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81.
Gabriele Cruciani Francesca Milletti Loriano Storchi Gianluca Sforna Laura Goracci 《化学与生物多样性》2009,6(11):1812-1821
Improving the ADME profile of drug candidates is a critical step in lead optimization, and because pKa affects most ADME properties such as lipophilicity, solubility, and metabolism, it is extremely advantageous to predict pKa in order to guide the design of new compounds. However, accurately (<0.5 log units) predicting pKa by empirical methods can be challenging especially for novel series, because of lack of knowledge on determinants of pKa (steric effects, ring effects, H‐bonding, etc.), and because of limited experimental data on the effects of specific chemical groups on the ionization of an atom. To address these issues, we recently developed the computational package MoKa, which integrates graphical and command line tools designed for computational and medicinal chemists to predict the pKa values of organic compounds. Here, we present the major issues considered when we developed MoKa, such as the accurate selection of training data, the fundamentals of the methodology (which has also been extended to predict protein pKa), the treatment of multiprotic compounds, and the selection of the dominant tautomer for the calculation. Last, we illustrate some specific applications of MoKa to predict solubility, lipophilicity, and metabolism. 相似文献
82.
Serruys P Grines C Stone G Garcia E Kiemeney F Morice M Sousa J Hamm C Costantini C Probst P Rutsch W Penn I Fernandez-Aviles F Vandormael M Bartorelli A Bilodeau L Eijgelshoven M 《International journal of cardiovascular interventions》1998,1(1):19-27
Preliminary experience with primary stenting in myocardial infarction has suggested a greater benefit in clinical outcome than has been obtained with direct balloon angioplasty. However, subacute thrombosis (SAT) remains a limitation for this new mode of therapy. In the BENESTENT II Pilot and main trials, the incidence of SAT with the heparin-coated Palmaz-Schatz stent was only 0.15%. Therefore, as a preamble to a large randomized trial, the feasibility and safety of the use of the Heparin-Coated Palmaz-Schatz trade mark Stent in Acute Myocardial Infarction (AMI) was tested in 101 patients enrolled between April and September 1996 in 18 clinical centres. In 101 stent-eligible AMI patients, as dictated by protocol, a heparin-coated stent was implanted. The primary objectives were to determine the in-hospital incidence of major adverse cardiac events (MACE: death, MI, target lesion revascularization) and bleeding complications, while the secondary objectives were the procedural success rate and the MACE, the restenosis and reocclusion rates at 6.5 months. Stent implantation (n 3 129 stents) was successful in 97 patients of the 101 who were included in this trial. During their hospital stay, two patients died and no patient experienced re-infarction, ischaemia prompting re-PTCA or CABG. Four patients suffered a bleeding complication, three major and one minor, of whom three required surgical repair. At 210 days follow-up, 81% of the patients were event free. At 6.5 months restenosis was documented in 18% of the 88 patients who underwent follow-up angiography, including three total occlusions. The results, both with respect to QCA and the occurrence of MACE, compare favourably with studies using elective stenting in both stable and unstable angina patients. As a result of this pilot study, a large randomized trial comparing direct balloon angioplasty with direct stenting in 900 patients with AMI was initiated in December 1996. 相似文献
83.
Nucleotide sequence of the D-loop region of the sperm whale (Physeter macrocephalus) mitochondrial genome 总被引:4,自引:0,他引:4
We have amplified, by the polymerase chain reaction, and have sequenced the
D-loop region of the mitochondrial DNA from the sperm whale (Physeter
macrocephalus). The sperm whale D-loop was aligned with D- loop sequences
from four other cetaceans (Commerson's dolphin, orca, fin whale, and minke
whale) and an out-group (cow). This alignment showed the sperm whale
sequence to be larger than that of other cetaceans. In addition, some
sequence blocks were highly conserved among all six species, suggesting
roles in the functioning of mitochondrial DNA. Other blocks that were
previously reported to be well conserved among cetaceans showed little
sequence conservation with the sperm whale D-loop, which argues against the
functional importance of these sequence blocks in cetaceans.
相似文献
84.
Many experiments show that serotonin (5-HT) controls thyroidal function at hypothalamic level, inhibiting the TRH secretion. The majority of experiments are done in an acute way, consisting of a single serotonin dose injected intraperitoneally (ip) or intracerebroventricularly (ic) with the effect registered after a short time (usually 1 h) as in normal environmental conditions similar to the TSH stimulation test, that consists of transfer of the experimental animals from 30°C to 4°C for 30 min, thus inducing stimulation of the hypothalamus-hypophysis-thyroid axis. The aim of the present research was to study the correlation between 5-HT and the thyroidal function, measuring plasmatic thyroid hormone levels in rats ip treated in chronic (injected daily for 10 days with different doses of 5-HT), and in acute way (after 1 h from a single 2.0 mg/kg bw 5-HT dose) in normal environmental conditions to evidence the serotonin site action activity outside the blood-brain barrier. The results of the chronic experiment show an inhibitory effect of 5-HT, on T3 and T4 plasmatic level, only when it is injected at medium doses (0.2 and 0.4 mg/kg bw for T3, and 0.2 for T4), while the results of the acute experiment do not evidence any modification. These results show that in normal environmental conditions the outside 5-HT site action is active only when the 5-HT is injected chronically at defined doses, probably for a down-regulation phenomenon. 相似文献
85.
86.
87.
Kwok WK Picioreanu C Ong SL van Loosdrecht MC Ng WJ Heijnen JJ 《Biotechnology and bioengineering》1998,58(4):400-407
The influence of process conditions (substrate loading rate and detachment force) on the structure of biofilms grown on basalt particles in a Biofilm Airlift Suspension (BAS) reactor was studied. The structure of the biofilms (density, surface shape, and thickness) and microbial characteristics (biomass yield) were investigated at substrate loading rates of 5, 10, 15, and 20 kg COD/m3. day with basalt concentrations of 60 g/L, 150 g/L, and 250 g/L. The basalt concentration determines the number of biofilm particles in steady state, which is the main determining factor for the biofilm detachment in these systems. In total, 12 experimental runs were performed. A high biofilm density (up to 67 g/L) and a high biomass concentration was observed at high detachment forces. The higher biomass content is associated with a lower biomass substrate loading rate and therefore with a lower biomass yield (from 0.4 down to 0.12 gbiomass/gacetate). Contrary to general beliefs, the observed biomass detachment decreased with increasing detachment force. In addition, smoother (fewer protuberances), denser and thinner compact biofilms were obtained when the biomass surface production rate decreased and/or the detachment force increased. These observations confirmed a hypothesis, postulated earlier by Van Loosdrecht et al. (1995b), that the balance between biofilm substrate surface loading (proportional to biomass surface production rate, when biomass yield is constant) and detachment force determines the biofilm structure. When detachment forces are relatively high only a patchy biofilm will develop, whereas at low detachment forces, the biofilm becomes highly heterogeneous with many pores and protuberances. With the right balance, smooth, dense and stable biofilms can be obtained. Copyright 1998 John Wiley & Sons, Inc. 相似文献
88.
89.
Zimmerman PA; Katholi CR; Wooten MC; Lang-Unnasch N; Unnasch TR 《Molecular biology and evolution》1994,11(3):384-392
Polymerase chain reaction (PCR) products were characterized for a repeated
sequence family (designated "O-150") of the human filarial parasite
Onchocerca volvulus. In phylogenetic inferences, the O-150 sequences
clustered into closely related groups, suggesting that concerted evolution
maintains sequence homology in this family. Using a novel mathematical
model based on a nested application of an analysis of variance, we
demonstrated that African rainforest and savannah strain parasite
populations are significantly different. In contrast, parasites collected
in the New World are indistinguishable from African savannah strains of O.
volvulus. This finding supports the hypothesis that onchocerciasis was
recently introduced into the New World, possibly as a result of the slave
trade.
相似文献
90.
Willeke MC van Roon-Mom Barry A Pepers Peter AC 't Hoen Carola ACM Verwijmeren Johan T den Dunnen Josephine C Dorsman GertJan B van Ommen 《BMC molecular biology》2008,9(1):84