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Sugiyama T  Galea GL  Lanyon LE  Price JS 《Endocrinology》2010,151(12):5582-5590
Accumulating evidence indicates that estrogen receptors (ERs) are involved in the mechano-adaptive mechanisms by which loading influences the mass and architecture of bones to establish and maintain their structural load-bearing competence. In the present study, we assessed the effects of the ER modulators tamoxifen and fulvestrant (ICI 182,780) on loading-related changes in the volume and structure of trabecular and cortical bone in the tibiae of female mice. Ten days after actual or sham ovariectomy, 17-wk-old female C57BL/6 mice were treated with vehicle (peanut oil), tamoxifen (0.02, 0.2, or 2 mg/kg · d), fulvestrant (4 mg/kg · d), or their combination and the right tibiae subjected to a short period of noninvasive axial loading (40 cycles/d) on 5 d during the subsequent 2 wk. In the left control tibiae, ovariectomy, tamoxifen, or fulvestrant did not have any significant effect on cortical bone volume, whereas trabecular bone volume was decreased by ovariectomy, increased by tamoxifen, and unaffected by fulvestrant. In the right tibiae, loading was associated with increases in both trabecular and cortical bone volume. Notably, the medium dose of tamoxifen synergistically enhanced loading-related gain in trabecular bone volume through an increase in trabecular thickness. Fulvestrant had no influence on the effects of loading but abrogated the enhancement of loading-related bone gain by tamoxifen. These data demonstrate that, at least in female mice, the adaptive response to mechanical loading of trabecular bone can be enhanced by ER modulators, in this case by tamoxifen.  相似文献   
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Increasing evidence suggests that parentally supplied RNA plays crucial roles during eukaryotic development. This epigenetic contribution may regulate gene expression from the earliest stages. Although present in a variety of eukaryotes, maternally inherited characters are especially prominent in ciliated protozoa, in which parental noncoding RNA molecules instruct whole-genome reorganization. This includes removal of nearly all noncoding DNA and sorting the remaining fragments, producing extremely gene-rich somatic genomes. Chromosome fragmentation and extensive replication produce variable DNA copy numbers in the somatic genome. Understanding the forces that drive and regulate copy number change is fundamental. We show that RNA molecules present in parental cells during sexual reproduction can regulate chromosome copy number in the developing nucleus of the ciliate Oxytricha. Experimentally induced changes in RNA abundance can both increase and decrease the levels of corresponding DNA molecules in progeny, demonstrating epigenetic inheritance of chromosome copy number. These results suggest that maternal RNA, in addition to controlling gene expression or DNA processing, can also program DNA amplification levels.  相似文献   
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Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate.  相似文献   
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Objective

To evaluate a hospice-based advanced pharmacy practice experience (APPE).

Design

Two years of data gathered from student evaluation forms and reflective journals were analyzed.

Assessment

Students completed reflective journals and expressed a high level of satisfaction with the hospice-based learning experience. They gained a better understanding of end-of-life care provided by a hospice and the pharmacist''s role in optimizing supportive care for patients receiving hospice care.

Conclusion

Hospice-based APPEs can provide a rich interdisciplinary learning environment for pharmacy students interested in developing knowledge, attitudes, and skills to effectively manage the pharmacotherapy of patients receiving end-of-life care.  相似文献   
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Background  

Once effective therapy for a previously untreatable condition is made available, a normalisation of the disease often occurs. As part of a broader initiative to monitor the implementation of the national antiretroviral therapy (ART) programme, this qualitative study investigated the impact of ART availability on perceptions of HIV in a rural ward of North Tanzania and its implications for prevention.  相似文献   
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