Ribosylurea Accumulates in Yeast urc4 Mutants Björnberg, O.; Vodnala, M.; Domkin, V. ...
Nucleosides, nucleotides & nucleic acids,
06/2010, Letnik:
29, Številka:
4-6
Journal Article
Recenzirano
Yeast Saccharomyces (Lachancea) kluyveri urc4 mutants, unable to grow on uracil, biotransformed
14
C
2
-uracil into two labeled compounds, as detected by high performance liquid chromatography ...(HPLC). These two compounds could also be obtained following organic synthesis of ribosylurea. This finding demonstrates that in the URC pyrimidine degradation pathway, the opening of the uracil ring takes place when uracil is attached to the ribose moiety. Ribosylurea has not been reported in the cell metabolism before and the two observed compounds likely represent an equilibrium mixture of the pyranosyl and furanosyl forms.
As methodology the ex-post analysis deserves more attention as a device to calibrate energy sector models. This paper studies the impact of energy prices and taxes on energy efficiency and carbon ...emissions of ten industrial sectors in the three Scandinavian countries. A database with sector-specific energy prices and taxes has been established, which allows the analysis to take various price reductions and tax exemptions better into account. A translog factor demand system estimation for a cross industry pooled model is explored and fixed effects across industries and time is estimated. The findings here confirm recent analyses which indicate higher long-term elasicities for industries than normally assumed in Scandinavian energy-sector models. With the observations on differences in energy-intensities among sectors and countries the findings allow for some optimism as to the opportunities for further decoupling between trends in gross value added, carbon emissions and energy consumption.
A neurological surveillance was combined with prospective recording of upper respiratory and gastrointestinal infections and serological diagnosis of five common viral infections in 60 benign ...multiple sclerosis patients, with a mean follow-up of 31 months. During 4-week at risk (AR) periods encompassing common infections, a significant excess of MS relapses was found in the AR period, with a relative risk of 1.3. A seasonal variation of the MS relapse rate was found with a minimum in summer. There was a significant correlation between the number of AR relapses and the number of common infections per month explaining the periannual distribution of relapses. The non-AR relapses showed no seasonal variation. There was a significant correlation between adenovirus CF titre rises associated with upper respiratory infections and the occurrence of a major MS relapse in the AR period (n = 7), while influenza infections were not followed by a major MS relapse (n = 6). Linear homologies have been demonstrated between adenovirus and basic myelin protein. The epidemiological approach is essential to our understanding of systemic antigens triggering multiple sclerosis activity.
A prospective, randomized, open, multicentre (n = 3) study was conducted to compare the efficacy and efficiency of a fixed daily dose of 150 IU (3×50 IU) recombinant follicle stimulating hormone ...(recFSH, Puregon®) and 225 IU (3×75 IU) highly purified urinary FSH (uFSH-HP, Metrodin-HP®) in women undergoing ovarian stimulation prior to in-vitro fertilization treatment. A total of 165 women were treated with FSH, 83 subjects with recFSH and 82 subjects with uFSH-HP. In the recFSH group a mean number of 8.8 oocytes were retrieved, compared with 9.8 in the uFSH-HP group (not statistically significant). In the recFSH group, a significantly lower total dose was required compared to the uFSH-HP group, 1479 versus 2139 IU, respectively (P < 0.0001; 95% confidence interval –747 to –572). Treatment with recFSH resulted in a significantly higher embryo development rate (69.6 versus 56.2%; P = 0.003) and more embryos accessible for the embryo freezing programme (3.3 versus 2.0; P = 0.02) compared to uFSH-HP. The vital pregnancy rate per cycle started was 30.2 versus 28.3% in the recombinant and urinary FSH group, respectively. It is concluded that treatment outcome of a fixed daily dose of 150 IU recFSH is comparable to a fixed daily dose of 225 IU uFSH-HP. However, a significantly lower total dose was needed in the recFSH group (nearly 700 IU less).
Abstract 530
An open, multi-center, randomized phase III trial performed by the Nordic Myeloma Study Group (NMSG) was designed to explore the effect of a 21-week consolidation period of single agent ...bortezomib, given during months 3-8 after ASCT. Primary end-point was event free survival and secondary end-points were response rate, toxicity, overall survival, quality of life and cost utility.
Between November 2005 and April 2009 404 patients were included, 372 of whom were randomized. This report comprises preliminary data concerning feasibility, toxicity and response rate for the initial 299 randomized patients.
Patients were randomized 3 months post ASCT to either no consolidation therapy (current standard in Scandinavia), or to a period of bortezomib consolidation. Initial treatment before ASCT was optional. Patients were stratified for single or double ASCT. Bortezomib was given in a dose of 1.3 mg/m2 twice weekly (days 1, 4, 8 and 11) in a 3 week schedule for the first 2 cycles. In the following four cycles, bortezomib was given once weekly (days 1, 8 and 15) in a 4 week schedule, in total 20 injections over 21 weeks. Before each dose of study drug, the patients were evaluated for possible toxicities.
Baseline characteristics were well balanced between the 149 patients in the bortezomib group and the 150 in the control group. All analyses were performed on an intention to treat basis.
The mean number of bortezomib injections was 15, median 19 of optimal 20. The mean total dose given was 82 %, median 90 %, of the planned dose. Thirty-one patients (21 %) had to reduce the dose to zero for one cycle or more, mainly due to neuropathy, 11 patients, or progression, 8 patients. Hematological toxicity according to CTC included neutropenia grade ≥ III in 33 patients (22 %), thrombocytopenia grade ≥ III in 14 patients (9 %). Neurological pain grade ≥ III was seen in 7 patients (5 %). Sensory neuropathy grade ' III was seen in 5 patients (3 %).
A significant difference in improvement of response was noted between the two arms. At the time of randomization the proportion of CR/nCR was 23 % for patients in the bortezomib arm and 21 % in the control arm. However, when measured six months after randomization (9 months after ASCT), the proportion of CR/nCR was 54 % in the bortezomib group versus 35 % for the controls, p < 0.005. The proportion of patients improving their response from PR to CR/nCR was 20 % and 12 % for the bortezomib and control groups respectively, p = 0.06 NS. The proportion of patients who relapsed during the initial 6 month observation period did differ significantly, 1 % versus 6 %, p<0.05.
Our results indicate that consolidation with bortezomib given as a single agent is feasible and does improve treatment response after ASCT.
Mellqvist:Jansen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Johnson and Johnson: Research Funding. Off Label Use: Bortezomib. Consolidation therapy after high dose melphalan.. Westin:Celgene: Membership on an entity's Board of Directors or advisory committees. Gimsing:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Schering-Plough: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Laane:Schering-Plough: Membership on an entity's Board of Directors or advisory committees. Remes:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Waage:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees.
Background: Much is unknown regarding the regulation of amyloid precursor protein (APP) processing in the human central nervous system. It has been hypothesized that amyloidogenic APP-processing ...preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of APP-derived molecules in CSF with chromogranin (Cg) derived peptides, representing the regulated secretion. Methods: Patients with Alzheimer's disease (AD, N = 32), multiple sclerosis (MS, N = 50) and healthy controls (N = 70) were enrolled. CSF was analyzed for the amyloid peptides Aβ1-42, Aβx-42, Aβx-40, Aβx-38, α-cleaved soluble APP (α-sAPP), β-cleaved soluble APP (β-sAPP), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes APP into Aβ, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. Results: CSF Cg levels correlated to sAPP and Aβ peptides in AD, MS and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. Conclusions: These results suggest that a large part of APP in the human central nervous system is processed in the regulated secretory pathway of neurons.
In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, ...(R)-1-4-2-(4-methoxyphenyl)phenylpiperazin-1-yl-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, (11)C(R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of (11)C(R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.
In response to starvation, Myxococcus xanthus initiates a developmental programme that results in the formation of spore-filled multicellular fruiting bodies. Fruiting body formation depends on the ...temporal and spatial coordination of aggregation and sporulation and involves temporally and spatially coordinated changes in gene expression. This paper reports the identification of two genes, hthA and hthB, that are important for fruiting body formation. hthA and hthB are co-transcribed, and transcription of the two genes decreases strongly during development. Loss of HthA and HthB function results in delayed aggregation, a reduction in the level of sporulation, and abnormal developmental gene expression. Extracellular complementation experiments showed that the developmental defects caused by loss of HthA and HthB function are not due to the inability to synthesize an intercellular signal required for fruiting body formation. HthA, independent of HthB, is required for aggregation. HthB, alone or in combination with HthA, is required for sporulation. HthA is predicted to contain a C-terminal helix-turn-helix DNA-binding domain. Intriguingly, the N-terminal part of HthA does not exhibit significant amino acid similarity to proteins in the databases. The HthB protein lacks homologues in the databases. The results suggest that HthA is a novel DNA-binding protein, which regulates transcription of genes important for aggregation, and that HthB, alone or in combination with HthA, stimulates sporulation.
To assess the present level of HIV-2 infection in an adult population in Bissau and to evaluate sex and age-specific changes in HIV-2 prevalence and incidence between 1987 and 1996.
Sex and ...age-specific changes in HIV-2 prevalence were evaluated comparing a survey from 1987 in a sample of 100 houses with a survey performed in 1996 in an independent sample of 212 houses from the same study area. HIV-2 incidence rates were examined in an adult population (age > or = 15 years) from 100 randomly selected houses followed with four consecutive HIV serosurveys from 1987 to 1996.
The HIV-2 prevalence in 1996 was 6.8% (men, 4.7%; women, 8.4%). Compared with the 1987 survey there was a significant decrease in prevalence among men age-adjusted relative risk (RR), 0.50; 95% confidence interval (CI), 0.31-0.83, whereas it remained unchanged in women (RR, 1.00; 95% CI, 0.67-1.48). The male-to-female RR decreased from 0.99 (95% CI, 0.61-1.61) in 1987 to 0.51 (95% CI, 0.34-0.76) in 1996. The overall annual incidence rate was 0.54 per 100 person-years of observation (PYO), being higher in women (0.72 per 100 PYO) than in men (0.31 per 100 PYO). With the observation time divided into an early and a late period, there was a decrease in incidence with time among men (0.66 to 0.00 per 100 PYO), but no major change among women (0.59 to 0.85 per 100 PYO). The two trends differed significantly (P = 0.03). We observed a higher annual incidence rate amongst older women aged > 44 years (1.77 per 100 PYO) than among younger women (0.55 per 100 PYO; P = 0.05).
There are no signs of an epidemic spread of HIV-2 in Bissau even though the HIV-1 prevalence is increasing rapidly. A significant reduction in the male HIV-2 prevalence and incidence rates has resulted in a major shift in the pattern of spread of HIV-2, from being equally distributed to being predominantly a female infection. Currently, older women in particular seem to have a high risk of getting infected.
Various issues related to decoupling of industrial energy consumption and carbon dioxide emissions in energy intensive industries in Scandinavia were presented. It was observed that the database with ...sector-specific energy prices and taxes was established, which allowed the analysis to take various price reductions and tax exemptions better into account. The findings confirmed analyses, which indicated higher long-term elasticities for industries than normally assumed in Scandinavian energy-sector models. With the observations on differences in energy-intensities among sectors and countries the findings allowed for some optimism as to the opportunities for further decoupling between trends in gross value added, carbon emissions and energy consumption.
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