p53 in polyoma virus transformed REF52 cells

While cellular transformation by small DNA tumour viruses usually involves targeting the product of the p53 tumour suppressor gene by a virally encoded protein, none of the three polyoma virus (Py) specified T antigens have been observed to interact with p53. We show that primary mouse embryo fibroblasts and REF52 cells, which resemble primary cells in requiring co-operating oncogenes for transformation, cannot be transformed by the Py oncogene, middle T-antigen (PyMT), alone. These cells can be transformed by the complete Py early region, which encodes the Py large, middle and small T-antigens. We find that PyMT can transform rodent cells lacking a functional p53 protein (p53 null mouse embryo fibroblasts and DN-REF52 cells which contain a dominant negative p53). In Py transformed REF52 cells (Py-REF52) there is no significant accumulation of p53 protein, as opposed to SV40 transformed REF52 cells (SV-REF52) in which the amount of steady state p53 protein is elevated. However accumulation of p53 is observed following exposure of Py-REF52 cells to u.v. Treatment of Py-REF52 cells with X-rays results in a rapid increase in the levels of the p53-induced proteins p21/WAF1 and MDM2. In untransformed REF52 cells, X-irradiation causes p53 activation, which results in induction of both G1/S and G2/M blocks. In SV-REF52 and DN-REF52 cells, p53 abrogation results in the absence of both the G1/S and G2/M blocks. Only the absence of a G1/S block is observed in Py-REF52 cells exposed to X-irradiation. Together these results indicate that in contrast to most other DNA tumour viruses, Py does not appear to interfere with the DNA damage induced transactivation activities of the p53 protein but absence of a functional p53 protein can mediate transformation by the PyMT oncogene in the absence of other co-operating oncogenes. Possible modes of transformation by Py are discussed.     

Performance analysis of Drever-Hall laser frequency stabilizationusing a proportional+integral servo

In this paper, we derive analytical expressions for finite gain, finite bandwidth laser frequency locking systems. The common case of Drever-Hall (FM sideband) locking to a Fabry-Perot cavity is discussed, using a proportional+integral (PI) controller as an example. The effects of nonnegligible loop time-delay on stability are discussed, and an optimal design procedure for a frequency locking system is given     

Dyadic perfectionism as a predictor of relationship continuity and distress among college students.

This study examined the nature and impact of dyadic perfectionism over a 3-month interval within a sample of 116 college students who were currently involved in an intimate heterosexual relationship. Dyadic perfectionism scores were stable and correlated as expected with scores on concurrent measures of adult attachment orientations and relationship satisfaction. Logistic regression analyses revealed that, controlling for initial commitment status and adult attachment orientations, Time 1 dyadic perfectionism scores significantly and uniquely predicted relationship continuity 3 months later. Lastly, controlling for social desirability, relationship commitment status, and Time 1 adult attachment orientation scores, Time 1 dyadic perfectionism scores also uniquely predicted Time 2 relationship distress. Findings provide additional evidence that dyadic perfectionism is a risk factor for relationship dysfunction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chalcogenide Glasses Based on Germanium Disulfide for Second Harmonic Generation

High second‐order susceptibilities are created by thermal poling in bulk germanium disulfide based chalcogenide glasses. Experimental conditions of the poling treatment (temperature, voltage, time) were optimized for each glass composition. The second‐order nonlinear signals were recorded by using the Maker fringes experiment and a second‐order coefficient χ⁽²⁾ up to 8 pm V^–1 was measured in the Ge₂₅Sb₁₀S₆₅ glass. This value is obtained using a simulation based on accurate knowledge of the thickness of the nonlinear layer. Two mechanisms are proposed to explain the creation of a nonlinear layer under the anode: the formation and the migration of charged defects towards the anode may mainly occur in Ge₂₀Ga₅Sb₁₀S₆₅ and Ge₂₅Ga₅S₇₀ glasses, whereas the migration of Na⁺ ions towards the cathode may be responsible for the accumulation of negative charges under the anode in Ge₃₃S₆₇ and Ge₂₅Sb₁₀S₆₅ glasses. Different electronic conductivity behaviors seem to be at the origin of the phenomenon. In parallel, the potential effect of the poling treatment on the structural and electronic properties is studied using Raman spectroscopy and secondary ion mass spectroscopy measurements.     

Molecular recognition in the sphingosine 1-phosphate receptor family

Computational modeling and its application in ligand screening and ligand receptor interaction studies play important roles in structure-based drug design. A series of sphingosine 1-phosphate (S1P) receptor ligands with varying potencies and receptor selectivities were docked into homology models of the S1P(1-5) receptors. These studies provided molecular insights into pharmacological trends both across the receptor family as well as at single receptors. This study identifies ligand recognition features that generalize across the S1P receptor family, features unique to the S1P(4) and S1P(5) receptors, and suggests significant structural differences of the S1P(2) receptor. Docking results reveal a previously unknown sulfur-aromatic interaction between the S1P(4) C5.44 sulfur atom and the phenyl ring of benzimidazole as well as pi-pi interaction between F3.33 of S1P(1,4,5) and aromatic ligands. The findings not only confirm the importance of a cation-pi interaction between W4.64 and the ammonium of S1P at S1P(4) but also predict the same interaction at S1P(5). S1P receptor models are validated for pharmacophore development including database mining and new ligand discovery and serve as tools for ligand optimization to improve potency and selectivity.     

Intergranular films at Au-sapphire interfaces

The existence of nanometer-thick amorphous equilibrium films at metal-ceramic interfaces has been experimentally verified for the Au–Al₂O₃ system. The films were formed using a novel experimental approach, in which thin sputtered films of Au were dewetted on a sapphire substrate which was previously partially wetted with drops of anorthite glass (CaO–2SiO₂–Al₂O₃). High-resolution transmission electron microscopy and qualitative analytical transmission electron microscopy were used to confirm the existence of the amorphous films. In addition, positive and relatively large Hamaker constants were calculated for the Au-film-Al₂O₃ interface, which indicates the existence of an attractive van der Waals force which stabilizes the film, similar to equilibrium films at grain boundaries in ceramics. A ∼ 1 nm thick surface film was also detected on the (0001) surface of sapphire substrates partially wetted by anorthite glass. The refractive index required to stabilize the surface films, via a positive Hamaker constant, is explored.     

A short term −12° head down tilt does not mimic microgravity in terms of human gonadal function

A significant reversible decrease in testosterone (T) has been associated with microgravity in male rodents and humans. Urinary T excretion increases in primates under hypergravity. Hypogonadism is somehow related to abnormally high levels of leptin (L), a hormone produced by the adipose tissue which has been found to increase under microgravity simulation conditions like head down bed rest (HDBR). The aim of this study was to assess hemodynamic and pituitary-adrenal and -gonadal adaptation to an acute HDBR test to be eventually used on a routine basis to get better prepared to next space flights. The Authors performed a 1 hour ?12° HDBR in 6 male and 6 female volunteers who underwent heart rate and blood pressure measurement together with a blood draw three times at 30 min intervals from the start to the end of the test for L, T, estradiol (E₂), LH, androstenedione (A), cortisol (F), ACTH. 12 age- and sexmatched control subjects followed the same protocol except for keeping the sitting position all the time. According to the ANOVA for repeated measures, no changes occurred in L, T, E₂ or LH whereas A, F and ACTH significantly decreased independently of gender. During HDBR systolic blood pressure decreased in both genders, diastolic blood pressure decreased significantly only in men and HR showed a more clear-cut decrease in women than in men. As a conclusion, such an acute steep-slope HDBR protocol may be efficiently used to testing immediate individual haemodynamic or adrenal response to microgravity but is not suitable for studies concerning gonadal adaptation.     

N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT₂-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT₁ and MT₂ binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.     

Key factors that influence the UX of a dual-player game for the cognitive stimulation and motor rehabilitation of older adults

Universal Access in the Information Society - In this work, the results of usability and user experience (UX) evaluation of a serious video game for the cognitive stimulation and motor...