BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptora- negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability.We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. © 2014 American Association for Cancer Research.

Finite element modelling of the formation of pre-load damage in cement mantles of orthopaedic joint replacements

Finite element modeling of the formation of pre-loaded damage in cement mantles of orthopaedic joint replacements was presented. The existence of cracking suggested a high level of residual stress. The direction of maximum principal stress vectors corresponded well with the observed crack orientation. Results suggested that cracking depends upon a combination of residual stress, porosity and temperature rise during polymerization.

An application of bi-directional evolutionary structural optimisation for optimising energy absorbing structures using a material damage model

The Bi-directional Evolutionary Structural Optimisation (BESO) method is a numerical topology optimisation method developed for use in finite element analysis. This paper presents a particular application of the BESO method to optimise the energy absorbing capability of metallic structures. The optimisation objective is to evolve a structural geometry of minimum mass while ensuring that the kinetic energy of an impacting projectile is reduced to a level which prevents perforation. Individual elements in a finite element mesh are deleted when a prescribed damage criterion is exceeded. An energy absorbing structure subjected to projectile impact will fail once the level of damage results in a critical perforation size. It is therefore necessary to constrain an optimisation algorithm from producing such candidate solutions. An algorithm to detect perforation was implemented within a BESO framework which incorporated a ductile material damage model.

Vibration based seismic damage identification procedure for a steel concentrically braced frame structure

An approach for seismic damage identification of a single-storey steel concentrically braced frame (CBF) structure is presented through filtering and double integration of a recorded acceleration signal. A band-pass filter removes noise from the acceleration signal followed by baseline correction being used to reduce the drift in velocity and displacement during numerical integration. The pre-processing achieves reliable numerical integration that predicts the displacement response accurately when compared to the measured lateral in-plane displacement of the CBF structure. The lateral displacement of the CBF structure is used to infer buckling and yielding of bracing members through seismic tests. The level of interstorey drift of the CBF during a seismic excitation allows the yield and buckling of the bracing members to be identified and indirectly detects damage based on exceedance of calculated displacement limits. The calculated buckling and yielding displacement threshold limits used to identify damage are demonstrated to accurately identify initial buckling and yielding in the bracing members.

Structural damage diagnosis of steel truss bridges by outlier detection

This study discusses structural damage diagnosis of real steel truss bridges by measuring trafficinduced vibration of bridges and utilizing a damage indicator derived from linear system parameters of a time series model. On-site damage experiments were carried out on real steel truss bridges. Artificial damage was applied to the bridge by severing a truss member with a cutting machine.Vehicle-induced vibrations of the bridges before and after applying damagewere measured and used in structural damage diagnosis of the bridges. Changes in the damage indicator are detected by Mahalanobis-Taguchi system (MTS) which is one of multivariate outlier analyses. The damage indicator and outlier detection was successfully applied to detect anomalies in the steel truss bridges utilizing vehicle-induced vibrations. Observations through this study demonstrate feasibility of the proposed approach for real world applications.

The use of an instrumented vehicle in a wavelet based damage detection approach for bridge structures

Periodic monitoring of structures such as bridges is necessary as their condition can deteriorate due to environmental conditions and ageing, causing the bridge to become unsafe. This monitoring - so called Structural Health Monitoring (SHM) - can give an early warning if a bridge becomes unsafe. This paper investigates an alternative wavelet-based approach for the monitoring of bridge structures which consists of the use of a vehicle fitted with accelerometers on its axles. A simplified vehicle-bridge interaction model is used in theoretical simulations to examine the effectiveness of the approach in detecting damage in the bridge. The accelerations of the vehicle are processed using a continuous wavelet transform, allowing a time-frequency analysis to be performed. This enables the identification of both the existence and location of damage from the vehicle response. Based on this analysis, a damage index is established. A parametric study is carried out to investigate the effect of parameters such as the bridge span length, vehicle speed, vehicle mass, damage level, signal noise level and road surface roughness on the accuracy of results. In addition, a laboratory experiment is carried out to validate the results of the theoretical analysis and assess the ability of the approach to detect changes in the bridge response.

Identification of the Dynamic Parameters of a Real Bridge under Different Damage Conditions in a Field Experiment

This paper presents the results of a real bridge field experiment in which damage was applied artificially to a steel truss bridge. The aim of this paper is to identify the dynamic parameters of this bridge using conventional techniques and investigate the effect of various damage conditions on those parameters. In the field experiment, acceleration measurements were recorded at a number of locations on the bridge deck. To excite the bridge, a two-axle van was driven across the bridge at constant speed. Dynamic parameters, such as the bridge mode shape, natural frequency and damping constant, are identified from the acceleration signals using existing techniques such as the fast Fourier transform, logarithmic decrement and frequency domain decomposition. The variation of these parameters under the influence of artificially applied damage conditions is investigated in order to evaluate their sensitivity to the bridge damage.