observed in somatic cells, in which UBR2 is a chromatin-binding protein involved in chromatin-associated ubiquitylation upon DNA damage. UBR2-deficient somatic cells show an array of chromosomal abnormalities, including hyperproliferation, chromosome instability, and hypersensitivity to DNA damage-inducing reagents. UBR2-deficient mice enriched in C57 background die upon birth with defects in lung expansion and neural development. Thus, UBR2, known as the recognition component of a major cellular proteolytic system, is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells

An Anisotropic Tertiary Creep Damage Constitutive Model For Anisotropic Materials

When an anisotropic material is subject to creep conditions and a complex state of stress, an anisotropic creep damage behavior is observed. Previous research has focused on the anisotropic creep damage behavior of isotropic materials but few constitutive models have been developed for anisotropic creeping solids. This paper describes the development of a new anisotropic tertiary creep damage constitutive model for anisotropic materials. An advanced tensorial damage formulation is implemented which includes both material orientation relative to loading and the degree of creep damage anisotropy in the model. A variation of the Norton-power law for secondary creep is implemented which includes the Hill\u27s anisotropic analogy. Experiments are conducted on the directionally-solidified bucket material DS GTD-111. The constitutive model is implemented in a user programmable feature (UPF) in ANSYS FEA software. The ability of the constitutive model to regress to the Kachanov-Rabotnov isotropic tertiary creep damage model is demonstrated through comparison with uniaxial experiments. A parametric study of both material orientation and stress rotation are conducted. Results indicate that creep deformation is modeled accurately; however an improved damage evolution law may be necessary. © 2011 Elsevier Ltd

An Improved Anisotropic Tertiary Creep Damage Formulation

Directionally solidified (DS) Ni-base superalloys are commonly used as gas turbine materials to primarily extend the operational lives of components under high load and temperature. The nature of DS superalloy grain structure facilitates an elongated grain orientation, which exhibits enhanced impact strength, high temperature creep and fatigue resistance, and improved corrosion resistance compared with off-axis orientations. Of concern to turbine designers are the effects of cyclic fatigue, thermal gradients, and potential stress concentrations when dealing with orientation-dependent materials. When coupled with a creep environment, accurate prediction of crack initiation and propagation becomes highly dependent on the quality of the constitutive damage model implemented. This paper describes the development of an improved anisotropic tertiary creep damage model implemented in a general-purpose finite element analysis software. The creep damage formulation is a tensorial extension of a variation in the Kachanov-Rabotnov isotropic tertiary creep damage formulation. The net/effective stress arises from the use of the Rabotnov second-rank symmetric damage tensor. The Hill anisotropic behavior analogy is used to model secondary creep and tertiary creep damage behaviors. Using available experimental data for a directionally solidified Ni-base superalloy, the improved formulation is found to accurately model intermediate oriented specimen. © 2011 American Society of Mechanical Engineers

Microstructure, Tensile, and Fatigue Properties of Large-Scale Austenitic Lightweight Steel

High-Mn lightweight steel, Fe-0.9C-29Mn-8Al, was manufactured using steelmaking, ingot-making, forging, and rolling processes. After the final rolling process, a typical austenite single phase was observed on all sides of the thick plate. The microstructural changes after annealing and aging heat-treatments were observed, using optical and transmission electron microscopy. The annealed coupon exhibited a typical austenite single phase, including annealing twins in several grains; the average grain size was 153 μm. After aging heat treatment, κ-carbide was observed within the grains and on the grain boundaries. Additionally, the effect of aging heat treatment on the mechanical properties was analyzed, using a tensile test. The fine κ-carbide that precipitated within the grains in the aged coupon improved the 0.2% offset yield and the tensile stresses, as compared to the as-annealed coupon. To estimate the applicability of high-Mn lightweight steel for low-pressure (LP) steam turbine blades, a low-cycle fatigue (LCF) test was carried out at room temperature. At a total strain amplitude of 0.5 to 1.2%, the LCF life of high-Mn lightweight steel was approximately three times that of 12% Cr steel, which is used in commercial LP steam turbine blades. The LCF behavior of high-Mn lightweight steel followed the Coffin–Manson equation. The LCF life enhancement in the high-Mn lightweight steel results from the planar dislocation gliding behavior

Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs