The Saccharomyces cerevisiae TIF3 gene encodes the yeast homologue of mammalian translation initiation factor eIF-4B. We have added six histidine residues to the C-terminus of Tif3 protein ...(Tif3-His6p) and purified the tagged protein by affinity chromatography. Tif3-His6p stimulates translation and mRNA binding to ribosomes in a Tif3-dependent in vitro system. Furthermore, it binds to single-stranded RNA and catalyses the annealing of partially complementary RNA strands in vitro. In parallel experiments, RNA annealing activity could also be demonstrated for mammalian eIF-4B. A role for Tif3/eIF-4B and RNA annealing activity in the scanning process is proposed.
The TIF3 gene of Saccharomyces cerevisiae was cloned and sequenced. The deduced amino acid sequence shows 26% identity with the sequence of mammalian translation initiation factor eIF-4B. The TIF3 ...gene is not essential for growth; however, its disruption results in a slow growth and cold-sensitive phenotype. In vitro translation of total yeast RNA in an extract from a TIF3 gene-disrupted strain is reduced compared with a wild-type extract. The translational defect is more pronounced at lower temperatures and can be corrected by the addition of wild-type extract or mammalian eIF-4B, but not by addition of mutant extract. In vivo translation of beta-galactosidase reporter mRNA with varying degree of RNA secondary structure in the 5' leader region in a TIF3 gene-disrupted strain shows preferential inhibition of translation of mRNA with more stable secondary structure. This indicates that Tif3 protein is an RNA helicase or contributes to RNA helicase activity in vivo.
To directly compare the efficacy and safety of etoricoxib, 30 mg once daily, ibuprofen, 800 mg 3 times daily, and placebo for treatment of osteoarthritis (OA) of the hip and knee.
A randomized, ...double-blind, placebocontrolled trial of patients with OA of the knee or hip was performed between February 2003 and November 2003 in 61 medical centers in the United States. Qualified patients aged 40 to 89 years were randomized to receive placebo, etoricoxib, 30 mg once daily, or ibuprofen, 800 mg 3 times daily, for 12 weeks. Primary efficacy end points included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales and Patient Global Assessment of Disease Status. Response to treatment was assessed by the time-weighted average change from baseline over 12 weeks.
In 528 patients, baseline values for the 3 primary end points ranged from 67.78 to 72.60 mm (0-100 mm visual analog scale). Near-maximal efficacy was achieved by week 2 with both active treatments and sustained over the course of the trial. During the 12-week period, least squares mean changes in the primary end points (Western Ontario and McMaster Universities Osteoarthritis Index and Patient Global Assessment of Disease Status subscales) ranged from −16.53 to −13.55 mm, −27.89 to −23.68 mm, and −26.53 to −22.97 mm in the placebo, etoricoxib, and ibuprofen groups, respectively. Both etoricoxib and ibuprofen were more effective (P<001) than placebo for all primary end points. Etoricoxib and ibuprofen treatment responses for the primary end points were determined to be comparable with use of prespecified comparability criteria. Results for all other efficacy end points were consistent with responses observed for the primary end points. Etoricoxib and ibuprofen generally were well tolerated.
For patients with OA, treatment with etoricoxib, 30 mg/d, is well tolerated and provides sustained clinical effectiveness that is superior to placebo and comparable to ibuprofen, 2400 mg/d.
Surface barrier particle detectors, processed in Aachen using SI GaAs from several manufacturers, have been irradiated with neutrons (peak energy ∼1 MeV) up to fluences of 4.0 × 10
14 n/cm
2 and with ...photons from a
60Co source with a dose of 100 Mrad. All detectors work well after the irradiation. Detectors biased with 200 V during the neutron irradiation show no significant difference from those not biased. After irradiation with 4.0 × 10
14 n/cm
2 the leakage currents at 200 V are a factor of 4 greater than those before irradiation. At the highest radiation level the signal for minimum ionizing particles corresponds to 7200 electrons (at 200 V bias voltage) independent of peaking times between 40 ns and 2.2 μs. The signals for α-particles (2.2 μs peaking time, 200 V bias voltage) are about 20% of those before irradiation. The exposure to the 100 Mrad photon dose caused little change of the detector performance. The leakage currents were even reduced by about 10%.
We investigated the noise behaviour of surface barrier detectors (double sided Schottky contact) made of Semiinsulating GaAs. Two types of measurements were performed: Equivalent Noise Charge (ENC) ...and noise power density spectra in a frequency range from 10 Hz to 500 kHz. The shape of the density spectra are a powerful tool to examine the physical origin of the noise, before irradiation it is dominated by Generation-Recombination processes caused by deep levels. Temperature dependent noise measurements reveal the deep level parameters like activation energy and cross section, which are also extracted by analyzing the time transients of the charge pulse from α-particles. After irradiation with protons, neutrons and pions the influence of the deep levels being originally responsible for the noise is found to decrease and a reduction of the noise over the entire frequency range with increasing fluence is observed.
We report on the fabrication of GaAs microstrip detectors with integrated coupling capacitors and biasing resistors. The characteristics of the dielectrica SiO
2 and Si
3N
4 are compared. The SiO
2 ...layers were fabricated by evaporation. The Si
3N
4 layers were grown by plasma enhanced vapour deposition. The IV-properties and the yield of the devices is investigated. First results of ion implanted back side contacts without an annealing step are presented.
Surface barrier detectors processed in Aachen using SI-GaAs from several manufacturers have been irradiated with high fluences of neutrons (mean energy 1 MeV, fluence up to
Φ
n ∼ 5 × 10
14cm
−2), ...pions (191 MeV, fluence up to
Φ
π
∼ 0.6 × 10
14cm
−2) and protons (23 GeV, fluence up to
Φ
p ∼ 2 × 10
14cm
−2). The detectors have been characterized in terms of macroscopic quantities like
I-
V characteristic curves and charge collection efficiencies for incident minimum ionizing- (mip) as well as α-particles. All detectors work well after the exposure. At the highest fluences a sizable degradation concerning the charge collection efficiencies has been observed for all investigated materials. SI-GaAs material with low carbon content (LC material from FCM, Freiberg) seems to be less affected than substrates with a higher carbon concentration. At the highest irradiation level the mip signal from a 250 μm thick detector made of LC material amounts to 8000 electrons (at 400 V bias voltage) independent of peaking times between 40 ns and 2.2 μs. The leakage currents for this material are even reduced after the irradiation.
Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and ...chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD.
This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 μg/F 10 μg via a metered-dose inhaler (MF/F MDI; DULERA(®)/ZENHALE(®)) without a spacer device, MF/F MDI with a spacer, or MF 400 μg via a dry-powder inhaler (DPI; ASMANEX(®) TWISTHALER(®)) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons.
Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported.
Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.
Surface barrier detectors processed in Aachen using semi-insulating (SI) GaAs from several manufacturers have been irradiated with high fluences of neutrons (mean energy 1 MeV, fluence up to
Φ
n ∼ 5 ...× 10
14 cm
−2), pions (191 MeV, fluence up to
Φ
π
∼ 0.6 × 10
14 cm
−2) and protons (23 GeV, fluence up to
Φ
p ∼ 2 × 10
14 cm
−2). The detectors have been characterized in terms of macroscopic quantities like
I–V characteristic curves and charge collection efficiencies for incident minimum ionizing- (mip) as well as α-particles. All detectors work well after the exposure. At the highest fluences a sizable degradation in the charge collection efficiencies has been observed for all investigated materials. SI-GaAs material with low carbon (LC) content seems to be less affected than substrates with a higher carbon concentration. At the highest irradiation level the mip signal from a 250 μm thick detector made of LC material amounts to 8000 electrons (at 400 V bias voltage) independent of peaking times between 40 ns and 2.2 μs. The leakage currents for this material are even reduced after the irradiation.
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