The Role of Osteocytes in Targeted Bone Remodeling: A Mathematical Model

Until recently many studies of bone remodeling at the cellular level have focused on the behavior of mature osteoblasts and osteoclasts, and their respective precursor cells, with the role of osteocytes and bone lining cells left largely unexplored. This is particularly true with respect to the mathematical modeling of bone remodeling. However, there is increasing evidence that osteocytes play important roles in the cycle of targeted bone remodeling, in serving as a significant source of RANKL to support osteoclastogenesis, and in secreting the bone formation inhibitor sclerostin. Moreover, there is also increasing interest in sclerostin, an osteocyte-secreted bone formation inhibitor, and its role in regulating local response to changes in the bone microenvironment. Here we develop a cell population model of bone remodeling that includes the role of osteocytes, sclerostin, and allows for the possibility of RANKL expression by osteocyte cell populations. This model extends and complements many of the existing mathematical models for bone remodeling but can be used to explore aspects of the process of bone remodeling that were previously beyond the scope of prior modeling work. Through numerical simulations we demonstrate that our model can be used to theoretically explore many of the most recent experimental results for bone remodeling, and can be utilized to assess the effects of novel bone-targeting agents on the bone remodeling process

Towards a New Spatial Representation of Bone Remodeling

Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed. There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes. We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur \emph{in vitro} and \emph{in vivo}. By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as \emph{in vitro} and \emph{in vivo}. This makes it possible to perform \emph{in silica} experiments more closely resembling experimental observations.Comment: Math. Biosci. Eng., 9(2), 201

Observations on regeneration of the pedipalp and legs of scorpions

An Opisthacanthus asper (Peters, 1861) (Hormuridae) shows a relatively rare example of pedipalp regeneration in which the lost tibia and tarsus was replaced by a smaller, curved element of uncertain homology to either the fixed or free finger. A comparable abnormal palp described in the literature hints that pedipalps can only regenerate a structure of this form, regardless of the site of amputation. An Olivierus caucasicus (Nordmann, 1840) (Buthidae) is described in which claws (pretarsus) of leg III regenerated directly at the distal end of the tibia, while in leg IV the claws regenerated at the end of a truncated section of the metatarsus. This supports previous observations that scorpions can only regenerate the pretarsus of the leg, again irrespective of where on the limb the original breakage occurred

Development of a new scale to measure ambiguity tolerance in veterinary students

The ability to cope with ambiguity and feelings of uncertainty is an essential element of professional practice. Research with physicians has identified that intolerance of ambiguity or uncertainty is linked to stress and some authors have hypothesised that there could be an association between intolerance of ambiguity and burnout (e.g. Cooke et al 2013). We describe the adaptation of the TAMSAD (Tolerance of Ambiguity in Medical Students and Doctors) scale for use with veterinary students. Exploratory factor analysis supports a unidimensional structure for the Ambiguity tolerance construct. Although internal reliability of the 29 item TAMSAD scale is reasonable (α = 0.50), an alternative 27 item scale (drawn from the original 41 items used to develop TAMSAD) shows higher internal reliability for veterinary students (α = 0.67). We conclude that there is good evidence to support the validity of this latter TAVS (Tolerance of Ambiguity in Veterinary students) scale to study ambiguity tolerance in veterinary students

Cas Adaptor Proteins Coordinate Sensory Axon Fasciculation.

Development of complex neural circuits like the peripheral somatosensory system requires intricate mechanisms to ensure axons make proper connections. While much is known about ligand-receptor pairs required for dorsal root ganglion (DRG) axon guidance, very little is known about the cytoplasmic effectors that mediate cellular responses triggered by these guidance cues. Here we show that members of the Cas family of cytoplasmic signaling adaptors are highly phosphorylated in central projections of the DRG as they enter the spinal cord. Furthermore, we provide genetic evidence that Cas proteins regulate fasciculation of DRG sensory projections. These data establish an evolutionarily conserved requirement for Cas adaptor proteins during peripheral nervous system axon pathfinding. They also provide insight into the interplay between axonal fasciculation and adhesion to the substrate

New fabrication technique for highly sensitive qPlus sensor with well-defined spring constant

A new technique for the fabrication of highly sensitive qPlus sensor for atomic force microscopy (AFM) is described. Focused ion beam was used to cut then weld onto a bare quartz tuning fork a sharp micro-tip from an electrochemically etched tungsten wire. The resulting qPlus sensor exhibits high resonance frequency and quality factor allowing increased force gradient sensitivity. Its spring constant can be determined precisely which allows accurate quantitative AFM measurements. The sensor is shown to be very stable and could undergo usual UHV tip cleaning including e-beam and field evaporation as well as in-situ STM tip treatment. Preliminary results with STM and AFM atomic resolution imaging at $4.5\,K$ of the silicon $Si(111)-7\times 7$ surface are presented.Comment: 5 pages, 3 figure

Modeling and Simulation of the Effects of Cyclic Loading on Articular Cartilage Lesion Formation

We present a model of articular cartilage lesion formation to simulate the effects of cyclic loading. This model extends and modifies the reaction-diffusion-delay model by Graham et al. 2012 for the spread of a lesion formed though a single traumatic event. Our model represents "implicitly" the effects of loading, meaning through a cyclic sink term in the equations for live cells. Our model forms the basis for in silico studies of cartilage damage relevant to questions in osteoarthritis, for example, that may not be easily answered through in vivo or in vitro studies. Computational results are presented that indicate the impact of differing levels of EPO on articular cartilage lesion abatement