Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P = 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ZnO based nanowires grown by chemical vapour deposition for selective hydrogenation of acetylene alcohols

Vertically aligned ZnO nanowires (NWs) with a length of 1.5-10 mu m and a mean diameter of ca. 150 nm were grown by chemical vapour deposition onto a c-oriented ZnO seed layer which was deposited by atomic layer deposition on Si substrates. The substrates were then spin-coated with an ethanol solution containing Pd nanoparticles with an average size of 2.7 and 4.5 nm. A homogeneous distribution of the Pd nanoparticles on ZnO NWs has been obtained using both Pd particle series. The catalytic activity of the ZnO NWs and Pd/ZnO NWs catalysts was measured in the semihydrogenation of 2-methyl-3-butyn-2-ol at 303-343 K and a pressure of 2-10 bar. The effect of the solvent used on the catalytic performance of the Pd/ZnO NWs catalyst was studied. The Pd/ZnO catalysts showed alkene selectivity of up to 95% at an alkyne conversion of 99%. A kinetic model is proposed to explain the activity and selectivity of the ZnO support and Pd/ZnO catalysts.

Spitzer Secondary Eclipses of WASP-18b

The transiting exoplanet WASP-18b was discovered in 2008 by the Wide Angle Search for Planets project. The Spitzer Exoplanet Target of Opportunity Program observed secondary eclipses of WASP-18b using Spitzer's Infrared Array Camera in the 3.6 µm and 5.8 µm bands on 2008 December 20, and in the 4.5 µm and 8.0 µm bands on 2008 December 24. We report eclipse depths of 0.30% ± 0.02%, 0.39% ± 0.02%, 0.37% ± 0.03%, 0.41% ± 0.02%, and brightness temperatures of 3100 ± 90, 3310 ± 130, 3080 ± 140, and 3120 ± 110 K in order of increasing wavelength. WASP-18b is one of the hottest planets yet discovered—as hot as an M-class star. The planet's pressure-temperature profile most likely features a thermal inversion. The observations also require WASP-18b to have near-zero albedo and almost no redistribution of energy from the day side to the night side of the planet.

PHOTOMINERALIZATION OF 4-CHLOROPHENOL SENSITIZED BY TITANIUM-DIOXIDE - A STUDY OF THE INITIAL KINETICS OF CARBON-DIOXIDE PHOTOGENERATION

The kinetics of photomineralization of 4-chlorophenol (4-CP) sensitized by Degussa P25 TiO2 in O2-saturated solution is studied as a function of the following different experimental parameters: pH, [TiO2], percentage O2 [O2], [4-CP], T, I, lambda and [KNO3]. At pH 2 and T=30-degrees-C the initial relative rate of CO2 photogeneration R(CO2) conforms to a Langmuir-Hinshelwood-type kinetic scheme and the relationship between R(CO2) and the various experimental parameters may be summarized as follows: R(CO2) = gammaK(O2)[O2](I(a))(theta)K(4-CP]0/(1 + K(O2])(1 + K(4-CP)[4-CP]0) where gamma is a proportionality constant, K(O2) = 0.044 +/- 0.005[O2]-1, theta = 0.74 +/- 0.05 and K(4-CP) = (29 +/- 3) x 10(3) dm3 mol-1. The overall activation energy for this photosystem was determined as 16 +/- 2 kJ mol-1. This work forms part of an overall characterization study in which it is proposed that the 4-CP-TiO2-O2 photosystem is adopted as a standard test system for incorporation into all future semiconductor-sensitized photomineralization studies in order to facilitate comparisons between the results of the different studies.

A specificity-enhanced time-resolved fluoroimmunoassay for zeranol employing the dry reagent all-in-one-well principle

A simple dry chemistry time-resolved fluorescence immunoassay (TR-FIA) method was developed for the measurement of zeranol in bovine urine samples. The samples were purified by immunoaffinity chromatography and a specificity-enhanced zeranol antibody was employed in the immunoassay. This resulted in a highly selective method, which had only negligible reactivity with Fusarium spp, toxins. The all-in-one-well dry chemistry concept made the assay very simple to use because all the assay-specific reagents were already present in the reaction wells in dry form. Only the addition of diluted sample extract was required to perform the competitive one-step TR-FIA and the results were available in less than 1 h. The analytical limit of detection (mean + 3s) for the immunoassay was 0.16 ng ml(-1) (n=12) and the functional limit of detection for the whole method, estimated by the analysis of zeranol-free samples, was 1.3 ng ml(-1) (n=20). The recovery of zeranol at the level of 2 ng ml(-1) was 99% (n=18) and the within-assay variation ranged between 4.5 and 9.0%.

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323: 147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative co-operativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

ON THE PROGENITOR AND EARLY EVOLUTION OF THE TYPE II SUPERNOVA 2009kr

We identify a source coincident with SN 2009kr in Hubble Space Telescope pre-explosion images. The object appears to be a single point source with an intrinsic color V - I = 1.1 +/- 0.25 and M-V = -7.6 +/- 0.6. If this is a single star, it would be a yellow supergiant of log L/L-circle dot similar to 5.1 and a mass of 15(-4)(+5) M-circle dot. The spatial resolution does not allow us yet to definitively determine if the progenitor object is a single star, a binary system, or a compact cluster. We show that the early light curve is similar to a Type IIL SN, but the prominent H alpha P-Cygni profiles and the signature of the end of a recombination phase are reminiscent of a Type IIP. The evolution of the expanding ejecta will play an important role in understanding the progenitor object.

Metallicities of 4 blue supergiants near the Galactic centre

High resolution optical spectra of four blue supergiants (HD148422 B0.5 Ib; HD178487 B0.5 Ib; HD179407 B1 Ib, HD163522 B1 Ib) which lie within 4.5 kpc of the Galactic centre are presented. Careful differential LTE model atmosphere analyses are used to quantify the differences in photospheric metal abundances between these stars and MK spectral standards in the solar neighborhood. A detailed non-LTE model atmosphere analysis of one star (HD163522) confirms that the LTE differential abundances should be reliable, provided we use a comparison star with similar atmospheric parameters.

A Systems Biology Approach Identifies SART1 as a Novel Determinant of Both 5-Fluorouracil and SN38 Drug Resistance in Colorectal Cancer

Chemotherapy response rates for advanced colorectal cancer remain disappointingly low, primarily because of drug resistance, so there is an urgent need to improve current treatment strategies. To identify novel determinants of resistance to the clinically relevant drugs 5-fluorouracil (5-FU) and SN38 (the active metabolite of irinotecan), transcriptional profiling experiments were carried out on pretreatment metastatic colorectal cancer biopsies and HCT116 parental and chemotherapy-resistant cell line models using a disease-specific DNA microarray. To enrich for potential chemoresistance-determining genes, an unsupervised bioinformatics approach was used, and 50 genes were selected and then functionally assessed using custom-designed short interfering RNA(siRNA) screens. In the primary siRNA screen, silencing of 21 genes sensitized HCT116 cells to either 5-FU or SN38 treatment. Three genes (RAPGEF2, PTRF, and SART1) were selected for further analysis in a panel of 5 colorectal cancer cell lines. Silencing SART1 sensitized all 5 cell lines to 5-FU treatment and 4/5 cell lines to SN38 treatment. However, silencing of RAPGEF2 or PTRF had no significant effect on 5-FU or SN38 sensitivity in the wider cell line panel. Further functional analysis of SART1 showed that its silencing induced apoptosis that was caspase-8 dependent. Furthermore, silencing of SART1 led to a downregulation of the caspase-8 inhibitor, c-FLIP, which we have previously shown is a key determinant of drug resistance in colorectal cancer. This study shows the power of systems biology approaches for identifying novel genes that regulate drug resistance and identifies SART1 as a previously unidentified regulator of c-FLIP and drug-induced activation of caspase-8. Mol Cancer Ther; 11(1); 119-31. (C) 2011 AACR.

Synthesis and in Vitro and in Vivo Evaluation of a Series of Dihydroisocoumarin Derivatives Conjugated with Fatty Acids, Alcohols, and Amines as Potential Anticancer Agents

In this paper, we report the synthesis and biological activity of a series of dihydroisocoumarin analogues Conjugated with fatty acids, alcohols, or amines, of varying hydrocarbon chain length and degree of unsaturation, to (he dihydroisocoumarins, kigelin and mellein, at the C-7 and C-8 positions on the core dihydroisocoumarin structure. These compounds were evaluated for their antiproliferative activity against human breast cancer (MCF-7 and MDA-MB-468) and melanoma cells (SK-MEL-28 and Malme-3M) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Two compounds Conjugated with gamma-linolenyl alcohol (18:3 n-6) demonstrated potent antiproliferative activity in vitro with one of these 4-hydroxy-3-oxo-1.3-dihydro-isobenzofuran-5-carboxylic acid octadeca-6,9,12-trienyl ester, demonstrating significant antitumor activity in vivo ill a number of human tumor xenograft models.

Spin-orbit effects on photoionization-produced alignment of the Ar+ 3p(4)(P-3)4p levels

We have determined photoionization spectra of Ar with excitation of the 3p(4)(P-3)4p states emphasizing the effects of two different classes of Ar+ spin-orbit interactions. The spin-orbit splitting of each Ar+ state adequately describes the resonant excitation of the quartet states of Ar+, and gives Ar photoionization cross sections with excitation of the 3p4(3P)4p P-2(3/2)o and P-4(5/2)o levels of Ar+ in sufficiently good agreement with experiment to identify the observed resonances and to estimate the excitation strengths. In addition, we demonstrate the importance of spin-orbit induced mixing of different Ar+ LS-coupled states for observables such as the alignment of the 3p(4)(P-3)4p P-4(5/2)o level and the excitation of Rydberg series converging to the 3p(4)(P-3)4p S-2(o) and S-4(o) thresholds.

Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia

Nuclear factor-kappaB (NF-kappaB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF-kappaB in human myeloid blasts and a clear correlation between NF-kappaB expression and in vitro cytoprotection. High NF-kappaB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French-American-British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC-1, a novel dimethylamino-parthenolide analogue, were assessed in 62 primary untreated AML samples. LC-1 was found to be cytotoxic to AML cells in a dose-dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4.5 micromol/l for AML cells, compared with 12.8 micromol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-kappaB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-kappaB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-kappaB activity. Consequently, LC-1 treatment provides a proof of principle for the use of NF-kappaB inhibitors in the treatment of AML.

Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations

BACKGROUND AND PURPOSE:
The purpose of this study was to define the risk of rebleeding after stereotactic radiosurgery (SRS) for hemorrhagic arteriovenous malformations with or without associated intracranial aneurysms.

METHODS:
Between 1987 and 2006, we performed Gamma Knife SRS on 996 patients with brain arteriovenous malformations; 407 patients had sustained an arteriovenous malformation hemorrhage. Sixty-four patients (16%) underwent prior embolization and 84 (21%) underwent prior surgical resection. The median target volume was 2.3 mL (range, 0.1-20.7 mL). The median margin dose was 20 Gy (range, 13.5-27 Gy).

RESULTS:
The overall rate of total obliteration defined by angiography or MRI was 56%, 77%, 80%, and 82% at 3, 4, 5, and 10 years, respectively. Before obliteration, 33 patients (8%) sustained an additional hemorrhage after SRS. The overall annual hemorrhage rate until obliteration after SRS was 1.3%. The presence of a patent aneurysm was significantly associated with an increased rehemorrhage risk after SRS (annual hemorrhage rate, 6.4%) compared with patients with a clipped or embolized aneurysm (annual hemorrhage rate, 0.8%; P=0.033).

CONCLUSIONS:
When an aneurysm is identified in patients with arteriovenous malformations selected for SRS, additional endovascular or surgical strategies should be considered to reduce the risk of bleeding during the latency interval.

Role of basal extracellular Ca2+ entry during 5-HT-induced vasoconstriction of canine pulmonary arteries.

1. Measurements of artery contraction, cytosolic [Ca(2+)], and Ca(2+) permeability were made to examine contractile and cytosolic [Ca(2+)] responses of canine pulmonary arteries and isolated cells to 5-hydroxytryptamine (5-HT), and to determine the roles of intracellular Ca(2+) release and extracellular Ca(2+) entry in 5-HT responses. 2. The EC(50) for 5-HT-mediated contractions and cytosolic [Ca(2+)] increases was approximately 10(-7) M and responses were inhibited by ketanserin, a 5-HT(2A)-receptor antagonist. 3. 5-HT induced cytosolic [Ca(2+)] increases were blocked by 20 microM Xestospongin-C and by 2-APB (IC(50)=32 microM inhibitors of InsP(3) receptor activation. 4. 5-HT-mediated contractions were reliant on release of InsP(3) but not ryanodine-sensitive Ca(2+) stores. 5. 5-HT-mediated contractions and cytosolic [Ca(2+)] increases were partially inhibited by 10 microM nisoldipine, a voltage-dependent Ca(2+) channel blocker. 6. Extracellular Ca(2+) removal reduced 5-HT-mediated contractions further than nisoldipine and ablated cytosolic [Ca(2+)] increases and [Ca(2+)] oscillations. Similar to Ca(2+) removal, Ni(2+) reduced cytosolic [Ca(2+)] and [Ca(2+)] oscillations. 7. Mn(2+) quench of fura-2 and voltage-clamp experiments showed that 5-HT failed to activate any significant voltage-independent Ca(2+) entry pathways, including store-operated and receptor-activated nonselective cation channels. Ni(2+) but not nisoldipine or Gd(3+) blocked basal Mn(2+) entry. 8. Voltage-clamp experiments showed that simultaneous depletion of both InsP(3) and ryanodine-sensitive intracellular Ca(2+) stores activates a current with linear voltage dependence and a reversal potential consistent with it being a nonselective cation channel. 5-HT did not activate this current. 9. Basal Ca(2+) entry, rather than CCE, is important to maintain 5-HT-induced cytosolic [Ca(2+)] responses and contraction in canine pulmonary artery.