Comparative study of normal, Crouzon, and Apert craniofacial morphology using finite element scaling analysis

Finite element scaling analysis is used to study differences in morphology between the craniofacial complex of normal individuals and those affected with the syndromes of Apert and Crouzon. Finite element scaling quantifies the differences in shape and size between forms without reference to any fixed, arbitrary registration point or orientation line and measures the amount of form change required to deform one object into another. Two-dimensional coordinates of landmarks digitized from annual sets of cephalometric radiographs were used in the analysis. A simple tabulation shows no difference in variances between the normal and pathological samples. A test of mean differences depicts the Apert and Crouzon morphologies as significantly different from normal. The Apert palate differs from normal in shape in the older age groups analyzed, and palatal size differences are most common at the posterior nasal spine. The Apert pituitary fossa and basi-occiput are significantly larger than normal. The Crouzon pituitary fossa is also larger than normal, but the difference is not always significant. The typical morphology of the Crouzon nose is due more to differences in shape than size. The Crouzon basi-occiput is significantly smaller than normal. An age association of the differences between the normal and pathological craniofacies was found in Apert syndrome but not in Crouzon syndrome. Apert syndrome is characterized by a more homogeneous pattern of craniofacial dysmorphology from 6 months to 18 years of age than Crouzon syndrome.     

Bayesian analysis of genetic architecture of quantitative trait using data of crosses of multiple inbred lines

Using the data of crosses of multiple of inbred lines for mapping QTL can increase QTL detecting power compared with only cross of two inbred lines. Although many fixed-effect model methods have been proposed to analyze such data, they are largely based on one-QTL model or main effect model, and the interaction effects between QTL are always neglected. However, effectively separating the interaction effects from the residual error can increase the statistical power. In this article, we both extended the novel Bayesian model selection method and Bayesian shrinkage estimation approaches to multiple inbred line crosses. With two extensions, interacting QTL are effectively detected with high solution; in addition, the posterior variances for both main effects and interaction effects are also subjected to full Bayesian estimate, which is more optimal than two step approach involved in maximum-likelihood. A series of simulation experiments have been conducted to demonstrate the performance of the methods. The computer program written in FORTRAN language is freely available on request.     

Correlation between genetic distances based on single loci and on skeletal morphology in inbred mice

Genetic and morphometric distances between 12 inbred strains of mice ranging from closely related substrains to a sub-species were estimated using published data on single locus polymorphisms, and on the basis of up to 44 measurements on seven different bones, respectively. Simulation was also used to investigate sampling effects for the single loci. There were strong and statistically highly significant correlations among all measures of genetic distance ranging from 0.58 for the comparison of single loci with the logarithm of the Mahalanobis distance based on 24 measurements on four bones, to 0.72 for estimates of genetic distance based on single loci and the morphology of the mandible. These findings are in sharp contrast with those of Wayne & O'Brien (1986) who claimed that 'structural gene and morphometric variation of mandible traits are uncoupled between mouse strains'. Their failure to find such a correlation is probably because their sample of inbred strains included only a single pair of closely related substrains, and no substrains separated for less than 40 years, and because they failed to correct for non-linearity between morphometric and single-locus measurement scales. Simulations and regression analysis suggested that genetic distances could be estimated with approximately equal precision using morphological data on bone measurements or about 10 cladistically informative single loci, which would usually involve sampling about 50 loci. Data based on single-gene markers is usually more informative than morphometric data for studying the similarity of independently-derived strains. However, similarities among closely related populations such as sublines of an inbred strain can usually be studied more efficiently using morphometry.     

Genetic analysis of cholesterol accumulation in inbred mice.

Genetic linkage analysis in the laboratory mouse identified chromosomal regions containing genes that contribute to cholesterol accumulation in the liver and plasma. Comparisons between five inbred strains of mice obtained from the Jackson Laboratory (DBA/2, AKR, C57BL/6, SJL, and 129P3) revealed a direct correlation between intestinal cholesterol absorption and susceptibility to diet-induced hypercholesterolemia. This correlation was lost in the F1 generation arising from crosses between high- and low-absorbing strains. Linkage analyses in AKxD recombinant inbred strains and 129xSJL129F1 N2 backcross mice identified four quantitative trait loci (QTL) that influenced Liver cholesterol accumulation (Lcho1-4) and one locus that affected Plasma cholesterol accumulation (Pcho1). These loci map to five chromosomes and, with one exception, are different from the seven QTL identified previously that influence intestinal cholesterol absorption. We conclude that a large number of genes affects the amount of cholesterol absorbed in the small intestine and its accumulation in the liver and plasma of inbred mice.     

Tissue-fluid interface analysis using biphasic finite element method

Numerical studies on fluid-structure interaction have primarily relied on decoupling the solid and fluid sub-domains with the interactions treated as external boundary conditions on the individual sub-domains. The finite element applications for the fluid-structure interactions can be divided into iterative algorithms and sequential algorithms. In this paper, a new computational methodology for the analysis of tissue-fluid interaction problems is presented. The whole computational domain is treated as a single biphasic continuum, and the same space and time discretisation is carried out for the sub-domains using a penalty-based finite element model. This procedure does not require the explicit modelling of additional boundary conditions or interface elements. The developed biphasic interface finite element model is used in analysing blood flow through normal and stenotic arteries. The increase in fluid flow velocity when passing through a stenosed artery and the drop in pressure at the region are captured using this method.     

Mechanical properties of coronary stents determined by using finite element analysis.

The mechanical function of a stent deployed in a damaged artery is to provide a metallic tubular mesh structure. The purpose of this study was to determine the exact mechanical characteristics of stents. In order to achieve this, we have used finite-element analysis to model two different type of stents: tubular stents (TS) and coil stents (CS). The two stents chosen for this modeling present the most extreme mechanical characteristics of the respective types. Seven mechanical properties were studied by mathematical modeling with determination of: (1) stent deployment pressure, (2) the intrinsic elastic recoil of the material used, (3) the resistance of the stent to external compressive forces, (4) the stent foreshortening, (5) the stent coverage area, (6) the stent flexibility, and (7) the stress maps. The pressure required for deployment of CS was significantly lower than that required for TS, over 2.8 times greater pressure was required for the tubular model. The elastic recoil of TS is higher than CS (5.4% and 2.6%, respectively). TS could be deformed by 10% at compressive pressures of between 0.7 and 1.3 atm whereas CS was only deformed at 0.2 and 0.7 atm. The degree of shortening observed increases with deployment diameter for TS. CS lengthen during deployment. The metal coverage area is two times greater for TS than for CS. The ratio between the stiffness of TS and that of CS varies from 2060 to 2858 depending on the direction in which the force is applied. TS are very rigid and CS are significantly more flexible. Stress mapping shows stress to be localized at link nodes. This series of finite-element analyses illustrates and quantifies the main mechanical characteristics of two different commonly used stents. In interventional cardiology, we need to understand their mechanisms of implantation and action.     

A comprehensive SNP-based genetic analysis of inbred mouse strains

Dense genetic maps of mammalian genomes facilitate a variety of biological studies including the mapping of polygenic traits, positional cloning of monogenic traits, mapping of quantitative or qualitative trait loci, marker association, allelic imbalance, speed congenic construction, and evolutionary or phylogenetic comparison. In particular, single nucleotide polymorphisms (SNPs) have proved useful because of their abundance and compatibility with multiple high-throughput technology platforms. SNP genotyping is especially suited for the genetic analysis of model organisms such as the mouse because biallelic markers remain fully informative when used to characterize crosses between inbred strains. Here we report the mapping and genotyping of 673 SNPs (including 519 novel SNPs) in 55 of the most commonly used mouse strains. These data have allowed us to construct a phylogenetic tree that correlates and expands known genealogical relationships and clarifies the origin of strains previously having an uncertain ancestry. All 55 inbred strains are distinguishable genetically using this SNP panel. Our data reveal an uneven SNP distribution consistent with a mosaic pattern of inheritance and provide some insight into the changing dynamics of the physical architecture of the genome. Furthermore, these data represent a valuable resource for the selection of markers and the design of experiments that require the genetic distinction of any pair of mouse inbred strains such as the generation of congenic mice, positional cloning, and the mapping of quantitative or qualitative trait loci.The content of this publication does not necessarily reflect the view or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.     

Genetic analysis of intestinal cholesterol absorption in inbred mice.

A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.     

Large-scale in silico mapping of complex quantitative traits in inbred mice

Understanding the genetic basis of common disease and disease-related quantitative traits will aid in the development of diagnostics and therapeutics. The processs of gene discovery can be sped up by rapid and effective integration of well-defined mouse genome and phenome data resources. We describe here an in silico gene-discovery strategy through genome-wide association (GWA) scans in inbred mice with a wide range of genetic variation. We identified 937 quantitative trait loci (QTLs) from a survey of 173 mouse phenotypes, which include models of human disease (atherosclerosis, cardiovascular disease, cancer and obesity) as well as behavioral, hematological, immunological, metabolic, and neurological traits. 67% of QTLs were refined into genomic regions <0.5 Mb with approximately 40-fold increase in mapping precision as compared with classical linkage analysis. This makes for more efficient identification of the genes that underlie disease. We have identified two QTL genes, Adam12 and Cdh2, as causal genetic variants for atherogenic diet-induced obesity. Our findings demonstrate that GWA analysis in mice has the potential to resolve multiple tightly linked QTLs and achieve single-gene resolution. These high-resolution QTL data can serve as a primary resource for positional cloning and gene identification in the research community.     

New quantitative trait loci for the genetic variance in circadian period of locomotor activity between inbred strains of mice

Provisional quantitative trait loci (QTL) for circadian locomotor period and wheel-running period have been identified in recombinant inbred (RI) mouse strains. To confirm those QTL and identify new ones, the genetic component of variance of the circadian period was partitioned among an F2 intercross of RI mouse strains (BXD19 and CXB07). First, a genomic survey using 108 SSLP markers with an average spacing of 15 cM was carried out in a population of 259 (BXD19 x CXB07)F2 animals. The genome-wide survey identified two significant QTL for period of locomotor activity measured by infrared photobeam crossings on mouse chromosomes 1 (lod score 5.66) and 14 (lod score 4.33). The QTL on distal chromosome 1 confirmed a previous report based on congenic B6.D2-Mtv7a/Ty mice. Lod scores greater than 2.0 were found on chromosomes 1, 2, 6, 12, 13, and 14. In a targeted extension study, additional genotyping was performed on these chromosomes in the full sample of 341 F2 progeny. The 6 chromosome-wide surveys identified 3 additional QTL on mouse chromosomes 6, 12, and 13. The QTL on chromosome 12 overlaps with circadian period QTL identified in several prior studies. For wheel-running period, the chromosome-wide surveys identified QTL on chromosomes 2 and 13 and one highly suggestive QTL on proximal chromosome 1. The results are compared to other published studies of QTL of circadian period.     

A finite element analysis of masticatory stress hypotheses

Understanding how the skull transmits and dissipates forces during feeding provides insights into the selective pressures that may have driven the evolution of primate skull morphology. Traditionally, researchers have interpreted masticatory biomechanics in terms of simple global loading regimes applied to simple shapes (i.e., bending in sagittal and frontal planes, dorsoventral shear, and torsion of beams and cylinders). This study uses finite element analysis to examine the extent to which these geometric models provide accurate strain predictions in the face and evaluate whether simple global loading regimes predict strains that approximate the craniofacial deformation pattern observed during mastication. Loading regimes, including those simulating peak loads during molar chewing and those approximating the global loading regimes, were applied to a previously validated finite element model (FEM) of a macaque (Macaca fascicularis) skull, and the resulting strain patterns were compared. When simple global loading regimes are applied to the FEM, the resulting strains do not match those predicted by simple geometric models, suggesting that these models fail to generate accurate predictions of facial strain. Of the four loading regimes tested, bending in the frontal plane most closely approximates strain patterns in the circumorbital region and lateral face, apparently due to masseter muscle forces acting on the zygomatic arches. However, these results indicate that no single simple global loading regime satisfactorily accounts for the strain pattern found in the validated FEM. Instead, we propose that FE models replace simple cranial models when interpreting bone strain data and formulating hypotheses about craniofacial biomechanics.     

Variation in pattern of mystacial vibrissae in mice. A quantitative study of ICR stock and several inbred strains

We report on the variation in the pattern of mystacial vibrissae in ICR mice, of which one-half of the about 600 animals investigated showed one or more supernumerary whiskers (SWs). The SWs and their follicles--in all respects identical to the units of the standard pattern except for their smaller size--occurred at a restricted number of sites. In addition, a limited number of mice from two BALB/c strains were analyzed. Half of them also had one or more SWs, but mainly at one site. Mice of the C3H/HeJ and DBA/2J(a) strains were virtually without SWs, whereas animals from the NMRI strain were standard without exception. Nearly all animals of the C57BL/6J strain lacked between 1 and 4 vibrissae, always from one or two of the same adjacent sites. There was a slight overall predominance for the left side of the face to bear SWs and there was no clear-cut association with sex; the entire population was without obvious defects. The sites where extra or lacking whiskers occur are associated with the lines of fusion between the medial and the lateral nasal fold, and between the latter and the maxillary arch. Where tested, we always found a topologic equivalency between the pattern of the whisker follicles and the contralateral pattern of the "barrels"--multineuronal units in layer IV of the parietal cerebral cortex--whether the pattern was standard, "enriched," or lacking in elements. The data presented in this paper provided a basis for several studies carried out subsequently on animals that are the offspring of those characterized here, studies suggesting that the occurrence of supernumerary and of lacking whiskers has a genetic basis.     

QTL and quantitative genetic analysis of beak morphology reveals patterns of standing genetic variation in an Estrildid finch

The intra- and interspecific diversity of avian beak morphologies is one of the most compelling examples for the power of natural selection acting on a morphological trait. The development and diversification of the beak have also become a textbook example for evolutionary developmental biology, and variation in expression levels of several genes is known to causally affect beak shape. However, until now, no genomic polymorphisms have been identified, which are related to beak morphology in birds. QTL mapping does reveal the location of causal polymorphisms, albeit with poor spatial resolution. Here, we estimate heritability and genetic correlations for beak length, depth and width and perform a QTL linkage analysis for these traits based on 1404 informative single-nucleotide polymorphisms genotyped in a four-generation pedigree of 992 captive zebra finches (Taeniopygia guttata). Beak size, relative to body size, was sexually dimorphic (larger in males). Heritability estimates ranged from 0.47 for beak length to 0.74 for beak width. QTL mapping revealed four to five regions of significant or suggestive genome-wide linkage for each of the three beak dimensions (nine different regions in total). Eight out of 11 genes known to influence beak morphology are located in these nine peak regions. Five QTL do not cover known candidates demonstrating that yet unknown genes or regulatory elements may influence beak morphology in the zebra finch.     

Deriving indicators for breast conserving surgery using finite element analysis

Breast conserving therapy (BCT), comprising a complete surgical excision of the tumour (partial mastectomy) with post-operative radiotherapy to the remaining breast tissue, is feasible for most women undergoing treatment for breast cancer. The goal of BCT is to achieve local control of the cancer, as well as to preserve a breast that satisfies a woman's cosmetic concerns. Although most women undergo partial mastectomy with satisfactory cosmetic results, in many patients the remaining breast is left with major cosmetic defects including concave deformities, distortion of the nipple–areolar complex, asymmetry and changes in tissue density characterised by excessive density associated with parenchymal scarring, as well as breast pain. There are currently no tools, other than surgical experience and judgement, which can predict the impact of partial mastectomy on the contour, the deformity of the treated breast and the mechanical stress that it induces. In this study, we use a finite element model to execute virtual surgery and carry out a sensitivity analysis on the resection location, the resection size, the breast tissue mechanical property and the different post-surgery recovery stage. We output the result in two different built-in indicators labelled as the cosmetic and the functional indicators. This study used the breast model for three women with breast cancer who have been elected to undergo BCT and are being treated at the Methodist Hospital in Houston, TX. The goal of this study was to propose a first glimpse of the key parameter leading to satisfactory post-BCT cosmetic results.     

Mapping genetic variants associated with Beta-adrenergic responses in inbred mice

β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.     

Brugia pahangi: quantitative analysis of infection in several inbred rat strains.

We report a comprehensive study of the infectivity of Brugia pahangi in male and female rats of eight different inbred strains. A single infection of any inbred rat strain will produce rats that become microfilaremic, have occult infection, or clear the primary infection. The proportion belonging to any category is determined by the basic susceptibility level of that strain. Patency rates (blood microfilaria+) ranged from 24% (AO rats) to 73% (WKA rats). The period for which microfilaria were in the circulation was directly related to microfilarial burden, with rats carrying less than 50 mf/ml of blood patent for 11.8 weeks +/- 12.2; for 50-499 mf/ml it was 37.6 +/- 14.8 and for 500+ mf/ml it was 63.3 +/- 34.2 weeks. Suckling rats were resistant to infection (0 patent) and weanlings were intermediate in resistance between suckling and adult rats. Female rats were highly resistant to infection. Approximately half of amicrofilaremic rats have occult infections. A high proportion of patent infections involve the testes or testicular lymphatics. In the most susceptible rat strains, more than 95% of the administered L3 or developing L4 parasites were killed within 28 days. During the course of the first 6 months, the ratio of males to females fell significantly, suggesting a shorter life span in male worms. The features of the infectivity/patency patterns in rats are compared with recognized patterns obtaining in human populations. We conclude that rats provide a valuable and underutilized model for the experimental analysis of filarial infections.     

A voxel-based formulation for contact finite element analysis

To date, voxel-based finite element models have not been feasible for contact problems, owing to the inherent stair-step boundary discontinuities. New preprocessing techniques are reported herein to mesh these boundaries smoothly, for purposes of contact stress analysis. Further, new techniques are reported to concentrate the mesh resolution automatically near the articular surface, thus reducing the problem size to levels compatible with executing nonlinear problems on contemporary engineering workstations. Close approximations to Hertzian analytical solutions were obtained for spherical and cylindrical geometries meshed in this manner, and an illustrative anatomical contact problem of the human hip joint is presented.