Lai Yau Ming. / "August 2006." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 260-290). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (doctoral)--Universität, München, 2001. / Includes bibliographical references (p. 117-127) and index.

No description available.

published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Kinesins are motor proteins responsible for the anterograde transport on microtubules. Kinesin-1 is the first characterized kinesin, and it consists of two heavy chains and two light chains. KIF5B is a form of Kinesin-1 heavy chains that is ubiquitously expressed in mammals. The head domain of KIF5B is responsible for ATP-dependent mechanical movement along microtubules, while the tail region is well-known for its interaction with cell specific cargos. Recent studies reveal a second microtubule binding site in the tail, suggesting special functions of KIF5B in microtubule sliding and bundling. To understand the role of KIF5B in long bone development, a conditional knockout mouse model was generated, in which Kif5b is deleted in early limb mesenchyme using Prx1-cre/LoxP mediated recombination. Unlike Col2a1-cre directed Kif5b knockout in chondrocytes, the expression of Prx1-cre in limb mesenchyme results in Kif5b knockout in both chondrocyte and osteoblast lineages. The Prx1-cre mediated Kif5b conditional knockout mice develop malformed long bones characterized by their bowed shape, shortened length and multiple fractures, which reflects a combination of defects in bone matrix and growth plate. The mutant mice demonstrate impaired bone matrix formation, as indicated by both collagen density reduction and collagen matrix disorganization. Also, the growth plate does not retain its normal organization, and the hypertrophic zone is absent. The KIF5B deficient chondrocytes not only lose planar cell polarity, but also undergo early apoptosis and fail in terminal differentiation. Interestingly, the binucleation rate is significantly increased in these chondrocytes, suggesting a severe cytokinesis defect. Besides, the intracellular retention of extracellular matrix (ECM) molecules and the uneven distribution of ECM in the cartilage imply both blockage and inappropriate direction of secretion. Cytokinetic defect in chondrocytes is closely associated with growth plate abnormality and growth retardation. In Kif5b knockout chondrocytes, cytokinetic defect is also one of the earliest and principal phenotypes. Therefore the underlying mechanism of cytokinetic defect was further investigated at cellular level. Since Kif5b knockout chondrocytes cannot survive in primary culture, RNA interference approach was adopted to generate a Kif5b-knockdown chondrogenic cell line. As expected, the Kif5b knockdown cells demonstrate cytokinetic defects characterized by increased binucleation rate and prolonged cytokinesis phase. In control cells, KIF5B becomes concentrated in the midbody during cytokinesis, and the midbody organization is disrupted in Kif5b knockdown cells. Furthermore, transient expression of full-length KIF5B significantly reduces the binucleation rate of these KIF5B deficient cells, whereas over-expression of a truncated KIF5B (without microtubule binding sites in tail region) cannot rescue the defect. Additionally, KIF5B is found to interact with midbody components PRC1 and Aurora B kinase by GST pull-down assay. This study demonstrates the multiple functions of KIF5B in long bone development and emphasizes its significant role as a key modulator in chondrocyte cytokinesis. More importantly, the study also brings new insights into the mechanisms of cytokinesis: we propose that KIF5B may participate in cytokinesis by regulating the midbody organization and stability via microtubule bundling and transporting or anchoring important components to the midbody. / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Increased bone density has been observed following physical training. However, it is not known whether the mechanical forces of muscular contraction, gravitational pull, or a combination of these forces are required to cause this adaptation. Therefore, the purpose of this study was to determine which mechanical force, muscular contraction or gravitational pull, offered the greatest contribution to increased bone mineral content observed following either swim or run training. METHODS: Female Wistar rats were randomly assigned to one of three groups: 1) Sedentary Control (SC; n = 12), 2) Run Trained (RT; 27.7 m/m, 8% incline, 2 hrs/day; n = 20), and 3) Swim Trained (ST; 2 hrs/day, 2Y/ body weight; n = 14). The animals were sacrificed after 9 weeks of training and the humeri and femurs were removed for analysis.RESULTS: Femur weight, length, diameter, and ponderal index (a measure of robustness), and bone mineral content (BMC) were not different between the three treatment groups. However, femur cortical thickness was significantly (p < 0.01) smaller in the RT when compared to ST and SC rats. The ST humeri were significantly (p < 0.05) heavier, wider, and had a greater BMC when compared with those of the RT and SC rats, while cross sectional area was unaffected by physical training. CONCLUSION: The results of this study indicate that the mechanical forces applied by the swim training protocol produced marked bone adaptation in the ST animals following 9 weeks of physical training. Whereas, the combined mechanical and gravitational forces applied during running by the RT rats produced minimal adaptation of bone following 9 weeks of physical training.

Approved for public release; distribution is unlimited. / The objective of this study was to develop an analytical model of the basic hierarchical structure of the human bone. The model computed the stiffness of composite collagen fibers comprised of collagen fibrils and hydroxyapatite mineral crystals. Next, the stiffness of the concentric lamella was computed utilizing the stiffness of the collagen fibers and layer information. Finally, the effective stiffness of the bone was estimated. In order to determine the stiffness of the collagen fiber, a three-dimensional finite element model was developed and a simple analytical model was derived. The simple analytical model was validated using the finite element results. The lamination theory of unidirectional fibrous composites was used to calculate the stiffness of the lamella and eventually the bone stiffness. A series of parametric studies were conducted to understand what parameter(s) affected the stiffness of the bone most significantly. This information will be useful when an artificial bone structure is designed. / http://hdl.handle.net/10945/1123 / Lieutenant, United States Navy

Introduction Ethnic differences in bone growth and proportions have previously been investigated in relation to bone fragility. Differential growth in the axial and appendicular skeletons has been suggested to predispose to differential susceptibility to fracture. The developmental origins of bone size and osteoporosis have also been investigated. However, the impact of foetal programming on body proportions and limb lengths in unknown. Objectives The aim of this study was to investigate the presence of ethnic and sex differences in axial and appendicular growth. Additionally, it was to investigate the impact of early life factors on skeletal dimensions and proportions in childhood . Methods Anthropometric measurements of stature, weight, sitting height and limb lengths were taken on 368 black and white, male and female 9 year old children. DXA scans of the distal ulna;distal radius; hip and lumbar spine were also obtained. The same measurements were obtained for 197 of the black children who had birthweight and weight and length data at 1 year. For the first part of the analyses, Analyses of Covariance were performed to assess differences in limb lengths adjusted for differences in stature. Multiple regression analyses were used to assess significant predictors of site-specific bone mass. Comparisons were made after adjustment for weight, weight and stature and weight and regional segment lengths. For the second part of the analyses, Analyses of Covariance were performed to assess differences in stature and regional segment lengths at different tertiles of birthweight, and weight and height at 1 year. Stepwise multiple regressions were performed with early life growth patterns to assess significant predictors of stature and regional segment lengths at 10 years. Results Black children had longer limbs but shorter trunks than white children. Regional segment length were a more significant predictor of site-specific bone mass than stature. In black boys birthweight had positive but weak associations with stature and regional segment length while in girls the association were marginal. In contrast, weight and height at 1yr had strong associations with stature and regional segment lengths. Conclusion There is a differential effect of ethnicity and sex on the growth of the axial and appendicular skeletons, and regional segment length is a better predictor of site-specific bone mass than stature. Early life growth has a long-term influence on stature, as well as on regional segment lengths but marginal effect on body proportions.