Characterization of peroxisome proliferator-activated receptor alpha in normal rat mammary gland and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary gland tumors from rats fed high and low fat diets

Normal Sprague-Dau ley rat mammary gland epithelial cells and mammary gland carcinomas induced by 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine, a carcinogen found in the diet, were examined for the expression of peroxisome proliferator-activated receptor alpha (PPAR alpha). PPAR alpha mRNA and protein was detected in normal and tumor tissue by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. By quantitative RT-PCR, carcinomas had a 12-fold higher expression than control mammary glands, a statistically significant difference. PPAR alpha expression was examined in carcinomas and normal tissues from rats on high fat (23.5/% corn oil) and low fat (5% corn oil) diets. Although neither carcinomas, nor control tissues showed statistically significant differences between the two diet groups, PPAR alpha expression was the highest in carcinomas from rats on the high fat diet. The expression of PPAR alpha in normal mammary gland and its significant elevation in mammary gland carcinomas raises the possibility of its involvement in mammary gland physiology and pathophysiology. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.

Opposite roles of O-2 in NO- and N2O-carbon reactions: An ab initio study

Previous experimental studies showed that the presence of O-2 greatly enhances NO-carbon reaction while it depresses N2O-carbon reaction on carbon surfaces. A popular explanation for the rate increase is that the addition of O-2 results in a large number of reactive carbon-oxygen complexes, and decomposition of these complexes produces many more active sites. The explanation for the latter is that excess O-2 simply blocks the active sites, thus reducing the rate of N2O-carbon reaction. The contradiction is that O-2 can also occupy active sites in NO-carbon reaction and produce active sites in N2O-carbon reduction. By using ab initio calculation, we find that the opposite roles of O-2 are caused by the different manners of N2O and NO adsorption on the carbon surface. In the presence of excess O-2, most Of the active sites are occupied by oxygen groups. In the competition for the remaining active sites, NO is more likely to chemisorb in the form of NO2 and NO chemisorption is mon thermodynamically favorable than O-2 chemisorption. By contrast, the presence of excess O-2 makes N2O chemisorption much less thermally stable either on the consecutive edge sites or edge sites isolated by semiquinone oxygen. A detailed analysis and discussion of the reaction mechanism of N-2 formation from NO- and N2O-carbon reaction in the presence of O-2 is presented in this paper.

Quantum spin ladder systems associated with su(2 vertical bar 2)

Two integrable quantum spin ladder systems will be introduced associated with the fundamental su(2 \2) solution of the Yang-Baxter equation. The first model is a generalized quantum Ising system with Ising rung interactions. In the second model the addition of extra interactions allows us to impose Heisenberg rung interactions without violating integrability. The existence of a Bethe ansatz solution for both models allows us to investigate the elementary excitations for antiferromagnetic rung couplings. We find that the first model does not show a gap whilst in the second case there is a gap for all positive values of the rung coupling.

Mutant GABA(A) receptor gamma 2-subunit in childhood absence epilepsy and febrile seizures

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants(1,2). We have found a mutation in a gene encoding a GABA, receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), There is a recognized genetic: relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Porous clays and pillared clays-based catalysts. Part 2: A review of the catalytic and molecular sieve applications

Metal oxide pillared clay (PILC) possesses several interesting properties, such as large surface area, high pore volume and tunable pore size (from micropore to mesopore), high thermal stability, strong surface acidity and catalytic active substrates/metal oxide pillars. These unique characteristics make PILC an attractive material in catalytic reactions. It can be made either as catalyst support or directly used as catalyst. This paper is a continuous work from Kloprogge's review (J.T. Kloprogge, J. Porous Mater. 5, 5 1998) on the synthesis and properties of smectites and related PILCs and will focus on the diverse applications of clay pillared with different types of metal oxides in the heterogeneous catalysis area and adsorption area. The relation between the performance of the PILC and its physico-chemical features will be addressed.

Lentiviral vector-mediated tyro sinase-related protein 2 gene transfer to dendritic cells for the therapy of melanoma

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a vital role in primary immune responses. Introducing genes into DCs will allow constitutive expression of the encoded proteins and thus prolong the presentation of the antigens derived therefrom. In addition, multiple and unidentified epitopes encoded by the entire tumor-associated antigen (TAA) gene may enhance T cell activation. This study demonstrated that an HIV-1-based lentiviral vector conferred efficient gene transfer to DCs. The transgene, murine tyrosinase-related protein 2 (mTRP-2), encodes a clinically relevant melanoma-associated antigen (MAA), which has been found to be a tumor rejection antigen for B16 melanoma. The transfer and proper processing of mTRP-2 in DCs, in terms of RNA transcription activity and protein expression, were verified by RT-PCR and specific antibody, respectively. Administration of mTRP-2 gene-modified DCs (DC-HR'CmT2) to C57BL/6 mice evoked strong protection against tumor challenge, for which the presence of CD4(+) and CD8(+) cells during both the priming and challenge phase was essential. In a therapy model, our results showed that four of seven mice with preestablished tumor remained tumor free for 80 days after therapeutic vaccination. Given the results shown in this study, mTRP-2 gene transfer to DCs provides a potential therapeutic strategy for the management of melanoma, especially in the early stage of the disease.

Truncation of the GABA(A)-receptor gamma 2 subunit in a family with generalized epilepsy with febrile seizures plus

Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 subunit are associated with generalized epilepsies and febrile seizures. Here we describe a family that has generalized epilepsy with febrile seizures plus (GEFS(+)), including an individual with severe myoclonic epilepsy of infancy, in whom a third GABA(A)-receptor gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.

Sex pheromone biosynthesis in the female olive fruit-fly. Double labelling from [O-18(2)]-dioxygen into 1,7-dioxaspiro[5.5]undecane

The demonstration that both oxygen atoms of 1,7-dioxaspiro[5.5] undecane (1), the sex-pheromone of the female olive fly, originate from dioxygen, strongly implicates monooxygenase mediated processes in assembly of (1), and reveals unexpected complexity in the formation of its nine-carbon precursor.

Altered kinetics and benzodiazepine sensitivity of a GABA(A) receptor subunit mutation [gamma(2)(R43Q)] found in human epilepsy

The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imiclazopyricline zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.

Experimental study of phase equilibria in the "FeO"-ZnO-(CaO+SiO2) system with CaO/SiO2 weight ratios of 0.33, 0.93, and 1.2 in equilibrium with metallic iron

The pseudoternary sections FeO-ZnO-(CaO + SiO2) with CaO/SiO2 weight ratios of 0.33, 0.93, and 1.2 in equilibrium with metallic iron have been experimentally investigated in the temperature range from 1000 degreesC to 1300 degreesC (1273 to 1573 K). The liquidus surfaces in these pseudoternary sections have been experimentally determined in the composition range from 0 to 33 wt pct ZnO and 30 to 70 wt pct (CaO + SiO2). The sections contain primary-phase fields of wustite (FexZn1-xO1+y), zincite (ZnzFe1-zO), fayalite (Fu(w)Zn(2-w)SiO(4)), melilite (Ca2ZnuFe1-uSi2O7), willemite (ZnvFe2-vSiO4), dicalcium silicate (Ca2SiO4), pseudowollastonite and wollastonite (CaSiO3), and tridymite (SiO2). The phase equilibria involving the liquid phase and the solid solutions-have also been measured.

Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: Phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation

Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (K-i 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.