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991.
Morphine is a poor inducer of micro-opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [D-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy-terminal residue 375 (Ser(375)). Ser(375) phosphorylation was sufficient and required for morphine-induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO-desensitized receptors were rapidly dephosphorylated. In contrast, morphine-desensitized receptors remained at the plasma membrane in a Ser(375)-phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser(375).  相似文献   
992.
Ethylene regulates entry into several types of plant developmental cell death and senescence programs besides mediating plant responses to biotic and abiotic stress. The response of cereals to conditions of drought includes loss of leaf function and premature onset of senescence in older leaves. In this study, ACC synthase ( ACS ) mutants, affecting the first step in ethylene biosynthesis, were isolated in maize and their effect on leaf function examined. Loss of ZmACS6 expression resulted in delayed leaf senescence under normal growth conditions and inhibited drought-induced senescence. Zmacs6 leaves continued to be photosynthetically active under both conditions indicating that leaf function was maintained. The delayed senescence phenotype associated with loss of ZmACS6 expression was complemented by exogenous ACC. Surprisingly, elevated levels of foliar chlorophyll, Rubisco, and soluble protein as well as improved leaf performance was observed for all Zmasc6 leaves, including young and fully expanded leaves which were far from initiating senescence. These observations suggest that ethylene may serve to regulate leaf performance throughout its lifespan as well as to determine the onset of natural senescence and mediate drought-induced senescence.  相似文献   
993.
Discovery stage pharmacokinetics using dried blood spots   总被引:1,自引:0,他引:1  
Early in the discovery stage, the measurement of drug candidates in biological fluids as a function time provides important information used in decision making for lead optimization. The detection methodology primarily used is liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS). Sample preparation is an important aspect of these experiments and robotic-based automation is commonly used. The often overlooked aspect of these experiments is the sample collection itself. Typically, several hundred microliters of whole blood is collected and the plasma fraction separated for each time-point. The plasma is then transferred to an appropriate vessel for subsequent aliquoting and processing. We describe a method for performing discovery stage pharmacokinetic analysis using whole blood dried onto filter paper. The use of dried blood spots is a well established technique for neo-natal screening, and its application to early screening of drug candidates proves to be robust, reliable and reproducible.  相似文献   
994.
The impact of ethanol and temperature on the dynamic behaviour of Saccharomyces cerevisiae in ethanol biofuel production was studied using an isothermal fed-batch process at five different temperatures. Fermentation parameters and kinetics were quantified. The best performances were found at 30 and 33°C around 120 g l-1 ethanol produced in 30 h with a slight benefit for growth at 30°C and for ethanol production at 33°C. Glycerol formation, enhanced with increasing temperatures, was coupled with growth for all fermentations; whereas, a decoupling phenomenon occurred at 36 and 39°C pointing out a possible role of glycerol in yeast thermal protection.  相似文献   
995.
Thermoluminescence glow curve parameters were used to access the functional features of PS II in the Balkan endemic Haberlea rhodopensis. This representative of the higher desiccation-tolerant plants is unique for the European flora. An unusual high temperature of TL emission from Haberlea leaves after excitation by one flash at 5 degrees C was observed. The position of the main TL B band (S (2)Q (B)(-)) was at 45 - 47 degrees C, while this temperature was 30 - 32 degrees C in drought-sensitive mesophytic spinach. Consistent with the up-shift in TL emission, the lifetime of the S (2) state was also increased, showing a stabilization of charge storage in PS II complex in this resurrection plant. In addition, a part of PS II centres was less susceptible to DCMU. We consider the observed unusual TL characteristics of Haberlea rhodopensis reflect some structural modifications in PS II (especially in D1 protein), which could be related to the desiccation tolerance of this plant. This suggestion was supported by the different manner in which dehydration affected the TL properties in desiccation-tolerant Haberlea and desiccation-sensitive spinach plants.  相似文献   
996.
Quantitative trait loci (QTL) analysis for pre-harvest sprouting tolerance (PHST) in bread wheat was conducted following single-locus and two-locus analyses, using data on a set of 110 recombinant inbred lines (RILs) of the International Triticeae Mapping Initiative population grown in four different environments. Single-locus analysis following composite interval mapping (CIM) resolved a total of five QTLs with one to four QTLs in each of the four individual environments. Four of these five QTLs were also detected following two-locus analysis, which resolved a total of 14 QTLs including 8 main effect QTLs (M-QTLs), 8 epistatic QTLs (E-QTLs) and 5 QTLs involved in QTL × environment (QE) or QTL × QTL × environment (QQE) interactions, some of these QTLs being common. The analysis revealed that a major fraction (76.68%) of the total phenotypic variation explained for PHST is due to M-QTLs (47.95%) and E-QTLs (28.73%), and that only a very small fraction of variation (3.24%) is due to QE and QQE interactions. Thus, more than three-quarters of the genetic variation for PHST is fixable and would contribute directly to gains under selection. Two QTLs that were detected in more than one environment and at LOD scores above the threshold values were located on 3BL and 3DL presumably in the vicinity of the dormancy gene TaVp1. Another QTL was found to be located on 3B, perhaps in close proximity to the R gene for red grain colour. However, these associations of QTLs for PHST with genes for dormancy and grain colour are only suggestive. The results obtained in the present study suggest that PHST is a complex trait controlled by large number of QTLs, some of them interacting among themselves or with the environment. These QTLs can be brought together through marker-aided selection, leading to enhanced PHST.  相似文献   
997.
Recently, instrumental variables methods have been used to address non-compliance in randomized experiments. Complicating such analyses is often the presence of missing data. The standard model for missing data, missing at random (MAR), has some unattractive features in this context. In this paper we compare MAR-based estimates of the complier average causal effect (CACE) with an estimator based on an alternative, nonignorable model for the missing data process, developed by Frangakis and Rubin (1999, Biometrika, 86, 365-379). We also introduce a new missing data model that, like the Frangakis-Rubin model, is specially suited for models with instrumental variables, but makes different substantive assumptions. We analyze these issues in the context of a randomized trial of breast self-examination (BSE). In the study two methods of teaching BSE, consisting of either mailed information about BSE (the standard treatment) or the attendance of a course involving theoretical and practical sessions (the new treatment), were compared with the aim of assessing whether teaching programs could increase BSE practice and improve examination skills. The study was affected by the two sources of bias mentioned above: only 55% of women assigned to receive the new treatment complied with their assignment and 35% of the women did not respond to the post-test questionnaire. Comparing the causal estimand of the new treatment using the MAR, Frangakis-Rubin, and our new approach, the results suggest that for these data the MAR assumption appears least plausible, and that the new model appears most plausible among the three choices.  相似文献   
998.
The immune system has evolved a variety of mechanisms to achieve and maintain tolerance both centrally and in the periphery. Central tolerance is achieved through negative selection of autoreactive T cells, while peripheral tolerance is achieved primarily via three mechanisms: activation-induced cell death, anergy, and the induction of regulatory T cells. Three forms of these regulatory T cells have been described: those that function via the production of the cytokine IL-10 (T regulatory 1 cells), transforming growth factor beta (Th3 cells), and a population of T cells that suppresses proliferation via a cell-contact-dependent mechanism (CD4+CD25+ TR cells). The present review focuses on the third form of peripheral tolerance - the induction of regulatory T cells. The review will address the induction of the three types of regulatory T cells, the mechanisms by which they suppress T-cell responses in the periphery, the role they play in immune homeostasis, and the potential these cells have as therapeutic agents in immune-mediated disease.  相似文献   
999.
Cold tolerance in plants is an ecologically important trait that has been under intensive study for basic and applied reasons. Determining the fitness benefits and costs of cold tolerance has previously been difficult because cold tolerance is normally an induced trait that is not expressed in warm environments. The recent creation of transgenic plants constitutively expressing cold tolerance genes enables the investigation of the fitness consequences of cold tolerance in multiple temperature environments. We studied three genes from the CBF (C-repeat/dehydration responsive element binding factor) cold tolerance pathway, CBF1, 2 and 3, in Arabidopsis thaliana to test for benefits and costs of constitutive cold tolerance. We used multiple insertion lines for each transgene and grew the lines in cold and control conditions. Costs of cold tolerance, as determined by fruit number, varied by individual transgene. CBF2 and 3 overexpressers showed costs of cold tolerance, and no fitness benefits, in both environments. CBF1 overexpressing plants showed no fitness cost of cold tolerance in the control environment and showed a marginal fitness benefit in the cold environment. These results suggest that constitutive expression of traits that are normally induced in response to environmental stress will not always lead to costs in the absence of that stress, and that the ecological risks of CBF transgene escape should be assessed prior to their use in commercial agriculture.  相似文献   
1000.
We report that protein kinase C (PKC) plays a regulatory role in early cleavage in Chaetopterus eggs. Using Western blotting, we assayed the expression patterns of conventional PKCs (cPKC), novel PKCs (nPKC), and atypical PKCs (aPKC). During early development after fertilization, PKC protein levels varied independently by isoform. PKC protein expression during differentiation, without cleavage and after parthenogenetic activation, was very similar to that during normal development indicating that PKC gene expression does not require cellularization. Since PKC has been shown to regulate meiosis in this organism, we also assayed the membrane association of these isoforms as an indicator of their activation during meiosis and early cleavage. PKC-gamma transiently associated with membranes and therefore became activated before meiotic division and cleavage, whereas PKC-alpha and -beta transiently dissociated from membranes and therefore became inactivated at these times. Inhibition of these PKC isoforms by bisindolylmaleimide I had no effect on cleavage or early development to the trochophore larva, indicating that PKC-gamma activation is not essential for cleavage or early development. However, their persistent activation by thymeleatoxin blocked cleavage. The results indicate that the dissociation of PKC-alpha and/or -beta from the membrane fraction, and therefore their inactivation, is essential for normal cleavage. Elevated PKC activity is essential for nuclear envelope breakdown and spindle formation at meiosis I. By contrast, down-regulation of this activity is essential for cleavage after fertilization.  相似文献   
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