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A novel open framework U−O material with composition (NH4)3(H2O)2{[(UO2)10O10(OH)][(UO4)(H2O)2]} was synthesized hydrothermally. The structure [monoclinic, a = 11.627(2) Å, b = 21.161(3) Å, c = 14.706(2) Å, β = 103.930(3)°, V = 3511.97 ų] was solved by direct methods and refined on the basis of F² for all 4230 unique reflections in space group C2/c to an agreement factor (R1) of 7.7%, calculated using 2180 unique observed reflections (|Fo| ≥ 4σF). The structure contains six symmetrically distinct U⁶⁺ sites, five of which occur as approximately linear (UO2)²⁺ uranyl ions that are coordinated by four or five additional ligands, giving square and pentagonal bipyramids. One U⁶⁺ cation occurs in distorted octahedral coordination. The structure contains β-U3O8-type sheets parallel to (001) that are cross-linked through U2O12 pentagonal bipyramid dimers, resulting in an open framework structure composed only of uranium polyhedra. The (NH4)⁺ and H2O groups are located in the interconnected three-dimensional channels along [100] that are bounded by 10-membered rings of uranyl polyhedra. A new layered uranyl material with composition Cs3[(UO2)3O2(OH)3]2Cl(H2O)3 was obtained by treatment of the framework phase in CsCl solution at 180 °C for 33 h. The structure [monoclinic, space group C2, a = 19.615(5) Å, b = 7.239(2) Å, c = 12.064(3) Å, β = 127.929(4)°, V = 1351.2(6) ų] was refined on the basis of F² using 2462 unique reflections to R1 = 7.2%, calculated using the 1800 unique observed reflections (|Fo| ≥ 4σF). The structure contains α-U3O8-type sheets of uranyl pentagonal bipyramids, with two symmetrically distinct Cs cations, a single Cl anion, and two H2O groups located in the interlayer regions.

In Caenorhabditis elegans, an insulin-like signaling pathway to phosphatidylinositol 3-kinase (PI 3-kinase) and AKT negatively regulates the activity of DAF-16, a Forkhead transcription factor. We show that in mammalian cells, C. elegans DAF-16 is a direct target of AKT and that AKT phosphorylation generates 14-3-3 binding sites and regulates the nuclear/cytoplasmic distribution of DAF-16 as previously shown for its mammalian homologs FKHR and FKHRL1. In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element. In HepG2 cells, insulin signaling to PI 3-kinase/AKT inhibits the ability of a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription via the insulin-like growth factor binding protein-1-insulin response element, but not the GAL4 DNA binding site, which suggests that insulin inhibits the interaction of DAF-16 with its cognate DNA site. Elimination of the DAF-16/1433 association by mutation of the AKT/14-3-3 sites in DAF-16, prevents 14-3-3 inhibition of DAF-16 DNA binding and insulin inhibition of DAF-16 function. Similarly, inhibition of the DAF-16/14-3-3 association by exposure of cells to the PI 3-kinase inhibitor LY294002, enhances DAF-16 DNA binding and transcription activity. Surprisingly constitutively nuclear DAF-16 mutants that lack AKT/14-3-3 binding sites also show enhanced DNA binding and transcription activity in response to LY294002, pointing to a 14-3-3-independent mode of regulation. Thus, our results demonstrate at least two mechanisms, one 14-3-3-dependent and the other 14-3-3-independent, whereby PI 3-kinase signaling regulates DAF-16 DNA binding and transcription function.

The amyloid precursor protein (APP) has been associated with Alzheimer's disease (AD) because APP is processed into the beta-peptide that accumulates in amyloid plaques, and APP gene mutations can cause early onset AD. Inflammation is also associated with AD as exemplified by increased expression of interleukin-1 (IL-1) in microglia in affected areas of the AD brain. Here we demonstrate that IL-1alpha and IL-1beta increase APP synthesis by up to 6-fold in primary human astrocytes and by 15-fold in human astrocytoma cells without changing the steady-state levels of APP mRNA. A 90-nucleotide sequence in the APP gene 5'-untranslated region (5'-UTR) conferred translational regulation by IL-1alpha and IL-1beta to a chloramphenicol acetyltransferase (CAT) reporter gene. Steady-state levels of transfected APP(5'-UTR)/CAT mRNAs were unchanged, whereas both base-line and IL-1-dependent CAT protein synthesis were increased. This APP mRNA translational enhancer maps from +55 to +144 nucleotides from the 5'-cap site and is homologous to related translational control elements in the 5'-UTR of the light and and heavy ferritin genes. Enhanced translation of APP mRNA provides a mechanism by which IL-1 influences the pathogenesis of AD.

The structure of QUI-MnGS-1 has been determined from single-crystal X-ray diffraction on a ~0.03 × 0.03 × 0.02 mm sample using synchrotron radiation. This material [(C7H13N)Mn0.25Ge1.75S4·H2O] crystallizes in space group I&fourmacr;2d with unit cell a = 11.581(1) and c = 18.741(3) Å. The extended framework of this structure consists of corner-linked [Ge4S10]^4- clusters, the centers of which occupy nodes of a distorted diamond lattice. The 6-rings defined by this lattice form channels that contain the water and organic components of this compound. In situ synchrotron X-ray diffraction studies of its synthesis indicate that an Mn-free precursor phase forms prior to transformation to QUI-MnGS-1. In situ calcination experiments demonstrate that this material is thermally stable to approximately 360 °C.

Coadministration of p.o. hydralazine and d-propranolol or dl-propranolol in six conscious dogs caused a significant increase in peak plasma concentration and area under the p.o. plasma concentration-time curve of propranolol (P less than .01, P less than .01, peak plasma concentration; P less than .01 and P less than .05, area under the plasma concentration-time curve; d-propranolol and dl-propranolol, respectively). Coadministration of p.o. hydralazine with p.o. dl-propranolol resulted in a small trend toward an increase in systemic clearance of i.v. dl-[3H]propranolol; however, this did not reach statistical significance (P less than .2, P less than .1, d-propranolol and dl-propranolol, respectively). When a mixture of d-propranolol and 14C-labeled dl-propranolol was administered into the jejunum of seven anesthetised dogs, the absorption into portal vein of the 14C-labeled dl-propranolol paralleled closely that of d-propranolol both in terms of time to peak and absorption as measured by a percentage of total area under the plasma concentration-time curve at an arbitrary time (10 min) postdose. Assessment of hepatic extraction (E) showed similar close parallels (d-propranolol, E = 0.85 +/- 0.02; dl-[14C]propranolol, E = 0.86 +/- 0.03: mean +/- S.E.M., n = 5, P less than .70). Hepatic extraction of propranolol and blood flow in mesenteric artery and hepatic artery were measured in 23 anesthetised dogs given a constant infusion of d-propranolol into portal vein (11 micrograms/kg/min), made up to 6 control and 17 hydralazine-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Heat shock factor 1 activates the promoters of heat shock genes at elevated temperatures through its interaction with heat shock elements. We have examined a new role for heat shock factor 1 in the repression of the prointerleukin 1beta gene in human monocytes responding to stimulation with lipopolysaccharide. Both exposure to elevated temperatures and heat-independent heat shock factor 1 expression repressed the transcription of the prointerleukin 1beta gene, and repression was strictly dependent on an intact consensus heat shock element in the prointerleukin 1beta promoter to which heat shock factor 1 bound. This is the first demonstration of heat shock factor 1 as a transcriptional repressor and suggests a role for the factor in the counter-regulation of cytokine gene transcription.

Release of adenosine from the spinal cord contributes to spinal antinociception by morphine. Morphine induces a Ca(++)-dependent release of adenosine from dorsal spinal cord synaptosomes, which is augmented under partially depolarizing conditions. The present study examined the opioid receptor subtypes involved in this release, and determined whether adenosine is an important mediator of antinociception induced by the spinal administration of selective opioid agonists in rats. Nanomolar and micromolar concentrations of the selective mu opioid agonists DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin) and PLO17 ([N-MePhe3,D-Pro4]morphiceptin) induced release of adenosine in a biphasic manner in the presence of a partial depolarization (addition of 6 mM K+ to the Krebs' medium). The delta opioid agonists DPDPE ([D-Pen2,D-Pen5]enkephalin) and DELT ([D-Ala2,Cys4]deltorphin) and the kappa opioid agonist U50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrroli-zemeacetamid e) had little effect on the release of adenosine except at high micromolar concentrations. Release of adenosine by mu (nanomolar) and delta (micromolar) ligands is Ca(++)-dependent, whereas the kappa (micromolar) receptor ligand releases adenosine via a Ca(++)-independent mechanism. Behavioral antinociception using the hot-plate threshold test revealed that intrathecal administration of the mu and delta opioid receptor agonists produced dose-dependent antinociception with an order of potency of DAMGO, PLO17 > morphine, DELT > DPDPE. An ED75 dose of morphine, DAMGO or PLO17 was attenuated dose-dependently by intrathecal pretreatment with the adenosine receptor antagonist caffeine. Caffeine did not block the antinociceptive response to delta agonists, but in fact augmented antinociception when combined with DPDPE and DELT. This augmentation was dose-dependent. This study demonstrates that activation of the mu receptor subtype is responsible for the opioid-induced release of adenosine from the spinal cord, that such release contributes to the spinal antinociception by mu agonists and that only release evoked by low doses of opioids is behaviorally relevant.

Single crystals of Dabco−MnGS−SB1 (MnGe4S10·(C6H14N2)·3H2O) were synthesized hydrothermally in the presence of Dabco (1,4-diazabicyclo[2.2.2]octane). This material (Pna21, a = 18.367(2), b = 14.184(2), and c = 9.410(1) Å) contains [Ge4S10]^4- adamantine clusters corner-linked through distorted Mn²⁺ centers. The alternating Mn²⁺ centers and [Ge4S10]^4- clusters lie at the nodes of a distorted Li-A(BW) net containing elliptical 8-rings. Channels defined by these 8-rings contain the template and water molecules. The distortion of S−Mn−S from the ideal tetrahedral angles is a result of the strain associated with ring system of the framework.