Brownian dynamics simulations of associating diblock copolymers.

A novel coarse-grained computational model for associating polymers is proposed that is based on a Gaussian "blob" representation of the polymer chains. The model allows a large number of model polymers to be simulated at moderate computational cost over a wide packing fraction range using the Brownian dynamics, BD, technique. The attraction of the hydrophobic part of the polymer to those on other molecules can lead to strong aggregation of the polymer molecules in real systems, and this is included in the model by an attractive potential felt by the Gaussian blobs to a common "nodal" point that represents the center of the micelle. Attention here is confined to model AB diblock copolymers in which the hydrophilic block, A, has a much higher mass than the hydrophobic moiety, B, which leads to relatively small aggregation numbers, Nagg, of approximately 8. The aggregation number at low packing fractions is found to increase with packing fraction, as observed in experiments, with a functional form that closely follows a simple theory derived here that is based on entropy-derived mean-field terms for the free-energy change associated with the incorporation of the polymer molecule into the micelle. The computational model exhibits an extremely low critical micelle concentration (cmc), and micelles with Nagg approximately 5 are observed at the lowest packing fractions, phi, simulated ( approximately 10-4), which is consistent with experiment. The long-time self-diffusion coefficient of the polymers (and hence micelles) decreases logarithmically with packing fraction, and the viscosity increased with concentration according to the Huggins equation. The spherical blob coarse graining results in the simulable time scales being longer than the Rouse time of the chain, and hence for the nonassociating polymers the intrinsic viscosity is an input parameter in the model. The introduction of association leads to the partial inclusion of the intrinsic viscosity in the simulation and has an effect on the computed Huggins coefficient, kH, which is found to be approximately 6 in those cases.

Stability of separation-shifted Lennard-Jones fluids.

Ruelle's thermodynamic stability criteria are applied to the separation-shifted Lennard-Jones (SSLJ) fluid, and the domain of its parameters giving "normal" thermodynamic stability in the thermodynamic limit is established. Fluids interacting with the SSLJ both conforming to and breaking these stability criteria were modeled using molecular dynamics computer simulation. For system sizes typical of most simulations, the transition between the two patterns of behavior was found to be smeared out over a range of parameter values. Thermodynamic instability is marked by a collapse of the system into a small "ball" or volume. The collapsed state nevertheless has some statistical mechanical properties typical of systems exhibiting normal thermodynamics (e.g., the kinetic and configurational temperatures were found to be the same in the collapsed state within statistics).

Self-diffusion coefficient of the hard-sphere fluid: system size dependence and empirical correlations.

Molecular dynamics simulations have been used to calculate the self-diffusion coefficient, D, of the hard sphere fluid over a wide density range and for different numbers of particles, N, between 32 and 10 976. These data are fitted to the relationship D = D(infinity) - AN(-alpha) where the parameters D(infinity), A, and alpha are all density-dependent (the temperature dependence of D can be trivially scaled out in all cases). The value alpha = 1/3 has been predicted on the basis of hydrodynamic arguments. In the studied system size range, the best value of alpha is approximately 1/3 at intermediate packing fractions of approximately 0.35, but increases in the low- and high-density extremes. At high density, the scaling follows more closely that of the thermodynamic properties, that is, with an exponent of order unity. At low packing fractions (less than approximately 0.1), the exponent increases again, appearing to approach a limiting value of unity in the zero-density limit. The origin of this strong N dependence at low density probably lies in the divergence in the mean path between collisions, as compared with the dimensions of the simulation cell. A new simple analytical fit formula based on fitting to previous simulation data is proposed for the density dependence of the shear viscosity. The Stokes-Einstein relationship and the dependence of D on the excess entropy were also explored. The product Deta(s)p with p = 0.975 was found to be approximately constant, with a value of 0.15 in the packing fraction range between 0.2 and 0.5.

The relationship between job satisfaction and health: a meta-analysis.

BACKGROUND: A vast number of published studies have suggested a link between job satisfaction levels and health. The sizes of the relationships reported vary widely. Narrative overviews of this relationship have been published, but no systematic meta-analysis review has been conducted. METHODS: A systematic review and meta-analysis of 485 studies with a combined sample size of 267 995 individuals was conducted, evaluating the research evidence linking self-report measures of job satisfaction to measures of physical and mental wellbeing. RESULTS: The overall correlation combined across all health measures was r = 0.312 (0.370 after Schmidt-Hunter adjustment). Job satisfaction was most strongly associated with mental/psychological problems; strongest relationships were found for burnout (corrected r = 0.478), self-esteem(r = 0.429), depression (r = 0.428), and anxiety(r = 0.420). The correlation with subjective physical illness was more modest (r = 0.287). CONCLUSIONS: Correlations in excess of 0.3 are rare in this context. The relationships found suggest that job satisfaction level is an important factor influencing the health of workers. Organisations should include the development of stress management policies to identify and eradicate work practices that cause most job dissatisfaction as part of any exercise aimed at improving employee health. Occupational health clinicians should consider counselling employees diagnosed as having psychological problems to critically evaluate their work-and help them to explore ways of gaining greater satisfaction from this important aspect of their life.

Grain morphology and trapping effects on electron transport in dye-sensitized nanocrystalline solar cells.

We have examined the combined effects of grain morphology and electron trapping on the transient response of photoelectrons moving through the TiO2 grains in a dye-sensitized nanocrystalline solar cell using a multi-time-scale random walk Monte Carlo model. Our use of a multi-time-scale approach enables us to simulate transport for electrons moving through spherical connected grains in a three-dimensional (3D) voided network and look at the effect of the size of interparticle boundaries on carrier dynamics. We can also address similar times to those over which measurements are taken, namely, 0.1 ms. These times are long because of deep traps in the TiO2 grains. The grains have 2-fold connectivity in one dimension (linear chains) or 4-fold or 6-fold connectivity in three dimensions and traps with an exponential distribution of energies. Photoelectrons are generated by a light pulse of short duration. The spatial distribution of the photogenerated electron density from this pulse either has a uniform profile or is peaked on the electrolyte side. We show that the constrictions at the grain necks slow the electrons, making trapping more likely and hence further delaying their passage to the extracting electrode. By comparing our results for 4-fold and 6-fold coordinated particles on a cubic lattice with 2-fold coordinated particles on linear chains, we show that transport is slowed in the former case due to the additional paths available to the electrons in the 3D network. We also find that the charge and current transients cannot be fit to an analytical solution of the continuum equations with an effective diffusion coefficient even at long times. Therefore, caution must be exercised when attempting to fit experimental transient data with an effective diffusion coefficient.

Ala217 is important for the catalytic function and autoactivation of prostate-specific human kallikrein 2.

Prostate-specific human kallikrein, hK2, is a serine protease found in prostate tissues that has 78% amino acid sequence identity with prostate-specific antigen (PSA). We have previously reported the affinity purification of hK2 heterologously expressed in a hamster cell line and demonstrated an arginine-restricted substrate specificity. Here, we describe the cloning, expression, purification, and enzymatic activity of a mutant form of hK2 containing an alanine to valine substitution at residue 217 ([Val217]hK2). This mutant form was secreted into the serum-free spent media of recombinant cells as the stable proenzyme form ([Val217]phK2). Mild trypsin treatment was used to convert [Val217]phK2 to the active form, which had reduced catalytic function compared to the wild-type hK2. Kinetic studies using the chromogenic substrate D-H-Pro-Phe-Arg-4-nitroanilide showed that [Val217]hK2 has significantly decreased substrate binding, with a K(m) of 4200 microM compared to 11 microM for wild-type hK2. The k(cat) for [Val217]hK2 was more than 100-fold lower than for hK2. hK2, but not [Val217]hK2, was able to activate [Val217]phK2. [Val217]hK2 also showed altered specificity on a synthetic peptide substrate compared to wild-type hK2, which exhibited partial hydrolysis at a PSA chymotrypsin-like cleavage site as well as the trypsin-like site cleaved by hK2. These results indicate that Ala217 is a key residue affecting the catalytic properties of hK2.

P300 from a single-stimulus paradigm: auditory intensity and tone frequency effects.

The P300 component of the event-related brain potential (ERP) was elicited with auditory stimuli in two different tasks. The oddball paradigm presented both target and standard stimuli; the single-stimulus paradigm presented a target but no standard tone stimulus, with the inter-target interval the same as that for the oddball condition. Experiment 1 manipulated stimulus intensity and Experiment 2 manipulated tone stimulus frequency, with the relative target probability maintained 0.20 for both tasks. P300 amplitude and latency were highly similar for the oddball and single-stimulus procedures in both experiments across independent variables. The findings suggest that the single-stimulus paradigm may prove useful in experimental and applied contexts that require very simple ERP task conditions.

Photography and densitometry to measure skin pigmentation caused by ultraviolet exposure.

This was a project that a final year physiotherapy student was undertaking. Part of the project required the measurement of skin pigmentation before and after treatment with a standard E2 UV dose. The measurement of skin redness was undertaken using an erythema meter, and it was necessary to use photographic and densitometric techniques to measure skin pigmentation. The results of this experiment proved to be consistent with other published papers on the way that skin types react on exposure to standard UV doses. This paper describes the photographic method and procedures that were used and the way the raw data was treated so that it could be used for statistical analysis by the physiotherapy student.

Overexpression of a human prostate-specific glandular kallikrein, hK2, in E. coli and generation of antibodies.

The genomic and the cDNA clones of human glandular kallikrein (hK2), a member of the kallikrein family, have been isolated; however, the hK2 protein has not yet been identified and characterized. The deduced sequence of hK2 is highly homologous to prostate specific antigen (PSA), a widely accepted prognostic indicator of prostate carcinoma. Also, hK2 mRNA, like PSA mRNA, is exclusively expressed in prostatic epithelia. These two properties make hK2 a potentially useful marker for studying prostate cancer. In this paper, we describe for the first time the overexpression of the entire hK2 protein (pre-pro hK2:pphK2) in the E. coli system. Our system yields high levels of authentic pphK2 (as determined by partial amino acid sequence analysis) comprising about 40% of total cellular protein. pphK2 was purified to near homogeneity by preparative SDS/PAGE and used to generate anti-pphK2 antibodies in rabbits. The antibodies recognize the recombinant hK2 protein and a major band of approximately 34 kDa in seminal fluid.

Laterality, sexual orientation, and immune system functioning: is there a relationship?

There have been numerous recent investigations of the possibility that laterality (the extent to which an individual is right or left-sided or, more usually, right- or left-handed), sexual orientation (homosexual, bisexual, or heterosexual), and immune system functioning are related. The reasons for inconsistencies in the literature and failures to reject the null hypothesis are discussed. Additional data are presented that show a positive relationship between left-sided laterality and homosexuality for a sample of HIV positive males. Immune system disorders were not associated with any of the other variables. It is concluded that increased left-sidedness is more likely in homosexual men as a group, but laterality cannot be used to differentiate homosexual men further into categories that vary in their susceptibility to immune disorders.

Prenatal diagnosis of cystinosis utilizing chorionic villus sampling.

The prenatal diagnosis of cystinosis is currently based on the increased amount of free-cystine present in amniotic fluid cells. Amniocyte cultures must be grown for at least 2 weeks to obtain sufficient cells for such measurements. Thus, the diagnosis cannot be made until close to 20 weeks gestational age by this method. We report a case in which chorionic villi were used for direct cystine measurement resulting in the in utero diagnosis of cystinosis at 9 weeks gestational age. The diagnosis was confirmed by the study of cultured chorionic villus cells, and of the 10-week abortus.

Brain dysfunction in an adolescent with the neuromuscular form of hexosaminidase deficiency.

A 14-year-old girl of Ashkenazi Jewish background is described who has severe deficiency of hexosaminidase A. She presented with slowly progressive motor neuron degeneration and was found to have subtle deficiencies on neuropsychological testing, abnormal cortical evoked potentials and structural abnormalities of the cerebellum on CT scan. This patient extends the reported clinical findings for adolescents and suggests the possibility of similar abnormalities in others with neuromuscular deterioration.

A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

A five-year-old-girl with a history of recurrent hypoglycemia presented with acidosis, intractable vomiting, and abdominal tenderness; the diagnosis of acute pancreatitis was made by abdominal ultrasonography and supportive biochemical studies. Urinary organic acid analysis revealed metabolites suggestive of HMG-CoA lyase deficiency, and subsequent enzyme assays of lymphocytes and fibroblasts confirmed this diagnosis. Acute pancreatitis, an uncommon condition in childhood, is seen with increased frequency in patients with Reye syndrome, a metabolic disorder with which HMG-CoA lyase deficiency may be confused. The pathogenesis of pancreatitis in Reye syndrome or in HMG-CoA lyase deficiency has not been determined.

Effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis.

The effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis is investigated at various doses (5 to 50 mg/100 g body weight) and for various lengths of time (1 to 24 hr). The results show that this carcinogen is a potent inhibitor of both nuclear and nucleolar RNA synthesis. Like other carcinogens studied previously in this laboratory, e.g., N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and actinomycin D, methylazoxymethanol acetate inhibits RNA synthesis at multiple sites. It impairs chromatin template function and selectively inhibits the activity of RNA polymerase II. Experimental evidence suggests the mechanism of inhibition of RNA polymerase II activity is due to a decrease in catalytic efficiency rather than in the total number of the enzyme. In addition, it is found that methylazoxymethanol acetate induces a dramatic condensation of nucleoplasmic chromatin.

Tissue, sex, and animal species specificity of aflatoxin B1 inhibition of nuclear RNA polymerase II activity.

Recent studies from this laboratory have shown that several chemical carcinogens, i.e., aflatoxin B1, N-OH-2-acetyl-aminofluorene, actinomycin D, and methylazoxymethanol acetate, when administered in vivo, have all produced a selective and dramatic inhibition of rat liver nuclear RNA polymerase II activity. To determine whether this inhibition is related to carcinogenesis, aflatoxin B1 is used as a model system to test tissue, sex, and animal species specificity that is known to be characteristic of carcinogenesis. The results show that aflatoxin B1 (3 mg/kg body weight, i.p., 2h) inhibits RNA polymerase II activity only in the target tissue, liver, and not in the non-target tissues, e.g., lung and brain. It inhibits liver RNA polymerase II activity preferentially in male over female rats, and has no effect on mouse liver RNA polymerase II activity. These results are in good agreement with the specificities of aflatoxin B1 carcinogenesis in the whole animal systems. Furthermore, with the four principal aflatoxins tested, the order of inhibitor effect on RNA polymerase II is: B1 greater than G1 greater than B2, G2. It is concluded, therefore, that the inhibition of RNA polymerase II activity and carcinogenesis are likely to be related and that it is theoretically sound to use this inhibition as a diagnostic tool to screen potential carcinogens.

gamma-L-Glutaminyl-4-hydroxybenzene, an inducer of cryptobiosis in Agaricus bisporus and a source of specific metabolic inhibitors for melanogenic cells.

A stable phenol, gamma-L-glutaminyl-4-hydroxybenzene (GHB), is oxidized by tyrosinase in the gill tissues of the mushroom Agaricus bisporus to a quinone and a second oxidation product which together suppress mitochondrial energy production and the synthesis of proteins and nucleic acids in the zygote, thus establishing dormancy in the spores. Brief incubation of cultured murine L1210 leukemia and B-16 melanoma cells with muM concentrations of the purified quinone notably prolonged survival times or blocked tumor growth in histocompatible mice inoculated i.p. with high concentrations of the exposed cells. The instability of the quinone precluded in vivo administration. The short incubation of cultured B-16 melanoma cells with mM concentrations of GHB markedly prolonged survival times or abolished tumor growth in histocompatible C57BL/6J mice inoculated i.p. with 5 X 10(6) exposed cells. This response did not occur with L1210 leukemia cells, which lack the enzyme tyrosinase. The survival times of mice bearing B-16 melanoma, but not of those with L1210 leukemia, were slightly prolonged by a single injection and were significantly extended by daily i.p. injections of GHB. Normal C57BL/6J mice, given GHB i.p. as single or multiple 400-mg/kg doses, manifested no systemic toxicity but showed depigmentation of the hair after 2 to 3 weeks. These studies provide evidence that GHB exerts cytotoxicity specifically for cells that by their content of tyrosinase convert the phenol to the quinone. This targeted response minimizes systemic toxocity and underscores the potential therapeutic application of this agent to melanocarcinoma.