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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Risk analysis 19 (1999), S. 711-726 
    ISSN: 1539-6924
    Schlagwort(e): variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Energietechnik
    Notizen: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
    Materialart: Digitale Medien
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  • 2
    ISSN: 1539-6924
    Schlagwort(e): MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Energietechnik
    Notizen: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1573-0646
    Schlagwort(e): pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1573-0646
    Schlagwort(e): docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
    Materialart: Digitale Medien
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  • 5
    ISSN: 1573-8744
    Schlagwort(e): pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
    Materialart: Digitale Medien
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  • 6
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    ISSN: 1573-8744
    Schlagwort(e): muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
    Materialart: Digitale Medien
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  • 7
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    ISSN: 1573-8744
    Schlagwort(e): anesthetic techniques ; continuous infusion ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
    Materialart: Digitale Medien
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  • 8
    ISSN: 1573-8744
    Schlagwort(e): psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
    Materialart: Digitale Medien
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 531-554 
    ISSN: 1573-8744
    Schlagwort(e): drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
    Materialart: Digitale Medien
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  • 10
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
    ISSN: 1573-8744
    Schlagwort(e): propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
    Materialart: Digitale Medien
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  • 11
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    ISSN: 1573-8744
    Schlagwort(e): desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
    Materialart: Digitale Medien
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  • 12
    ISSN: 1573-8744
    Schlagwort(e): prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
    Materialart: Digitale Medien
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  • 13
    Digitale Medien
    Digitale Medien
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    ISSN: 1573-8744
    Schlagwort(e): T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
    Materialart: Digitale Medien
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  • 14
    ISSN: 1573-904X
    Schlagwort(e): etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
    Materialart: Digitale Medien
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  • 15
    ISSN: 1573-904X
    Schlagwort(e): bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
    Materialart: Digitale Medien
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  • 16
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 1392-1398 
    ISSN: 1573-904X
    Schlagwort(e): topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
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  • 17
    ISSN: 1573-904X
    Schlagwort(e): submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
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  • 18
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 587-591 
    ISSN: 1573-904X
    Schlagwort(e): quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 19
    ISSN: 1573-904X
    Schlagwort(e): C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
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  • 20
    ISSN: 1573-904X
    Schlagwort(e): HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
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  • 21
    ISSN: 1573-904X
    Schlagwort(e): pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
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  • 22
    ISSN: 1573-904X
    Schlagwort(e): bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
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  • 23
    Digitale Medien
    Digitale Medien
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 309-323 
    ISSN: 1573-6830
    Schlagwort(e): cytochrome P450 ; enzyme inhibition ; enzyme induction ; pharmacokinetics ; drug interaction ; in vitro assessment ; clinical assessment
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract 1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man. 2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes. 3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data. 4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.
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  • 24
    Digitale Medien
    Digitale Medien
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 355-372 
    ISSN: 1573-6830
    Schlagwort(e): enantiomers ; racemic ; chiral ; stereoselective ; pharmacokinetics ; cytochrome P450 ; geometric isomers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract 1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.
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  • 25
    Digitale Medien
    Digitale Medien
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 443-466 
    ISSN: 1573-6830
    Schlagwort(e): selective serotonin reuptake inhibitors ; metabolism ; pharmacokinetics ; fluoxetine ; fluvoxamine ; paroxetine ; sertraline ; citalopram ; cytochrome P450
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract 1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.
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  • 26
    Digitale Medien
    Digitale Medien
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 373-409 
    ISSN: 1573-6830
    Schlagwort(e): antidepressants ; tricyclic ; metabolism ; hydroxy metabolites ; pharmacokinetics ; pharmacogenetics ; drug–drug interactions ; toxicity ; plasma concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract 1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.
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  • 27
    ISSN: 1573-904X
    Schlagwort(e): antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
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  • 28
    ISSN: 1573-904X
    Schlagwort(e): nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
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  • 29
    ISSN: 1573-904X
    Schlagwort(e): antisense phosphorothioate oligonucleotide ; stealth liposome ; pharmacokinetics ; monkey ; capillary gel electrophoresis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
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  • 30
    ISSN: 1573-904X
    Schlagwort(e): aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
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  • 31
    ISSN: 1573-904X
    Schlagwort(e): diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
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  • 32
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 1608-1615 
    ISSN: 1573-904X
    Schlagwort(e): tenidap ; pharmacokinetics ; EM algorithm ; nonlinear mixed-effects modelling ; covariates
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. Methods. Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. Results. Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. Conclusions. The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
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  • 33
    ISSN: 1573-904X
    Schlagwort(e): amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
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  • 34
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 176-185 
    ISSN: 1573-904X
    Schlagwort(e): pharmacokinetics ; pharmacodynamics ; pharmacology ; modeling
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
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  • 35
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 261-265 
    ISSN: 1573-904X
    Schlagwort(e): crystal habit ; trimethoprim suspension ; physical stability ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.
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  • 36
    Digitale Medien
    Digitale Medien
    Springer
    Pharmaceutical research 16 (1999), S. 309-313 
    ISSN: 1573-904X
    Schlagwort(e): hyperlipidemia ; hypercholesterolemia ; nifedipine ; pharmacokinetics ; protein binding ; rat
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg−1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82−2.02 to 5.27−11.05 mmol L−1 48 h post P407 administration (Ig kg−1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC0−∞, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0−∞ was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.
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  • 37
    ISSN: 1573-904X
    Schlagwort(e): WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The purpose of the present study was to examine the pharma-codynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
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  • 38
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Normile, D -- New York, N.Y. -- Science. 1998 Dec 11;282(5396):1975-6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874644" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animal Husbandry/*methods ; Animals ; Blastocyst ; Cattle/embryology/*genetics ; Cell Differentiation ; Cells, Cultured ; *Cloning, Organism ; Embryo Transfer/veterinary ; Fallopian Tubes/cytology ; Female ; Japan ; *Nuclear Transfer Techniques ; Oocytes ; Ovarian Follicle/cytology ; Pregnancy
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 39
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spear, P G -- New York, N.Y. -- Science. 1998 Dec 11;282(5396):1999-2000.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Northwestern University Medical School, Department of Microbiology-Immunology, Chicago, IL 60611, USA. p-spear@nwu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874652" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Bacterial Adhesion ; Cytoskeletal Proteins/genetics/*metabolism ; Dystroglycans ; Humans ; Laminin/metabolism ; Lassa Fever/*virology ; Lassa virus/*metabolism ; Leprosy/*microbiology ; Lymphocytic choriomeningitis virus/metabolism ; Membrane Glycoproteins/genetics/*metabolism ; Models, Biological ; Mycobacterium leprae/*metabolism ; Receptors, Virus/metabolism ; Schwann Cells/microbiology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 40
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abramson, P R -- Pinkerton, S D -- New York, N.Y. -- Science. 1998 Dec 11;282(5396):1993-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874650" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Anura/*genetics/physiology ; *Biological Evolution ; Male ; Selection, Genetic ; *Sexual Behavior, Animal ; *Vocalization, Animal
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 41
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adams, M W -- Stiefel, E I -- New York, N.Y. -- Science. 1998 Dec 4;282(5395):1842-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA. adams@bmb.uga.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874636" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Binding Sites ; Carbon Monoxide/chemistry ; Clostridium/*enzymology ; Crystallography, X-Ray ; Cyanides/chemistry ; Humans ; Hydrogen/*metabolism ; Hydrogenase/*chemistry/*metabolism ; Iron/chemistry ; Ligands ; Oxidation-Reduction ; Pyruvic Acid/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 42
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penney, B K -- New York, N.Y. -- Science. 1998 Dec 11;282(5396):1992-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874647" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Biological Evolution ; Drosophila/*genetics/physiology ; *Drosophila Proteins ; GTP-Binding Proteins/*genetics ; Genes, Helminth ; Genes, Insect ; Longevity ; Nematoda/*genetics/physiology ; Receptors, Cell Surface/*genetics ; *Receptors, G-Protein-Coupled ; Selection, Genetic
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 43
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, E -- New York, N.Y. -- Science. 1998 Dec 11;282(5396):1972-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874643" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Caenorhabditis elegans/cytology/*genetics/physiology ; Cell Lineage ; Chromosome Mapping ; DNA, Helminth/chemistry/genetics ; Evolution, Molecular ; Gene Expression Regulation ; *Genes, Helminth ; Genetic Techniques ; *Genome ; Humans ; Mutation ; *Sequence Analysis, DNA
    Print ISSN: 0036-8075
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 44
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-05
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, E -- New York, N.Y. -- Science. 1998 Dec 4;282(5395):1796.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9874626" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Crosses, Genetic ; Drosophila/*genetics ; Female ; *Genes, Insect ; HSP90 Heat-Shock Proteins/genetics/*physiology ; Insect Proteins/genetics/physiology ; Male ; *Mutation ; Temperature
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 45
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-09-15
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagmann, M -- New York, N.Y. -- Science. 1999 Aug 20;285(5431):1200-1, 1203.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10484727" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Acetylation ; Acetyltransferases/chemistry/metabolism ; Animals ; Cell Cycle Proteins/chemistry/metabolism ; Chromatin/chemistry/*metabolism/*ultrastructure ; *Gene Expression Regulation ; Histone Acetyltransferases ; Histones/*metabolism ; Methylation ; *Mitosis ; Phosphorylation ; Protein Structure, Secondary ; Protein-Arginine N-Methyltransferases/metabolism ; Transcription Factors ; p300-CBP Transcription Factors
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 46
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-12-28
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collignon, P -- New York, N.Y. -- Science. 1999 Dec 3;286(5446):1855-7.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10610574" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antibodies, Viral/analysis ; *Gammaretrovirus/immunology ; Humans ; Retroviridae Infections/diagnosis/*transmission ; *Swine/virology ; *Transplantation, Heterologous/adverse effects
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 47
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-05-18
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Service, R F -- New York, N.Y. -- Science. 1999 Apr 23;284(5414):578-9.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10328734" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cells, Cultured ; Electric Stimulation ; Electrodes ; Electrodes, Implanted ; *Electronics ; Electrophysiology ; Humans ; Nerve Net/*physiology ; Nervous System Diseases/*therapy ; Neurons/*physiology ; Rats ; Silicon ; *Transistors, Electronic
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 48
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-23
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lawler, C -- Erbisch, F -- New York, N.Y. -- Science. 1999 Jan 1;283(5398):33-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9917260" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Biotechnology ; Mice ; Mice, Transgenic ; *Patents as Topic ; Plants, Genetically Modified/*genetics ; United States
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 49
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-05-21
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagmann, M -- New York, N.Y. -- Science. 1999 Apr 30;284(5415):723, 725.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10336390" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Apoptosis ; Breast Neoplasms/*genetics/pathology ; *Disease Models, Animal ; Female ; *Genes, BRCA1 ; Genes, p53 ; Humans ; Mammary Glands, Animal/pathology ; Mammary Neoplasms, Animal/*genetics/pathology ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutation
    Print ISSN: 0036-8075
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 50
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-30
    Beschreibung: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs. Notch activity affects the implementation of differentiation, proliferation, and apoptotic programs, providing a general developmental tool to influence organ formation and morphogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Artavanis-Tsakonas, S -- Rand, M D -- Lake, R J -- NS26084/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 1999 Apr 30;284(5415):770-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Department of Cell Biology, Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10221902" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Apoptosis ; Cell Communication ; Cell Division ; Cell Nucleus/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Ligands ; Membrane Proteins/*physiology ; Receptors, Cell Surface/*physiology ; Receptors, Notch ; *Signal Transduction ; Transcription, Genetic
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 51
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-03
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crow, J F -- New York, N.Y. -- Science. 1999 Mar 12;283(5408):1651-2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, University of Wisconsin, Madison, WI 53706, USA. jfcrow@facstaff.wisc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10189318" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Carrier Proteins/*genetics/physiology ; Cell Nucleus/metabolism ; Cloning, Molecular ; Drosophila/*genetics/physiology ; *Drosophila Proteins ; *GTPase-Activating Proteins ; *Genes, Insect ; Male ; *Meiosis ; Nuclear Proteins/*genetics/physiology ; Sperm Maturation ; Spermatozoa/*physiology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 52
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-24
    Beschreibung: The lack of an adequate hominid fossil record in eastern Africa between 2 and 3 million years ago (Ma) has hampered investigations of early hominid phylogeny. Discovery of 2.5 Ma hominid cranial and dental remains from the Hata beds of Ethiopia's Middle Awash allows recognition of a new species of Australopithecus. This species is descended from Australopithecus afarensis and is a candidate ancestor for early Homo. Contemporary postcranial remains feature a derived humanlike humeral/femoral ratio and an apelike upper arm-to-lower arm ratio.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asfaw, B -- White, T -- Lovejoy, O -- Latimer, B -- Simpson, S -- Suwa, G -- New York, N.Y. -- Science. 1999 Apr 23;284(5414):629-35.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rift Valley Research Service, Post Office Box 5717, Addis Ababa, Ethiopia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10213683" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Biological Evolution ; Bones of Upper Extremity/anatomy & histology ; Dentition ; Ethiopia ; *Fossils ; History, Ancient ; Hominidae/anatomy & histology/*classification ; Humans ; Leg Bones/anatomy & histology ; Paleodontology ; Phylogeny ; Skull/anatomy & histology ; Terminology as Topic ; Tooth/anatomy & histology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 53
    facet.materialart.
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-12-28
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wickelgren, I -- New York, N.Y. -- Science. 1999 Dec 3;286(5446):1826-7.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10610569" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Astrocytes/cytology ; Cell Differentiation ; Cell Survival ; Embryo, Mammalian ; Mice ; Neurons/cytology ; Oligodendroglia/cytology ; Rats ; Spinal Cord/cytology/*physiology ; Spinal Cord Injuries/*therapy ; *Stem Cell Transplantation ; Stem Cells/cytology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 54
    facet.materialart.
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-12-28
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wickelgren, I -- New York, N.Y. -- Science. 1999 Nov 12;286(5443):1265-6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10610528" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Astrocytes/*enzymology ; Brain/*enzymology ; Cloning, Molecular ; Glutamic Acid/metabolism ; Neurons/metabolism ; Racemases and Epimerases/*genetics/metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism ; Serine/*biosynthesis/metabolism ; Stereoisomerism ; Synapses/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 55
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-05-21
    Beschreibung: Ran, a small guanosine triphosphatase, is suggested to have additional functions beyond its well-characterized role in nuclear trafficking. Guanosine triphosphate-bound Ran, but not guanosine diphosphate-bound Ran, stimulated polymerization of astral microtubules from centrosomes assembled on Xenopus sperm. Moreover, a Ran allele with a mutation in the effector domain (RanL43E) induced the formation of microtubule asters and spindle assembly, in the absence of sperm nuclei, in a gammaTuRC (gamma-tubulin ring complex)- and XMAP215 (Xenopus microtubule associated protein)-dependent manner. Therefore, Ran could be a key signaling molecule regulating microtubule polymerization during mitosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilde, A -- Zheng, Y -- GM56312-01/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1999 May 21;284(5418):1359-62.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Carnegie Institution of Washington, Department of Embryology, Baltimore, MD 21210, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10334991" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cell Extracts ; Cell Nucleus/metabolism ; Centrosome/physiology ; Dimethyl Sulfoxide/pharmacology ; Dyneins/physiology ; GTP Phosphohydrolases/genetics/*metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/*metabolism ; Male ; Microtubule-Associated Proteins/metabolism ; Microtubules/*metabolism/ultrastructure ; Mutation ; Nuclear Proteins/analysis/genetics/*metabolism/pharmacology ; Ovum ; Recombinant Fusion Proteins/metabolism/pharmacology ; Sperm Head/physiology ; Spindle Apparatus/chemistry/*metabolism/ultrastructure ; Tubulin/analysis/metabolism ; Xenopus ; *Xenopus Proteins ; ran GTP-Binding Protein
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 56
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-12-03
    Beschreibung: Polypeptides emerging from the ribosome must fold into stable three-dimensional structures and maintain that structure throughout their functional lifetimes. Maintaining quality control over protein structure and function depends on molecular chaperones and proteases, both of which can recognize hydrophobic regions exposed on unfolded polypeptides. Molecular chaperones promote proper protein folding and prevent aggregation, and energy-dependent proteases eliminate irreversibly damaged proteins. The kinetics of partitioning between chaperones and proteases determines whether a protein will be destroyed before it folds properly. When both quality control options fail, damaged proteins accumulate as aggregates, a process associated with amyloid diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wickner, S -- Maurizi, M R -- Gottesman, S -- New York, N.Y. -- Science. 1999 Dec 3;286(5446):1888-93.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4255, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10583944" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adenosine Triphosphatases/metabolism ; Amyloid/metabolism ; Animals ; Endopeptidases/*metabolism ; Eukaryotic Cells/metabolism ; Humans ; Models, Biological ; Molecular Chaperones/*metabolism ; Prions/metabolism ; Prokaryotic Cells/metabolism ; Protein Biosynthesis ; *Protein Folding ; Proteins/*chemistry/*metabolism ; Ubiquitins/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 57
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-23
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wickelgren, I -- New York, N.Y. -- Science. 1999 Jan 1;283(5398):14-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9917254" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Brain/metabolism ; Cells, Cultured ; Dimerization ; Drug Design ; Humans ; Neurons/*metabolism ; Potassium Channels/metabolism ; Rats ; Receptors, GABA-B/*chemistry/*metabolism ; Signal Transduction ; gamma-Aminobutyric Acid/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 58
    Publikationsdatum: 1999-04-30
    Beschreibung: Infection of macaques with chimeric simian-human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)-specific enveloped virus, SHIVSF162P, was compared with infection with the CXCR4 (X4)-specific SHIVSF33A.2. Despite comparable levels of viral replication, animals infected with the R5 and X4 SHIV had distinct pathogenic outcomes. SHIVSF162P caused a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion in peripheral CD4+ T cells, whereas infection with SHIVSF33A.2 caused a profound loss in peripheral T cells that was not paralleled in the intestine. These results suggest a critical role of co-receptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harouse, J M -- Gettie, A -- Tan, R C -- Blanchard, J -- Cheng-Mayer, C -- AI41945/AI/NIAID NIH HHS/ -- CA72822/CA/NCI NIH HHS/ -- R01 AI041945/AI/NIAID NIH HHS/ -- R01 CA072822/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1999 Apr 30;284(5415):816-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, 7th Floor, New York, NY 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10221916" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Acquired Immunodeficiency Syndrome/immunology/*virology ; Animals ; *CD4 Lymphocyte Count ; CD4-CD8 Ratio ; Chimera ; Colon/immunology ; HIV-1/genetics/*pathogenicity/physiology ; Immunity, Mucosal ; Intestinal Mucosa/immunology ; Jejunum/immunology ; Macaca mulatta ; Reassortant Viruses ; Receptors, CCR5/*metabolism ; Receptors, CXCR4/*metabolism ; Simian Acquired Immunodeficiency Syndrome/immunology/virology ; Simian Immunodeficiency Virus/genetics/*pathogenicity/physiology ; Viral Load ; Viremia ; Virus Replication
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 59
    Publikationsdatum: 1999-10-03
    Beschreibung: Precursors of alpha-defensin peptides require activation for bactericidal activity. In mouse small intestine, matrilysin colocalized with alpha-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors. Matrilysin-deficient (MAT-/-) mice lacked mature cryptdins and accumulated precursor molecules. Intestinal peptide preparations from MAT-/- mice had decreased antimicrobial activity. Orally administered bacteria survived in greater numbers and were more virulent in MAT-/- mice than in MAT+/+ mice. Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, C L -- Ouellette, A J -- Satchell, D P -- Ayabe, T -- Lopez-Boado, Y S -- Stratman, J L -- Hultgren, S J -- Matrisian, L M -- Parks, W C -- New York, N.Y. -- Science. 1999 Oct 1;286(5437):113-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, Division of Allergy and Pulmonary Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. wilson_c@kids.wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10506557" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Amino Acid Sequence ; Animals ; Catalysis ; Cytoplasmic Granules/enzymology ; Escherichia coli/growth & development ; Escherichia coli Infections/immunology/microbiology ; Female ; Humans ; *Immunity, Innate ; *Immunity, Mucosal ; Intestinal Mucosa/enzymology/immunology/microbiology ; Intestine, Small/enzymology/*immunology/microbiology ; Male ; Matrix Metalloproteinase 7 ; Metalloendopeptidases/genetics/*metabolism ; Mice ; Molecular Sequence Data ; Paneth Cells/enzymology ; Protein Precursors/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; Salmonella typhimurium/growth & development/pathogenicity ; Tissue Extracts/pharmacology
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  • 60
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    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-05-18
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Culotta, E -- New York, N.Y. -- Science. 1999 Apr 23;284(5414):572-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10328732" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Biological Evolution ; Ethiopia ; Facial Bones/anatomy & histology ; *Fossils ; History, Ancient ; *Hominidae/anatomy & histology/classification ; Humans ; Paleodontology ; Skull/anatomy & histology ; Tooth/anatomy & histology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 61
    Publikationsdatum: 1999-09-18
    Beschreibung: The antifungal defense of Drosophila is controlled by the spaetzle/Toll/cactus gene cassette. Here, a loss-of-function mutation in the gene encoding a blood serine protease inhibitor, Spn43Ac, was shown to lead to constitutive expression of the antifungal peptide drosomycin, and this effect was mediated by the spaetzle and Toll gene products. Spaetzle was cleaved by proteolytic enzymes to its active ligand form shortly after immune challenge, and cleaved Spaetzle was constitutively present in Spn43Ac-deficient flies. Hence, Spn43Ac negatively regulates the Toll signaling pathway, and Toll does not function as a pattern recognition receptor in the Drosophila host defense.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levashina, E A -- Langley, E -- Green, C -- Gubb, D -- Ashburner, M -- Hoffmann, J A -- Reichhart, J M -- New York, N.Y. -- Science. 1999 Sep 17;285(5435):1917-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UPR 9022 CNRS, Institut de Biologie Moleculaire et Cellulaire, 15 Rue Rene Descartes, Strasbourg 67084, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10489372" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antifungal Agents/*metabolism ; *Antimicrobial Cationic Peptides ; Body Patterning ; Drosophila/embryology/genetics/*immunology ; *Drosophila Proteins ; Escherichia coli/genetics/immunology ; Genes, Insect ; Hemolymph/metabolism ; Insect Proteins/*biosynthesis/genetics/metabolism/*physiology ; Membrane Glycoproteins/genetics/*physiology ; Micrococcus luteus/immunology ; Molecular Sequence Data ; Mutagenesis ; Peptides/genetics/metabolism ; *Receptors, Cell Surface ; Recombinant Fusion Proteins/genetics/metabolism ; Serine Proteinase Inhibitors/genetics/*metabolism ; Serpins/genetics/*metabolism ; Signal Transduction ; Toll-Like Receptors ; Up-Regulation
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 62
    Publikationsdatum: 1999-10-16
    Beschreibung: Dense genetic maps of human, mouse, and rat genomes that are based on coding genes and on microsatellite and single-nucleotide polymorphism markers have been complemented by precise gene homolog alignment with moderate-resolution maps of livestock, companion animals, and additional mammal species. Comparative genetic assessment expands the utility of these maps in gene discovery, in functional genomics, and in tracking the evolutionary forces that sculpted the genome organization of modern mammalian species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Brien, S J -- Menotti-Raymond, M -- Murphy, W J -- Nash, W G -- Wienberg, J -- Stanyon, R -- Copeland, N G -- Jenkins, N A -- Womack, J E -- Marshall Graves, J A -- New York, N.Y. -- Science. 1999 Oct 15;286(5439):458-62, 479-81.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702-1201, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10521336" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Animals, Domestic/genetics ; Base Sequence ; *Chromosome Mapping ; *Evolution, Molecular ; Genetic Markers ; *Genome ; *Genome, Human ; Humans ; Mammals/*genetics ; Mutation ; *Phylogeny ; Rodentia/genetics
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 63
    Publikationsdatum: 1999-06-12
    Beschreibung: To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein (GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediatedtransmission observed during long-term potentiation and activity-dependent synaptic maturation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shi, S H -- Hayashi, Y -- Petralia, R S -- Zaman, S H -- Wenthold, R J -- Svoboda, K -- Malinow, R -- New York, N.Y. -- Science. 1999 Jun 11;284(5421):1811-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10364548" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cells, Cultured ; Dendrites/*metabolism/ultrastructure ; Electric Stimulation ; Hippocampus/cytology/physiology ; Humans ; Long-Term Potentiation ; *Neuronal Plasticity ; Neurons/*physiology ; Organ Culture Techniques ; Rats ; Receptor Aggregation ; Receptors, AMPA/*metabolism ; Receptors, N-Methyl-D-Aspartate/*physiology ; Recombinant Fusion Proteins/metabolism ; Synapses/metabolism/*physiology ; Synaptic Transmission ; Tetany
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 64
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-12-28
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, I A -- New York, N.Y. -- Science. 1999 Dec 3;286(5446):1867-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. wilson@scripps.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10610577" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antigens/*chemistry/immunology/metabolism ; Binding Sites ; CD4-Positive T-Lymphocytes/immunology/metabolism ; CD8-Positive T-Lymphocytes/immunology/metabolism ; Crystallography, X-Ray ; Histocompatibility Antigens Class I/chemistry/immunology/metabolism ; Histocompatibility Antigens Class II/*chemistry/immunology/metabolism ; Mice ; Models, Molecular ; Peptides/chemistry/immunology/metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Receptors, Antigen, T-Cell, alpha-beta/*chemistry/immunology/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 65
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-02-05
    Beschreibung: Traditionally, the interest of population and evolutionary biologists in infectious diseases has been almost exclusively in their role as agents of natural selection in higher organisms. Recently, this interest has expanded to include the genetic structure and evolution of microparasite populations, the mechanisms of pathogenesis and the immune response, and the population biology, ecology, and evolutionary consequences of medical and public health interventions. This article describes recent work in these areas, emphasizing the ways in which quantitative, population-biological approaches have been contributing to the understanding of infectious disease and the design and evaluation of interventions for their treatment and prevention.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levin, B R -- Lipsitch, M -- Bonhoeffer, S -- New York, N.Y. -- Science. 1999 Feb 5;283(5403):806-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Emory University, 1510 Clifton Road, Atlanta, GA 30322, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9933155" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Bacterial Physiological Phenomena ; *Biological Evolution ; Drug Resistance, Microbial ; Humans ; Infection/immunology/*microbiology ; Molecular Epidemiology ; Parasites/genetics/physiology ; Parasitic Diseases/immunology/*parasitology ; Population Dynamics ; Vaccination ; Virus Physiological Phenomena
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 66
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-08-28
    Beschreibung: Class II transactivator (CIITA) is a global transcriptional coactivator of human leukocyte antigen-D (HLA-D) genes. CIITA contains motifs similar to guanosine triphosphate (GTP)-binding proteins. This report shows that CIITA binds GTP, and mutations in these motifs decrease its GTP-binding and transactivation activity. Substitution of these motifs with analogous sequences from Ras restores CIITA function. CIITA exhibits little GTPase activity, yet mutations in CIITA that confer GTPase activity reduce transcriptional activity. GTP binding by CIITA correlates with nuclear import. Thus, unlike other GTP-binding proteins, CIITA is involved in transcriptional activation that uses GTP binding to facilitate its own nuclear import.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harton, J A -- Cressman, D E -- Chin, K C -- Der, C J -- Ting, J P -- AI29564/AI/NIAID NIH HHS/ -- AI41751/AI/NIAID NIH HHS/ -- AI45580/AI/NIAID NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Aug 27;285(5432):1402-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10464099" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; COS Cells ; Cell Line ; Cell Nucleus/*metabolism ; GTP-Binding Proteins/chemistry/genetics/*metabolism ; *Genes, MHC Class II ; Guanosine Triphosphate/*metabolism ; HLA-DR Antigens/genetics ; Humans ; Mutation ; *Nuclear Proteins ; Promoter Regions, Genetic ; Temperature ; Trans-Activators/chemistry/genetics/*metabolism ; Transcription Factors/metabolism ; *Transcriptional Activation
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 67
    Publikationsdatum: 1999-09-25
    Beschreibung: Mass mortalities due to disease outbreaks have recently affected major taxa in the oceans. For closely monitored groups like corals and marine mammals, reports of the frequency of epidemics and the number of new diseases have increased recently. A dramatic global increase in the severity of coral bleaching in 1997-98 is coincident with high El Nino temperatures. Such climate-mediated, physiological stresses may compromise host resistance and increase frequency of opportunistic diseases. Where documented, new diseases typically have emerged through host or range shifts of known pathogens. Both climate and human activities may have also accelerated global transport of species, bringing together pathogens and previously unexposed host populations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harvell, C D -- Kim, K -- Burkholder, J M -- Colwell, R R -- Epstein, P R -- Grimes, D J -- Hofmann, E E -- Lipp, E K -- Osterhaus, A D -- Overstreet, R M -- Porter, J W -- Smith, G W -- Vasta, G R -- 1PO1 ES09563/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 1999 Sep 3;285(5433):1505-10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10498537" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Aquaculture ; *Climate ; Cnidaria ; *Disease Outbreaks/*veterinary ; Humans ; Infection/epidemiology/*etiology/transmission/*veterinary ; *Marine Biology ; Oceans and Seas ; Water Pollution
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 68
    Publikationsdatum: 1999-12-11
    Beschreibung: Natural antibodies are often dismissed from immunological analysis as "background," but they may play an important role in conferring immunity against infections. In antibody-free mice infected with various viruses or with Listeria monocytogenes, viral or bacterial titers in peripheral organs, including the kidney and brain, were 10 to 100 times greater than in antibody-competent mice (and enhanced their susceptibility to some infections), and titers in secondary lymphoid organs were 10 to 100 times lower than in antibody-competent mice. Thus, natural antibodies play a crucial role by preventing pathogen dissemination to vital organs and by improving immunogenicity through enhanced antigen-trapping in secondary lymphoid organs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ochsenbein, A F -- Fehr, T -- Lutz, C -- Suter, M -- Brombacher, F -- Hengartner, H -- Zinkernagel, R M -- New York, N.Y. -- Science. 1999 Dec 10;286(5447):2156-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Experimental Immunology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10591647" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antibodies, Bacterial/blood/immunology ; Antibodies, Viral/blood/immunology ; Bacterial Infections/*immunology/microbiology ; Germ-Free Life ; *Immunity, Innate ; Immunoglobulin M/blood/*immunology ; Kidney/microbiology/virology ; Listeria monocytogenes/immunology/physiology ; Listeriosis/immunology ; Lymphocytic choriomeningitis virus/immunology/physiology ; Lymphoid Tissue/immunology/microbiology/virology ; Mice ; Mice, Inbred C57BL ; Neutralization Tests ; Rhabdoviridae Infections/immunology/virology ; Specific Pathogen-Free Organisms ; Spleen/microbiology/virology ; Vaccinia virus/immunology/physiology ; Vesicular stomatitis Indiana virus/immunology/physiology ; Virus Diseases/*immunology/virology ; Virus Replication
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 69
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-23
    Beschreibung: The plant hormone abscisic acid (ABA) regulates potassium and chloride ion channels at the plasma membrane of guard cells, leading to stomatal closure that reduces transpirational water loss from the leaf. The tobacco Nt-SYR1 gene encodes a syntaxin that is associated with the plasma membrane. Syntaxins and related SNARE proteins aid intracellular vesicle trafficking, fusion, and secretion. Disrupting Nt-Syr1 function by cleavage with Clostridium botulinum type C toxin or competition with a soluble fragment of Nt-Syr1 prevents potassium and chloride ion channel response to ABA in guard cells and implicates Nt-Syr1 in an ABA-signaling cascade.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leyman, B -- Geelen, D -- Quintero, F J -- Blatt, M R -- New York, N.Y. -- Science. 1999 Jan 22;283(5401):537-40.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Plant Physiology and Biophysics, University of London, Wye College, Wye, Kent TN25 5AH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9915701" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Abscisic Acid/*pharmacology ; Amino Acid Sequence ; Animals ; Botulinum Toxins/metabolism ; Cell Membrane/physiology ; Chloride Channels/*physiology ; Genes, Plant ; Genetic Complementation Test ; Ion Channel Gating/drug effects ; Membrane Proteins/chemistry/genetics/*physiology ; Molecular Sequence Data ; Oocytes ; Patch-Clamp Techniques ; Plant Growth Regulators/*pharmacology ; Plant Leaves/*physiology ; *Plants, Toxic ; Potassium Channels/*physiology ; Qa-SNARE Proteins ; Saccharomyces cerevisiae/genetics/growth & development ; Signal Transduction ; Tobacco/genetics/*physiology ; Xenopus
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 70
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-10-16
    Beschreibung: Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic phenomena have major economic and medical relevance, and several, such as imprinting and paramutation, violate Mendelian principles. Recent discoveries link the recognition of nucleic acid sequence homology to the targeting of DNA methylation, chromosome remodeling, and RNA turnover. Although epigenetic mechanisms help to protect cells from parasitic elements, this defense can complicate the genetic manipulation of plants and animals. Essential for normal development, epigenetic controls become misdirected in cancer cells and other human disease syndromes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolffe, A P -- Matzke, M A -- New York, N.Y. -- Science. 1999 Oct 15;286(5439):481-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Embryology, National Institute of Child Heath and Human Development, NIH, Building 18T, Room 106, Bethesda, MD 20892-5431, USA. awlme@helix.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10521337" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; DNA Methylation ; Evolution, Molecular ; *Gene Expression Regulation ; Gene Expression Regulation, Developmental ; *Gene Silencing ; Genetic Diseases, Inborn/genetics ; Genome ; Humans ; Neoplasms/genetics ; RNA/genetics/metabolism ; Repetitive Sequences, Nucleic Acid
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  • 71
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-06-26
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉L'Heureux, N -- Germain, L -- Auger, F A -- New York, N.Y. -- Science. 1999 Jun 4;284(5420):1621-2.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10383338" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Biomedical Engineering ; *Blood Vessels/physiology/transplantation ; *Culture Techniques ; Dogs ; Endothelium, Vascular ; Graft Survival ; Humans ; Transplantation, Heterologous
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 72
    Publikationsdatum: 1999-10-09
    Beschreibung: CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shih, N Y -- Li, J -- Karpitskii, V -- Nguyen, A -- Dustin, M L -- Kanagawa, O -- Miner, J H -- Shaw, A S -- New York, N.Y. -- Science. 1999 Oct 8;286(5438):312-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Immunology and Department of Pathology, Washington University, Saint Louis, MO 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10514378" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adaptor Proteins, Signal Transducing ; Animals ; Basement Membrane/ultrastructure ; Cytoskeletal Proteins ; Epithelial Cells/metabolism/ultrastructure ; Extracellular Matrix Proteins/metabolism ; Glomerular Mesangium/metabolism/ultrastructure ; Intercellular Junctions/metabolism/ultrastructure ; Kidney Glomerulus/blood supply/*metabolism/*ultrastructure ; Lymphocyte Activation ; Membrane Proteins ; Mice ; Mice, Knockout ; Microscopy, Electron ; Nephrotic Syndrome/*congenital/genetics/metabolism/pathology ; Proteins/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; T-Lymphocytes/immunology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 73
    Publikationsdatum: 1999-11-05
    Beschreibung: Glutamatergic neurotransmission is controlled by presynaptic metabotropic glutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-terminal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate-binding protein (G protein) betagamma subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmodulin antagonists inhibit G protein-mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neurotransmission via presynaptic mGluRs. These results reveal a novel mechanism of presynaptic modulation in which Ca(2+)-calmodulin is required to release G protein betagamma subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Connor, V -- El Far, O -- Bofill-Cardona, E -- Nanoff, C -- Freissmuth, M -- Karschin, A -- Airas, J M -- Betz, H -- Boehm, S -- New York, N.Y. -- Science. 1999 Nov 5;286(5442):1180-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10550060" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Amino Acid Sequence ; Animals ; Calcium/metabolism ; Calmodulin/antagonists & inhibitors/*metabolism ; Cells, Cultured ; Dimerization ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; GTP-Binding Proteins/*metabolism ; Glutamic Acid/*metabolism ; Hippocampus/cytology/metabolism ; Humans ; Mice ; Molecular Sequence Data ; Neurons/metabolism ; Potassium Channels/metabolism ; *Potassium Channels, Inwardly Rectifying ; Presynaptic Terminals/metabolism ; Propionates/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/antagonists & inhibitors/*metabolism ; Recombinant Fusion Proteins/metabolism ; Sesterterpenes ; Signal Transduction ; Swine ; *Synaptic Transmission ; Terpenes/pharmacology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 74
    Publikationsdatum: 1999-02-26
    Beschreibung: Chlamydia infections are epidemiologically linked to human heart disease. A peptide from the murine heart muscle-specific alpha myosin heavy chain that has sequence homology to the 60-kilodalton cysteine-rich outer membrane proteins of Chlamydia pneumoniae, C. psittaci, and C. trachomatis was shown to induce autoimmune inflammatory heart disease in mice. Injection of the homologous Chlamydia peptides into mice also induced perivascular inflammation, fibrotic changes, and blood vessel occlusion in the heart, as well as triggering T and B cell reactivity to the homologous endogenous heart muscle-specific peptide. Chlamydia DNA functioned as an adjuvant in the triggering of peptide-induced inflammatory heart disease. Infection with C. trachomatis led to the production of autoantibodies to heart muscle-specific epitopes. Thus, Chlamydia-mediated heart disease is induced by antigenic mimicry of a heart muscle-specific protein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bachmaier, K -- Neu, N -- de la Maza, L M -- Pal, S -- Hessel, A -- Penninger, J M -- New York, N.Y. -- Science. 1999 Feb 26;283(5406):1335-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Amgen Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10037605" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adoptive Transfer ; Amino Acid Sequence ; Animals ; Antigens, Bacterial/chemistry/immunology ; Autoantibodies/biosynthesis ; Autoimmune Diseases/immunology/*microbiology/pathology ; B-Lymphocytes/immunology ; Bacterial Outer Membrane Proteins/chemistry/*immunology ; CD4-Positive T-Lymphocytes/immunology ; Chlamydia/*immunology ; Chlamydia Infections/complications/*immunology ; Chlamydia trachomatis/immunology ; CpG Islands ; Humans ; Immunization ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; *Molecular Mimicry ; Molecular Sequence Data ; Myocarditis/immunology/*microbiology/pathology ; Myocardium/immunology/pathology ; Myosin Heavy Chains/chemistry/*immunology ; Oligodeoxyribonucleotides/immunology ; Sequence Homology, Amino Acid
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 75
    Publikationsdatum: 1999-05-29
    Beschreibung: Endoglin is a transforming growth factor-beta (TGF-beta) binding protein expressed on the surface of endothelial cells. Loss-of-function mutations in the human endoglin gene ENG cause hereditary hemorrhagic telangiectasia (HHT1), a disease characterized by vascular malformations. Here it is shown that by gestational day 11.5, mice lacking endoglin die from defective vascular development. However, in contrast to mice lacking TGF-beta, vasculogenesis was unaffected. Loss of endoglin caused poor vascular smooth muscle development and arrested endothelial remodeling. These results demonstrate that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, D Y -- Sorensen, L K -- Brooke, B S -- Urness, L D -- Davis, E C -- Taylor, D G -- Boak, B B -- Wendel, D P -- K08 HL03490-03/HL/NHLBI NIH HHS/ -- T35 HL07744-06/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 1999 May 28;284(5419):1534-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Human Molecular Biology and Genetics, Department of Human Genetics, Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112-5330, USA. dean.li@hci.utah.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10348742" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antigens, CD ; Antigens, CD31/analysis ; Blood Vessels/cytology/*embryology/metabolism ; Cell Differentiation ; Crosses, Genetic ; Endothelium, Vascular/cytology/*embryology/metabolism ; Female ; Gene Targeting ; In Situ Hybridization ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron ; Muscle, Smooth, Vascular/cytology/*embryology ; *Neovascularization, Physiologic ; Receptors, Cell Surface ; Signal Transduction ; Transforming Growth Factor beta/metabolism ; Vascular Cell Adhesion Molecule-1/genetics/*physiology ; Yolk Sac/ultrastructure
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 76
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-07-03
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolpoff, M H -- New York, N.Y. -- Science. 1999 Jun 11;284(5421):1774-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10391795" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Biological Evolution ; Hominidae/*classification/genetics ; Humans ; Phylogeny
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 77
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-03-26
    Beschreibung: The carboxyl-terminal domain of colicin E5 was shown to inhibit protein synthesis of Escherichia coli. Its target, as revealed through in vivo and in vitro experiments, was not ribosomes as in the case of E3, but the transfer RNAs (tRNAs) for Tyr, His, Asn, and Asp, which contain a modified base, queuine, at the wobble position of each anticodon. The E5 carboxyl-terminal domain hydrolyzed these tRNAs just on the 3' side of this nucleotide. Tight correlation was observed between the toxicity of E5 and the cleavage of intracellular tRNAs of this group, implying that these tRNAs are the primary targets of colicin E5.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ogawa, T -- Tomita, K -- Ueda, T -- Watanabe, K -- Uozumi, T -- Masaki, H -- New York, N.Y. -- Science. 1999 Mar 26;283(5410):2097-100.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biotechnology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10092236" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Anticodon/*metabolism ; Bacterial Proteins/biosynthesis/genetics/pharmacology ; Base Sequence ; Cloning, Molecular ; Colicins/genetics/*metabolism/pharmacology ; Escherichia coli/drug effects/metabolism ; *Escherichia coli Proteins ; Guanine/analogs & derivatives/analysis ; Molecular Sequence Data ; RNA, Bacterial/chemistry/*metabolism ; RNA, Ribosomal, 16S/metabolism ; RNA, Transfer, Amino Acid-Specific/chemistry/*metabolism ; RNA, Transfer, Asn/chemistry/metabolism ; RNA, Transfer, Asp/chemistry/metabolism ; RNA, Transfer, His/chemistry/metabolism ; RNA, Transfer, Tyr/chemistry/metabolism ; Ribonucleases/genetics/*metabolism/pharmacology ; Ribosomes/metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 78
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-07-31
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wong, V -- Goodenough, D A -- New York, N.Y. -- Science. 1999 Jul 2;285(5424):62.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10428705" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Calcium Channels/metabolism ; Cell Membrane/metabolism/ultrastructure ; Claudins ; Cloning, Molecular ; Humans ; Ion Channels ; Ion Transport ; Kidney Diseases/genetics/*metabolism ; Kidney Tubules/*metabolism/ultrastructure ; Lipid Bilayers/metabolism ; Magnesium/blood/*metabolism ; Magnesium Deficiency/genetics/*metabolism ; Membrane Proteins/genetics/*physiology ; Mutation ; Tight Junctions/*metabolism
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 79
    Publikationsdatum: 1999-07-20
    Beschreibung: Graft versus host disease, an alloimmune attack on host tissues mounted by donor T cells, is the most important toxicity of allogeneic bone marrow transplantation. The mechanism by which allogeneic T cells are initially stimulated is unknown. In a murine allogeneic bone marrow transplantation model it was found that, despite the presence of numerous donor antigen-presenting cells, only host-derived antigen-presenting cells initiated graft versus host disease. Thus, strategies for preventing graft versus host disease could be developed that are based on inactivating host antigen-presenting cells. Such strategies could expand the safety and application of allogeneic bone marrow transplantation in treatment of common genetic and neoplastic diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shlomchik, W D -- Couzens, M S -- Tang, C B -- McNiff, J -- Robert, M E -- Liu, J -- Shlomchik, M J -- Emerson, S G -- P50HL-54516/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 1999 Jul 16;285(5426):412-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10411505" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antigen-Presenting Cells/*immunology ; Bone Marrow Transplantation/adverse effects/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Dendritic Cells/immunology ; Graft vs Host Disease/immunology/*prevention & control ; H-2 Antigens/immunology ; Lymph Nodes/immunology ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Mice, Knockout ; Minor Histocompatibility Antigens/immunology ; Spleen/immunology ; Transplantation Chimera
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 80
    Publikationsdatum: 1999-04-09
    Beschreibung: Imprinted genes display parent-of-origin-dependent monoallelic expression that apparently regulates complex mammalian traits, including growth and behavior. The Peg3 gene is expressed in embryos and the adult brain from the paternal allele only. A mutation in the Peg3 gene resulted in growth retardation, as well as a striking impairment of maternal behavior that frequently resulted in death of the offspring. This result may be partly due to defective neuronal connectivity, as well as reduced oxytocin neurons in the hypothalamus, because mutant mothers were deficient in milk ejection. This study provides further insights on the evolution of epigenetic regulation of imprinted gene dosage in modulating mammalian growth and behavior.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, L -- Keverne, E B -- Aparicio, S A -- Ishino, F -- Barton, S C -- Surani, M A -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 1999 Apr 9;284(5412):330-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome CRC Institute of Cancer and Developmental Biology, and Physiological Laboratory, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10195900" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Animals, Newborn ; Brain/metabolism ; Crosses, Genetic ; Female ; Gene Expression ; Gene Targeting ; *Genomic Imprinting ; *Growth ; Hypothalamus/cytology/metabolism ; Kruppel-Like Transcription Factors ; Lactation ; Male ; *Maternal Behavior ; Mice ; Mutation ; Neural Pathways ; Neurons/metabolism ; Oxytocin/metabolism ; Phenotype ; *Protein Kinases ; Proteins/genetics/*physiology ; *Transcription Factors ; *Weight Gain
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 81
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-02-19
    Beschreibung: A single kinesin molecule can move "processively" along a microtubule for more than 1 micrometer before detaching from it. The prevailing explanation for this processive movement is the "walking model," which envisions that each of two motor domains (heads) of the kinesin molecule binds coordinately to the microtubule. This implies that each kinesin molecule must have two heads to "walk" and that a single-headed kinesin could not move processively. Here, a motor-domain construct of KIF1A, a single-headed kinesin superfamily protein, was shown to move processively along the microtubule for more than 1 micrometer. The movement along the microtubules was stochastic and fitted a biased Brownian-movement model.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Y -- Hirokawa, N -- New York, N.Y. -- Science. 1999 Feb 19;283(5405):1152-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10024239" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; Catalytic Domain ; Diffusion ; Drosophila ; Kinesin/chemistry/*metabolism ; Kinetics ; Microscopy, Fluorescence ; Microtubules/*metabolism ; Models, Chemical ; Molecular Motor Proteins/chemistry/*metabolism ; Molecular Sequence Data ; Nerve Tissue Proteins/chemistry/*metabolism ; Recombinant Fusion Proteins ; Stochastic Processes ; Thermodynamics
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 82
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-02
    Beschreibung: A general problem in biology is how to incorporate information about evolutionary history and adaptation into taxonomy. The problem is exemplified in attempts to define our own genus, Homo. Here conventional criteria for allocating fossil species to Homo are reviewed and are found to be either inappropriate or inoperable. We present a revised definition, based on verifiable criteria, for Homo and conclude that two species, Homo habilis and Homo rudolfensis, do not belong in the genus. The earliest taxon to satisfy the criteria is Homo ergaster, or early African Homo erectus, which currently appears in the fossil record at about 1.9 million years ago.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wood, B -- Collard, M -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 1999 Apr 2;284(5411):65-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anthropology, George Washington University, 2110 G Street NW, Washington, DC 20052, USA. bwood@gwu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10102822" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adaptation, Physiological ; Animals ; Biological Evolution ; Body Constitution ; Brain/anatomy & histology ; *Fossils ; Hominidae/anatomy & histology/*classification ; Humans ; Jaw/anatomy & histology ; Locomotion ; Phylogeny ; Terminology as Topic
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 83
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-09-04
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bagla, P -- New York, N.Y. -- Science. 1999 Aug 13;285(5430):997.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10475848" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): *Animal Experimentation ; *Animal Welfare ; Animals ; *Animals, Laboratory ; *Drug Evaluation, Preclinical ; Government Regulation ; India ; *Macaca mulatta
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 84
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-24
    Beschreibung: Retroviral DNA integration is catalyzed by the viral protein integrase. Here, it is shown that DNA-dependent protein kinase (DNA-PK), a host cell protein, also participates in the reaction. DNA-PK-deficient murine scid cells infected with three different retroviruses showed a substantial reduction in retroviral DNA integration and died by apoptosis. Scid cell killing was not observed after infection with an integrase-defective virus, suggesting that abortive integration is the trigger for death in these DNA repair-deficient cells. These results suggest that the initial events in retroviral integration are detected as DNA damage by the host cell and that completion of the integration process requires the DNA-PK-mediated repair pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Daniel, R -- Katz, R A -- Skalka, A M -- AI40721/AI/NIAID NIH HHS/ -- AI40835/AI/NIAID NIH HHS/ -- CA71515/CA/NCI NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Apr 23;284(5414):644-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10213687" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Apoptosis ; CHO Cells ; Cell Survival ; Cells, Cultured ; Cricetinae ; DNA Damage ; *DNA Repair ; DNA, Viral/*genetics/metabolism ; DNA-Activated Protein Kinase ; *DNA-Binding Proteins ; Genetic Vectors ; HIV-1/genetics ; Integrases/genetics/metabolism ; Mice ; Mutation ; Protein-Serine-Threonine Kinases/*metabolism ; Retroviridae/*genetics/physiology ; *Virus Integration ; Virus Replication
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 85
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-07-31
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bagla, P -- New York, N.Y. -- Science. 1999 Jul 9;285(5425):180-1.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10428709" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): *Animal Experimentation ; Animal Welfare/*legislation & jurisprudence ; Animals ; *Animals, Laboratory ; *Government Regulation ; India ; *Research
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 86
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-05-21
    Beschreibung: The nucleotide exchange activity of RCC1, the only known nucleotide exchange factor for Ran, a Ras-like small guanosine triphosphatase, was required for microtubule aster formation with or without demembranated sperm in Xenopus egg extracts arrested in meiosis II. Consistently, in the RCC1-depleted egg extracts, Ran guanosine triphosphate (RanGTP), but not Ran guanosine diphosphate (RanGDP), induced self-organization of microtubule asters, and the process required the activity of dynein. Thus, Ran was shown to regulate formation of the microtubule network.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ohba, T -- Nakamura, M -- Nishitani, H -- Nishimoto, T -- New York, N.Y. -- Science. 1999 May 21;284(5418):1356-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Maidashi Higashi-ku, Fukuoka 812-8582, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10334990" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Cell Cycle Proteins ; Cell Extracts ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism ; Dyneins/metabolism ; Female ; GTP Phosphohydrolases/*metabolism ; *Guanine Nucleotide Exchange Factors ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/*metabolism ; Male ; Microtubules/chemistry/*metabolism/ultrastructure ; Nuclear Proteins/analysis/*metabolism ; Ovum ; Recombinant Proteins/metabolism ; Sperm Head/physiology ; Spindle Apparatus/chemistry/*metabolism/ultrastructure ; Xenopus ; *Xenopus Proteins ; ran GTP-Binding Protein
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 87
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-08-24
    Beschreibung: Clathrin-mediated endocytosis is initiated by the recruitment of the clathrin adaptor protein AP-2 to the plasma membrane where the membrane protein synaptotagmin is thought to act as a docking site. AP-2 also interacts with endocytic motifs present in other cargo proteins. Peptides with a tyrosine-based endocytic motif stimulated binding of AP-2 to synaptotagmin and enhanced AP-2 recruitment to the plasma membrane of neuronal and non-neuronal cells. This suggests a mechanism by which nucleation of clathrin-coated pits is stimulated by the loading of cargo proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haucke, V -- De Camilli, P -- CA46128/CA/NCI NIH HHS/ -- NS36252/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 1999 Aug 20;285(5431):1268-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10455054" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adaptor Protein Complex alpha Subunits ; Adaptor Proteins, Vesicular Transport ; Animals ; Binding Sites ; CHO Cells ; *Calcium-Binding Proteins ; Cattle ; Cell Membrane/metabolism ; Clathrin/*metabolism ; Coated Pits, Cell-Membrane/*metabolism ; Cricetinae ; *Endocytosis ; Membrane Glycoproteins/chemistry/*metabolism ; Membrane Proteins/*metabolism ; Nerve Tissue Proteins/chemistry/*metabolism ; Neurons/metabolism ; Oligopeptides/chemistry/metabolism/*pharmacology ; Phospholipase D/metabolism ; Protein Binding ; Rats ; Recombinant Fusion Proteins/metabolism ; Synaptic Membranes/*metabolism ; Synaptotagmins ; Tyrosine/chemistry
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 88
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-08-24
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Woodruff, D S -- New York, N.Y. -- Science. 1999 Aug 6;285(5429):836.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10454930" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Behavior, Animal ; Culture ; *Genetic Variation ; Pan troglodytes/*genetics
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 89
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-07-31
    Beschreibung: Many immune receptors are composed of separate ligand-binding and signal-transducing subunits. In natural killer (NK) and T cells, DAP10 was identified as a cell surface adaptor protein in an activating receptor complex with NKG2D, a receptor for the stress-inducible and tumor-associated major histocompatibility complex molecule MICA. Within the DAP10 cytoplasmic domain, an Src homology 2 (SH2) domain-binding site was capable of recruiting the p85 subunit of the phosphatidylinositol 3-kinase (PI 3-kinase), providing for NKG2D-dependent signal transduction. Thus, NKG2D-DAP10 receptor complexes may activate NK and T cell responses against MICA-bearing tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, J -- Song, Y -- Bakker, A B -- Bauer, S -- Spies, T -- Lanier, L L -- Phillips, J H -- AI30581/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 1999 Jul 30;285(5428):730-2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10426994" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Amino Acid Sequence ; Animals ; Binding Sites ; Cell Line ; Cytotoxicity, Immunologic ; Humans ; Killer Cells, Natural/*immunology/metabolism ; Ligands ; *Lymphocyte Activation ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Molecular Sequence Data ; NK Cell Lectin-Like Receptor Subfamily K ; Neoplasms/immunology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Phosphotyrosine/metabolism ; Receptors, Immunologic/chemistry/genetics/*metabolism ; Receptors, Natural Killer Cell ; Signal Transduction ; T-Lymphocytes/*immunology/metabolism ; Tumor Cells, Cultured ; src Homology Domains
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 90
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-09-25
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bagla, P -- New York, N.Y. -- Science. 1999 Sep 3;285(5433):1480-1.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10498530" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): *Animal Communication ; Animals ; Anura/*physiology ; Female ; Grasshoppers/*physiology ; Male
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 91
    Publikationsdatum: 1999-07-03
    Beschreibung: Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayakawa, K -- Asano, M -- Shinton, S A -- Gui, M -- Allman, D -- Stewart, C L -- Silver, J -- Hardy, R R -- New York, N.Y. -- Science. 1999 Jul 2;285(5424):113-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA. K_Hayakawa@fccc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10390361" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Aging/immunology ; Animals ; Antigens, CD5/analysis ; Antigens, Thy-1/*immunology ; Autoantibodies/*biosynthesis/blood/immunology ; Autoantigens/*immunology ; B-Lymphocyte Subsets/*immunology ; Genes, Immunoglobulin ; Hybridomas ; Immunity, Innate ; Immunologic Surveillance ; Mice ; Mice, SCID ; Mice, Transgenic ; Receptors, Antigen, B-Cell/immunology ; Signal Transduction ; T-Lymphocytes/immunology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 92
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    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-09
    Beschreibung: Phosphorylation of inhibitor of kappa B (IkappaB) proteins is an important step in the activation of the transcription nuclear factor kappa B (NF-kappaB) and requires two IkappaB kinases, IKK1 (IKKalpha) and IKK2 (IKKbeta). Mice that are devoid of the IKK2 gene had extensive liver damage from apoptosis and died as embryos, but these mice could be rescued by the inactivation of the gene encoding tumor necrosis factor receptor 1. Mouse embryonic fibroblast cells that were isolated from IKK2-/- embryos showed a marked reduction in tumor necrosis factor-alpha (TNF-alpha)- and interleukin-1alpha-induced NF-kappaB activity and an enhanced apoptosis in response to TNF-alpha. IKK1 associated with NF-kappaB essential modulator (IKKgamma/IKKAP1), another component of the IKK complex. These results show that IKK2 is essential for mouse development and cannot be substituted with IKK1.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Q -- Van Antwerp, D -- Mercurio, F -- Lee, K F -- Verma, I M -- New York, N.Y. -- Science. 1999 Apr 9;284(5412):321-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Salk Institute, La Jolla, CA 92037, USA. Signal Pharmaceuticals, San Diego, CA 92121, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10195897" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Apoptosis ; Cell Line ; DNA-Binding Proteins/metabolism ; Embryonic and Fetal Development ; Gene Targeting ; I-kappa B Kinase ; I-kappa B Proteins ; Interleukin-1/pharmacology ; Liver/cytology/*embryology ; Mice ; NF-kappa B/metabolism ; Phosphorylation ; Polymerase Chain Reaction ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Receptors, Tumor Necrosis Factor/genetics/metabolism ; Recombinant Fusion Proteins/metabolism ; Sequence Deletion ; Signal Transduction ; Transcription Factor RelA ; Transcription Factors/metabolism ; Tumor Necrosis Factor-alpha/pharmacology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 93
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-09-11
    Beschreibung: Deleterious mutations with very small phenotypic effects could be important for several evolutionary phenomena, but the extent of their contribution has been unknown. Fitness effects of induced mutations in lines of Caenorhabditis elegans were measured using a system for which the number of deleterious point mutations in the DNA can be estimated. In fitness assays, only about 4 percent of the deleterious mutations fixed in each line were detectable. The remaining 96 percent, though cryptic, are significant for mutation load and, potentially, for the evolution of sex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davies, E K -- Peters, A D -- Keightley, P D -- New York, N.Y. -- Science. 1999 Sep 10;285(5434):1748-51.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Cell, Animal and Population Biology, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10481013" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Caenorhabditis elegans/*genetics/*physiology ; Computer Simulation ; Crosses, Genetic ; Disorders of Sex Development ; Ethyl Methanesulfonate/pharmacology ; *Genes, Helminth ; Likelihood Functions ; Models, Biological ; Models, Statistical ; Mutagens/pharmacology ; *Point Mutation ; Reproduction ; Selection, Genetic
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
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  • 94
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-03-12
    Beschreibung: A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of naive T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of naive cells into post-effector memory T cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opferman, J T -- Ober, B T -- Ashton-Rickardt, P G -- 5T32 AI07090/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 1999 Mar 12;283(5408):1745-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Committee on Immunology, Department of Pathology, Committee on Developmental Biology, The University of Chicago, Gwen Knapp Center for Lupus and Immunology Research, Chicago, IL 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10073942" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adoptive Transfer ; Animals ; Apoptosis ; CD8-Positive T-Lymphocytes/*cytology/*immunology ; Cell Differentiation ; Cell Division ; Cell Lineage ; Cells, Cultured ; Cytotoxicity, Immunologic ; Dose-Response Relationship, Immunologic ; H-Y Antigen/immunology ; *Immunologic Memory ; Lymphocyte Activation ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Perforin ; Pore Forming Cytotoxic Proteins ; T-Lymphocyte Subsets/cytology/*immunology ; T-Lymphocytes, Cytotoxic/cytology/*immunology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 95
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-08-07
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liburdy, R P -- New York, N.Y. -- Science. 1999 Jul 16;285(5426):337.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10438295" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Calcium/*blood ; Calcium Radioisotopes ; *Electromagnetic Fields ; Lymphocytes/metabolism/*radiation effects ; Publishing ; *Radiation ; Scientific Misconduct
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 96
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-09-25
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bains, S -- New York, N.Y. -- Science. 1999 Sep 3;285(5433):1472.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10498527" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Diptera/*physiology ; Flight, Animal ; Microcomputers ; *Models, Biological ; *Motion Perception ; Photoreceptor Cells, Invertebrate/*physiology ; *Robotics
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 97
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-30
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lieberman, P -- New York, N.Y. -- Science. 1999 Jan 8;283(5399):175.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9925475" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Fossils ; Hominidae/*anatomy & histology/physiology ; Humans ; Hyoid Bone/*anatomy & histology ; *Speech ; Tongue/*anatomy & histology
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 98
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-17
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayflick, L -- New York, N.Y. -- Science. 1999 Mar 26;283(5410):2019.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10206905" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Aging/*genetics ; Animals ; Drosophila/*genetics ; Genes, Insect ; *Genome ; Longevity/*genetics
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 99
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-04-03
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, D L -- Garry, R F -- New York, N.Y. -- Science. 1999 Mar 12;283(5408):1644.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10189316" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Breast Implants/*adverse effects ; Female ; Humans ; Silicone Gels/*adverse effects
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 100
    facet.materialart.
    Unbekannt
    American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 1999-01-29
    Beschreibung: The protein encoded by the c-MYC proto-oncogene is a transcription factor that can both activate and repress the expression of target genes, but few of its transcriptional targets have been identified. Here, c-MYC is shown to repress the expression of the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron, and to stimulate the expression of the iron regulatory protein-2 (IRP2), which increases the intracellular iron pool. Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC. These results indicate that c-MYC coordinately regulates genes controlling intracellular iron concentrations and that this function is essential for the control of cell proliferation and transformation by c-MYC.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, K J -- Polack, A -- Dalla-Favera, R -- CA-37165/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1999 Jan 29;283(5402):676-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology, Department of Pathology, Columbia University, New York, NY 10032, USA. an.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9924025" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cell Division ; Cell Line ; Cell Line, Transformed ; Cell Transformation, Neoplastic ; DNA/biosynthesis ; Down-Regulation ; Ferritins/*genetics/metabolism ; *Gene Expression Regulation ; Genes, myc ; Homeostasis ; Iron/*metabolism ; Iron Regulatory Protein 2 ; Iron-Regulatory Proteins ; Iron-Sulfur Proteins/*genetics/metabolism ; Proto-Oncogene Proteins c-myc/*physiology ; RNA/metabolism ; RNA-Binding Proteins/*genetics/metabolism ; Receptors, Transferrin/genetics ; Transcription, Genetic ; Transfection
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    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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