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1.
P-glycoprotein as multidrug transporter: a critical review of current multidrug resistant cell lines
MDR has been studied extensively in mammalian cell lines. According to usual practice, the MDR phenotype is characterized by the following features: cross resistance to multiple chemotherapeutic agents (lipophilic cations), defective intracellular drug accumulation and retention, overexpression of P-gp (often accompanied by gene amplification), and reversal of the phenotype by addition of calcium channel blockers. An hypothesis for the function of P-gp has been proposed in which P-gp acts as a carrier protein that actively extrudes MDR compounds out of the cells. However, basic questions, such as what defines the specificity of the pump and how is energy for active efflux transduced, remain to be answered. Furthermore, assuming that P-gp acts as a drug transporter, one will expect a relationship between P-gp expression and accumulation defects in MDR cell lines. A review of papers reporting 97 cell lines selected for resistance to the classical MDR compounds has revealed that a connection exists in most of the reported cell lines. However, several exceptions can be pointed out. Furthermore, only a limited number of well characterized series of sublines with different degrees of resistance to a single agent have been reported. In many of these, a correlation between P-gp expresson and transport properties can not be established. Co-amplification of genes adjacent to the mdr1 gene, mutations [122], splicing of mdr1 RNA [123], modulation of P-gp by phosphorylation [124] or glycosylation [127], or experimental conditions [26,78] could account for some of the complexity of the phenotype and the absence of correlation in some of the cell lines. However, both cell lines with overexpression of P-gp without increased efflux [i.e., 67,75] and cell lines without P-gp expression and accumulation defects/increased efflux [i.e., 25,107] have been reported. Thus, current results from MDR cell lines contradict - but do not exclude - that P-gp acts as multidrug transporter. Other models for the mechanism of resistance have been proposed: (1) An energy-dependent permeability barrier working with greater efficacy in resistant cells. This hypothesis is supported by studies of influx which, although few, all except one demonstrate decreased influx in resistant cells; (2) Resistant cells have a greater endosomal volume, and a greater exocytotic activity accounts for the efflux. Furthermore, large amounts of P-gp in the plasma membrane altering the ultrastructure and generalized changes, such as increases or decreases in membrane fluidity, alterations in lipid composition, changes in transmembrane pH gradient and membrane potential have been described in MDR cell lines and could account for some of the findings. 相似文献
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A new species of Mallomonas, M. nuussuaqensis was found to be common in samples collected from waterbodies on Nuussuaq/Nûgssuaq (70N-71N, West Greenland). The species has very compact silica scales with a thick broad marginal rim and a very thick and broad hood, which often occupies more than two thirds of the shield. 相似文献
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Joan Thiesen Torben S. Christensen Thomas G. Kristensen Rikke D. Andersen Brit Brunoe Trine K. Gregersen Mikkel Thrane Bo P. Weidema 《The International Journal of Life Cycle Assessment》2008,13(2):104-114
Goal, Scope and Background Traditionally, comparative life cycle assessments (LCA) have not considered rebound effects, for instance in case of significant
price differences among the compared products. No justifications have been made for this delimitation in scope. This article
shows that price differences and the consequent effects of marginal consumer expenditure may influence the conclusions of
comparative LCA significantly. We also show that considerations about rebound effects of price differences can be included
in LCAs.
Methods The direct rebound effect of a price difference is marginal consumption. Based on statistical data on private consumption
in different income groups (Statistics Denmark 2005a, 2005b), the present article provides an estimate of how an average Danish
household will spend an additional 1 DKK for further consumer goods, when the household has gained money from choosing a cheaper
product alternative. The approach is to use marginal income changes and the following changes in consumption patterns as an
expression for marginal consumption. Secondly, the environmental impact potentials related to this marginal consumption are
estimated by the use of environmental impact intensity data from an IO-LCA database (Weidema et al. 2005). Finally, it is
discussed whether, and in which ways the conclusions of comparative LCAs can be affected by including the price difference
between product alternatives. This is elucidated in a case study of a comparative LCA screening of two different kinds of
Danish cheese products (Fricke et al. 2004).
Results Car purchase and driving, use and maintenance of dwelling, clothing purchase and insurance constitutes the largest percentages
of the marginal consumption. In a case study of two cheeses, the including the impact potentials related to the price difference
results in significant changes in the total impact potentials. Considering the relatively small price difference of the two
products, it is likely also to have a significant influence on the results of comparative LCAs more generally.
Discussion The influence of marginal consumption in comparative LCAs is relevant to consider in situations with large differences in
the price of the product alternatives being compared, and in situations with minor differences in the impact potentials related
to the alternatives. However, different uncertainties are linked to determining the pattern for marginal consumption and the
environmental impact potential related to this. These are first of all related to the method used, but also include inaccurate
data of consumption in households, aggregation and weighting of income groups, aggregation of product groups, estimation and
size of the price difference, and the general applicability of the results.
Conclusion Incorporating marginal consumption in consequential LCAs is possible in practice. In the case study used, including the rebound
effects of the price difference has a significant influence on the result of the comparative LCA, as the result for the impact
categories acidification and nutrient enrichment changes in favour of the expensive product.
Recommendations and Perspectives It is recommended that the rebound effects of price differences should be included more frequently in LCAs. In order to ensure
this, further research in marginal consumption and investment patterns and IO data for different countries or regions is required.
Furthermore, this study does not consider the economic distributional consequences of buying an expensive product instead
of a cheaper product (e.g. related to how the profit is spent by those who provided the product). It should also be noted,
that more expensive products not necessarily result in less consumption, as those who provided the product also will spend
the money they have earned from the sale. Ideally, these consequences should also be further investigated. Likewise, the development
of databases to include marginal consumption in PC-tools is needed. In general, considerations of marginal consumption would
favour expensive product alternatives, depending, however, on the type of consumer.
ESS-Submission Editor: Dr. David Hunkeler (david.hunkeler@aquaplustech.ch) 相似文献
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Nikola Vukovic Brian Hansen Torben Ellegaard Lund Sune Jespersen Yury Shtyrov 《PLoS biology》2021,19(6)
Despite the clear importance of language in our life, our vital ability to quickly and effectively learn new words and meanings is neurobiologically poorly understood. Conventional knowledge maintains that language learning—especially in adulthood—is slow and laborious. Furthermore, its structural basis remains unclear. Even though behavioural manifestations of learning are evident near instantly, previous neuroimaging work across a range of semantic categories has largely studied neural changes associated with months or years of practice. Here, we address rapid neuroanatomical plasticity accompanying new lexicon acquisition, specifically focussing on the learning of action-related language, which has been linked to the brain’s motor systems. Our results show that it is possible to measure and to externally modulate (using transcranial magnetic stimulation (TMS) of motor cortex) cortical microanatomic reorganisation after mere minutes of new word learning. Learning-induced microstructural changes, as measured by diffusion kurtosis imaging (DKI) and machine learning-based analysis, were evident in prefrontal, temporal, and parietal neocortical sites, likely reflecting integrative lexico-semantic processing and formation of new memory circuits immediately during the learning tasks. These results suggest a structural basis for the rapid neocortical word encoding mechanism and reveal the causally interactive relationship of modal and associative brain regions in supporting learning and word acquisition.This combined neuroimaging and brain stimulation study reveals rapid and distributed microstructural plasticity after a single immersive language learning session, demonstrating the causal relevance of the motor cortex in encoding the meaning of novel action words. 相似文献
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Chromosomal rearrangements, which can lead to oncogene activation and tumour suppressor loss, are a hallmark of cancer cells. Such outcomes can result from both the repair and misrepair of DNA ends, which arise from a variety of lesions including DNA double strand breaks (DSBs), collapsed replication forks and dysfunctional telomeres. Here we review the mechanisms by which non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways can both promote chromosomal rearrangements and also suppress them in response to such lesions, in accordance with their increasingly recognised tumour suppressor function. Further, we consider how chromosomal rearrangements, together with a modular approach towards understanding their etiology, may be exploited for cancer therapy. 相似文献