Evidence for associations between common polymorphisms of estrogen receptor beta gene with homocysteine and nitric oxide

Background Homocysteine and asymmetric dimethylarginine (ADMA) affect nitric oxide (NO) concentration, thereby contributing to cardiovascular disease (CVD). Both amino acids can be reduced in vivo by estrogen. Variation in the estrogen receptor (ER) may influence homocysteine and ADMA, yet no information is available on associations with single nucleotide polymorphisms in the estrogen receptor genes ER alpha (PvuII and XbaI) and ER beta (1730G -> A and cx+56 G -> A). Objective To find relationships between common polymorphisms associated with cardiovascular disease and cardiovascular risk factors homocysteine and ADMA. Methods In a cross-sectional study with healthy postmenopausal women (n = 89), homocysteine, ADMA, nitric oxide metabolites (NOx), plasma folate and ER alpha and beta polymorphisms ER alpha PvuII, ER alpha XbaI; ER beta 1730G -> A (AluI), ER beta cx+56 G -> A (Tsp5091) were analyzed. Results Women who are homozygotic for ER beta cx+56 G -> A A/A exhibited higher homocysteine (p = 0.012) and NOx (p = 0.056) levels than wildtype or heterozygotes. NOx concentration was also significantly affected by ER beta 1730 G -> A polymorphism (p = 0.025). The ER beta (p < 0.001) and ER alpha (p < 0.001) polymorphisms were in linkage disequilibrium. Conclusions Women who are homozygotic for ER beta cx+S6 G -> A A/A may be at increased risk for cardiovascular disease due to higher homocysteine levels.

alpha-tocopherol affects androgen metabolism in male rat

The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study has provided the first evidence implicating vitamin E in hormone synthesis. The effect of vitamin E on stereoidogenesis in testes and adrenal glands was assessed in growing rats using Affymetrix gene-chip technology. Dietary supplementation of rats with vitamin E (60 mg/kg feed) for a period of 429 days caused a significant repression of genes encoding for proteins centrally involved in the uptake (low-density lipoprotein receptor) and de novo synthesis (for example, 7-dehydrocholesterol reductase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, isopentenyl-diphosphate delta-isomerase, and farnesyl pyrophosphate synthetase) of cholesterol, the precursor of all steroid hormones. The present investigation indicates that dietary vitamin E may induce changes in stereoidogenesis by affecting cholesterol homeostasis.

Retinoid-Related Receptor (ROR) alpha mRNA Expression Is Altered in the Brain of Male Mice Lacking All Ligand-Binding Thyroid Hormone Receptor (TR) Isoforms

In the vertebrate brain, the thalamus serves as a relay and integration station for diverse neuronal information en route from the periphery to the cortex. Deficiency of TH during development results in severe cerebral abnormalities similar to those seen in the mouse when the retinoic acid receptor (ROR)α gene is disrupted. To investigate the effect of the thyroid hormone recep-tors (TRs) on RORalpha gene expression, we used intact male mice, in which the genes encoding the α and beta TRs have been deleted. In situ hybridization for RORalpha mRNA revealed that this gene is expressed in specific areas of the brain including the thalamus, pons, cerebellum, cortex, and hippocampus. Our quantitative data showed differences in RORalpha mRNA expression in different subthalamic nuclei between wild-type and knock-out mice. For example, the centromedial nucleus of the thalamus, which plays a role in mediating nociceptive and visceral information from the brainstem to the basal ganglia and cortical regions, has less expression of RORalpha mRNA in the knockout mice (-37%) compared to the wild-type controls. Also, in the dorsal geniculate (+72%) and lateral posterior nuclei (+58%) we found more RORalpha mRNA in dKO as compared to dWT animals. Such differences in RORalpha mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Structure and Mode of Action of Microplusin, a Copper II-chelating Antimicrobial Peptide from the Cattle Tick Rhipicephalus (Boophilus) microplus

Microplusin, a Rhipicephalus (Boophilus) microplus antimicrobial peptide (AMP) is the first fully characterized member of a new family of cysteine-rich AMPs with histidine-rich regions at the N and C termini. In the tick, microplusin belongs to the arsenal of innate defense molecules active against bacteria and fungi. Here we describe the NMR solution structure of microplusin and demonstrate that the protein binds copper II and iron II. Structured as a single alpha-helical globular domain, microplusin consists of five alpha-helices: alpha 1 (residues Gly-9 to Arg-21), alpha 2 (residues Glu-27 to Asn-40), alpha 3 (residues Arg-44 to Thr-54), alpha 4 (residues Leu-57 to Tyr-64), and alpha 5 (residues Asn-67 to Cys-80). The N and C termini are disordered. This structure is unlike any other AMP structures described to date. We also used NMR spectroscopy to map the copper binding region on microplusin. Finally, using the Gram-positive bacteria Micrococcus luteus as a model, we studied of mode of action of microplusin. Microplusin has a bacteriostatic effect and does not permeabilize the bacterial membrane. Because microplusin binds metals, we tested whether this was related to its antimicrobial activity. We found that the bacteriostatic effect of microplusin was fully reversed by supplementation of culture media with copper II but not iron II. We also demonstrated that microplusin affects M. luteus respiration, a copper-dependent process. Thus, we conclude that the antibacterial effect of microplusin is due to its ability to bind and sequester copper II.

Biological Response to Wollastonite Doped alpha-Tricalcium Phosphate Implants in Hard and Soft Tissues in Rats

The biological response following subcutaneous and bone implantation of beta-wollastonite(beta-W)-doped alpha-tricalcium phosphate bioceramics in rats was evaluated. Tested materials were: tricalciurn phosphate (TCP), consisting of a mixture of alpha- and beta-polymorphs; TCP doped with 5 wt. % of beta-W (TCP5W), composed of alpha-TCP as only crystalline phase; and TCP doped with 15 wt. % of beta-W (TCP15), containing crystalline alpha-TCP and beta-W. Cylinders of 2x1 mm were implanted in tibiae and backs of adult male Rattus norvegicus, Holtzman rats. After 7, 30 and 120 days, animals were sacrificed and the tissue blocks containing the implants were excised, fixed and processed for histological examination. TCP, TCP5W and TCP15W implants were biocompatible but neither bioactive nor biodegradable in rat subcutaneous tissue. They were not osteoinductive in connective tissue either. However, in rat bone tissue beta-W-doped alpha-TCP implants (TCP5W and TCP15W) were bioactive, biodegradable and osteoconductive. The rates of biodegradation and new bone formation observed for TCP5W and TCP15W implants in rat bone tissue were greater than for non-doped TCP.

Structural Basis of Importin-alpha-Mediated Nuclear Transport for Ku70 and Ku80

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Crystallization and preliminary X-ray diffraction analysis of the catalytic subunit of ADP-glucose pyrophosphorylase from potato tuber

ADP-glucose pyrophosphorylase is the key regulatory enzyme in the biosynthesis of starch in plants and glycogen in bacteria. The enzyme from potato tuber is comprised of a regulatory subunit and a catalytic subunit and is present as a heterotetramer (alpha(2)beta(2)) the catalytic subunit from potato tuber (50 kDa) was crystallized in four different forms, two of which are suitable for structural studies. A tetragonal crystal form obtained in the presence of the substrate analog Cr-ATP diffracted to 2.2 Angstrom and belongs to space group P4(1) (or its enantiomorph), with unit-cell parameters a = b = 110.57, c = 190.14 Angstrom. A second crystal form obtained diffracted to 2.8 Angstrom and belongs to space group PZ, with unit-eel parameters a = 80.06, b = 138.84, c = 92.20 Angstrom, beta = 112.40 degrees. As this protein displays no significant homology to any currently known protein structure, a search for heavy-atom derivatives has been initiated.

Determination of the strong coupling constant from the inclusive jet cross section in pp collisions at s=1.96 TeV

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Development of alpha-SiAlON-SiC ceramic composites by liquid phase sintering

In this work, in situ alpha-SiAlON-SiC ceramic composites were obtained,by, liquid phase sintering, using SiC as reinforcement. Different beta-SiC powder contents (0-20 wt.%), were added to Si3N4-AlN-RE2O3. powder mixtures, and compacted by cold isostatic pressing. The samples were sintered at 1950 degrees C for 1 h, in N-2 atmosphere. Sintered: samples were characterized by relative density, weight loss, X-ray diffraction and scanning electron microscopy. Furthermore, mechanical properties such as hardness and fracture toughness were determined by Vickers indentation method. Lattice parameters of the alpha' phase did not considerably change with increase of SiC content. However, morphology, average grain size and aspect ratio of the alpha' phase were considerably changed with increase of the SiC content. These behavior influences significantly the mechanical properties of this hard ceramic composite. (C) 2006 Elsevier Ltd. All rights reserved.

Revisiting the S-matrix approach to the open superstring low energy effective lagrangian

The conventional S-matrix approach to the (tree level) open string low energy effective lagrangian assumes that, in order to obtain all its bosonic alpha'(N) order terms, it is necessary to know the open string (tree level) (N + 2)-point amplitude of massless bosons, at least expanded at that order in alpha'. In this work we clarify that the previous claim is indeed valid for the bosonic open string, but for the supersymmetric one the situation is much more better than that: there are constraints in the kinematical bosonic terms of the amplitude (probably due to Spacetime Supersymmetry) such that a much lower open superstring n-point amplitude is needed to find all the alpha'(N) order terms. In this 'revisited' S-matrix approach we have checked that, at least up to alpha'(4) order, using these kinematical constraints and only the known open superstring 4-point amplitude, it is possible to determine all the bosonic terms of the low energy effective lagrangian. The sort of results that we obtain seem to agree completely with the ones achieved by the method of BPS configurations, proposed about ten years ago. By means of the KLT relations, our results can be mapped to the NS-NS sector of the low energy effective lagrangian of the type II string theories implying that there one can also find kinematical constraints in the N -point amplitudes and that important informations can be inferred, at least up to alpha'(4) order, by only using the (tree level) 4-point amplitude.

Atividade dos neurônios noradrenérgicos do Locus coeruleus e o conteúdo de GnRH em ratas Wistar acíclicas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

O movimento de inclinação lateral associado ao uso de calços na escoliose idiopática

INTRODUCTION: Scoliosis is a three-dimensional deformity and it can be influenced by the use of shoe lifts and lateral inclination in order to correct postural asymmetries. OBJECTIVE: To verify the effect of the use of the shoe lifts (lower and high) unilateral (right and left) during the movement of lateral inclination (right and left) for an evaluation of the postural angles in patients with idiopathic scoliosis. METHODS: A control group with ten participants without scoliosis and an experimental group with 10 participants with idiopathic scoliosis of double curves (thoracic right and lumbar to the left). Ten reflexive markers were fixed in the spine to determine the postural angles (alpha 1=T2T4-T4T6, alpha 2=T6T8-T8T10, alpha 3=T10T12-T12L2 and alpha 4=L2L4-L4S1)... (Complete abstract click electronic access below)

alpha-SiAlON-SiC composites obtained by gas-pressure sintering and hot-pressing

The objective of this work was the obtaining in situ of alpha-SiAlON-SiC composite, using an alternative rare-earth oxide mixture, RE2O3, as sintering additive, by two different sintering processes. As sintering additive, 20 vol.% of AlN-RE2O3 in a molar ratio of 90: 10 was mixed to the alpha-Si3N4 powder. In the Si3N4-AlN-RE2O3 powder mixture, 0, 10, 15 and 20wt.% of SiC were added. The powder batches were milled, dried and compacted by cold isostatic pressing. Two different sintering processes were used: gas-pressure sintering at 1950 degrees C for 1 h under 1.5 MPa of N-2 atmosphere, or uniaxial hot-pressing at 1750 degrees C, for 30 min under pressure of 20 MPa. The sintered samples were characterized by X-ray diffraction, scanning electron microscopy and mechanical properties. XRD patterns indicate only alpha-SiAlON (alpha') and beta-SiC as crystalline phases. It was observed that the SiC addition did not influence the alpha-SiAlON formation, although the growth of elongated alpha'-grains is substantially decreased. The hot-pressed composites presented better mechanical properties, exhibiting fracture toughness of 5 MPa m(1/2) and hardness around 21.5 GPa. (c) 2007 Elsevier B.V. All rights reserved.

Preclinical testing of strategies for therapeutic targeting of human T-cell trafficking in vivo

Naive T cells are migratory cells that continuously recirculate between blood and lymphoid tissues. Antigen-specific stimulation of T cells within the lymph nodes reprograms the trafficking properties of T cells by inducing a specific set of adhesion molecules and chemokine receptors on their surface which allow these activated and effector T cells to effectively and specifically home to extralymphoid organs. The observations of organ-specific homing of T cells initiated the development of therapeutic strategies targeting adhesion receptors for organ-specific inhibition of chronic inflammation. As most adhesion receptors have additional immune functions besides mediating leukocyte trafficking, these drugs may have additional immunomodulatory effects. Therapeutic targeting of T-cell trafficking to the central nervous system is the underlying concept of a novel treatment of relapsing remitting multiple sclerosis with the humanized anti-alpha-4-integrin antibody natalizumab. In this chapter, we describe a possible preclinical in vivo approach to directly visualize the therapeutic efficacy of a given drug in inhibiting T-cell homing to a certain organ at the example of the potential of natalizumab to inhibit the trafficking of human T cells to the inflamed central nervous system in an animal model of multiple sclerosis.