From micro to macroevolution: drivers of shape variation in an island radiation of Podarcis lizards.

Phenotypictraits have been shown to evolve in response to variation in the environment. However, the evolutionary processes underlying the emergence of phenotypic diversity can typically only be understood at the population level. Consequently, how subtle phenotypic differences at the intraspecific level can give rise to larger-scale changes in performance and ecology remains poorly understood. We here tested for the covariation between ecology, bite force, jaw muscle architecture, and the three-dimensional shape of the cranium and mandible in 16 insular populations of the lizards Podarcis melisellensis and P. sicula. We then compared the patterns observed at the among-population level with those observed at the interspecific level. We found that three-dimensional head shape as well as jaw musculature evolve similarly under similar ecological circumstances. Depending on the type of food consumed or on the level of sexual competition, different muscle groups were more developed and appeared to underlie changes in cranium and mandible shape. Our findings show that the local selective regimes are primary drivers of phenotypic variation resulting in predictable patterns of form and function. Moreover, intraspecific patterns of variation were generally consistent with those at the interspecific level, suggesting that microevolutionary variation may translate into macroevolutionary patterns of ecomorphological diversity.

Back to the bones: do muscle area assessment techniques predict functional evolution across a macroevolutionary radiation?

Measures of attachment or accommodation area on the skeleton are a popular means of rapidly generating estimates of muscle proportions and functional performance for use in large-scale macroevolutionary studies. Herein, we provide the first evaluation of the accuracy of these muscle area assessment (MAA) techniques for estimating muscle proportions, force outputs and bone loading in a comparative macroevolutionary context using the rodent masticatory system as a case study. We find that MAA approaches perform poorly, yielding large absolute errors in muscle properties, bite force and particularly bone stress. Perhaps more fundamentally, these methods regularly fail to correctly capture many qualitative differences between rodent morphotypes, particularly in stress patterns in finite-element models. Our findings cast doubts on the validity of these approaches as means to provide input data for biomechanical models applied to understand functional transitions in the fossil record, and perhaps even in taxon-rich statistical models that examine broad-scale macroevolutionary patterns. We suggest that future work should go back to the bones to test if correlations between attachment area and muscle size within homologous muscles across a large number of species yield strong predictive relationships that could be used to deliver more accurate predictions for macroevolutionary and functional studies.

Towards an early 3D-diagnosis of craniofacial asymmetry by computing the accurate midplane: A PCA-based method.

BACKGROUND AND OBJECTIVE: Craniofacial asymmetry is a common growth disorder often caused by unilateral chewing. Although an early orthodontic treatment would avoid surgical procedures later in life, the uncertainty of defining the accurate sagittal midplane potentially leads to misdiagnosis and therefore inaccurate orthodontic treatment plans. This novel study aims to 3D-diagnose craniofacial complex malformations in children with unilateral crossbite (UXB) considering a midplane which compensates the asymmetric morphology. METHODS: The sagittal midplane of 20 children, fifteen of whom exhibited UXB, was computed by a PCA-based method which compensates the asymmetry mirroring the 3D models obtained from cone-beam computed tomography data. Once determined, one side of the data was mirrored using the computed midplane to visualize the malformations on the hard and soft tissues by 3D-computing the distances between both halves. Additionally, 31 skull's landmarks were manually placed in each model to study the principal variation modes and the significant differences in the group of subjects with and without UXB through PCA and Mann-Whitney U test analyses respectively. RESULTS: Morphological 3D-analysis showed pronounced deformities and aesthetic implications for patients with severe asymmetry (jaw deviation > 0.8 mm) in whole craniofacial system, while initial signs of asymmetry were found indistinctly in the mandible or maxilla. We detected significant (p < 0.05) malformations for example in mandibular ramus length (0.0086), maxillary palate width (0.0481) and condylar head width (0.0408). Craniofacial malformations increased the landmarks' variability in the group of patients with UXB over the control group requiring 8 variation modes more to define 99% of the sample' variability. CONCLUSIONS: Our findings demonstrated the viability of early diagnosis of craniofacial asymmetry through computing the accurate sagittal midplane which compensates the individual's asymmetrical morphology. Furthermore, this study provides important computational insights into the determination of craniofacial deformities which are caused by UXB, following some empirical findings of previous clinical studies. Hence, this computational approach can be useful for the development of new software in craniofacial surgery or for its use in biomedical research and clinical practice.

Mathematical modelling of bone remodelling cycles including the NFκB signalling pathway.

RANKL can promote the differentiation of osteoclast precursors into mature osteoclasts by binding to RANK expressed on the surfaces of osteoclast progenitor cells during bone remodelling. The NF-κB signalling pathway is downstream of RANKL and transmits the RANKL signal to nuclear promoter-bound protein complexes from cell surface receptors, which then regulates target gene expression to facilitate osteoclastogenesis. However, this important role of the NF-κB signalling pathway is usually ignored in published mathematical models of bone remodelling. This paper describes the construction of a mathematical model of bone remodelling in a normal bone microenvironment with inclusion of the NF-κB signalling pathway. The model consisted of a set of ordinary differential equations and reconstructed variations in the bone cells, resultant bone volume, and biochemical factors involved in the NF-κB signalling pathway over time. The model was used to investigate how the NF-κB pathway is activated in osteoclast precursors to promote osteoclastogenesis during bone remodelling. Model simulations agreed well with published experimental data. It is hoped that this model can improve our understanding of bone remodelling. It has the obvious potential to examine the influence of NF-κB dysregulation on bone remodelling, and even propose potential therapeutic strategies to combat related bone diseases in future research.

Modelling human skull growth: a validated computational model.

During the first year of life, the brain grows rapidly and the neurocranium increases to about 65% of its adult size. Our understanding of the relationship between the biomechanical forces, especially from the growing brain, the craniofacial soft tissue structures and the individual bone plates of the skull vault is still limited. This basic knowledge could help in the future planning of craniofacial surgical operations. The aim of this study was to develop a validated computational model of skull growth, based on the finite-element (FE) method, to help understand the biomechanics of skull growth. To do this, a two-step validation study was carried out. First, an in vitro physical three-dimensional printed model and an in silico FE model were created from the same micro-CT scan of an infant skull and loaded with forces from the growing brain from zero to two months of age. The results from the in vitro model validated the FE model before it was further developed to expand from 0 to 12 months of age. This second FE model was compared directly with in vivo clinical CT scans of infants without craniofacial conditions (n = 56). The various models were compared in terms of predicted skull width, length and circumference, while the overall shape was quantified using three-dimensional distance plots. Statistical analysis yielded no significant differences between the male skull models. All size measurements from the FE model versus the in vitro physical model were within 5%, with one exception showing a 7.6% difference. The FE model and in vivo data also correlated well, with the largest percentage difference in size being 8.3%. Overall, the FE model results matched well with both the in vitro and in vivo data. With further development and model refinement, this modelling method could be used to assist in preoperative planning of craniofacial surgery procedures and could help to reduce reoperation rates.

The Impact of Vein Mechanical Compliance on Arteriovenous Fistula Outcomes.

BACKGROUND: Arteriovenous fistulae (AVFs) are the preferred access for hemodialysis but suffer a high early failure rate. The aim of this study was to determine how venous distensibility, as measured in vitro, relates to early outcomes of AVF formed with the sampled vein. METHODS: Ethical approval was obtained for all aspects of this study. During AVF formation a circumferential segment of the target vein was sampled. Mechanical stress testing of the venous segments was undertaken using a dynamic mechanical analyzer, with progressive stress loading at 2 N/min to a maximum of 10 N or until sample disruption. Stress-strain curves were obtained for vein samples and Young's modulus (YM) calculated. Duplex assessment of the fistulae was undertaken at 30 days. RESULTS: Thirty patients consented to participate with 29 samples obtained for analysis. Statistical comparison of YM demonstrated no relationship with common cardiovascular risk factors or dialysis status. Subject age greater than 65 was the only patient factor which showed a significant difference in YM (P = 0.05). Furthermore, a negative correlation was confirmed between age and YM (Pearson's r = -0.465, P < 0.05). Nine of the 29 subjects suffered an early AVF failure. Mann-Whitney U testing for differences in distribution reported that YM was significantly higher in those fistulas which failed (P < 0.005). CONCLUSIONS: Reduced venous compliance appears to result in higher failure rates of AVFs. With the advancement of clinical tools such as speckle tracing ultrasound identification of vessel compliance in vivo may produce valuable additional information for clinicians planning AVF surgery.

Skeletal immaturity, rostral sparing, and disparate hip morphologies as biomechanical causes for Legg-Calvé-Perthes' disease.

Legg-Calvé-Perthes' (Perthes') disease is a developmental disease of the hip joint that may result in numerous short and long term problems. The etiology of the disease remains largely unknown, but the mechanism is believed to be vascular and/or biomechanical in nature. There are several anatomical characteristics that tend to be prevalent in children with Perthes' disease, namely: skeletal immaturity, reduced height, and rostral sparing. We present an overview of the literature, summarizing the current understanding of the pathogenesis, particularly related to how the formation of the vasculature to the femoral epiphysis places children aged 5-8 at a higher risk for Perthes' disease, how skeletal immaturity and rostral sparing could increase the probability of developing Perthes' disease, and how animal models have aided our understanding of the disease. In doing so, we also explore why Perthes' disease is correlated to latitude, with populations at higher latitudes having higher incidence rates than populations closer to the Equator. Finally, we present five hypotheses detailing how Perthes' disease could have a biomechanical cause. Clin. Anat. 29:759-772, 2016. © 2016 Wiley Periodicals, Inc.

A virtual approach to evaluate therapies for management of multiple myeloma induced bone disease.

Multiple myeloma bone disease is devastating for patients and a major cause of morbidity. The disease leads to bone destruction by inhibiting osteoblast activity while stimulating osteoclast activity. Recent advances in multiple myeloma research have improved our understanding of the pathogenesis of multiple myeloma-induced bone disease and suggest several potential therapeutic strategies. However, the effectiveness of some potential therapeutic strategies still requires further investigation and optimization. In this paper, a recently developed mathematical model is extended to mimic and then evaluate three therapies of the disease, namely: bisphosphonates, bortezomib and TGF-ß inhibition. The model suggests that bisphosphonates and bortezomib treatments not only inhibit bone destruction, but also reduce the viability of myeloma cells. This contributes to the current debate as to whether bisphosphonate therapy has an anti-tumour effect. On the other hand, the analyses indicate that treatments designed to inhibit TGF-ß do not reduce bone destruction, although it appears that they might reduce the viability of myeloma cells, which again contributes to the current controversy regarding the efficacy of TGF-ß inhibition in multiple myeloma-induced bone disease.

A predator-prey based mathematical model of the bone remodelling cycle: exploring the relationship between the model parameters and biochemical factors.

Bone remodelling is a vital process which enables bone to repair, renew and optimize itself. Disorders in the bone remodelling process are inevitably manifested in bone-related diseases, such as hypothyroidism, primary hyperparathyroidism and osteoporosis. In our previous work, a predator-prey based mathematical model was developed to simulate bone remodelling cycles under normal and two pathological conditions, hypothyroidism and primary hyperparathyroidism, for trabecular bone at a fixed point. However, the biochemical meanings of the model parameters were not fully explored. This article first extends the previous work by proposing relationships between the model parameters and biochemical factors involved in the bone remodelling process and by examining whether those relationships do predict the behaviours observed in vivo. The model is then applied to the simulation and investigation of bone remodelling of postmenopausal osteoporosis. The proposed connections are supported by good agreement between the model simulations and published experimental observations for the normal condition and all three pathological variations in bone remodelling.

Investigating the efficacy of bisphosphonates treatment against multiple myeloma induced bone disease using a computational model.

Multiple myeloma (MM)-induced bone disease is mortal for most MM patients. Bisphosphonates are first-line treatment for MM-induced bone disease, since it can inhibit osteoclast activity and the resultant bone resorption by suppressing the differentiation of osteoclast precursors into mature osteoclasts, promoting osteoclast apoptosis and disrupting osteoclast function. However, it is still unclear whether bisphosphonates have an anti-tumour effect. In our previous work, a computational model was built to simulate the pathology of MM-induced bone disease. This paper extends this proposed computational model to investigate the efficacy of bisphosphonates treatment and then clear the controversy of this therapy. The extended model is validated through the good agreement between simulation results and experimental data. The simulation results suggest that bisphosphonates indeed have an anti-tumour effect.

Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease.

Multiple myeloma (MM) is the second most common haematological malignancy and results in destructive bone lesions. The interaction between MM cells and the bone microenvironment plays an important role in the development of the tumour cells and MM-induced bone disease and forms a 'vicious cycle' of tumour development and bone destruction, intensified by suppression of osteoblast activity and promotion of osteoclast activity. In this paper, a mathematical model is proposed to simulate how the interaction between MM cells and the bone microenvironment facilitates the development of the tumour cells and the resultant bone destruction. It includes both the roles of inhibited osteoblast activity and stimulated osteoclast activity. The model is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after the invasion and then removal of the tumour cells and explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The behaviour of the model compares well with published experimental data. The model serves as a first step to understand the development of MM-induced bone disease and could be applied further to evaluate the current therapies against MM-induced bone disease and even suggests new potential therapeutic targets.

Peak wall stress measurement in elective and acute abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) rupture occurs when wall stress exceeds wall strength. Engineering principles suggest that aneurysm diameter is only one aspect of its geometry that influences wall stress. Finite element analysis considers the complete geometry and determines wall stresses throughout the structure. This article investigates the interoperator and intraoperator reliability of finite element analysis in the calculation of peak wall stress (PWS) in AAA and examines the variation in PWS in elective and acute AAAs. METHOD: Full ethics and institutional approval was obtained. The study recruited 70 patients (30 acute, 40 elective) with an infrarenal AAA. Computed tomography (CT) images were obtained of the AAA from the renal vessels to the aortic bifurcation. Manual edge extraction, three-dimensional reconstruction, and blinded finite element analysis were performed to ascertain location and value of PWS. Ten CT data sets were analyzed by four different operators to ascertain interoperator reliability and by one operator twice to ascertain intraoperator reliability. An intraclass correlation coefficient was obtained. The Mann-Whitney U test and independent samples t test compared groups for statistical significance. RESULTS: The intraclass correlation coefficient was 0.71 for interoperator reliability and 0.84 for intraoperator reliability. There was no statistically significant difference in the mean (SD) maximal AAA diameter between elective (6.47 [1.30] cm) and acute (7.08 [1.39] cm) patients (P = .073). The difference in PWS between elective (0.67 [0.30] MPa) and acute (1.11 [0.51] MPa) patients (P = .008) was statistically significant, however. CONCLUSION: Interoperator and intraoperator reliability in the derivation of PWS is acceptable. PWS, but not maximal diameter, was significantly higher in acute AAAs than in elective AAAs.