Control of bone remodelling by applied dynamic loads

The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued

Static versus dynamic loads as an influence on bone remodelling

Bone remodelling activity in the avian ulna was assessed under conditions of disuse alone, disuse with a superimposed continuous compressive load, and disuse interrupted by a short daily period of intermittent loading. The ulna preparation is made by two submetaphyseal osteotomies, the cut ends of the bone being covered with stainless steel caps which, together with the bone they enclosed, are pierced by pins emerging transcutaneously on the dorsal and ventral surfaces of the wing. The 110 mm long undisturbed section of the bone shaft can be protected from functional loading, loaded continuously in compression by joining the pins with springs, or loaded intermittently in compression by engaging the pins in an Instron machine. Similar loads (525 n) were used in both static and dynamic cases engendering similar peak strains at the bone's midshaft (-2000 x 10-6). The intermitent load was applied at a frequency of 1 Hz during a single 100 second period per day as a ramped square wave, with a rate of change of strain during the ramp of 0.01 per second

Sclerostin's role in bone's adaptive response to mechanical loading

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis

Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice

AbstractBones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engendering local bone strain. To investigate whether these physiological responses influence bones' adaptive responses to mechanical strain we examined whether a period of treadmill exercise influenced the adaptive response to an associated period of artificial loading in young adult (17-week) and old (19-month) mice. After treadmill acclimatization, mice were exercised for 30min three times per week for two weeks. Three hours after each exercise period, right tibiae were subjected to 40cycles of non-invasive axial loading engendering peak strain of 2250με. In both young and aged mice exercise increased cross-sectional muscle area and serum sclerostin concentration. In young mice it also increased serum IGF1. Exercise did not affect bone's adaptation to loading in any measured parameter in young or aged bone. These data demonstrate that a level of exercise sufficient to cause systemic changes in serum, and adaptive changes in local musculature, has no effect on bone's response to loading 3h later. This study provides no support for the beneficial effects of exercise on bone in the elderly being mediated by systemic or local muscle-derived effects rather than local adaptation to altered mechanical strain

Calculating Unknown Eigenvalues with a Quantum Algorithm

Quantum algorithms are able to solve particular problems exponentially faster than conventional algorithms, when implemented on a quantum computer. However, all demonstrations to date have required already knowing the answer to construct the algorithm. We have implemented the complete quantum phase estimation algorithm for a single qubit unitary in which the answer is calculated by the algorithm. We use a new approach to implementing the controlled-unitary operations that lie at the heart of the majority of quantum algorithms that is more efficient and does not require the eigenvalues of the unitary to be known. These results point the way to efficient quantum simulations and quantum metrology applications in the near term, and to factoring large numbers in the longer term. This approach is architecture independent and thus can be used in other physical implementations

Asymmetry of bipartite quantum discord

It is known from the analysis of the density matrix for bipartite systems that the quantum discord (as a measure of quantum correlations) depends on the particular subsystem chosen for the projective measurements. We study asymmetry of the discord in a simple physical model of two spin-1/2 particles with the dipole-dipole interaction governed by the XY Hamiltonian in the inhomogeneous magnetic field. The dependence of the above discord asymmetry on the Larmour frequencies at both T=0 (the ground state) and $T>0$ has been investigated. It is demonstrated, in particular, that the asymmetry is negligible for high temperatures but it may become significant with the decrease in temperature.Comment: 5 pages 3 figure

Adding control to arbitrary unknown quantum operations

While quantum computers promise significant advantages, the complexity of quantum algorithms remains a major technological obstacle. We have developed and demonstrated an architecture-independent technique that simplifies adding control qubits to arbitrary quantum operations-a requirement in many quantum algorithms, simulations and metrology. The technique is independent of how the operation is done, does not require knowledge of what the operation is, and largely separates the problems of how to implement a quantum operation in the laboratory and how to add a control. We demonstrate an entanglement-based version in a photonic system, realizing a range of different two-qubit gates with high fidelity.Comment: 9 pages, 8 figure

Quantification of Alterations in Cortical Bone Geometry Using Site Specificity Software in Mouse models of Aging and the Responses to Ovariectomy and Altered Loading

Investigations into the effect of (re)modelling stimuli on cortical bone in rodents normally rely on analysis of changes in bone mass and architecture at a narrow cross-sectional site. However, it is well established that the effects of axial loading produce site-specific changes throughout bones’ structure. Non-mechanical influences (e.g. hormones) can be additional to or oppose locally-controlled adaptive responses and may have more generalized effects. Tools currently available to study site-specific cortical bone adaptation are limited. Here we applied novel Site-Specificity software to measure bone mass and architecture at each 1% site along the length of the mouse tibia from standard micro-computed tomography (μCT) images. Resulting measures are directly comparable to those obtained through μCT analysis (R2 > 0.96). Site-Specificity Analysis was used to compare a number of parameters in tibiae from young adult (19-week-old) versus aged (19-month-old) mice; ovariectomized and entire mice; limbs subjected to short periods of axial loading or disuse induced by sciatic neurectomy. Age was associated with uniformly reduced cortical thickness and site-specific decreases in cortical area most apparent in the proximal tibia. Mechanical loading site-specifically increased cortical area and thickness in the proximal tibia. Disuse uniformly decreased cortical thickness and decreased cortical area in the proximal tibia. Ovariectomy uniformly reduced cortical area without altering cortical thickness. Differences in polar moment of inertia between experimental groups were only observed in the proximal tibia. Ageing and ovariectomy also altered eccentricity in the distal tibia. In summary, Site-Specificity Analysis provides a valuable tool for measuring changes in cortical bone mass and architecture along the entire length of a bone. Changes in the (re)modelling response determined at a single site may not reflect the response at different locations within the same bone

Experimental realisation of Shor's quantum factoring algorithm using qubit recycling

Quantum computational algorithms exploit quantum mechanics to solve problems exponentially faster than the best classical algorithms. Shor's quantum algorithm for fast number factoring is a key example and the prime motivator in the international effort to realise a quantum computer. However, due to the substantial resource requirement, to date, there have been only four small-scale demonstrations. Here we address this resource demand and demonstrate a scalable version of Shor's algorithm in which the n qubit control register is replaced by a single qubit that is recycled n times: the total number of qubits is one third of that required in the standard protocol. Encoding the work register in higher-dimensional states, we implement a two-photon compiled algorithm to factor N=21. The algorithmic output is distinguishable from noise, in contrast to previous demonstrations. These results point to larger-scale implementations of Shor's algorithm by harnessing scalable resource reductions applicable to all physical architectures.Comment: 7 pages, 3 figure

Protein kinase Cα (PKCα) Regulates Bone Architecture and Osteoblast Activity*

Bones' strength is achieved and maintained through adaptation to load bearing. The role of the protein kinase PKCα in this process has not been previously reported. However, we observed a phenotype in the long bones of Prkca−/− female but not male mice, in which bone tissue progressively invades the medullary cavity in the mid-diaphysis. This bone deposition progresses with age and is prevented by disuse but unaffected by ovariectomy. Castration of male Prkca−/− but not WT mice results in the formation of small amounts of intramedullary bone. Osteoblast differentiation markers and Wnt target gene expression were up-regulated in osteoblast-like cells derived from cortical bone of female Prkca−/− mice compared with WT. Additionally, although osteoblastic cells derived from WT proliferate following exposure to estradiol or mechanical strain, those from Prkca−/− mice do not. Female Prkca−/− mice develop splenomegaly and reduced marrow GBA1 expression reminiscent of Gaucher disease, in which PKC involvement has been suggested previously. From these data, we infer that in female mice, PKCα normally serves to prevent endosteal bone formation stimulated by load bearing. This phenotype appears to be suppressed by testicular hormones in male Prkca−/− mice. Within osteoblastic cells, PKCα enhances proliferation and suppresses differentiation, and this regulation involves the Wnt pathway. These findings implicate PKCα as a target gene for therapeutic approaches in low bone mass conditions