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991.
Bcl-xL and Bcl-2 are phosphorylated in response to microtubule inhibitors, but the kinase(s) responsible and the functional significance have remained unclear. In this study, we investigated the characteristics of Bcl-xL and Bcl-2 phosphorylation in KB-3 carcinoma cells treated with vinblastine. In both asynchronous and synchronous cell cultures, Bcl-xL and Bcl-2 underwent a well-defined and coordinated cycle of phosphorylation and dephosphorylation, with a lengthy period of phosphorylation preceding apoptosis induction, and with dephosphorylation closely correlated with initiation of apoptosis. Internally, validated inhibitors of JNK, ERK, p38(MAPK), or CDK1 failed to inhibit vinblastine-induced phosphorylation of Bcl-xL or Bcl-2. In vitro, Bcl-xL and Bcl-2 were poor substrates relative to c-Jun and ATF2 for active recombinant JNK1. Both Bcl-xL and Bcl-2 were localized primarily to the mitochondrial fraction in both control and vinblastine-treated cells, indicating that phosphorylation did not promote subcellular redistribution. Bcl-xL kinase activity was demonstrated in mitochondrial extracts from vinblastine-treated, but not control, cells. These findings suggest that phosphorylation of these key antiapoptotic proteins may be catalysed by a novel or unsuspected kinase that is activated or induced in response to microtubule damage. Furthermore, the same kinase and phosphatase system may be operating in tandem on both proteins, and phosphorylation appears to maintain their antiapoptotic function, whereas dephosphorylation may trigger apoptosis. These results provide evidence for a novel signaling pathway connecting microtubule damage to apoptosis induction, and help to clarify some of the controversy concerning the role of Bcl-2 phosphorylation in microtubule inhibitor-induced apoptosis. 相似文献
992.
In vitro differences between keratinocyte stem cells and transit-amplifying cells of the human hair follicle 总被引:7,自引:0,他引:7
Epithelial stem cells within the human hair follicle are critical for hair development, hair cycling, wound healing, and tumorigenesis. We and others have previously shown that the hair follicle bulge area contains keratinocyte stem cells, whereas the hair matrix represents the proliferating and differentiating transit-amplifying (TA) cell compartment. In order to better characterize the phenotypic differences between human keratinocyte stem cells and their daughter TA cells, we compared the in vitro properties of cell adhesion, cell migration, clonogenicity, and in vitro life span. Epithelial outgrowths from the hair matrix appeared within 2 d of explant, whereas stem cell outgrowths appeared between 7 and 10 d after explant. Both populations form colonies; however, stem cells from telogen follicles formed more total colonies, and more colonies greater than 3 mm. Upon subculture, stem cells formed colonies until passage 6 and terminally differentiated at passage 7, whereas TA cells only formed colonies until passage 2. Stem cells express more beta1 integrin and adhere more rapidly to collagen IV. Most strikingly, TA cells showed a 7-fold greater mobility on migration assays than stem cells (0.704 vs 0.102 microm per min). These results help define the human hair follicle stem cell and TA cell phenotypes and correlate with the in vivo properties of these compartments. 相似文献
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Lyytikainen O Ziese T Schwartlander B Matzdorff P Kuhnhen C Burger C Krug W Petersen LR 《Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin》1997,2(2):9-11
Q fever is an acute (and sometimes chronic) febrile illness caused by the rickettsial organism Coxiella burnetii. The commonest animal reservoirs for C. burnetiiare cattle, sheep, and goats. Infected animals shed the organisms, which resist desiccation, i 相似文献
997.
PURPOSE: Interocular brightness differences such as those caused by asymmetrical cataract have been found to have a minimal effect on interocular brightness matches. In the present study, the measured binocular visual response to interocular differences in retinal illuminance was measured over time. METHODS: Interocular differences in retinal illuminance of magnitudes 0.3, 0.6, and 0.9 log units were induced using neutral density (ND) filters under two conditions: (1) naturally mobile pupils and (2) with fixed artificial pupils (3 mm). Interocular brightness differences were quantified by measuring interocular brightness matches using the simultaneous interocular brightness sense test every 15 minutes over a 2-hour period in eight visually normal subjects. RESULTS: Initial interocular brightness matches were as predicted by the induced interocular differences in retinal illuminance (P > 0.05). A significant reduction in the interocular difference in brightness was observed over time (P < 0.01). These reductions in the interocular difference in brightness over time followed a logarithmic progression reaching asymptotic values equal to the reciprocal of the square root of the interocular retinal illuminance ratio. This value is equal to the midpoint of the induced interocular difference in retinal illuminance at time 0 and that found without the introduction of the ND filters. Binocular visual adaptation to interocular brightness differences occurred with both mobile and fixed pupils. CONCLUSIONS: Visual adaptation occurs in response to interocular brightness differences induced by asymmetrical ND filters. The level of visual adaptation can be predicted by Fechner's Paradox and is independent of interocular differences in pupil diameter. 相似文献
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Lyle G. Best Kelly A. Duffy Andrew M. George Arupa Ganguly Jennifer M. Kalish 《American journal of medical genetics. Part A》2023,191(2):348-356
Beckwith-Wiedemann Spectrum (BWSp) is an overgrowth and cancer predisposition disorder characterized by a wide spectrum of phenotypic manifestations including macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40 years of follow-up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in CDKN1C, consistent with the most common cause of familial BWSp. CDKN1C mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the CDKN1C mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the CDKN1C variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long-term follow-up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and/or (epi)genotype associations. 相似文献