Continuum modeling and numerical simulation of cell motility.

This work proposes a continuum-mechanical model of cell motility which accounts for the dynamics of motility-relevant protein species. For the special case of fish epidermal keratocytes, the stress and cell-substrate traction responses are postulated to depend on selected protein densities in accordance with the structural features of the cells. A one-dimensional version of the model is implemented using Arbitrary Lagrangian-Eulerian finite elements in conjunction with Lagrange multipliers for the treatment of kinematic constraints related to surface growth. Representative numerical tests demonstrate the capacity of the proposed model to simulate stationary and steady crawling states.

New Equations for Hydrostatic Weighing without Head Submersion.

New equations were derived to predict the density of the body (DB) by hydrostatic weighing with the head above water (HWHAW). Hydrostatic weighing with the head below water (HWHBW) was the criterion for DB measurement in 90 subjects (44 M, 46 F). Head volume by immersion (HVIMM) was determined by subtracting the mass in water with the head below water (MWHBW) from the mass in water with the head above water (MWHAW), with subjects at residual lung volume. Equations were derived for head volume prediction (HVPRED) from head measurements and used to correct DB by HWHAW. Equations were also derived for HWHAW using direct regression of DB from uncorrected density (with MWHAW in place of MWHBW). Prediction equations were validated in 45 additional subjects (21 M, 24 F). Results were evaluated using equivalence testing, linear regression, Bland−Altman plots, and paired t-tests. Head girth, face girth, and body mass produced the smallest errors for HVPRED. In both M and F validation groups, equivalence (±2% fat by weight) was demonstrated between body fat percent (BF%) by HWHBW and BF% by HWHAW with HVPRED. Variance in computer-averaged samples of MWHAW was significantly less (p < 0.05) than MWHBW. Prediction error was smaller for BF% by HWHAW with HVPRED than for alternative methods. Conclusions: Equivalence between BF% by HWHBW and BF% by HWHAW with HVPRED was demonstrated and differences were not statistically significant. Weight fluctuations were smaller for HWHAW than HWHBW.

The Role of the Rhythm Step on Pro-Agility Test Performance in Division I Football Players.

Purpose: The pro-agility test is a common test in multiple sports. A common way to start is the crossover step (CS) where athletes start the drill by crossing one leg over the other. However, the rhythm step (RS), initiated by moving one foot medially before crossing the opposite foot over the first, may result in faster time. Therefore, the purpose of this study was to compare the RS to the CS in the pro-agility test. Methods: Thirteen division I college football players (age 21 ± 1.5 years, mass 103.5 ± 18 kg, and stature 1.87 ± .078 m) were recruited to perform both step techniques. Video was analyzed to determine times during the first five yards (t1), the second ten yards (t2), the last five yards (t3), and the total time (ttotal). Additionally, maximum acceleration (amax), time to maximum acceleration (tamax), maximum body lean angle (θlean), and time to reach θlean (tθlean) were measured. Results: Descriptive statistics (mean ± SD) were calculated for all variables. A significant difference between the two techniques was observed at t1 (RS mean 1.56 ± 0.09 s, CS mean 1.62 ± 0.11 s), ttotal (RS mean 4.99 ± 0.35 s, CS mean 5.09 ± 0.35 s), and tamax (RS mean 0.38 ± 0.67, CS mean 0.46 ± 0.61). Conclusion: Overall, the RS appeared to be superior to the CS for reaching peak acceleration faster during the initial phase of the pro-agility drill as well as short distance sprints that are initiated from a standing position.

Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population.

Inability to correctly repair DNA damage is known to play a role in the development of breast cancer. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been identified, which modify the DNA repair capacity, which in turn may affect the risk of developing breast cancer. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 62 SNPs in 29 genes in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. Five SNPs were associated with breast cancer. SNPs rs13312840 and rs769416 in the NBS1 gene were associated with a decrease in breast cancer risk (OR TT vs. TC/CC = 0.58; 95% CI, 0.37-0.92; P = 0.019 and OR GG vs. GT/TT = 0.23, 95% CI 0.06-0.85, P = 0.017, respectively). The variant allele of MRE11A rs556477 was also associated with a reduced risk of developing the disease (OR AA vs. AG/GG = 0.76; 95% CI, 0.64-0.91; P = 0.0022). MUS81 rs545500 and PBOV1 rs6927706 SNPs were associated with an increased risk of developing breast cancer (OR GG vs. GC/CC = 1.21, 95% CI, 1.02-1.45; P = 0.031; OR AA vs. AG/GG = 1.53, 95% CI, 1.07-2.18; P = 0.019, respectively). Finally, haplotype-based tests identified significant associations between specific haplotypes in MRE11A and NBS1 genes and breast cancer risk. Further large-scale studies are needed to confirm these results.

An investigation of breast cancer risk factors in Cyprus: a case control study.

BACKGROUND: Breast cancer is the most common form of malignancy affecting women worldwide. It is also the leading cancer in females in Cyprus, with approximately 400 new cases diagnosed annually. It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. The main aim of this study was to assess the strength of associations between recognized risk factors and breast cancer among Cypriot women. This is the first epidemiological investigation on risk factors of breast cancer among the Cypriot female population. METHODS: We carried out a case-control study, involving 1,109 breast cancer patients and a group of 1,177 controls who were recruited while participating in the National screening programme for breast cancer. Information on demographic characteristics and potential risk factors were collected from both groups during a standardized interview. Logistic regression analysis was used to assess the strength of the association between each risk factor and breast cancer risk, before and after adjusting for the possible confounding effect of other factors. RESULTS: In multivariable models, family history of breast cancer (OR 1.64, 95% CI 1.23, 2.19) was the strongest predictor of breast cancer risk in the Cypriot population. Late menarche (OR 0.64, 95% CI 0.45, 0.92 among women reaching menarche after the age of 15 vs. before the age of 12) and breastfeeding (OR 0.74, 95% CI 0.59, 0.92) exhibited a strong protective effect. In the case of breastfeeding, the observed effect appeared stronger than the effect of pregnancy alone. Surprisingly, we also observed an inverse association between hormone replacement therapy (HRT) although this may be a product of the retrospective nature of this study. CONCLUSION: Overall the findings of our study corroborate with the results of previous investigations on descriptive epidemiology of risk factors for breast cancer. This investigation provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Cypriot population, including the study of gene-environment interactions. Furthermore, our study provides the first scientific evidence for formulating targeted campaigns for prevention and early diagnosis of breast cancer in Cyprus.

A homogeneous nonequilibrium molecular dynamics method for calculating the heat transport coefficient of mixtures and alloys.

This work generalizes Evans' homogeneous nonequilibrium method for estimating heat transport coefficient to multispecies molecular systems described by general multibody potentials. The proposed method, in addition to being compatible with periodic boundary conditions, is shown to satisfy all the requirements of Evans' original method, namely, adiabatic incompressibility of phase space, equivalence of the dissipative and heat fluxes, and momentum preservation. The difference between the new equations of motion, suitable for mixtures and alloys, and those of Evans' original work are quantified by means of simulations for fluid Ar-Kr and solid GaN test systems.

Numerical modeling of stress in stenotic arteries with microcalcifications: a micromechanical approximation.

Most finite element models of atherosclerotic arteries do not account for the heterogeneity of the plaque constituents at the microscale. Failure of plaque lesions has been shown to be a local event, linked to stress concentrations caused by cap thinning, inflammation, macroscopic heterogeneity, and recently, the presence of microcalcifications. There is growing evidence that microcalcifications exist in the fibrous cap of plaque lesions. However, their role is not yet fully understood. The goal of the present work is to investigate the effects of localized regions of microcalcifications on the stress field of atherosclerotic plaque caps in a section of carotid artery. This is achieved by performing finite element simulations of three-dimensional fluid-structure interaction models. The material response in the region of microcalcification is modeled using a combination of finite elements, homogenization theory, and a stress concentration function that approximates the average local stresses in the fibrous tissue and microcalcification phases. The results indicate that the circumferential stress in the fibrous tissue phase increases as the volume fraction of microcalcifications is increased, and that the stress exceeds a critical threshold when the fibrous cap thickness is decreased. Furthermore, the presence of the microcalcifications significantly influences the distribution of stress by shifting the maximum circumferential stress away from the cap shoulders, where failure is most common when the effective region of microcalcification is located at the center of the cap. This is a possible explanation of why 40% of plaque ruptures occur away from the shoulder region of the cap.

DNA-repair genetic polymorphisms and risk of breast cancer in Cyprus.

The DNA repair pathway is known to play a role in the etiology of breast cancer. A number of studies have demonstrated that common germline variants in genes involved in the DNA repair pathway influence breast cancer risk. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 12 single nucleotide polymorphisms (SNPs) in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. We found significant associations with breast cancer for SNPs in the BRCA2 and MRE11A genes. Carriers of the BRCA2 rs1799944 variant (991 Asp) were found to have an increased risk of breast cancer (OR = 1.41, 95% CI 1.08-1.83, P = 0.01) with P (trend) = 0.0076. Homozygous carriers of the MRE11A rs601341 A allele had an increased risk of breast cancer (OR = 1.36, 95% CI 1.08-1.71, P = 0.009) with P (trend) = 0.0087. This study suggests that genetic variants in BRCA2 and MRE11A are associated with breast cancer risk.

A homogeneous nonequilibrium molecular dynamics method for calculating thermal conductivity with a three-body potential.

In this work, Evans' homogeneous nonequilibrium molecular dynamics method for estimating thermal conductivity is extended to systems employing three-body potentials. This extension is put on a firm theoretical basis and applied to a silicon lattice modeled by the Stillinger-Weber potential. Two new methods are suggested for estimating the thermal conductivity based on a range of values of the fictitious force. Also, kinetic theory is used to estimate the linear range of the fictitious force necessary to bias the heat flow, thereby potentially reducing the number of simulations needed to estimate thermal conductivity.

Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus.

Population-based studies have reported significant associations between specific genetic polymorphisms and breast cancer susceptibility. A number of studies have demonstrated that common variants of genes involved in the DNA repair pathway act as low penetrance breast cancer susceptibility alleles. We aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the DNA repair genes XRCC1, XRCC2 and XRCC3 and breast cancer in MASTOS, a population-based case-control study of 1,109 Cypriot women with breast cancer diagnosed between 40 and 70 years and 1,177 age-matched healthy controls. Five coding SNPs were genotyped including rs1799782, rs25489 and rs25487 in XRCC1, rs3218536 in XRCC2 and rs861539 in XRCC3. Homozygous XRCC1 280His carriers had an increased risk of breast cancer (odds ratio 4.68; 95% CI 1.01-21.7; P = 0.03). The XRCC2 188His allele was associated with a marginal protective effect for breast cancer (odds ratio 0.79; 95% CI 0.62-1.00; P = 0.05). No significant associations were observed between the other three SNPs and breast cancer. This study suggests that genetic variation in SNPs in XRCC1 and XRCC2 genes may influence breast cancer susceptibility.

Influence of bone volume fraction and architecture on computed large-deformation failure mechanisms in human trabecular bone.

Large-deformation bending and buckling have long been proposed as failure mechanisms by which the strength of trabecular bone can be affected disproportionately to changes in bone density, and thus may represent an important aspect of bone quality. We sought here to quantify the contribution of large-deformation failure mechanisms on strength, to determine the dependence of these effects on bone volume fraction and architecture, and to confirm that the inclusion of large-deformation effects in high-resolution finite element models improves predictions of strength versus experiment. Micro-CT-based finite element models having uniform hard tissue material properties were created from 54 cores of human trabecular bone taken from four anatomic sites (age = 70+/-11; 24 male, 27 female donors), which were subsequently biomechanically tested to failure. Strength predictions were made from the models first including, then excluding, large-deformation failure mechanisms, both for compressive and tensile load cases. As expected, strength predictions versus experimental data for the large-deformation finite element models were significantly improved (p < 0.001) relative to the small deformation models in both tension and compression. Below a volume fraction of about 0.20, large-deformation failure mechanisms decreased trabecular strength from 5-80% for compressive loading, while effects were negligible above this volume fraction. Step-wise nonlinear multiple regression revealed that structure model index (SMI) and volume fraction (BV/TV) were significant predictors of these reductions in strength (R2 = 0.83, p < 0.03). Even so, some low-density specimens having nearly identical volume fraction and SMI exhibited up to fivefold differences in strength reduction. We conclude that within very low-density bone, the potentially important biomechanical effect of large-deformation failure mechanisms on trabecular bone strength is highly heterogeneous and is not well explained by standard architectural metrics.

Vertebral fragility and structural redundancy.

The mechanisms of age-related vertebral fragility remain unclear, but may be related to the degree of "structural redundancy" of the vertebra; ie, its ability to safely redistribute stress internally after local trabecular failure from an isolated mechanical overload. To better understand this issue, we performed biomechanical testing and nonlinear micro-CT-based finite element analysis on 12 elderly human thoracic ninth vertebral bodies (age 76.9 ± 10.8 years). After experimentally overloading the vertebrae to measure strength, we used nonlinear finite element analysis to estimate the amount of failed tissue and understand the failure mechanisms. We found that the amount of failed tissue per unit bone mass decreased with decreasing bone volume fraction (r(2) = 0.66, p < 0.01). Thus, for the weak vertebrae with low bone volume fraction, overall failure of the vertebra occurred after failure of just a tiny proportion of the bone tissue (<5%). This small proportion of failed tissue had two sources: the existence of fewer vertically oriented load paths to which load could be redistributed from failed trabeculae; and the vulnerability of the trabeculae in these few load paths to undergo bending-type failure mechanisms, which further weaken the bone. Taken together, these characteristics suggest that diminished structural redundancy may be an important aspect of age-related vertebral fragility: vertebrae with low bone volume fraction are highly susceptible to collapse because so few trabeculae are available for load redistribution if the external loads cause any trabeculae to fail.

Generalization of the homogeneous nonequilibrium molecular dynamics method for calculating thermal conductivity to multibody potentials.

This work provides a generalization of Evans' homogeneous nonequilibrium method for estimating thermal conductivity to molecular systems that are described by general multibody potentials. A perturbed form of the usual Nose-Hoover equations of motion is formally constructed and is shown to satisfy the requirements of Evans' original method. These include adiabatic incompressibility of phase space, equivalence of the dissipative and heat fluxes, and momentum preservation.

The modified super-ellipsoid yield criterion for human trabecular bone.

Despite the importance of multiaxial failure of trabecular bone in many biomechanical applications, to date no complete multiaxial failure criterion for human trabecular bone has been developed. By using experimentally validated nonlinear high-resolution, micromechanical finite-element models as a surrogate for multiaxial loading experiments, we determined the three-dimensional normal strain yield surface and all combinations of the two-dimensional normal-shear strain yield envelope. High-resolution finite-element models of three human femoral neck trabecular bone specimens obtained through microcomputed tomography were used. In total, 889 multiaxial-loading cases were analyzed, requiring over 41,000 CPU hours on parallel supercomputers. Our results indicated that the multiaxial yield behavior of trabecular bone in strain space was homogeneous across the specimens and nearly isotropic. Analysis of stress-strain curves along each axis in the 3-D normal strain space indicated uncoupled yield behavior whereas substantial coupling was seen for normal-shear loading. A modified super-ellipsoid surface with only four parameters fit the normal strain yield data very well with an arithmetic error +/-SD less than -0.04 +/- 5.1%. Furthermore, the principal strains associated with normal-shear loading showed excellent agreement with the yield surface obtained for normal strain loading (arithmetic error +/- SD < 2.5 +/- 6.5%). We conclude that the four-parameter "Modified Super-Ellipsoid" yield surface presented here describes the multiaxial failure behavior of human femoral neck trabecular bone very well.