Dynamic simulations of movement allow one to study neuromuscular coordination, analyze athletic performance, and estimate internal loading of the musculoskeletal system. Simulations can also be used ...to identify the sources of pathological movement and establish a scientific basis for treatment planning. We have developed a freely available, open-source software system (OpenSim) that lets users develop models of musculoskeletal structures and create dynamic simulations of a wide variety of movements. We are using this system to simulate the dynamics of individuals with pathological gait and to explore the biomechanical effects of treatments. OpenSim provides a platform on which the biomechanics community can build a library of simulations that can be exchanged, tested, analyzed, and improved through a multi-institutional collaboration. Developing software that enables a concerted effort from many investigators poses technical and sociological challenges. Meeting those challenges will accelerate the discovery of principles that govern movement control and improve treatments for individuals with movement pathologies.
The objective of this study was to develop an efficient methodology for generating muscle-actuated simulations of human walking that closely reproduce experimental measures of kinematics and ground ...reaction forces. We first introduce a residual elimination algorithm (REA) to compute pelvis and low back kinematic trajectories that ensure consistency between whole-body dynamics and measured ground reactions. We then use a computed muscle control (CMC) algorithm to vary muscle excitations to track experimental joint kinematics within a forward dynamic simulation. CMC explicitly accounts for delays in muscle force production resulting from activation and contraction dynamics while using a general static optimization framework to resolve muscle redundancy. CMC was used to compute muscle excitation patterns that drove a 21-degrees-of-freedom, 92 muscle model to track experimental gait data of 10 healthy young adults. Simulated joint kinematics closely tracked experimental quantities (mean root-mean-squared errors generally less than 1°), and the time histories of muscle activations were similar to electromyographic recordings. A simulation of a half-cycle of gait could be generated using approximately 30
min of computer processing time. The speed and accuracy of REA and CMC make it practical to generate subject-specific simulations of gait.
Abstract Muscles actuate walking by providing vertical support and forward progression of the mass center. To quantify muscle contributions to vertical support and forward progression (i.e., vertical ...and fore-aft accelerations of the mass center) over a range of walking speeds, three-dimensional muscle-actuated simulations of gait were generated and analyzed for eight subjects walking overground at very slow, slow, free, and fast speeds. We found that gluteus maximus, gluteus medius, vasti, hamstrings, gastrocnemius, and soleus were the primary contributors to support and progression at all speeds. With the exception of gluteus medius, contributions from these muscles generally increased with walking speed. During very slow and slow walking speeds, vertical support in early stance was primarily provided by a straighter limb, such that skeletal alignment, rather than muscles, provided resistance to gravity. When walking speed increased from slow to free, contributions to support from vasti and soleus increased dramatically. Greater stance-phase knee flexion during free and fast walking speeds caused increased vasti force, which provided support but also slowed progression, while contralateral soleus simultaneously provided increased propulsion. This study provides reference data for muscle contributions to support and progression over a wide range of walking speeds and highlights the importance of walking speed when evaluating muscle function.
X-linked hypophosphatemia (XLH) is caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX). Loss of functional PHEX ...results in elevated fibroblast growth factor 23 (FGF23), impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily by osteocytes, suppresses bone formation by antagonizing canonical Wnt-signaling and is reported to be elevated in XLH patients. Our previous study reported that a monoclonal antibody to sclerostin (Scl-Ab) decreases FGF23 and increases phosphate and bone mass in growing Hyp mice (XLH murine model). In the current study, we investigated the efficacy of Scl-Ab in treating XLH pathophysiology in adult Hyp mice that are past the period of rapid skeletal growth (12 and 20-weeks old). We hypothesized that Scl-Ab would not only increase bone formation, bone strength and bone mass, but would also normalize phosphate regulating hormones, FGF23, parathyroid hormone (PTH), and vitamin 1,25(OH)2D. Scl-Ab treatment increased cortical area, trabecular bone volume fraction, trabecular bone formation rate, and the bending moment in both sexes of both age groups. Scl-Ab treatment suppressed circulating levels of intact FGF23 and c-term FGF23 in treated male and female wild-type and Hyp mice of both age groups and improved both vitamin 1,25(OH)2D and PTH. Scl-Ab treated Hyp mice also showed evidence of increased renal expression of the sodium-phosphate co-transporter, NPT2a, specifically in the female Hyp mice. Our study suggests that Scl-Ab treatment can improve several skeletal and metabolic pathologies associated with XLH, further establishes the role of sclerostin in the regulation of FGF23 and provides evidence that Scl-Ab can improve phosphate regulation by targeting the bone-renal axis.
•Sclerostin antibody decreases fibroblast growth factor-23, increases vitamin 1,25(OH)2D, and decreases parathyroid hormone in adult Hyp mice.•Sclerostin antibody treatment increases bone mass, bone formation rate, and bone strength in adult Hyp mice.•Sclerostin antibody treatment increases NPT2a protein expression, particularly in female Hyp mice.
Dynamic optimization of human walking Anderson, F C; Pandy, M G
Journal of biomechanical engineering,
10/2001, Letnik:
123, Številka:
5
Journal Article
Recenzirano
A three-dimensional, neuromusculoskeletal model of the body was combined with dynamic optimization theory to simulate normal walking on level ground. The body was modeled as a 23 degree-of-freedom ...mechanical linkage, actuated by 54 muscles. The dynamic optimization problem was to calculate the muscle excitation histories, muscle forces, and limb motions subject to minimum metabolic energy expenditure per unit distance traveled. Muscle metabolic energy was calculated by slimming five terms: the basal or resting heat, activation heat, maintenance heat, shortening heat, and the mechanical work done by all the muscles in the model. The gait cycle was assumed to be symmetric; that is, the muscle excitations for the right and left legs and the initial and terminal states in the model were assumed to be equal. Importantly, a tracking problem was not solved. Rather only a set of terminal constraints was placed on the states of the model to enforce repeatability of the gait cycle. Quantitative comparisons of the model predictions with patterns of body-segmental displacements, ground-reaction forces, and muscle activations obtained from experiment show that the simulation reproduces the salient features of normal gait. The simulation results suggest that minimum metabolic energy per unit distance traveled is a valid measure of walking performance.
Increased osteoclastogenesis and angiogenesis occur in physiologic and pathologic conditions. However, it is unclear if or how these processes are linked. To test the hypothesis that osteoclasts ...stimulate angiogenesis, we modulated osteoclast formation in fetal mouse metatarsal explants or in adult mice and determined the effect on angiogenesis. Suppression of osteoclast formation with osteoprotegerin dose-dependently inhibited angiogenesis and osteoclastogenesis in metatarsal explants. Conversely, treatment with parathyroid hormone related protein (PTHrP) increased explant angiogenesis, which was completely blocked by osteoprotegerin. Further, treatment of mice with receptor activator of nuclear factor-κB ligand (RANKL) or PTHrP in vivo increased calvarial vessel density and osteoclast number. We next determined whether matrix metalloproteinase-9 (MMP-9), an angiogenic factor predominantly produced by osteoclasts in bone, was important for osteoclast-stimulated angiogenesis. The pro-angiogenic effects of PTHrP or RANKL were absent in metatarsal explants or calvaria in vivo, respectively, from Mmp9−/− mice, demonstrating the importance of MMP-9 for osteoclast-stimulated angiogenesis. Lack of MMP-9 decreased osteoclast numbers and abrogated angiogenesis in response to PTHrP or RANKL in explants and in vivo but did not decrease osteoclast differentiation in vitro. Thus, MMP-9 modulates osteoclast-stimulated angiogenesis primarily by affecting osteoclasts, most probably by previously reported migratory effects on osteoclasts. These results clearly demonstrate that osteoclasts stimulate angiogenesis in vivo through MMP-9.
Abstract
We determined the effect of attaching palmitate, tocopherol or cholesterol to PS ASOs and their effects on plasma protein binding and on enhancing ASO potency in the muscle of rodents and ...monkeys. We found that cholesterol ASO conjugates showed 5-fold potency enhancement in the muscle of rodents relative to unconjugated ASOs. However, they were toxic in mice and as a result were not evaluated in the monkey. In contrast, palmitate and tocopherol-conjugated ASOs showed enhanced potency in the skeletal muscle of rodents and modest enhancements in potency in the monkey. Analysis of the plasma-protein binding profiles of the ASO-conjugates by size-exclusion chromatography revealed distinct and species-specific differences in their association with plasma proteins which likely rationalizes their behavior in animals. Overall, our data suggest that modulating binding to plasma proteins can influence ASO activity and distribution to extra-hepatic tissues in a species-dependent manner and sets the stage to identify other strategies to enhance ASO potency in muscle tissues.
The purpose of this study was to quantify the contributions made by individual muscles to support of the whole body during normal gait. A muscle's contribution to support was described by its ...contribution to the time history of the vertical force exerted by the ground. The analysis was based on a three-dimensional, muscle-actuated model of the body and a dynamic optimization solution for normal walking. The results showed that, in early stance, before the foot was placed flat on the ground, support was provided mainly by the ankle dorsiflexors. After foot-flat, but before contralateral toe-off, support was generated primarily by gluteus maximus, vasti, and posterior gluteus medius/minimus; these muscles were responsible for the first peak seen in the vertical ground-reaction force. The majority of support in midstance was provided by gluteus medius/minimus, with gravity assisting significantly as well. The ankle plantarflexors generated nearly all support in late stance; these muscles were responsible for the second peak in the vertical ground-reaction force. The results showed also that centrifugal forces act to decrease the vertical ground-reaction force, but only by minor amounts, and that resistance of the skeleton to the force of gravity is no larger than 1/2 body weight throughout the gait cycle.
The highest-achieving figures in politics, business, academia, and the media dominate public discourse and wield great influence in society. Education—perhaps especially at “elite” colleges and ...universities—may lie at the heart of the divide between the general public and these top achievers. In this paper, we build a new data set for the American “elite” and systematically examine the link between selective schools and outstanding achievements. In Study 1, across 30 different achievement groups totaling 26,198 people, we document patterns of attendance at a set of 34 “Elite” 34 schools, the 8 Ivy League schools, and Harvard University in particular. In Study 2, we surveyed 1810 laypeople to estimate how well they are aware of the key empirical facts from Study 1. We found that exceptional achievement is surprisingly strongly associated with “elite” education, especially obtaining a degree from Harvard, and the general public tends to underestimate the size of this effect. Attending one of just 34 institutions of higher education out of the roughly 4000 in the U.S. appears to be a critical and surprising factor separating extraordinary achievers from others in their fields.
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