Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.

Changes in landing mechanics in patients following anterior cruciate ligament reconstruction when wearing an extension constraint knee brace.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is associated with a high incidence of second tears (graft tears and contralateral ACL tears). These secondary tears have been attributed to asymmetrical lower extremity mechanics. Knee bracing is one potential intervention that can be used during rehabilitation that has the potential to normalize lower extremity asymmetry; however, little is known about the effect of bracing on movement asymmetry in patients following ACL reconstruction. HYPOTHESIS: Wearing a knee brace would increase knee joint flexion and joint symmetry. It was also expected that the joint mechanics would become more symmetrical in the braced condition. OBJECTIVE: To examine how knee bracing affects knee joint function and symmetry over the course of rehabilitation in patients 6 months following ACL reconstruction. STUDY DESIGN: Controlled laboratory study. LEVEL OF EVIDENCE: Level 3. METHODS: Twenty-three adolescent patients rehabilitating from ACL reconstruction surgery were recruited for the study. The subjects all underwent a motion analysis assessment during a stop-jump activity with and without a functional knee brace on the surgical side that resisted extension for 6 months following the ACL reconstruction surgery. Statistical analysis utilized a 2 × 2 (limb × brace) analysis of variance with a significant alpha level of 0.05. RESULTS: Subjects had increased knee flexion on the surgical side when they were braced. The brace condition increased knee flexion velocity, decreased the initial knee flexion angle, and increased the ground reaction force and knee extension moment on both limbs. Side-to-side asymmetry was present across conditions for the vertical ground reaction force and knee extension moment. CONCLUSION: Wearing a knee brace appears to increase lower extremity compliance and promotes normalized loading on the surgical side. CLINICAL RELEVANCE: Knee extension constraint bracing in postoperative ACL patients may improve symmetry of lower extremity mechanics, which is potentially beneficial in progressing rehabilitation and reducing the incidence of second ACL tears.

Later Life Consequences of Developmental Mitochondrial DNA Damage in C. elegans

Mitochondria are responsible for producing the vast majority of cellular ATP, and are therefore critical to organismal health [1]. They contain thir own genomes (mtDNA) which encode 13 proteins that are all subunits of the mitochondrial respiratory chain (MRC) and are essential for oxidative phosphorylation [2]. mtDNA is present in multiple copies per cell, usually between 103 and 104 , though this number is reduced during certain developmental stages [3, 4]. The health of the mitochondrial genome is also important to the health of the organism, as mutations in mtDNA lead to human diseases that collectively affect approximately 1 in 4000 people [5, 6]. mtDNA is more susceptible than nuclear DNA (nucDNA) to damage by many environmental pollutants, for reasons including the absence of Nucleotide Excision Repair (NER) in the mitochondria [7]. NER is a highly functionally conserved DNA repair pathway that removes bulky, helix distorting lesions such as those caused by ultraviolet C (UVC) radiation and also many environmental toxicants, including benzo[a]pyrene (BaP) [8]. While these lesions cannot be repaired, they are slowly removed through a process that involves mitochondrial dynamics and autophagy [9, 10]. However, when present during development in C. elegans, this damage reduces mtDNA copy number and ATP levels [11]. We hypothesize that this damage, when present during development, will result in mitochondrial dysfunction and increase the potential for adverse outcomes later in life.

To test this hypothesis, 1st larval stage (L1) C. elegans are exposed to 3 doses of 7.5J/m2 ultraviolet C radiation 24 hours apart, leading to the accumulation of mtDNA damage [9, 11]. After exposure, many mitochondrial endpoints are assessed at multiple time points later in life. mtDNA and nucDNA damage levels and genome copy numbers are measured via QPCR and real-time PCR , respectively, every 2 day for 10 days. Steady state ATP levels are measured via luciferase expressing reporter strains and traditional ATP extraction methods. Oxygen consumption is measured using a Seahorse XFe24 extra cellular flux analyzer. Gene expression changes are measured via real time PCR and targeted metabolomics via LC-MS are used to investigate changes in organic acid, amino acid and acyl-carnitine levels. Lastly, nematode developmental delay is assessed as growth, and measured via imaging and COPAS biosort.

I have found that despite being removed, UVC induced mtDNA damage during development leads to persistent deficits in energy production later in life. mtDNA copy number is permanently reduced, as are ATP levels, though oxygen consumption is increased, indicating inefficient or uncoupled respiration. Metabolomic data and mutant sensitivity indicate a role for NADPH and oxidative stress in these results, and exposed nematodes are more sensitive to the mitochondrial poison rotenone later in life. These results fit with the developmental origin of health and disease hypothesis, and show the potential for environmental exposures to have lasting effects on mitochondrial function.

Lastly, we are currently working to investigate the potential for irreparable mtDNA lesions to drive mutagenesis in mtDNA. Mutations in mtDNA lead to a wide range of diseases, yet we currently do not understand the environmental component of what causes them. In vitro evidence suggests that UVC induced thymine dimers can be mutagenic [12]. We are using duplex sequencing of C. elegans mtDNA to determine mutation rates in nematodes exposed to our serial UVC protocol. Furthermore, by including mutant strains deficient in mitochondrial fission and mitophagy, we hope to determine if deficiencies in these processes will further increase mtDNA mutation rates, as they are implicated in human diseases.

Modelling of industrial multi-physics processes—a key role for computational mechanics.

In the analysis of industrial processes, there is an increasing emphasis on systems governed by interacting continuum phenomena. Mathematical models of such multi-physics processes can only be achieved for practical simulations through computational solution procedures—computational mechanics. Examples of such multi-physics systems in the context of metals processing are used to explore some of the key issues. Finite-volume methods on unstructured meshes are proposed as a means to achieve efficient rapid solutions to such systems. Issues associated with the software design, the exploitation of high performance computers, and the concept of the virtual computational-mechanics modelling laboratory are also addressed in this context.

CAPLib - A 'thin layer' message passing library to support computational mechanics codes on distributed memory parallel systems

The Computer Aided Parallelisation Tools (CAPTools) [Ierotheou, C, Johnson SP, Cross M, Leggett PF, Computer aided parallelisation tools (CAPTools)-conceptual overview and performance on the parallelisation of structured mesh codes, Parallel Computing, 1996;22:163±195] is a set of interactive tools aimed to provide automatic parallelisation of serial FORTRAN Computational Mechanics (CM) programs. CAPTools analyses the user's serial code and then through stages of array partitioning, mask and communication calculation, generates parallel SPMD (Single Program Multiple Data) messages passing FORTRAN. The parallel code generated by CAPTools contains calls to a collection of routines that form the CAPTools communications Library (CAPLib). The library provides a portable layer and user friendly abstraction over the underlying parallel environment. CAPLib contains optimised message passing routines for data exchange between parallel processes and other utility routines for parallel execution control, initialisation and debugging. By compiling and linking with different implementations of the library, the user is able to run on many different parallel environments. Even with today's parallel systems the concept of a single version of a parallel application code is more of an aspiration than a reality. However for CM codes the data partitioning SPMD paradigm requires a relatively small set of message-passing communication calls. This set can be implemented as an intermediate `thin layer' library of message-passing calls that enables the parallel code (especially that generated automatically by a parallelisation tool such as CAPTools) to be as generic as possible. CAPLib is just such a `thin layer' message passing library that supports parallel CM codes, by mapping generic calls onto machine specific libraries (such as CRAY SHMEM) and portable general purpose libraries (such as PVM an MPI). This paper describe CAPLib together with its three perceived advantages over other routes: - as a high level abstraction, it is both easy to understand (especially when generated automatically by tools) and to implement by hand, for the CM community (who are not generally parallel computing specialists); - the one parallel version of the application code is truly generic and portable; - the parallel application can readily utilise whatever message passing libraries on a given machine yield optimum performance.

CFD approach for solid mechanics analysis

A cell-centred finite volume(CC-FV) solid mechanics formulation, based on a computational fluid dynamics(CFD) procedure, is presented. A CFD code is modified such that the velocity variable is used as to the displacement variable. Displacement and pressure fields are considered as unknown variables. The results are validated with finite element(FE) and cell-vertex finite volume(CV-FV) predictions based on discretisation of the equilibrium equations. The developed formulation is applicable for both compressible and incompressible solids behaviour. The method is general and can be extended for the simultaneous analysis of problems involving flow-thermal and stress effects.

Multiphase mesh partitioning for parallel computational mechanics codes

We consider the load-balancing problems which arise from parallel scientific codes containing multiple computational phases, or loops over subsets of the data, which are separated by global synchronisation points. We motivate, derive and describe the implementation of an approach which we refer to as the multiphase mesh partitioning strategy to address such issues. The technique is tested on example meshes containing multiple computational phases and it is demonstrated that our method can achieve high quality partitions where a standard mesh partitioning approach fails.

Dynamic solid mechanics using finite volume methods

A procedure for evaluating the dynamic structural response of elastic solid domains is presented. A prerequisite for the analysis of dynamic fluid–structure interaction is the use of a consistent set of finite volume (FV) methods on a single unstructured mesh. This paper describes a three-dimensional (3D) FV, vertex-based method for dynamic solid mechanics. A novel Newmark predictor–corrector implicit scheme was developed to provide time accurate solutions and the scheme was evaluated on a 3D cantilever problem. By employing a small amount of viscous damping, very accurate predictions of the fundamental natural frequency were obtained with respect to both the amplitude and period of oscillation. This scheme has been implemented into the multi-physics modelling software framework, PHYSICA, for later application to full dynamic fluid structure interaction.

Dynamic mesh partitioning and load-balancing for parallel computational mechanics codes

In this Chapter we discuss the load-balancing issues arising in parallel mesh based computational mechanics codes for which the processor loading changes during the run. We briefly touch on geometric repartitioning ideas and then focus on different ways of using a graph both to solve the load-balancing problem and the optimisation problem, both locally and globally. We also briefly discuss whether repartitioning is always valid. Sample illustrative results are presented and we conclude that repartitioning is an attractive option if the load changes are not too dramatic and that there is a certain trade-off between partition quality and volume of data that the underlying application needs to migrate.

A vertex-based finite volume method applied to non-linear material problems in computational solid mechanics

A vertex-based finite volume (FV) method is presented for the computational solution of quasi-static solid mechanics problems involving material non-linearity and infinitesimal strains. The problems are analysed numerically with fully unstructured meshes that consist of a variety of two- and threedimensional element types. A detailed comparison between the vertex-based FV and the standard Galerkin FE methods is provided with regard to discretization, solution accuracy and computational efficiency. For some problem classes a direct equivalence of the two methods is demonstrated, both theoretically and numerically. However, for other problems some interesting advantages and disadvantages of the FV formulation over the Galerkin FE method are highlighted.

The effect of thermal cycle profiles on solder joint damage

The relationship between the damage caused at different thermal cycles is very important. The whole of accelerated thermal cycle testing is based on the premise that damage at one cycle is representative of damage at a different cycle. In this paper, the relative damage caused by six thermal cycle profiles are predicted using Finite Element (FE) modelling and the results validated against experiments. Both creep strain and strain energy density were used as damage indicators and creep strain was found to correlate better with experiment. The validated FE model is then used to investigate the effect of altering each of the thermal profile parameters (ramp and swell times, hot and cold temperatures). The components used for testing are surface mount resistors - 1206, 0805 and 0603. The solders investigated are eutectic SnAgCu and eutectic SnAg.

Analysis and modeling of heaping behavior of granular mixtures within a computational mechanics framework

This paper presents a continuum model of the flow of granular material during filling of a silo, using a viscoplastic constitutive relation based on the Drucker-Prager plasticity yield function. The performed simulations demonstrate the ability of the model to realistically represent complex features of granular flows during filling processes, such as heap formation and non-zero inclination angle of the bulk material-air interface. In addition, micro-mechanical parametrizations which account for particle size segregation are incorporated into the model. It is found that numerical predictions of segregation phenomena during filling of a binary granular mixture agree well with experimental results. Further numerical tests indicate the capability of the model to cope successfully with complex operations involving granular mixtures.