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1.
Phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) is mediated by a family of kinases that respond to various forms of environmental stress. The eIF2alpha kinases are critical for mRNA translation, cell proliferation, and apoptosis. Activation of the tumor suppressor p53 results in cell cycle arrest and apoptosis in response to various types of stress. We previously showed that, unlike the majority of stress responses that stabilize and activate p53, induction of endoplasmic reticulum stress leads to p53 degradation through an Mdm2-dependent mechanism. Here, we demonstrate that the endoplasmic reticulum-resident eIF2alpha kinase PERK mediates the proteasomal degradation of p53 independently of translational control. This role is not specific for PERK, because the eIF2alpha kinase PKR also promotes p53 degradation in response to double-stranded RNA. We further establish that the eIF2alpha kinases induce glycogen synthase kinase 3 to promote the nuclear export and proteasomal degradation of p53. Our findings reveal a novel cross-talk between the eIF2alpha kinases and p53 with implications in cell proliferation and tumorigenesis.  相似文献   
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  总被引:1,自引:0,他引:1  
This paper describes the process used to generate lower limb kinematics during single limb stance phase of gait, using musculoskeletal modelling, muscle driven forward simulation and gradient based optimisation techniques (including design of experiment techniques).Initial inputs to the forward simulation process were the normalised quantified muscle activation patterns of 22 muscles, and the initial segmental configuration (both angles and angular velocity) derived from Winter (The biomechanics and motor control of human gait, 1987, University of Waterloo Press, pp. 1-72). Two distinct musculoskeletal models (one including 6 DOF, the other 7 DOF) were defined and a muscle driven forward simulation was implemented.A series of optimisation sequences then were executed to modify the muscle activation patterns and initial segmental configuration, until the system output of the forward simulation approximated the angle data reported by. The accuracy and effectiveness of the analysis sequence proposed and the model response obtained using two distinct musculoskeletal models were verified and analysed with respect to the kinesiology of normal walking.  相似文献   
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The purpose of this study was to determine the incidence of cleft palatal fistula in a series of nonsyndromic children treated at the authors' institution. This retrospective analysis of 103 patients with cleft palate treated by five surgeons between 1982 and 1995 includes 60 boys and 33 girls, whose median age was 18.4 months at the time of surgery. The median length of follow-up was 4.9 years after primary palatoplasty. Cleft palatal fistula was defined as a failure of healing or a breakdown in the primary surgical repair of the palate. Intentionally unrepaired fistulas of the primary and secondary palate were excluded. Extent of clefting was described according to the Veau classification. Statistical examination of multiple variables was performed using contingency table analysis, multivariate logistic regression, and the Wilcoxon rank sum test. The incidence of cleft palatal fistula in this series was 8.7 percent. All of these fistulas were clinically significant. The rate of fistula recurrence was 33 percent. The incidence of cleft palatal fistula when compared by Veau classification was statistically significant, with nine fistulas occurring in patients with Veau 3 and 4 clefts and no fistulas occurring in patients with Veau 1 and 2 clefts (p = 0.0441). No significant differences between patients with and without fistulas were identified with respect to operating surgeon, patient sex, patient age at palatoplasty, type of palatoplasty, and use of presurgical orthopedics or palatal expansion. All three recurrent fistulas occurred in the anterior palate, two in patients with Veau class 3 clefts and one in a patient with a Veau class 4 cleft. The low rate of clinically significant fistula was attributed to early delayed primary closure, with smaller secondary clefts allowing repair with a minimum of dissection and disruption of vascularity.  相似文献   
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ABSTRACT: BACKGROUND: Knowledge translation (KT) research in long-term care (LTC) is still in its early stages. This protocol describes the evaluation of a multifaceted, interdisciplinary KT intervention aimed at integrating evidence-based osteoporosis and fracture prevention strategies into LTC care processes. Methods and design The Vitamin D and Osteoporosis Study (ViDOS) is underway in 40 LTC homes (n = 21 intervention, n = 19 control) across Ontario, Canada. The primary objectives of this study are to assess the feasibility of delivering the KT intervention, and clinically, to increase the percent of LTC residents prescribed [greater than or equal to]800 IU of vitamin D daily. Eligibility criteria are LTC homes that are serviced by our partner pharmacy provider and have more than one prescribing physician. The target audience within each LTC home is the Professional Advisory Committee (PAC), an interdisciplinary team who meets quarterly. The key elements of the intervention are three interactive educational sessions led by an expert opinion leader, action planning using a quality improvement cycle, audit and feedback reports, nominated internal champions, and reminders/point-of-care tools. Control homes do not receive any intervention, however both intervention and control homes received educational materials as part of the Ontario Osteoporosis Strategy. Primary outcomes are feasibility measures (recruitment, retention, attendance at educational sessions, action plan items identified and initiated, internal champions identified, performance reports provided and reviewed), and vitamin D ([greater than or equal to]800 IU/daily) prescribing at 6 and 12 months. Secondary outcomes include the proportion of residents prescribed calcium supplements and osteoporosis medications, and falls and fractures. Qualitative methods will examine the experience of the LTC team with the KT intervention. Homes are centrally randomized to intervention and control groups in blocks of variable size using a computer generated allocation sequence. Randomization is stratified by home size and profit/nonprofit status. Prescribing data retrieval and analysis are performed by blinded personnel. DISCUSSION: Our study will contribute to an improved understanding of the feasibility and acceptability of a multifaceted intervention aimed at translating knowledge to LTC practitioners. Lessons learned from this study will be valuable in guiding future research and understanding the complexities of translating knowledge in LTC. Trial registration ClinicalTrials.gov NCT01398527.  相似文献   
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We have used a sensitive electrophoretic technique for estimating the activity, or ratio, of two allozymes of the X-chromosome-linked enzyme phosphoglycerate kinase (PGK-1), in order to investigate the randomness of X-chromosome expression in the derivatives of the three primary cell lineages of the early mouse conceptus. The maternally derived Pgk-1 allele is preferentially expressed in the derivatives of the primitive endoderm and trophectoderm lineages at 6 1/2 days post coitum in Pgk-1a/Pgk-1b heterozygous conceptuses, and in the one informative 5 1/2-day heterozygous conceptus analysed. This evidence for preferential expression of the maternally derived X chromosome (Xm), so soon after the time of X-chromosome inactivation, favors the possibility that the preferential expression of Xm is a consequence of primary non-random X-chromosome inactivation, rather than a secondary selection phenomenon. The majority of embryos analysed at 4 1/2 and 5 1/2 days pc produced only a single PGK-1 band, corresponding to the allozyme produced by the Pgk-1 allele on Xm, although 50% of these embryos should have been heterozygous females. Possible explanations are discussed.  相似文献   
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Candida species is the fourth most commonly isolated organism in blood stream infections in the hospital setting. Patients with candidemia frequently succumb to this infection. For those that survive an initial candidemia, an increasing number of cases of breakthrough or recurrent candidemias have been reported in the literature. We report three episodes of C. parapsilosis fungemia in a cancer patient. Molecular testing was performed and confirmed that all these episodes occurring within an eight-month period were caused by the same organism. The incidence of recurrent candidemia is likely to increase in the near future. Studies and therapeutic interventions for patients at risk for recurrent candidemias are warranted.  相似文献   
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