α-Tocopherol induces proatherogenic changes to HDL2 & HDL3: An in vitro and ex vivo investigation

Introduction: High density lipoproteins (HDL) have considerable potential for improving cardiovascular health. Additionally, epidemiological studies have identified an inverse relationship between a-tocopherol intake and cardiovascular disease, which has not been translated in randomised controlled trials. Objectives: This study assessed if increased α-tocopherol within HDL2 and HDL3 (HDL2&3) influenced their antiatherogenic potential. In the first of two in vitro investigations, the oxidation potential of HDL2&3 was assessed when α-tocopherol was added following their isolation. In the second, their oxidation potential was assessed when HDL2&3 were isolated from serum pre-incubated with α-tocopherol. Additionally, a 6-week placebo-controlled intervention with α-tocopherol assessed if α-tocopherol influenced the oxidation potential and activities of HDL2&3-associated enzymes, paraoxonase-1 (PON-1) and lecithin cholesteryl acyltransferase (LCAT). Results: Conflicting results arose from the in vitro investigations, whereby increasing concentrations of α-tocopherol protected HDL2&3 against oxidation in the post-incubated HDL2&3, and promoted HDL2&3-oxidation when they were isolated from serum pre-incubated with α-tocopherol. Following the 6-week placebo-controlled investigation, α-tocopherol increased in HDL2&3, while HDL2&3 became more susceptible to oxidation, additionally the activities of HDL2&3-PON-1 and HDL2-LCAT decreased. Conclusion: These results have shown for the first time that α-tocopherol induces changes to HDL2&3, which could contribute to the pathophysiology of cardiovascular disease.

Pioglitazone protects HDL(2&3) against oxidation in overweight and obese men

The worldwide epidemic of obesity is a major public health concern and is persuasively linked to the rising prevalence of diabetes and cardiovascular disease. Obesity is often associated with an abnormal lipoprotein profile, which may be partly negated by pioglitazone intervention, as this can influence the composition and oxidation characteristics of low-density lipoprotein (LDL). However, as pioglitazone's impact on these parameters within high-density lipoprotein (HDL), specifically HDL(2&3), is absent from the literature, this study was performed to address this shortcoming.

Molecular Validation of the Schizophrenia Spectrum

Background: Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum? Methods: The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = s) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929). Results: The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample. Conclusions: In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.

Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia

Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.

Catechol-O-methyltransferase and the clinical features of psychosis

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P <0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia

Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.

Association between the 5q31.1 gene neurogenin1 and schizophrenia

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 <or = P <or = 0.06) and FBAT (0.02 <or = P <or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Interleukin 3 and schizophrenia:the impact of sex and family history

Chromosome 5q21-33 has been implicated in harboring risk genes for schizophrenia. In this paper, we report evidence that multiple single nucleotide polymorphisms in and around interleukin 3 (IL3) are associated with the disease in the Irish Study of High-Density Schizophrenia Families (ISHDSF), the Irish Case-Control Study of Schizophrenia (ICCSS) and the Irish Trio Study of Schizophrenia (ITRIO). The associations are sex-specific and depend on the family history (FH) of schizophrenia. In all three samples, rs31400 shows female-specific and FH-dependent associations (P=0.0062, 0.0647 and 0.0284 for the ISHDSF, ICCSS and ITRIO, respectively). Several markers have similar associations in one or two of the three samples. In haplotype analyses, identical risk and protective haplotypes are identified in the ISHDSF and ITRIO samples in several multimarker combinations. For ICCSS, the same haplotypes are implicated; however, the risk haplotypes observed in the family samples become protective. Several significant markers, rs440970, rs31400 and rs2069803, are located in and around known estrogen response elements, promoter and enhancer of the IL3 gene. They may explain the sex-specific associations and be functional for the expression of IL3 gene.

WASP-54b, WASP-56b and WASP-57b: Three new sub-Jupiter mass planets from SuperWASP

We present three newly discovered sub-Jupiter mass planets from the SuperWASP survey: WASP-54b is a heavily bloated planet of mass 0.636$^{+0.025}_{-0.024}$ \mj and radius 1.653$^{+0.090}_{-0.083}$ \rj. It orbits a F9 star, evolving off the main sequence, every 3.69 days. Our MCMC fit of the system yields a slightly eccentric orbit ($e=0.067^{+0.033}_{-0.025}$) for WASP-54b. We investigated further the veracity of our detection of the eccentric orbit for WASP-54b, and we find that it could be real. However, given the brightness of WASP-54 V=10.42 magnitudes, we encourage observations of a secondary eclipse to draw robust conclusions on both the orbital eccentricity and the thermal structure of the planet. WASP-56b and WASP-57b have masses of 0.571$^{+0.034}_{-0.035}$ \mj and $0.672^{+0.049}_{-0.046}$ \mj, respectively; and radii of $1.092^{+0.035}_{-0.033}$ \rj for WASP-56b and $0.916^{+0.017}_{-0.014}$ \rj for WASP-57b. They orbit main sequence stars of spectral type G6 every 4.67 and 2.84 days, respectively. WASP-56b and WASP-57b show no radius anomaly and a high density possibly implying a large core of heavy elements; possibly as high as $\sim$50 M$_{\oplus}$ in the case of WASP-57b. However, the composition of the deep interior of exoplanets remain still undetermined. Thus, more exoplanet discoveries such as the ones presented in this paper, are needed to understand and constrain giant planets' physical properties.

Tuneable magneto-optical metamaterials based on photonic resonances in nickel nanorod arrays

We investigate the magneto-optical properties of a nanostructured metamaterial comprised of arrays of nickel nanorods embedded in an anodized aluminum oxide template. The rods are grown using a self-assembly bottom-up technique that provides a uniform, quasi-hexagonal array over a large area, quickly and at low cost. The tuneability of the magneto-optic response of the material is investigated by varying the nanorod dimensions: diameter, length and inter-rod spacing as well as the overall thickness of the template. It is demonstrated that the system acts as a sub-wavelength light trap with enhanced magneto-optical properties occurring at reflectivity minima corresponding to photonic resonances of the metamaterial. Changes in dimensions of the nickel rods on the order of tens of nanometers cause a spectral blue-shift in the peak magneto-optical response of 270 nm in the visible range. A plasmonic enhancement is also observed at lower wavelengths, which becomes increasingly damped with larger diameters and increased volume fraction of nickel inclusions. This type of structure has potential applications in high density magneto-optical data storage (up to 1011–12 rods per square inch), ultrafast magneto-plasmonic switching and optical components for telecommunications.

Spin-wave modes in Ni nanorod arrays studied by Brillouin light scattering

Dynamic magnetic properties of arrays of Ni nanorods with a low aspect ratio have been investigated. It has been shown that the spectra of spin-wave resonances localized on nanorods with a low aspect ratio typically feature the presence of zones with high density of states resulting in a characteristic two-peak pattern of Stokes and anti-Stokes lines of magneto-optical (MO) Brillouin light scattering with pronounced Stokes–anti-Stokes (S-AS) asymmetry. A simple theoretical model based on the analysis of the elliptic character of the polarization of the optical wave interacting with a dipole magnetostatic wave has been proposed. It has been shown that the S-AS asymmetry is due entirely to the asymmetry of the MO interaction efficiency with respect to time reversal of the magnetic precession in a magnon.

Table-Top Laser-Based Source of Femtosecond, Collimated, Ultrarelativistic Positron Beams

The generation of ultrarelativistic positron beams with short duration (τ_e⁺≃30 fs), small divergence (θ_e⁺≃3 mrad), and high density (n _e⁺≃1014-1015 cm^-3) from a fully optical setup is reported. The detected positron beam propagates with a high-density electron beam and γ rays of similar spectral shape and peak energy, thus closely resembling the structure of an astrophysical leptonic jet. It is envisaged that this experimental evidence, besides the intrinsic relevance to laser-driven particle acceleration, may open the pathway for the small-scale study of astrophysical leptonic jets in the laboratory. 

Mechanical properties of polyamide 6 reinforced microfibrilar composites

The mechanical behavior of microfibrilar composites (MFC), consisting of a matrix of high-density polyethylene (HDPE) and reinforcement of polyamide 6 (PA6) fibrils, with and without compatibilization, was studied. The composites were produced by conventional processing techniques with various shape and arrangement of the PA6 reinforcing entities: long, unidirectional, or crossed bundles of fibrils (UDP and CPC, respectively), middle-length, randomly oriented bristles (MRB), or non-oriented micrometric PA6 spheres (NOM). The tensile, flexural, and impact properties of the MFC materials (UDP, CPC, and MRB) were determined as a function of the PA6 reinforcement shape, alignment and content, and compared with those of NOM, the non-fibrous composite. It was concluded that the in-situ MFC materials based on HDPE/PA6 blends display improvements in the mechanical behavior when compared with the neat HDPE matrix, e.g., up to 33% for the Young modulus, up to 119% for the ultimate tensile strength, and up to 80% for the flexural stiffness. Copyright © 2011 Society of Plastics Engineers.

A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes

Background

High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D.

Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL₂ and HDL₃ by rapid ultracentrifugation. Carotenoids were measured in serum, HDL₂ and HDL₃ by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL₂ and HDL₃ by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL₂ and HDL₃ by a fluorometric assay.

In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL₂ and particularly HDL₃, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL₃ (p = 0.006 and 0.044, respectively).

To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein.