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81.
82.
Dynamic methylations and demethylations of histone lysine residues are important for gene regulation and are facilitated by histone methyltransferases and histone demethylases (HDMs). KDM5B/Jarid1B/PLU1 is an H3K4me3/me2-specific lysine demethylase belonging to the JmjC domain-containing family of histone demethylases (JHDMs). Several studies have linked KDM5B to breast, prostate and skin cancer, highlighting its potential as a drug target. However, most inhibitor studies have focused on other JHDMs, and inhibitors for KDM5B remain to be explored. Here, we report the expression, purification and characterization of the catalytic core of recombinant KDM5B (ccKDM5B, residues 1-769). We show that ccKDM5B, recombinantly expressed in insect cells, demethylates H3K4me3 and H3K4me2 in vitro. The kinetic characterization showed that ccKDM5B has an apparent Michaelis constant (K(m) (app) ) value of 0.5 μm for its trimethylated substrate H3(1-15)K4me3, a considerably increased apparent substrate affinity than reported for related HDMs. Despite the presence of a PHD domain, the catalytic activity was not affected by additional methylation at the H3K9 position, suggesting that in vitro chromatin cross-talk between H3K4 and H3K9 does not occur for ccKDM5B. Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C. Structure-guided sequence alignment indicated that the binding mode of 2,4-PDCA is conserved between KDM4A/C and KDM5B.  相似文献   
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All nine wetland lakes in the CASSARINA North African suite of sample sites have been disturbed strongly by human activity during the 20th century. Dated lake sediment core were used to provide evidence of the extent of recent environmental change at each site. Sedimentary diatoms at seven sites were useful for inferring salinity change trends during the last century. At two sites preservation problems severely degraded the sedimentary diatom record. Sediment core integrity was otherwise established.Lithostratigraphic measurements indicated some site specific changes in soil erosion and sediment composition but, for the Egyptian Delta lakes, no physical signal synchronous with Aswan High Dam construction was found. Sedimentary diatom assemblages were generally site characteristic and halophilous taxa were common. At two sites planktonic diatoms indicated some recent eutrophication but generally the assemblages were more indicative of salinity changes. Diatom-inferred salinity trends for the seven sites typically indicated that reductions in water salinity occurred sometime during the early or mid 20th century.Rather than climate, hydrological modification of water resources is implicated as the primary driver of salinity changes during most of the 20th century. In the western North African region these modifications were mainly local land drainage and water diversion programmes to alleviate winter flooding and/or promote summer water availability. In the Delta region, the Nile has been intensively exploited since antiquity and intensively so from the late 19th century to release more fresh water for agriculture. Here, diatom records indicate that freshening began well before the Aswan High Dam but salinity fluctuations have tended to diminish during the latter part of the 20th century. A small reversal in the water freshening trend in the 1980/90s was possibly a response to land subsidence/sea-level change or to reduced freshwater supply.Freshwater supply to the sites is generally diminishing as former freshwater surpluses switch to deficit. One site (Merja Bokka, Morocco) became completely dry in 1998 as agriculture encroached and Megene Chitane, the only acid lake in Tunisia, is currently affected by excessive inflow abstraction. At the beginning of the 21st century, eight of the nine CASSARINA sites persist as viable but modified aquatic ecosystems. They nevertheless continue to support valuable aquatic biodiversity, especially in the Delta sites and in Chitane. The modern diatom communities are clearly tolerant of considerable environmental change but the remaining sites are increasingly threatened by major hydrological disturbance. Base-line floristic data for the late 20th century are given but continuous biomonitoring combined with effective management is needed urgently to help conserve North Africa's diminishing natural wetland lake resources.  相似文献   
85.
Activation of the anaphase-promoting complex (APC) is required for anaphase initiation and for exit from mitosis in mammalian cells. Cdc20, which specifically recognizes APC substrates involved in the metaphase-to-anaphase transition, plays a pivotal role in APC activation through direct interaction with the APC. The activation of the APC by Cdc20 is prevented by the interaction of Cdc20 with Mad2 when the spindle checkpoint is activated. Using deletion mutagenesis and peptide mapping, we have identified the sequences in Cdc20 that target it to Mad2 and the APC, respectively. These sequences are distinct but overlapping, providing a possible structural explanation for the internal modulation of the APC-Cdc20 complex by Mad2. In the course of these studies, a truncation mutant of Cdc20 (1-153) that constitutively binds Mad2 but fails to bind the APC was identified. Overexpression of this mutant induces the formation of multinucleated cells and increases their susceptibility to undergoing apoptosis when treated with microtubule-inhibiting drugs. Our experiments demonstrate that disruption of the Mad2-Cdc20 interaction perturbs the mitotic checkpoint, leading to premature activation of the APC, sensitizing the cells to the cytotoxic effects of microtubule-inhibiting drugs.  相似文献   
86.
Twenty light-skinned adults were measured at the upper inner arm site using two commonly used reflectance spectrophotometers. Each subject was measured by each of three investigators to assess the influence of interobserver error on the reflectance readings. A repeated measures design analysis of variance showed no significant variance component due to observers.  相似文献   
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Antigen stimulated release of histamine from chopped sensitized guinea-pig lung is inhibited by the addition of β-adrenoceptor agonists in a manner indicating a β2 response. Preaddition of β-adrenoceptor antagonists blocks this inhibition in a manner indicating a β1 response. This apparent dichotomy probably results from a hybrid receptor, though the danger of the use of chemical analogues for classifying receptors is highlighted. Inhibition of histamine release by β-stimulation is shown to be species rather than organ specific.  相似文献   
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