A homology model for rat mu class glutathione S-transferase 4-4

Glutathione S-transferases (GSTs) are an important class of phase II (de)toxifying enzymes, catalyzing the conjugation of glutathione (GSH) to electrophilic species. Recently, a number of cytosolic GSTs was crystallized. In the present study, molecular modeling techniques have been used to derive a three-dimensional homology model for rat GST 4-4 based upon the crystal structure of rat GST 3-3, both members of the mu class. GST 3-3 and GST 4-4 isoenzymes share a sequence homology of 88%. GST 4-4 distinguishes itself from GST 3-3 in being much more efficient and stereoselective in the nucleophilic addition of GSH to epoxides and alpha,beta-unsaturated ketones. GST 3-3, however, is much more efficient in catalyzing nucleophilic aromatic substitution reactions. In this study, several known substrates of GST 4-4 were selected and their GSH conjugates docked into the active site of GST 4-4. GSH conjugates of phenanthrene 9(S),10(R)-oxide and 4,5-diazaphenanthrene 9(S),10(R)-oxide were docked into the active site of both GST 3-3 and GST 4-4. From these homology modeling and docking data, the difference in stereoselectivity between GST 3-3 and GST 4-4 for the R- and S-configured carbons of the oxirane moiety could be rationalized. The data acquired from a recently derived small molecule model for GST 4-4 substrates were compared with the results of the present protein homology model of GST 4-4. The energy optimized positions of the conjugates in the protein model agreed very well with the original relative positions of the substrates within the substrate model, confirming the usefulness of small molecule models in the absence of structural protein data. The protein homology model, together with the substrate model, will be useful to further rationalize the substrate selectivity of GST 4-4, and to identify new potential GST 4-4 substrates.     

Isolation and characterization of a novel gene from human glioblastoma multiforme tumor tissue

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.     

Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma

The influence of concomitant administration of bovine lactoferrin (bLF) on induction of aberrant crypt foci (ACF) by azoxymethane was investigated in male F344 rats. Two percent bLF and 3% Bifidobacterium longum (B. longum), as a positive control, significantly decreased the numbers of ACF as well as the total numbers of aberrant crypts reproducibly in three independent studies (2% bLF, P < 0.01; 3% B. longum, P < 0.05). Most importantly large size foci composed of four or more crypts were always significantly decreased by 2% bLF (P < 0.05). Additional investigation of the natural killer activity of spleen cells demonstrated enhancement by bLF (P < 0.01) and B. longum (P < 0.01) in line with the levels of influence on foci induction, indicating a possible role for elevated immune cytotoxicity in the observed inhibition.     

Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery

OBJECTIVE: To investigate prospectively the proportion of patients actually operated on early in units that aim at surgery in the acute phase of aneurysmal subarachnoid haemorrhage (SAH) and what is the main current determinant of poor outcome. METHODS: A prospective analysis of all SAH patients admitted during a one year period at three neurosurgical units that aim at early surgery. The following clinical details were recorded: age, sex, date of SAH, date of admission to the neurosurgical centre, whether a patient was referred by a regional hospital or a general practitioner, Glasgow coma scale and grade of SAH (World Federation of Neurological Surgeons (WFNS) score) on admission at the neurosurgical unit, results of CT and CSF examination, the presence of an aneurysm on angiography, details of treatment with nimodipine or antifibrinolytic agents, and the date of surgery to clip the aneurysm. At follow up at three months, the patients' clinical outcome was determined with the Glasgow outcome scale and in cases of poor outcome the cause for this was recorded. RESULTS: The proportion of patients that was operated on early--that is, within three days after SAH--was 55%. Thirty seven of all 102 admitted patients had a poor outcome. Rebleeding and the initial bleeding were the main causes of this in 35% and 32% respectively of all patients with poor outcome. CONCLUSIONS: In neurosurgical units with what has been termed "modern management" including early surgery, about half of the patients are operated on early. Rebleeding is still the major cause of poor outcome.     

Accelerated numerical simulations of a heaving floating body by coupling a motion solver with a two-phase fluid solver

This paper presents a study on the coupling between a fluid solver and a motion solver to perform fluid–structure interaction (FSI) simulations of floating bodies such as point absorber wave energy converters heaving under wave loading. The two-phase fluid solver with dynamic mesh handling, interDyMFoam, is a part of the Computational Fluid Dynamics (CFD) toolbox OpenFOAM. The incompressible Navier–Stokes (NS) equations are solved together with a conservation equation for the Volume of Fluid (VoF). The motion solver is computing the kinematic body motion induced by the fluid flow. A coupling algorithm is needed between the fluid solver and the motion solver to obtain a converged solution between the hydrodynamic flow field around and the kinematic motion of the body during each time step in the transient simulation. For body geometries with a significant added mass effect, simple coupling algorithms show slow convergence or even instabilities. In this paper, we identify the mechanism for the numerical instability and we derive an accelerated coupling algorithm (based on a Jacobian) to enhance the convergence speed between the fluid and motion solver. Secondly, we illustrate the coupling algorithm by presenting a free decay test of a heaving wave energy converter. Thirdly and most challenging, a water impact test of a free falling wedge with a significant added mass effect is successfully simulated. For both test cases, the numerical results obtained by using the accelerated coupling algorithm are in a very good agreement with the experimental measurements.     

An open book on Facebook? Examining the interdependence of adolescents’ privacy regulation strategies

Users of social network sites (SNSs) use three main strategies that help to manage the privacy of their profile information: (1) limiting the level of data revealed, (2) using privacy settings to exert control over data and (3) audience/friendship management by being restrictive about whom to accept as a ‘friend’. Extant research does not show whether these strategies operate as independent mechanisms or whether they are interdependent and work as a system. Given what offline privacy theorist Irwin Altman (1977 Altman, Irwin. 1977. “Privacy Regulation: Culturally Universal or Culturally Specific?” Journal of Social Issues 33 (3): 66–84. doi: 10.1111/j.1540-4560.1977.tb01883.x[Crossref], [Web of Science ®] , [Google Scholar]) designates as the multi-mechanic nature of privacy protection, we test a model in which we expect to find that the three discerned strategies are related to one another. Structural equation modelling analysis performed on the subsample (n?=?1564) of our study’s data – collected among 1743 adolescents by means of a paper-and-pencil survey – demonstrates that, in line with Altman’s vision of privacy protection, the three discerned strategies effectively operate as an interdependent system. In congruence with the hypotheses derived from extant research, we found that adolescents’ level of disclosure influences adolescents’ involvement in the two other discerned strategies: Adolescents with high levels of personal information disclosure share an increased tendency to have many friends on SNSs and a lower level of using privacy settings.     

Lanthanide “Chameleon” Multistage Anti‐Counterfeit Materials

Hybrid materials displaying multistage security behavior, where a single material shows both wavelength‐ and temperature‐dependent luminescence properties, are reported. The materials consist of mixed‐lanthanide β‐diketonate complexes grafted into the pores of a nanosized 2,2′‐bipyridine‐5,5′‐dicarboxylate‐acid MOF. A very specific choice of lanthanides and their ratios, as well as β‐diketonate ligand, is crucial for obtaining the desired properties. The wavelength‐dependent luminescence properties of the materials are very well matched with the excitation wavelengths of a standard UV lamp, and a clearly visible change in luminescence is observed in a narrow temperature range (slightly below and above room temperature), proving them to be excellent materials for use in anti‐counterfeit technologies, which would be almost impossible to mimic.     

The electrochemistry of Pd-coated MgySc(1 − y) thin film electrodes: A thermodynamic and kinetic study

The thermodynamic and kinetic properties of Pd-coated Mg_ySc_(1 − y) thin film electrodes are investigated. These thin film electrodes can be described as a two-layer structure, in which the Pd and Mg_ySc_(1 − y) layer contribute to the overall electrochemical response. In order to identify the response of the Pd layer in the two-layer system, thin films consisting of solely Pd, with identical thickness and orientation, were measured. Based on the fact that the chemical potentials of the individual layers of the Pd-coated Mg_ySc_(1 − y) thin films are equal at equilibrium, the exact hydrogen concentration in each layer could be determined. It is shown that during the major part of the hydrogen extraction process of the Mg_ySc_(1 − y) thin films, the composition of the Pd topcoat is close to PdH_0.001. The kinetics of the surface reactions was investigated using electrochemical impedance spectroscopy and showed that, when cross-correlating the results of Mg_ySc_(1 − y) thin films (y = 0.65 − 0.85) and pure Pd films, the surface kinetics are completely dominated by the Pd topcoat. Additionally, it was shown that the charge transfer reaction, and not the absorption reaction is the rate-determining step. The impedance response, dominating the overall kinetic impedance at the hydrogen-depleted state, could be linked to the transfer of hydrogen across the Pd/Mg_ySc_(1 − y) interface in the two-layer thin film electrode.     

On Polarization-Induced Zero Temperature Spin Wave Damping in Dilute 3He

We have observed spin waves in dilute ³ He, spin polarized by a ⁴ He circulating dilution refrigerator. The maximum polarization is a factor 5 higher than the equilibrium polarization in the magnetic field of 10.54 T at temperatures between 10 and 20 mK. The measured spin wave damping is about a factor 4 lower than the damping expected from previous spin echo experiments in ³ He- ⁴ He mixtures, which confirmed the prediction of polarization-induced spin wave damping at zero temperature in Fermi liquids. Our experiment shows that the existence of polarization-induced spin wave damping remains an open question.     

A Predictive Model for the Growth/No Growth Boundary of Zygosaccharomyces bailii at 7?°C and Conditions Mimicking Acidified Sauces

The spoilage potential of Zygosaccharomyces bailii has been widely recognized within the food industry. However, few data are available on the growth characteristics of this yeast at low temperature and in the absence of chemical preservatives. In this study, the growth/no growth boundary of Z. bailii was defined at refrigeration temperature (7?°C) and at conditions relevant to high-sugar, low-pH foods (such as ketchup and salad dressing), i.e. pH?3.0?C5.0 (five levels), a _w 0.93?C0.97 (five levels) and acetic acid concentration 0?C2.5% (v/v; six levels). Yeast growth was followed during 90?days by optical density measurements, and logistic regression models were used to describe the data. Acetic acid had a significant effect on the relation between a _w and NaCl concentration and this interaction had important consequences for the model development. When data were modelled as a function of a _w or NaCl concentration, a stimulatory effect by acetic acid was observed. In contrast, as a function of (toxic) Na⁺ ions, no evidence was found of such a phenomenon. These results indicate that in cases where the relationship between a _w and solute concentration is not straightforward such as in the presence of acid preservatives, one must be critical towards the interpretation of data and correspondingly, the development of predictive models. On a practical note, the developed models, especially the one incorporating Na⁺ ions, may be used (1) to assess the stability of shelf-stable acidified foods stored under chilled conditions after opening or (2) to formulate new additive-free products intended for storage at 7?°C.