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The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE.

SYNOPTIC ABSTRACTThe two well-known unilateral specification process capability indices CPLand CPUare popularly used for measuring the process capability of larger-the-better type or smaller-the-better type products in the manufacturing industry. The practitioners can use them to determine whether their processes meet the capability requirement and select the better supplier. Under normal assumption, Chou (1994) developed an effective procedure using estimators of CPLand CPUfor practitioners to determine whether two processes have equal capability or not. His works will be extended to the case of kprocesses. We take the tests of testing the equality of coefficients of variation from kpopulations and a new proposed test, the Modified-Bartlett's test, to determine whether kprocesses have equal capability or not. By Monte Carlo experiments, we have demonstrated that Modified-Bartlett's test has appropriate empirical size and has higher power than others. We also present a testing procedure that is convenient for practitioners to select the better supplier step by step.

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the αvβ3 receptor. These compounds have excellent in vitro profiles (IC50 = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.

Polyimide-tethered polyhedral oligomeric silsesquioxane, (R7R‘Si8O12) (POSS), nanocomposites with well-defined architectures are prepared by the copolymerization reaction of a new type of diamine monomer:  POSS-diamine, 4,4‘-oxydianiline (ODA), and pyromellitic dianhydride (PMDA). This type of polyimide-side-chain-tethered POSS nanocomposite presents self-assembly characteristics when the amount of POSS exceeds10 mol %, as evidenced by transmission electron microscopy studies. Furthermore, POSS/polyimide nanocomposites have both lower and tunable dielectric constants, with the lowest value of 2.3, and controllable mechanical properties, as compared to that of pure polyimide.

3(S)-(6-Methoxypyridin-3-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl}propionic acid 6 was identified as a potent and selective antagonist of the αvβ3 receptor. This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.

Low-dielectric-constant nanoporous films (dielectric constant, k = 2.4) with thermal integrity and controllable mechanical strength have been prepared by covalently tethering nanoporous polyhedral oligomeric silsesquioxane (POSS) molecules, 1-nm size, to the side chains of polyimide. The tethered POSS molecules in the amorphous polyimide retain a nanoporous crystal structure, but form an additional ordered architecture due to microphase separation. With this approach, the dielectric constant of the film can be tuned by the amount of POSS molecules introduced in the nanocomposite film; the polyimide molecules offer additional advantages of maintaining certain thermal and mechanical strengths.

Nanoporous polyhedral oligomeric silsesquioxanes (POSS) containing amine groups (NH2−POSS) were reacted with poly(amic acid) having anhydride end groups to form porous POSS/polyimide nanocomposites. The van der Waals interaction between tethered POSS molecules is incompatible with the polar−polar interaction of imide segments, resulting in a self-assembled system of zigzag shaped cylinders or lamellas about 60 nm long and 5 nm wide, as determined by transmission electron microscopy. The incorporation of 2.5 mol % nanoporous POSS results in a reduction of the dielectric constant of the polyimide nanocomposite from 3.40 for the pure polyimide to 3.09 without any degradation in mechanical strength.

A binding model for nonpeptide antagonists of integrin αvβ3 has been developed through docking analyses utilizing the MMFFs force field and the recently published crystal structure, 1JV2. Results of this docking study have led to the identification of a novel binding model for selective antagonists of αvβ3 over αIIbβ3 integrins. Four different chemical classes are shown to bind in a similar fashion providing a measure of confidence in the proposed model. All αvβ3 and αIIbβ3 antagonists have a basic nitrogen separated some distance from a carboxylic acid to mimic RGD. For the αvβ3 antagonists under present consideration, these charged ends are separated by twelve bonds. The basic nitrogen of the active αvβ3 ligands are shown to interact with D150 of αv and the ligands' carboxylic acid interact with R214 of β3 while adopting an extended conformation with minimal protein induced internal strain. In addition, an energetically favorable interaction is found with all of the active αvβ3 molecules with Y178 of αv when docked to the crystallographically determined structure. This novel interaction may be characterized as π−π stacking for the most active of the αvβ3 selective antagonists. The proposed model is consistent with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the αvβ3 integrin.

Covalently bonded layered silicates/polyimide (BTDA-ODA) nanocomposites have been synthesized from γ-(aminopropyl)triethoxysilane (APTS) grafted kenyaite and poly(amic acid). The existence of covalent bonds between APTS and silicates and between APTS and the dianhydride end groups of the polymer have been confirmed by solid-state ¹³C and ²⁹Si nuclear magnetic resonance and infrared spectroscopy, respectively. The thermal, mechanical, and moistureabsorption retardation properties of these nanocomposites were found to improve substantially over those of neat BTDA-ODA. In particular, a maximum increase of 36 °C in the degradation temperature and a maximum reduction of 54% in moisture absorption are displayed by these nanocomposites.

Prostaglandin (PG) E(2) is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE(2) is well documented, the cellular and molecular mechanisms that mediate this effect remain unclear. This study was undertaken to examine the effect of pharmacological inactivation of the prostanoid receptor EP(4), one of the PGE(2) receptors, on PGE(2)-induced bone formation in vivo. We first determined the ability of EP(4)A, an EP(4)-selective ligand, to act as an antagonist. PGE(2) increases intracellular cAMP and suppresses apoptosis in the RP-1 periosteal cell line. Both effects were reversed by EP(4)A, suggesting that EP(4)A acts as an EP(4) antagonist in the cells at concentrations consistent with its in vitro binding to EP(4). We then examined the effect of EP(4) on bone formation induced by PGE(2) in young rats. Five- to 6-week-old rats were treated with PGE(2) (6 mg/kg/day) in the presence or absence of EP(4)A (10 mg/kg/day) for 12 days. We found that treatment with EP(4)A suppresses the increase in trabecular bone volume induced by PGE(2). This effect is accompanied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the reduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hypothesis that the bone anabolic effect of PGE(2) in rats is mediated by the EP(4) receptor.

A convergent approach to the preparation of dendritic macromolecules with an aromatic ether–imide inner structure and modifiable benzyl ether chain ends is described. The structural component that constitutes the branching regions was derived from 1-(4-aminophenyl)-1,1-bis(4-hydroxyphenyl)ethane. The key steps in ether–imide dendron synthesis involve an aromatic nucleophilic displacement of an activated nitro group with phenoxide leading to the ether linkage and cyclocondensation of the amino group with 3-nitrophthalic anhydride, to give rise to the imide ring containing an activated nitro functionality. The dendritic wedges are then coupled to a polyfunctional core to complete the synthesis. The benzyl ether chain ends can be selectively removed by catalytic hydrogenolysis to produce a dendrimer with phenolic chain ends. Further modification of the chain ends is accomplished by etherfication of the phenolic groups. Structures of these dendritic poly(ether–imide)s were confirmed by 1H NMR, 13C NMR and FTIR spectroscopy as well as by mass spectrometry. Properties such as the glass transition temperature and solubility of the dendrimer are greatly affected by the nature of the end groups.

Montmorillonite/polyimide (3,3‘,4,4‘-benzophenone tetracarboxylic dianhydride-4,4‘-oxydianiline, BTDA-ODA) nanocomposites displaying different morphological, thermal, and mechanical characteristics were synthesized by involving mono-, di-, and trifunctional group swelling-agent-modified montmorillonite and poly(amic acid). It was found that the dispersion of silicate layers in BTDA-ODA shifted from intercalated to exfoliated structures when the number of functional groups of the swelling agent increased to three as evidenced from X-ray diffraction and transmission electron microscopy studies. The improved morphology of the nanocomposites resulted in their enhanced mechanical and thermal properties. In particular, a 70% increase in Young's modulus, a 50% increase in the maximum stress, and a 30% reduction in the coefficients of thermal expansion for the case of BTDA-ODA nanocomposites containing 5 wt % trifunctional group swelling-agent-modified montmorillonite as compared to that of pure BTDA-ODA.

In this paper the synthesis and characterization of a hyperbranched poly(aryl ether oxazole) with terminal phenolic groups are described. An ABB‘ monomer containing a pair of phenolic groups and an aryl fluoride which is activated toward displacement by the attached oxazole ring was prepared. The nucleophilic substitution of the fluoride with the phenolic group leads to the formation of ether linkage and subsequently the hyperbranched poly(aryl ether oxazole) P1. As determined by a combination of model compound studies and ¹H NMR integration experiments, the degree of branching of P1 is approximately 50%. The polymer P1 is thermally stable and readily soluble in polar organic solvents. The terminal phenolic groups in P1 were easily functionalized, yielding hyperbranched polymers with a variety of functional chain ends. Physical properties, such as the glass transition temperature and the solubility of the hyperbranched poly(aryl ether oxazole)s, depended significantly on the nature of the chain ends.

Modification of the potent fibrinogen receptor (αIIbβ3) antagonist 1 generated compounds with high affinity for the vitronectin receptor αvβ3. Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7,8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor αvβ3. The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to αvβ3 is also reported.

Many reports on Iraq suggest that a rise in rates of death and disease have occurred since the Gulf War of January/February 1991 and the economic sanctions that followed it.

New dendritic poly(ether imide)s were synthesized by the convergent growth approach, using 1-(4-aminophenyl)-1,1-bis(4-hydroxyphenyl)ethane, as the building block. The aromatic nucleophilic substitution of the building block with 3-nitro-N-phenylphthalimide led to the first-generation dendron with aminophenyl group at the focal point, which was subsequently reacted with 3-nitrophthalic anhydride to yield the dendritic wedge containing an activated nitro group. The resulting nitro functionality was allowed to react with the building block to give the second-generation dendron, which was then condensed with 3-nitrophthalic anhydride, followed by ring closure to re-form the phthalimide ring and restore a reactive nitro group. Through an aromatic nucleophilic substitution, the dendritic wedges with an activated nitro group were coupled to the polyfunctional core to form the dendritic macromolecules. Structures of the ether−imide dendrimers were fully characterized by use of a combination of techniques including ¹H NMR, ¹³C NMR, IR, and mass spectrometry. The glass transition temperature of the dendrimers increased with molecular weight, and the variation was consistent with theoretical calculations. These dendritic poly(ether imide)s are soluble in various organic solvents and had a thermal stability comparable to linear poly(aryl ether imide)s.

The interaction of tumor necrosis factor-alpha with its receptor CD120a (p55) initiates downstream signaling cascades that include the activation of the mitogen-activated protein kinase (MAPK), p42(mapk/erk2). The membrane proximal region of CD120a (p55) is Ser-, Thr-, and Pro-rich and contains four mitogen-activated protein kinase consensus phosphorylation sites. In recent work, we showed that CD120a (p55) itself is a target of phosphorylation by p42(mapk/erk2), and after phosphorylation, the receptor is redistributed from the cell surface and Golgi complex to intracellular tubular structures associated with elements of the endoplasmic reticulum. The goal of this study was to define the specific amino acid residues that are phosphorylated. Deletional mutagenesis of the cytoplasmic domain of CD120a (p55) indicated that two sites located between residues 207-254 and 250-300 were phosphorylated predominantly on Thr and Ser residues, respectively. Site-directed mutagenesis of Ser and Thr residues contained within the extracellular signal-regulated kinase (ERK) consensus sequences indicated that the preferred residues were Thr-236 and Ser-270. Primary phosphorylation at these sites appeared to enable subsequent phosphorylation at Ser-240 and Ser-244, although the level of phosphorylation of these latter two sites was less than the preferred sites. Through the use of specific ligation of CD120a (p55) alone and mice deficient in CD120a (p55), CD120b (p75), or both receptors, CD120a (p55) was shown to be necessary and sufficient for the induction of kinase activity. These findings thus suggest that the phosphorylation of Thr-236 and Ser-270 within the membrane proximal region of CD120a (p55) are the preferred sites of phosphorylation by p42(mapk/erk2) and may set in motion phosphorylation at other sites.

A new procedure is described for the formation of a hyperbranched poly(ether ketone) with carboxylic acid terminal groups. This preparation was based on the one-step synthesis of an AB2-type monomer 5-phenoxyisophthalic acid using phosphorus pentoxide/methanesulfonic acid as the condensing agent and solvent. The electrophilic aromatic substitution reaction led to the formation of the aryl ketone linkage. With the help of model compounds, ¹H NMR studies revealed that the degree of branching of the poly(ether ketone) was about 55%. The terminated carboxylic acid groups were readily functionalized, yielding hyperbranched polymers with a variety of different functional chain ends. The nature of the chain ends was shown to dramatically affect physical properties of the hyperbranched macromolecules. The ammonium derivative was soluble in water and behaved as a unimolecular micelle.

Résumé

The melting and degassing equipment and the process used in the production of particulate aluminum matrix composites is proposed. Also presented is the successful preparation of A380/80 μm SiC particulate aluminum alloy composites, where SiC particulate was evenly dispersed throughout an aluminum alloy matrix and a die cast chain wheel had very little porosity. In addition, recycling equipment for particulate aluminum matrix composites was designed. The old material and new material of these composites are mixed in ratios of 1:1, 2:1, and 3:1 by weight. After the first, second, and third recyclings, it was found that the amount of porosity and inclusion is much less for recycled composites. In addition, from composition analysis, it was found that the Si content increases with an increase in the amount of old materials and recycling times. From tensile strength tests, it was found that tensile strength and elongation are the same for new materials and composites with old material to new material weight ratios of 1:1 and 2:1 for the first to the third recyclings. However, tensile strength and elongation decrease for composites with an old material to new material weight ratio of 3:1 for the first to the third recyclings, in particular for material of the third recycling. If Si was added before the recycling process, though the formation of Al3C4and Si crystal could be constrained, it would have no significant effect on the increase of elongation.

Injection of transforming growth factor $sZ1 (TGF-$sZ1) for five days during the late phase of the immunization process leading either to collagen type II induced arthritis (CIA) or to experimental allergic encephalomyelitis (EAE) protects against the development of these auto-immune diseases. Tumor necrosis factor a (TNF-$aL) injected during this same interval aggrevates CIA. In addition, anti-TGF-$sZ exacerbates and anti-TNF protects against CIA, acute and relapsing EAE, suggesting an important regulatory role for the endogenous production of the two cytokines on the severity of these diseases. More detailed studies about the mechanism of action of TGF-$sZ in acute EAE show that there is no detectable effect of TGF-$sZ on the development of sensitized T cells in vivo, as assayed by the proliferative responses of T cells from lymph nodes and peripheral blood to myelin antigens. Nevertheless, the number of lymphoid cells infiltrating the central nervous tissue is much greater in untreated than in TGF-$sZ-treated, protected mice. We conclude that it is likely that TGF-$sZ protects against experimental auto-immune diseases by interfering with the entry of lymphoid cells into the target organs through inhibition of the upregulation of adhesion molecule expression on endothelial cells, and with subsequent inflammatory processes inside the target organs by antagonizing both the production and the effects of TNF.

The protease of human immunodeficiency virus has been expressed in Escherichia coliand purified to apparent homogeneity. Immunoreactivity toward anti-protease peptide sera copurified with an activity that cleaved the structural polyprotein gagp55 and the peptide corresponding to the sequence gag128–135. The enzyme expressed as a nonfusion protein exhibits proteolytic activity with a pH optimum of 5.5 and is inhibited by the aspartic protease inhibitor pepstatin with a Kiof 1.1 µM. Replacement of the conserved residue Asp-25 with an Asn residue eliminates proteolytic activity. Analysis of the minimal peptide substrate size indicates that 7 amino acids are required for efficient peptide cleavage. Size exclusion chromatography is consistent with a dimeric enzyme and circular dichroism spectra of the purified enzyme are consistent with a proposed structure of the protease (Pearl, L.H., and Taylor, W.R. (1987) Nature329, 351–354). These data support the classification of the human immunodeficiency virus protease as an aspartic protease, likely to be structurally homologous with the well characterized family that includes pepsin and renin.

Alendronate (ALN), an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its molecular target is still unknown. This study examines the effects of ALN on the activity of osteoclast protein-tyrosine phosphatase (PTP; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), called PTPepsilon. Using osteoclast-like cells generated by coculturing mouse bone marrow cells with mouse calvaria osteoblasts, we found by molecular cloning and RNA blot hybridization that PTPepsilon is highly expressed in osteoclastic cells. A purified fusion protein of PTPepsilon expressed in bacteria was inhibited by ALN with an IC50 of 2 microM. Other PTP inhibitors--orthovanadate and phenylarsine oxide (PAO)-inhibited PTPepsilon with IC50 values of 0.3 microM and 18 microM, respectively. ALN and another bisphosphonate, etidronate, also inhibited the activities of other bacterially expressed PTPs such as PTPsigma and CD45 (also called leukocyte common antigen). The PTP inhibitors ALN, orthovanadate, and PAO suppressed in vitro formation of multinucleated osteoclasts from osteoclast precursors and in vitro bone resorption by isolated rat osteoclasts (pit formation) with estimated IC50 values of 10 microM, 3 microM, and 0.05 microM, respectively. These findings suggest that tyrosine phosphatase activity plays an important role in osteoclast formation and function and is a putative molecular target of bisphosphonate action.

Both tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) are found in synovial fluid from arthritic joints of humans and of rodents with experimental arthritis. The role of endogenously produced TGF-beta and TNF in the pathogenesis of collagen type II-induced arthritis (CIA) in DBA/1 mice was examined by determining the effect of neutralizing monoclonal antibodies to these factors on the course of the disease. Endogenously produced as well as systemically administered TGF-beta 1 and TNF-alpha had opposite effects, since TGF-beta 1 and anti-TNF protected against CIA, whereas anti-TGF-beta and TNF-alpha increased CIA incidence and/or severity. Intraperitoneally injected TGF-beta 1 at a dose of 2 micrograms per day for 14 days significantly ameliorated arthritis, even when started at the time of arthritis development, although it did not reverse established disease. The resistance to CIA induction caused by a prior intravenous injection of collagen type II was not significantly influenced by the simultaneous injection of TGF-beta 1, TNF-alpha, or interleukin 1 alpha. It is concluded that the endogenous production of TNF and TGF-beta is important in determining the course of CIA.

The aspartylprotease of the human immunodeficiency virus HIV-1 (NY5) has been crystallized in a form suitable for x-ray diffraction analysis. The crystals are tetragonal bipyramids and produce an x-ray diffraction pattern that exhibits the symmetry associated with space group P41212 (or its enantiomorph, P43212). The unit cell parameters are a = b = 50.3 Å, c = 106.8 A, α = β = γ = 90 ° measurable diffraction intensities are observed to a resolution of 2.5 A. Density measurements indicate one molecule of 9,400 daltons/asymmetric unit. The symmetry of this space group could accommodate the proposed active dimer species of the protease if the 2-fold axis were coincident with one of the crystallographic 2-fold axes.