Multi-dimensional study of the effect of early slip activity on fatigue crack initiation in a near-α titanium alloy

During service of gas turbine engines, high cycle fatigue of titanium is a leading cause of component failure highlighting the need for better understanding of the crack initiation mechanism to predict initiation sites. In this study, the relationship between plastic slip activity and fatigue crack initiation was investigated in a near-α titanium alloy using cyclic four-point bending at up to 90% of the proof stress. The finding from surface characterization show that plasticity at such low stress levels was dominated by the basal slip and two types of cracking were seen parallel to basal slip traces. Detailed 3D analysis of both crack types highlighted out-of-plane Burgers vector activity for the observed basal slip associated with crack initiation, consistent with the classic surface roughening mechanism. The transgranular crack initiation was accompanied by the formation of crystallographic facet which was identified to be 6° away from the basal plane due to additional prismatic slip activation during multi-step crack formation. The intergranular crack facet along the boundary between primary α grain pairs, which have their c-axes aligned nearly parallel to each other but with mis-aligned prismatic planes, was formed by an easy cleavage in one step along the basal plane. Statistical evaluation demonstrated that grains combining a moderately high Schmid factor for basal slip, high resolved tensile stress along the c-axis and the Burgers vector being oriented strongly out-of-surface plane favoured transgranular crack initiation. Based on those observations a new parameter involving these three geometrical factors was developed to predict transgranular surface crack initiation sites

Development of cordycepin formulations for preclinical and clinical studies

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin

Isothermal crystallization study on aqueous solution of poly(vinyl methyl ether) by DSC method

A study on the isothermal crystallization of water in aqueous solutions of poly(vinyl methyl ether) (PVME) was carried out by the differential scanning calorimetry (DSC). The influence of PVME concentration (49.5, 44.5 and 39.5 v%) and the crystallization temperature (T c) on crystallization rate G, crystallization enthalpy (?H c) and melting enthalpy (?H m) was investigated. Avrami equation cannot be used to describe the crystallization process of water in aqueous PVME solution. Within the measured temperature range, the crystallization rate G increases with the crystallization temperature T c and with the decreasing PVME content. The crystallization enthalpy ?H c linearly increases with the degree of supercooling. The influence of T c on the ?H c becomes more marked with increasing PVME concentration. For 49.5 and 44.5 v% PVME solutions, the amount of water arrested in solution during the isothermal crystallization and the final concentration of PVME-rich phase increase linearly with the T c, whereas for 39.5 v% PVME solution, these two values almost do not change with T c. The amount of frozen water in the subsequent cold crystallization is approximately proportional to the initial T c. The approximately constant ?H m for a given concentration at the different initial isothermal crystallization temperatures suggests that the total amount of ice from the first isothermal crystallization and the second cold crystallization is same. The quantitative relation of the amount of frozen water in the cold crystallization and the initial T c demonstrates that PVME/water complexes are thermodynamically unstable. © 2008 Elsevier Ltd. All rights reserve

Substrate-Induced Control of Product Formation by Protein Arginine Methyltransferase 1

Protein arginine methyltransferases (PRMTs) aid in the regulation of many biological processes. Accurate control of PRMT activity includes recognition of specific arginyl groups within targeted proteins and the generation of the correct level of methylation, none of which are fully understood. The predominant PRMT in vivo, PRMT1, has wide substrate specificity and is capable of both mono- and dimethylation, which can induce distinct biological outputs. What regulates the specific methylation pattern of PRMT1 in vivo is unclear. We report that PRMT1 methylates a multisite peptide substrate in a nonstochastic manner, with less C-terminal preference, consistent with the methylation patterns observed in vivo. With a single targeted arginine, PRMT1 catalyzed the dimethylation in a semiprocessive manner. The degree of processivity is regulated by substrate sequences. Our results identify a novel substrate-induced mechanism for modulating PRMT1 product specificity. Considering the numerous physiological PRMT1 substrates, as well as the distinct biological outputs of mono- and dimethylation products, such fine-tuned regulation would significantly contribute to the accurate product specificity of PRMT1 in vivo and the proper transmission of biochemical information