How a dc Electric Field Drives Mott Insulators Out of Equilibrium.

Out of equilibrium phenomena are a major issue of modern physics. In particular, correlated materials such as Mott insulators experience fascinating long-lived exotic states under a strong electric field. Yet, the origin of their destabilization by the electric field is not elucidated. Here we present a comprehensive study of the electrical response of canonical Mott insulators GaM_{4}Q_{8} (M=V, Nb, Ta, Mo; Q=S, Se) in the context of a microscopic theory of electrical breakdown where in-gap states allow for a description in terms of a two-temperature model. Our results show how the nonlinearities and the resistive transition originate from a massive creation of hot electrons under an electric field. These results give new insights for the control of the long-lived states reached under an electric field in these systems which has recently open the way to new functionalities used in neuromorphic applications.

Structural, optical, and dielectric properties of Bi(1.5-x)Zn(0.92-y)Nb(1.5)O(6.92-δ) thin films grown by PLD on R-plane sapphire and LaAlO3 substrates.

Bi(1.5-x)Zn(0.92-y)Nb(1.5)O(6.92-δ) thin films have the potential to be implemented in microwave devices. This work aims to establish the effect of the substrate and of the grain size on the optical and dielectric properties. Bi(1.5-x)Zn(0.92-y)Nb(1.5)O(6.92-δ) thin films were grown at 700 °C via pulsed-laser deposition on R-plane sapphire and (100)(pc) LaAlO(3) substrates at various oxygen pressures (30, 50, and 70 Pa). The structure, morphology, dielectric and optical properties were investigated. Despite bismuth and zinc deficiencies, with respect to the Bi(1.5)Zn(0.92)Nb(1.5)O(6.92) stoichiometry, the films show the expected cubic pyrochlore structure with a (100) epitaxial-like growth. Different morphologies and related optical and dielectric properties were achieved, depending on the substrate and the oxygen pressure. In contrast to thin films grown on (100)(pc) LaAlO(3), the films deposited on R-plane sapphire are characterized by a graded refractive index along the layer thickness. The refractive index (n) at 630 nm and the relative permittivity (ε(r)) measured at 10 GHz increase with the grain size: on sapphire, n varies from 2.29 to 2.39 and ε(r) varies from 85 to 135, when the grain size increases from 37 nm to 77 nm. On the basis of this trend, visible ellipsometry can be used to probe the characteristics in the microwave range quickly, nondestructively, and at a low cost.

Indirect reduction of aryldiazonium salts onto cathodically activated platinum surfaces: formation of metal-organic structures.

Platinum phases of general formula [Pt(n-), M+, MX] can be electrogenerated from cathodic polarization in dry dimethylformamide containing a supporting electrolyte, MX. The reaction of these electrogenerated Pt phases as reducing agent with aryldiazonium salts was investigated for preparing controlled metal-organic interfaces and characterizing the reactivity of the "reduced platinum phases". In a two-step process, the "reduced platinum phase" locally reacts with aryldiazonium salts, leading to the attachment of aryl groups onto the metal surface in the previously modified areas. Detailed experiments using cyclic voltammetry, X-ray photoelectron spectroscopy (XPS), and in situ electrochemical atomic force microscopy (EC-AFM) were carried out to follow the reaction in solution with the example of NaI as supporting electrolyte (MX = NaI). These studies demonstrate the irreversible attachment of aryl groups onto the platinum electrode. Comparison between the direct electroreduction of aryldiazonium compounds (4-nitrophenyl- and 4-bromophenyldiazonium) on a platinum electrode and their reaction with [Pt2-, Na+, NaI] suggests that a similar general mechanism is responsible for the grafting. However in the second case, no applied potential is required to stimulate the binding thanks to the reductive properties of [Pt2-, Na+, NaI]. Competitive reduction of the organic layer and growth of the layer were observed and analyzed as a function of the injected charge used to initially produce [Pt2-, Na+, NaI]. Similar reactions are highly probable with other MX salts owing to the redox properties observed for this type of platinum phase ([Pt(n-), M+, MX]).

Cathodic modifications of platinum surfaces in organic solvent: reversibility and cation type effects.

Cathodic modification of platinum surfaces leads to the formation of iono-platinic phases ([Pt(n-), M+, MX]), which involves the insertion of cations and salts into the platinum electrode. This process was investigated at the local scale by in situ observation of surface electrochemical processes by atomic force microscopy (EC-AFM) techniques as a function of the salt and the injected charge, with special attention about the process reversibility. AFM images recorded in solution after the cathodic modifications of well-defined platinum surfaces [epitaxial platinum deposit on (100) MgO substrate] show drastic modification on the morphology of the surface, confirming previous ex situ studies. The amplitude of the modifications directly depends on both the nature of supporting electrolyte and the quantity of charge injected into the platinum. As long as the injected charge remains small enough to maintain the adhesion of the Pt deposit onto the MgO substrate, the process was found to be fully reversible. Indeed, impressive morphology changes occur under the cathodic treatment (formation of [Pt(n-), M+, MX]) but the initial geometry is totally recovered after reoxidation of the iono-platinic phase. This cycle of reduction-reoxidation can be performed several times without any significant alteration of the recovered surface and of its structural characteristics. It is suggested that the modification starts at the interface solution platinum surface and then its insertion into the platinum surface.

[Glutathione S-transferases genetic polymorphisms and human diseases: overview of epidemiological studies]. / Polymorphismes des glutathion S-transférases et pathologies humaines : bilan des études épidémiologiques.

Glutathione S-transferases (GST), xenobiotic-metabolising enzymes, are involved in the metabolic detoxification of various environmental carcinogens. Particular genetic polymorphisms of these enzymes have been shown to influence individual susceptibility against various pathologies including cancer, cardiovascular and respiratory diseases. The results from the meta-analysis indicate that GSTM1*0 null allele was associated with enhanced risk for lung (OR (95% IC) = 1,17 (1,07-1,27)), bladder (OR = 1,44 (1,23-1,68) and larynx cancer (OR = 1,42 (1,10-1,84)). GSTT1 null genotype was associated with increased astrocytomas (OR = 2,36 (1,41-3,94)) and meningiomas (OR = 3,57 (1,82-6,92)) cancer risk. GSTP1 allelic polymorphism influence the development of bladder cancer in smokers (OR = 2,40 (1,12-4,95)) and occupational asthma (OR = 3,5 (2,7-4,6)). Finally, GSTM1*0 null allele and GSTT1*1 functional allele were associated with increased risk for coronary heart diseases in smokers (OR = 2,30 (1,40-9,00)) and OR = 2,5 (1,30-4,80), respectively). The GSTT1*1 functional allele was also significantly associated with increased risk of lower extremity arterial disease (OR = 3,60 (1,40-9,00). These epidemiological data suggest that genetic GST polymorphisms influence the individual susceptibility to these diseases. Contrary to cardiovascular disease, no evidence of interaction between GST genotype and smoking status was found in lung cancer but it has not been studied in other cancers. Consequently, other works are necessary to study the potential interaction between GST genotype and environmental carcinogens including tobacco smoke extract.

Apolipoproteins E and C-III in apo B- and non-apo B-containing lipoproteins in middle-aged women from the Stanislas cohort: effect of oral contraceptive use and common apolipoprotein E polymorphism.

Oral contraceptive (OC) use and common apo E polymorphism are well known to modify serum lipid and lipoprotein concentrations. The combined effect of OC use and apo E genotype on the concentration of apo E or apo C-III in apo B- (apo E-LpB or apo C-III-LpB) or in non-apo B-containing lipoparticles (apo E-Lp-non-B or apo C-III-Lp-non-B) are unknown. Our study comprised 613 women, aged 30-45 years, genotyped for common apo E polymorphism and who differed in their combined low-dose OC consumption. The concentrations of apo C-III, apo C-III-LpB and apo C-III-Lp-non-B were significantly higher in OC users than in non-users by 13, 23 and 8% respectively, without significant interaction with the apo E genotype. The concentrations of apo E and apo E-Lp-non-B were significantly lower (differences being -14% and -31% respectively) in OC users than in controls whereas the apo E-LpB concentration was significantly higher (+19%), resulting in a redistribution of apo E from Lp-non-B towards LpB. Total apo E and apo E-Lp-non-B concentrations were higher in subjects carrying the epsilon2 allele and lower in those with the epsilon4 allele when compared to epsilon3/epsilon3 subjects (P < 0.001). The opposite held for the apo E- LpB concentration (P < 0.05). The main finding is the significant interaction between apo E genotype and OC use (P < 0.01) on apo E-Lp-non-B concentration, the epsilon4 carriers showing the smallest differences between OC users and non-users in comparison with the epsilon2 or epsilon3/epsilon3 carriers. These results suggest that the common apo E polymorphism can modulate the OC use effect.

Microstructure of Cu(x)Mo6S8 Chevrel phase thin films on R-plane sapphire

Cu(x)Mo6S8 Chevrel phase thin films epitaxially grown on R-plane sapphire substrates have been studied using field emission scanning electron microscopy (FE-SEM) and high-resolution transmission electron microscopy (HREM). For samples grown in optimal conditions, the SEM images evidence oriented grains of about 100 nm average size; the HREM images of cross-section samples allow to deduce the local epitaxial relations between the substrates and films. HREM also evidences two grain families, previously deduced from X-ray and reflection high-energy electron diffraction studies. No defects have been observed in the films; a higher molybdenum content in the films results in Mo-precipitation at the film-substrate interface.

Apolipoprotein E polymorphisms and concentration in chronic diseases and drug responses.

Apolipoprotein (apo) E is an important circulating and tissue protein involved in cholesterol homeostasis and many other functions. The common polymorphism in the coding region of the gene, four polymorphisms in the promoter region, other additional single nucleotide polymorphisms, as well as several apo E variants have been identified. The common coding polymorphism strongly influences the lipid metabolism and the circulating concentration of apo E itself. This polymorphism is at the origin of the implication of apo E in cardiovascular and neurodegenerative diseases, but also of the relation of apo E with longevity. Probably due to its many metabolic and functional consequences, apo E polymorphism has been shown to influence the responses of patients to several drugs (fibrates, statins, hormone replacement therapy, anti-Alzheimer drugs) or environmental interventions (black tea, alcohol, diet). Apo E genotyping may be clinically helpful in defining the risk of patients and their responses to therapeutics. Finally, circulating apo E concentration appears to be altered in diseases and can be modulated by some of the drugs cited above. This parameter can thus also give interesting clinical information and could be a therapeutic target, providing it is validated. At the present time, we cannot exclude that apo E concentration may be the most prominent apo E parameter to be considered in health and disease, while apo E polymorphisms would represent only secondary parameters influencing apo E concentration.

Effect of short- and long-term storage on human serum and recombinant apolipoprotein E concentration.

In order to assess the short- and long-term stability of apolipoprotein (apo) E concentration in serum, we compared the apo E concentrations measured in fresh human serum samples with those determined after storage at +4 degrees C, -20 degrees C or -80 degrees C. The serum apo E concentration was measured by immunoturbidimetry using an anti-human apo E polyclonal antibody from goats. One week storage at +4 degrees C did not significantly affect the serum apo E concentration. At -20 degrees C or -80 degrees C no significant change in apo E concentration occurred during up to three months of storage. Moreover, the concentration of apo E was not modified after long-term storage of serum samples kept at -196 degrees C in liquid nitrogen for up to four years. In addition, 15 freeze-thaw cycles, over a 3-week period, did not affect the apo E concentration in serum. A similar freeze-thaw procedure applied to purified human recombinant apo E showed that apo E2 isoform was the most stable in comparison with the apo E3 and apo E4 isoforms.

Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project.

As part of the ApoEurope Project, the apolipoprotein E (apo E) serum concentration and polymorphism were determined in 6934 healthy subjects aged 25-64 years recruited in six European countries: Finland; France; Greece; Northern Ireland; Portugal and Spain. Age and sex influenced apo E concentration with concentrations being significantly higher in men than in women for those aged between 25 and 44 years. The age effect differed between the sexes after the age of 44 years, displaying a linear increase in women and a plateau in men. As expected, the serum apo E concentration was highest in varepsilon2 carriers and lowest in varepsilon4 carriers in each country with a significantly higher frequency of the varepsilon4 allele in the northern regions. The main finding of this study was a clear increasing North-South gradient in serum apo E concentration independent of age, sex and apo E genotype. In subjects aged <45 years and with the varepsilon3/varepsilon3 genotype, apo E concentration was higher in the South-East (Greece) as compared to the North by 20% for men and 32% for women. In addition to the genetic polymorphism, the geographical area is an important factor to take into account when studying serum apo E concentration in multicentre studies and defining reference values.

Short communication. The effects of drinking and smoking on the CYP2D6 metabolic capacity.

We studied the influence of drinking and smoking habits on CYP2D6 metabolic capacity measured by the use of debrisoquine as a substance test. We did not find any significant differences in the frequency of subjects with CYP2D6 deficiency (poor metabolizers) among four groups of healthy individuals: nonsmokers/nondrinkers, smokers/drinkers, nondrinkers/smokers, and nonsmokers/drinkers. We demonstrated that, among poor metabolizers, alcohol and tobacco consumption was associated with higher metabolic ratios than it was with the control group, but the differences were not statistically significant. Among extensive metabolizers, the lowest metabolic ratio (highest enzyme activity) was detected for nondrinkers/smokers, intermediate values for smokers/drinkers, and the highest metabolic ratio (lowest enzyme activity) for nonsmokers/drinkers. These variations were slight but statistically significant when logarithmic ratio values were applied. These results show that smoking and drinking habits do not need to be taken into account when humans are phenotyped for CYP2D6.

Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: a study of polymorphic human xenobiotic-metabolizing enzymes.

The steady increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the notion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence of RCC. Many of the enzymes dealing with such environmental factors are polymorphic and may, therefore, confer variable susceptibility to RCC. This case-control study was designed to test for an association between genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of sporadic RCC. Genomic DNA was obtained from 173 patients with RCC and 211 controls of Caucasian origin. We used PCR-RFLP to investigate polymorphism for the most common alleles at two cytochrome-P450 mono-oxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase (NQO1), three glutathione S-transferases (GSTM1, GSTT1, and GSTP1), and one N-acetyltransferase (NAT2) loci. The CYP1A1 (m) "variant" genotype, which contains at least one copy of the CYP1A1 variant alleles, was found to be associated with a 2.1-fold [95% confidence interval (CI), 1.1-3.9] increase in the risk of RCC. There was also a higher risk of RCC for subjects with the CYP1A1 (m) variant genotype combined with any of the following genotypes: GSTT1 (+) "active" [odds ratio (OR), 2.3; 95% CI, 1.2-4.5], GSTP1 (m) variant (OR, 2.4; 95% CI, 1.0-5.4), or NAT2 (-) "slow acetylator" (OR, 2.5; 95% CI, 1.1-5.5). A significant association was also found for the GSTM1 (-) "null" and GSTP1 (m) genotypes combined with either NAT2 (-) (OR, 2.6; 95% CI, 1.2-5.8) or CYP1A1 (m) (OR, 3.5; 95% CI, 1.1-11.2). The CYP2D6 (-) "poor metabolizer " and the NQO1 (-) "defective" genotypes were not clearly associated with a higher risk of RCC. Our data demonstrate for the first time a significant association between a group of pharmacogenetic polymorphisms and RCC risk. These positive findings suggest that interindividual variation in the metabolic pathways involved in the functionalization and detoxification of specific xenobiotics is an important susceptibility factor for RCC in Caucasians.

Biological variations and genetic reference values for apolipoprotein E serum concentrations: results from the STANISLAS cohort study.

Serum apolipoprotein (apo) E concentrations were determined by immunoturbidimetry in 4284 subjects from 4 to 71 years of age and belonging to 1003 nuclear families recruited for the STANISLAS cohort study between January 1994 and August 1995. Values for apo E ranged from 16 to 169 mg/L, with a geometric mean +/- SD values of 46.6 +/- 13.8 mg/L in the overall sample. The interindividual variability varied from 24.6% to 32.0% among family members. Females exhibited higher apo E values than males until the age of 17-26 years. Conversely, after the age of 26 years, serum apo E concentrations were higher in men than in women. Biological factors affecting serum apo E concentrations were described in fathers, mothers, sons, and daughters and explained up to 32.0% of the apo E variability in daughters and 19.0% in fathers. The main biological factors affecting apo E concentrations were the following: apo E polymorphism, waist-to-hip ratio, oral contraceptive intake, puberty, body mass index, age, and gender. Given the importance of apo E polymorphism in the regulation of apo E concentrations, we recommend the use of genetic-based reference values for the clinical interpretation of serum apo E concentrations.

Objectives, design and recruitment of a familial and longitudinal cohort for studying gene-environment interactions in the field of cardiovascular risk: the Stanislas cohort.

The main objective of the Stanislas cohort is to study the role and the contribution of genetic and environmental factors to cardiovascular status. We plan: a) to describe the degree of association of a large number of cardiovascular risk indicators with cardiovascular endpoints, b) to evaluate the contribution of genetic and that of environmental factors to this association, c) to follow the evolution of these risk indicators during a period of at least ten years, d) to search for the determinants influencing this evolution. The principal variables studied are: a) blood pressure, cardiac mass, and wall thickness of carotid and femoral arteries, b) obesity and fat mass, c) indicators of lipid metabolism, d) genetic polymorphisms of several cardiovascular risk candidate genes, e) food, tobacco and alcohol consumption, f) consumption of drugs and anti-oxidant vitamins. Between September 1993 and August 1995, 1006 families consisting of the two biological parents with at least two children were recruited totalling 4295 individuals. This cohort will be followed up until 2004. There will be two health examinations five and ten years after the initial examination. A bank of blood samples (serum and plasma) in liquid nitrogen and DNA (-80 degrees C) has been established.

Biological effects of eleven combined oral contraceptives on serum triglycerides, gamma-glutamyltransferase, alkaline phosphatase, bilirubin and other biochemical variables.

The objectives of this paper are to update and quantify the biological effects of the most commonly used oral contraceptives (OC) on 15 biochemical tests currently determined in clinical laboratories and to compare these effects between the different types of OC. The sample population was constituted by 1604 women using combined OCs and the control group comprised 3466 women in the same age range not taking medication. Women taking OC were divided into 11 groups according to the estrogen/progestogen combination. The effects of OCs were studied after adjustment for age, weight, height, body mass index and alcohol and tobacco consumption. The changes observed with the new progestogens were less important than in the past. In comparison with the controls, the mean serum triglyceride concentration was significantly increased by +8.5% to +36.0% (p<0.05 to p<0.001) in each group while those of total cholesterol and gamma-glutamyltransferase were increased only in 3 and 4 estrogen/progestogen combinations respectively. Conversely, the mean concentrations of alkaline phosphatase, total bilirubin, phosphate and albumin were significantly decreased. Using a discriminant analysis, three main groups according to the type of progestogen were defined: cyproterone acetate, DL-norgestrel and levonorgestrel, and all other progestogens. The changes in serum triglyceride concentration induced by OC intake must be considered by the clinician and are useful for taking a clinical and risk decision in an individual woman.

Apolipoprotein E genotype epsilon 4/epsilon 2 in the STANISLAS Cohort Study--dominance of the epsilon 2 allele?

Apolipoprotein (apo) E has been discussed as a marker for cardiovascular risk, but information about lipid traits in healthy individuals having one of the rare apoE genotypes (epsilon 4/epsilon 2, epsilon 2/epsilon 2 or epsilon 4/epsilon 4) is scarce. Our work was designed to answer the following questions: 1. Are the allelic effects of epsilon 2 and epsilon 4 on lipid traits additive or dominant? 2. If there is additivity, do the allelic effects of epsilon 2 and epsilon 4 have the same magnitude? 3. Are the allelic effects neutralised in epsilon 4/ epsilon 2 individuals who are under the influence of both rare alleles? Allelic effects on apoB and apoE serum levels were codominant. Allelic models are thus not adequate to study the influence of apoE polymorphism on these traits. Allelic effects were additive for total cholesterol, LDL-C, HDL-C and apoAI, with epsilon 2 having a greater impact than epsilon 4. Serum levels differed significantly between epsilon 4/epsilon 2 and epsilon 3/epsilon 3 individuals only for apoE (p < 0.001) and for apoB (p < 0.05).

An unequal cross-over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

1. The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI-9 kb allele was associated with the poor metabolizer phenotype. 2. A Polymerase Chain Reaction (PCR)-based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI-9 kb allele. 3. To explore the molecular basis of the poor metabolizer phenotype associated with the XbaI-9 kb allele, complete sequencing of the nine exons and intron-exon boundaries of the CYP2D6 gene was undertaken after amplification by PCR. 4. All the exons were successfully amplified using CYP2D6 gene-specific primers except exon 1 which required a combination of CYP2D7 gene-specific 5' primer and a CYP2D6 gene-specific 3' primer. 5. Sequence data derived from this amplified product revealed that the XbaI-9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 3' gene. 6. The chimeric gene is non-functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.