Damage Kinetics Research Articles

MODELLING DSB REPAIR KINETICS FOR DNA DAMAGE INDUCED BY PROTON AND CARBON IONS.

Proton and carbon therapy are the main choices of particle therapy for cancer treatment. Particle dose distribution is superior to conventional photon therapy dose distribution due to Bragg peak. However, the basic biology of cellular damage and cell death is not well understood. The aim of this work is to present a mechanistic model of double strand break (DSB) repair that predicts the repair kinetics of damage induced by particles employed in cancer therapy. Monte Carlo Track Damage Simulation (MCDS) was employed to model DNA damage. The frequency of DSB and SSB was computed for proton and carbon ions. DSBs were subjected to repair model to calculate the repair kinetics. Two distinct DSB repair models dependent on the cell cycle were proposed. The DSB repair model contains non-homologous end joining (NHEJ), homologous recombination (HR) and back up non-homologous end joining (B-NHEJ) repair processes. The DSB complexity results in the switch in the repair pathway from NHEJ to a slower process that starts with DSB end resection. DSB end resection in early S and G1 phases of the cell cycle enhances the B-NHEJ repair pathway, while in late S and G2 phases of the cell cycle promotes HR repair pathway. The repair model was transformed to a set of nonlinear differential equations. The model calculates the overall repair kinetics and protein temporal repair activity at the site of damage. The damage and repair model provides a detailed mechanistic understanding of all processes that are involved in the damage induction and repair. The number of DSB and their complexity increase as the particle energy decreases due to the proximity of particle interactions in water. The repair kinetics show a biphasic behaviour that is due to the NHEJ fast repair of simple type DSB and HR slow repair of complex type DSB.

Thermal aging influence on the damage mechanisms of fully recycled composite‐reinforced polypropylene/polyethylene blend

The main aim of this work is to study the effect of thermal aging on damage mechanisms of a totally recycled composite. The studied material was elaborated by injection molding from a mixture of both recycled matrix (polypropylene‐polyethylene blend) and reinforcement (short carbon fibers). Damage mechanisms analysis was carried out using scanning electron microscope (in situ three point bending tests performed on specimens taken at different times of oxidation under different temperatures: 120, 130, and 140°C. Damage mechanisms were identified for different material states. It was shown that thermal aging affects the fiber–matrix interfacial zone while good adhesion between the reinforcement and the matrix was observed for the virgin sample. Furthermore, a quantitative analysis was performed at the local scale in a representative zone of the tensile area. Representative local damage indicators were defined. Results display clearly that damage evolutions always begin during the induction period. Thermal aging effect was then analyzed through the comparison of damage thresholds and kinetics for different material states after different times of oxidation. POLYM. COMPOS., 40:3342–3350, 2019. © 2019 Society of Plastics Engineers

Menadione Induces DNA Damage and Superoxide Radical Level In HEK293 Cells

Reactive oxygen species (ROS) can damage cellular components, including mitochondrial and genomic DNA. Oxidized DNA can transgress into lethal double stranded breaks if not adequately repaired. Clinical reports of the major neurodegenerative diseases have denoted the presence of oxidized genomic DNA with no clear understanding of their role in disease progression. To date, little is known on the neuronal vulnerability and repair kinetics of oxidative damage. Here, we studied how DNA repair kinetics contributes to reduce neuronal viability in oxidative stress conditions. To induce internal oxidative stress, we exposed neuronal-like HEK293 and fibroblast cells to 2-Methyl-1, 4-napthoquinone (Menadione). We found HEK293 cells have a reduced viability in response to induced oxidative stress compared to fibroblasts. Furthermore data obtained from COMET analysis show increased level of DNA breaks and regressed DNA repair kinetics in treated cells. Our results show that HEK293 cells have a regressed repair kinetics that allows for oxidative damage to transgress into lethal forms of DNA damage. Our findings indicate that oxidative stress can play a key role in neurodegenerative diseases and alleviation of their presence could increase neuronal survival.

Infection of Human Lung Tissue Explants (HLTEs) with Legionella pneumophila.

Legionnaires' disease is a severe pneumonia caused by inhalation of Legionella pneumophila. Although powerful infection models ranging from monocellular host systems to mammals were developed, numerous intra- and extracellular interactions of L. pneumophila factors with human lung tissue structures remain unknown. Therefore, we developed and applied a novel infection model for Legionnaires' disease comprising living human lung tissue explants (HLTEs). This model allows analyzing Legionella infections at a unique level of complexity and narrows the gap between current infection models and postmortem histopathology analyses of infected patients. Here we describe the infection of tumor-free pulmonary tissue samples from patients undergoing lobe- or pneumectomy because of lung cancer. The method comprises bacterial cultivation, preparation of HLTEs, and infection of HLTEs. The infected tissue samples allow to characterize tissue damage, bacterial localization, dissemination and growth kinetics, and the host's molecular response.

Defects induced multiscale kinetics of damage-failure transition under very high cycle fatigue

Multiscale mechanisms of fatigue damage-failure transitions in metals are studied for High Cycle and Very High Cycle Fatigue and analyzed as duality of inherently linked two types of singularities related to the singularity of multiscale damage kinetics under crack nucleation and singularity of stress field at the crack tip as the classical framework of fracture mechanics. The singularity of multiscale damage kinetics was established as natural precursor of crack nucleation and specific nonlinearity (metastability) of free energy release in term of damage parameter (defect induced strain). Experimentally estimated scales and power exponents were used in the constitutive laws of crack advance as the structure sensitive parameters for characteristic damage-failure transition stages.

Estimation of the drill pipes residual resource under the multiaxial stress state

The object of research is the operation of drill pipes in a complex stress state. One of the most problematic places in this case is the process of fatigue, that is, the gradual accumulation of damage to the material of drill pipe under the influence of time-varying stresses. This leads to accidents, the elimination of which is accompanied by significant material and temporary losses.Based on the conducted critical analysis of scientific developments on this issue, it is noted that the use of kinetic diagrams of fatigue failure allows us to experimentally establish empirical parameters of fatigue of the material of drill pipe by laboratory research of small samples. And also to take into account the influence of the front shape of semi-elliptic and annular fatigue cracks on the residual resource. In addition, it is concluded that methods requiring additional attention, taking into account the combined effect on the kinetics of fatigue damage of normal and shear stresses.Therefore, in the course of the research, the positions of fracture mechanics were used. In particular, a feature of the proposed approach is the use in the formula for determining the stress intensity factor before the front of a semi-elliptical fatigue crack in the cross section of a tubular structure of equivalent stress, taking into account both the normal and shear component. This same stress, determined in accordance with the fourth theory of strength, is also used to calculate the critical crack depth.In order to assess the obtained results, a comparative calculation is made of the number of cycles of load change required to increase the depth of the specified crack from the initial to the critical value, not taking into account the value of the shear stress. It is established that the latter, with other unchanged conditions, can reduce the life of the drill pipe by up to two times.Thanks to the proposed method, it is possible to construct graphical dependencies of the fatigue life of drill pipes, taking into account the magnitude of the torque, other things being the same.

In-situ heat dissipation monitoring in adhesively bonded composite joints under dynamic compression loading using SHPB

It is well known that the mechanical energy transforms partly into heat under impact and this heat can affect the material integrity. In this research, heat generation in adhesively bonded composite joints during dynamic compression tests had been studied because of their frequent use in naval applications. Experiments were designed to identify the mechanisms that lead to the heat generation and to measure the temperature rise in the specimens under various loading conditions. Compression Split Hopkinson Pressure Bars (SHPB) coupled with a high-speed and infrared cameras were used for real-time monitoring of change in dynamic parameters, damage kinetics and heat generation in the samples with respect to variation in strain rates. In addition, small thermocouples were also attached with the specimens and inserted at the heart of the material for assessing the change in temperature. During the experiments, significant temperature rise was observed, primarily at high strain rates. Mechanical, thermal and high speed photographs results altogether indicate that the rise of temperature was mainly due to damage in material. Significant variation in the heat generation by changing strain rate was observed. This variation was explained as different damage modes were activated at each strain rate. These results have shown that thermomechanical coupling must be taken into account when developing damage models under impact.

Abstract 1848: A comprehensive image cytometry method to identify and functionally characterize a rare subpopulation of platinum-induced aneuploid tumor cells in high-grade serous carcinoma

Abstract Background: Although platinum treatment effectively reduces tumor bulk for high grade serous carcinomas of tubal-ovarian origin, there are often scattered tumor cells exhibiting reparative and aneuploid features that remained within the peritoneal cavity. The biological importance of these aneuploid cells has not been well elucidated. In this study, we used HGSC cell line models and developed an improved image cytometry approach to identify these aneuploid cells for functional interrogation. Methods: We have developed a comprehensive image cytometry approach to assess DNA ploidy and cell cycle phase distribution within a standard flow cytometry software platform and validated this methodology using phase-specific markers (EdU, pRb, Geminin, pH3). We further introduced a novel ‘brightness vs. nuclear size' scatter plot to enhance the cell cycle assessment at the single-nucleus level. The method was applied to correlate the kinetics of the DNA damage and checkpoint response with the cell cycle status and cell viability on HGSC cell lines (OVCAR3, TOV3133G) after in-vitro carboplatin treatment. Results: Using this improved image cytometry method, we identified the emergence of a rare subpopulation of large aneuploid tumor cells at 1 week after platinum treatment. These large aneuploid cells remained viable (PI- and cleaved-PARP negative) but were uniquely dependent on anti-apoptotic signaling for their continual survival. While the bulk population of treated tumor cells underwent mitotic catastrophe following premature G2-M checkpoint exit, a rare subpopulation escaped cell death likely via mitotic slippage as they exhibit characteristic features of aneuploidy. These large aneuploid cells remained KI-67 positive and clonal dilutional experiments are being performed to assess their regrowth potential. Conclusions: This study has identified a rare subpopulation of tumor cells that avoided mitotic cell death after platinum treatment and then survived in an aneuploid state. The derivation of aneuploid cells via mitotic slippage subsequent to platinum treatment is an under-recognized phenomenon but may pose as an important drug-resistant mechanism due to enhanced survival strategies co-opted by these aneuploid cells. Research funding: Ontario Institute for Cancer Research Citation Format: Yu Wing Yeung, Oliver Fung, Mikhail Bashkurov, Robert Rottapel, Andras Kapus. A comprehensive image cytometry method to identify and functionally characterize a rare subpopulation of platinum-induced aneuploid tumor cells in high-grade serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1848.

Dynamic behavior of top-hat bonded stiffened composite panels: Experimental characterization

Abstract One of the most applications of stiffened composite panels is the marine application. In this study, a new sandwich structure consists of long E-glass fibers reinforced Balsa composites is evaluated. The use of this material in marine applications for long periods and under different environmental conditions leads to degradation of mechanical properties of structures and the adhesive. Therefore, in order to guarantee the best functioning of structures for long time periods, an experimental characterization procedure is required. For this purpose, the dynamic mechanical behavior of top-hat bonded stiffened composite panels used in marine applications is studied. A special fixture was designed and fabricated for the impact testing of stiffened structures. Manufactured specimens were tested until finale failure and the effect of impact velocities on the load-displacement and strain-displacement behaviors are compared. We have also interested to the effect of impact velocity on the dynamic behavior and damage kinetics.

Radiation dosimetry and repair kinetics of DNA damage foci in mouse pachytene spermatocyte and round spermatid stages.

Accurate quantification of DNA double strand breaks (DSB) in testicular germ cells is difficult because of cellular heterogeneity and the presence of endogenous γH2AX. Here, we used confocal microscopy to quantify DNA damage and repair kinetics following γ-irradiation (0.5-4 Gy) in three major mouse male germ cell stages, early and late pachytene spermatocytes and round spermatids (RSs), following a defined post irradiation time course. Dose-response curves showing linear best fit validated γH2AX focus as a rapid biodosimetric tool in these substages in response to whole body in vivo exposure. Stage specific foci yield/dose and repair kinetics demonstrated differential radiosensitivity and repair efficiency: early pachytenes (EP) repaired most rapidly and completely followed by late pachytene (LP) and RSs. Repair kinetics for all three stages followed 'exponential decay' in response to each radiation dose. In pachytenes immediate colocalisation of γH2AX and 53BP1, which participates in non-homologous end-joining repair pathway, was followed by dissociation from the major focal area of γH2AX by 4 h demonstrating ongoing DSB repair. These results confirm the differential radiosensitivity and repair kinetics of DSBs in male germ cells at different stages. Taken together, our results provide a simple and accurate method for assessing DNA damage and repair kinetics during spermatogenesis.

Determination of the structural steels damage kinetics under non-stationary loading

Наведено адоптовані методики, що дозволяють проводити оцінювання пошкоджуваності сталей за багатоциклової втоми з амплітудою, що змінюється за випадковим законом. Методика, яка дозволяє проводити оцінювання пошкоджуваності матеріалу, базується на методі LM-твердості. А методика розрахункового оцінювання кінетики втомного пошкодження при випадковому асиметричному втомному навантаженні базується на використанні моделі граничного вичерпання циклічної пластичності (ГВЦП). Для підтвердження наведених методик отримано експериментальні результати, що свідчать про можливість їх використання для оцінювання залишкової довговічності сталей при нестаціонарному навантаженні. Описано створення методики, що дозволяє випробовувати лабораторні зразки за втоми з амплітудою, що змінюється за випадковим законом; аналіз залишкової довговічності з використанням запропонованої моделі та методу LM-твердості; створення аналітичної моделі, що дає можливість прогнозувати довговічність за втоми з амплітудою, що змінюється за випадковим законом. Наведені результати можуть бути використані для розрахункового оцінювання довговічності елементів конструкцій, які працюють у режимі жорсткого навантаження, з меншою похибкою у порівнянні з застосуванням стабілізованих значень непружних деформацій і відомих гіпотез підсумовування втомних пошкоджень.

Integrated Modelling of Cell Responses after Irradiation for DNA-Targeted Effects and Non-Targeted Effects

Intercellular communication after ionizing radiation exposure, so-called non-targeted effects (NTEs), reduces cell survival. Here we describe an integrated cell-killing model considering NTEs and DNA damage along radiation particle tracks, known as DNA-targeted effects (TEs) based on repair kinetics of DNA damage. The proposed model was applied to a series of experimental data, i.e., signal concentration, DNA damage kinetics, cell survival curve and medium transfer bystander effects (MTBEs). To reproduce the experimental data, the model considers the following assumptions: (i) the linear-quadratic (LQ) function as absorbed dose to express the hit probability to emit cell-killing signals, (ii) the potentially repair of DNA lesions induced by NTEs, and (iii) lower efficiency of repair for the damage in NTEs than that in TEs. By comparing the model results with experimental data, we found that signal-induced DNA damage and lower repair efficiency in non-hit cells are responsible for NTE-related repair kinetics of DNA damage, cell survival curve with low-dose hyper-radiosensitivity (HRS) and MTBEs. From the standpoint of modelling, the integrated cell-killing model with the LQ relation and a different repair function for NTEs provide a reasonable signal-emission probability and a new estimation of low-dose HRS linked to DNA repair efficiency.

A novel approach for the strain rate dependent modelling of woven composites

This study proposes a new computational model for polyamid-matrix woven composites that takes into account rate effects for high speed impact applications. The rate effects are captured solely through the use of a spectral viscoelastic model, used in parallel with a conventional damage elastic-plastic model. It appears that, for very different load rates, neither plasticity nor damage kinetics need any first order rate dependency to capture the nonlinear envelope response until failure. To verify this hypothesis, a dedicated experimental setup is proposed that allows strain-controlled interruption of high speed tension loadings. Cycled loading sequences may therefore be applied to a sample even in the dynamic regime, and loss of stiffness and irreversible strains may be measured until total failure. A specific and rigorous identification procedure is proposed to that effect. Our experimental findings confirm the ability of the model to predict both the envelope response curve and the evolution of the internal mechanisms at very different strain rates.

Analysis of the results of acoustic emission diagnostics of a structure during helicopter fatigue tests

The study is devoted to a perspective diagnostic method, which makes it possible to deal with diagnostic tasks – the acoustic non-destructive inspection method based on acoustic emission (AE) signal parameter analysis. The practical use of this method is related to the interpretation of diagnostic measurement data. The parameters of acoustic emission (AE) signals were measured during bench tests of the tail boom structure and fin, as well as the joint areas of the fin, tail boom, and fuselage of the helicopter (joint area No.1 and No.19, frames of the tail boom and fuselage respectively).The analysis of fatigue damage kinetics was carried out in several stages for groups of bolts and for characteristic structure loading intervals. Bolt fracture was predicted at least 26 to 44 flight hours before the actual collapse. Using the AE parameters, the micro crack origin intervals identified when the bolt bearing capacity after the occurrence of the damage reached 96%.

An investigation of in-plane dynamic behavior of adhesively-bonded composite joints under dynamic compression at high strain rate

This study examines the behaviour of adhesively-bonded composite joints under dynamic compression tests. The purpose of this work is to use the split Hopkinson pressure bar (SHPB) for the dynamic characterization of adhesively bonded joints subjected to in-plane compression loading and in particular, the effect of strain rate on the mechanical behaviour and the damage kinetics. These joints are studied using glass/vinylester composite materials which are frequently used in naval applications Compression tests are performed at different strain rates using SHPB and high speed camera has been used to follow the damage progression. The experimental results have shown that the dynamic properties change with respect to the change in strain rate. Fibre buckling and delamination are the main damage criterias seen in the specimens under in-plane compressive tests. Therefore, this study not only allows us to understand the dynamic response of the adhesively bonded joints under dynamic compression but also enables us to establish damage models based on strain rate effect, for structure design purposes.

Fatigue damage mechanisms of short fiber reinforced PA66 as observed by in-situ synchrotron X-ray microtomography

Abstract The understanding of fatigue damage mechanisms of short fiber reinforced thermoplastics are a key issue in order to optimize material processing and propose physically based multiscale fatigue damage models. The presented work aims at a fine description of 3D damage development as observed by synchrotron X-ray microtomography. Damage processes at the micro and mesoscale are fully described in order to extract the elementary damage mechanisms, their sequence and kinetics. The effects of local fiber configuration and orientation are particularly detailed. From observations it is clearly evidenced that cavitation plays a major role in the fatigue damage process as it triggers all elementary damage mechanisms observed at the microscale. It is also shown that a characteristic length appears in the fatigue damage development. This internal length is in the order of magnitude of the spherulite size, suggesting a strong impact of the spherulite size on the fatigue damage development. Finally the effect of local fiber orientation on the micro and meso crack orientation is presented.

Interrelation and kinetics of matersals fatigue damage under strain- and stress-control loading modes

Interrelation and kinetics of matersals fatigue damage under strain- and stress-control loading modes

Numerical analysis of damage kinetics in aluminium under axisymmetric loading

Based on the analysis of the results of two R-Damage experiments, this paper provides a variant of a relation to simulate the spall damage recollection under the effect of weak compression waves. This relation closes the kinetic fracture model, considering both growth and recollection of damage. Using this model makes it possible to simulate adequately (with good quantitative agreement) the sequence of the processes “shock-wave compression – spall fracture – convergence of spall layer – recollection of damaged medium”, including the dynamics of the compacting wave arrival to the internal surface of the hollow cylindrical targets since it passed through the damaged media.

Potential chromosome damage, cell-cycle kinetics/and apoptosis induced by epoxiconazole in bovine peripheral lymphocytes in vitro

The epoxiconazole was tested in vitro for its potential on induction of chromosome damage and/or cell cycle kinetics in cultured bovine peripheral lymphocytes. Cytogenetic endpoints such as: Chromosome Aberrations (CA); Sister Chromatid Exchanges (SCE); Micronuclei (MN); Mitotic Index (MI); Proliferation Index (PI); and Cytokinesis Block Proliferation Index (CBPI) were investigated for 24 h and 48 h of incubation. The cultured lymphocytes were exposed to the epoxiconazole at concentrations of 2.5, 5, 10, 25, 50 and 100 μg mL−1. From our results is evident that treatment of bovine peripheral lymphocytes with the epoxiconazole was not related to DNA damage; no genotoxic effect and/or clastogenic/aneugenic effects were recorded. However, epoxiconazole has ability to significantly affect cell cycle kinetics/and induce apoptosis. A decrease of proliferation in the MI, CBPI and identically in the PI were observed; hence, cytostatic/cytotoxic effects of epoxiconazole have been recorded. The prolonged time of exposure at the highest concentration caused an inhibition of the replication. Electrophoretic analysis confirmed the epoxiconazole potential to induce ladder-like patterns of DNA fragments that are a hallmark of apoptosis.

A thermo-viscoelastic-damage constitutive model for cyclically loaded rubbers. Part I: Model formulation and numerical examples

Cyclically loaded rubbers exhibit a complex history-dependent response characterized by fatigue-induced stress-softening and hysteresis along with dissipative heating. The coupling between these different inelastic effects usually appearing together is far from being fully established. In this Part I of two-part paper, we present a new thermo-viscoelastic-damage approach, in accordance with the thermodynamic principles, for the prediction of this set of inelastic fatigue phenomena. An interpretation of the underlying physical mechanisms is proposed in which two types of dissipative network rearrangements are considered, i.e. recoverable rearrangements inducing viscoelasticity and unrecoverable rearrangements inducing damage. The recoverable viscoelastic rearrangements are assumed to be induced by the move of entangled and non-entangled free chains superimposed on a purely elastic perfect rubber network. Each population of free chains is considered to be the main source of one aspect of the history-dependent mechanical cyclic features, i.e. stress-softening and hysteresis, respectively. The thermo-mechanical coupling is defined by postulating the existence of a free energy in which two internal state variables are introduced to account for the two types of dissipative network rearrangements. Network thermal kinetics, induced by the dissipative heating, as well as network damage kinetics, induced by the fatigue damage, are defined and used to alter the cyclically loaded perfect rubber network. The proposed constitutive model is implemented into a finite element program and a parametric study is presented via numerical applications on rubber structures in order to analyze the effects of key model parameters on the rubber inelastic fatigue response. A focus is especially made on the respective influence of temperature, viscoelasticity and damage on the rubber softening.