Fatigue damage behavior of a surface-mount electronic package under different cyclic applied loads

NASA Astrophysics Data System (ADS)

Ren, Huai-Hui; Wang, Xi-Shu

2014-04-01

This paper studies and compares the effects of pull-pull and 3-point bending cyclic loadings on the mechanical fatigue damage behaviors of a solder joint in a surface-mount electronic package. The comparisons are based on experimental investigations using scanning electron microscopy (SEM) in-situ technology and nonlinear finite element modeling, respectively. The compared results indicate that there are different threshold levels of plastic strain for the initial damage of solder joints under two cyclic applied loads; meanwhile, fatigue crack initiation occurs at different locations, and the accumulation of equivalent plastic strain determines the trend and direction of fatigue crack propagation. In addition, simulation results of the fatigue damage process of solder joints considering a constitutive model of damage initiation criteria for ductile materials and damage evolution based on accumulating inelastic hysteresis energy are identical to the experimental results. The actual fatigue life of the solder joint is almost the same and demonstrates that the FE modeling used in this study can provide an accurate prediction of solder joint fatigue failure.

Development of a Corrosion Sensor for AN Aircraft Vehicle Health Monitoring System

NASA Astrophysics Data System (ADS)

Scott, D. A.; Price, D. C.; Edwards, G. C.; Batten, A. B.; Kolmeder, J.; Muster, T. H.; Corrigan, P.; Cole, I. S.

2010-02-01

A Rayleigh-wave-based sensor has been developed to measure corrosion damage in aircraft. This sensor forms an important part of a corrosion monitoring system being developed for a major aircraft manufacturer. This system measures the corrosion rate at the location of its sensors, and through a model predicts the corrosion rates in nearby places on an aircraft into which no sensors can be placed. In order to calibrate this model, which yields corrosion rates rather than the accumulated effect, an absolute measure of the damage is required. In this paper the development of a surface wave sensor capable of measuring accumulated damage will be described in detail. This sensor allows the system to measure material loss due to corrosion regardless of the possible loss of historical corrosion rate data, and can provide, at any stage, a benchmark for the predictive model that would allow a good estimate of the accumulated corrosion damage in similar locations on an aircraft. This system may obviate the need for costly inspection of difficult-to-access places in aircraft, where presently the only way to check for corrosion is by periodic dismantling and reassembly.

Lagrangian methods for blood damage estimation in cardiovascular devices - How numerical implementation affects the results

PubMed Central

Marom, Gil; Bluestein, Danny

2016-01-01

Summary This paper evaluated the influence of various numerical implementation assumptions on predicting blood damage in cardiovascular devices using Lagrangian methods with Eulerian computational fluid dynamics. The implementation assumptions that were tested included various seeding patterns, stochastic walk model, and simplified trajectory calculations with pathlines. Post processing implementation options that were evaluated included single passage and repeated passages stress accumulation and time averaging. This study demonstrated that the implementation assumptions can significantly affect the resulting stress accumulation, i.e., the blood damage model predictions. Careful considerations should be taken in the use of Lagrangian models. Ultimately, the appropriate assumptions should be considered based the physics of the specific case and sensitivity analysis, similar to the ones presented here, should be employed. PMID:26679833

Analysis of dynamic accumulative damage about the lining structure of high speed railway’s tunnel based on ultrasonic testing technology

NASA Astrophysics Data System (ADS)

Wang, Xiang-qiu; Zhang, Huojun; Xie, Wen-xi

2017-08-01

Based on the similar material model test of full tunnel, the theory of elastic wave propagation and the testing technology of intelligent ultrasonic wave had been used to research the dynamic accumulative damage characteristics of tunnel’s lining structure under the dynamic loads of high speed train. For the more, the dynamic damage variable of lining structure of high speed railway’s tunnel was obtained. The results shown that the dynamic cumulative damage of lining structure increases nonlinearly with the times of cumulative vibration, the weakest part of dynamic cumulative damage is the arch foot of tunnel. Much more attention should be paid to the design and operation management of high speed railway’s tunnel.

Gear Damage Detection Using Oil Debris Analysis

NASA Technical Reports Server (NTRS)

Dempsey, Paula J.

2001-01-01

The purpose of this paper was to verify, when using an oil debris sensor, that accumulated mass predicts gear pitting damage and to identify a method to set threshold limits for damaged gears. Oil debris data was collected from 8 experiments with no damage and 8 with pitting damage in the NASA Glenn Spur Gear Fatigue Rig. Oil debris feature analysis was performed on this data. Video images of damage progression were also collected from 6 of the experiments with pitting damage. During each test, data from an oil debris sensor was monitored and recorded for the occurrence of pitting damage. The data measured from the oil debris sensor during experiments with damage and with no damage was used to identify membership functions to build a simple fuzzy logic model. Using fuzzy logic techniques and the oil debris data, threshold limits were defined that discriminate between stages of pitting wear. Results indicate accumulated mass combined with fuzzy logic analysis techniques is a good predictor of pitting damage on spur gears.

A continuous damage model based on stepwise-stress creep rupture tests

NASA Technical Reports Server (NTRS)

Robinson, D. N.

1985-01-01

A creep damage accumulation model is presented that makes use of the Kachanov damage rate concept with a provision accounting for damage that results from a variable stress history. This is accomplished through the introduction of an additional term in the Kachanov rate equation that is linear in the stress rate. Specification of the material functions and parameters in the model requires two types of constituting a data base: (1) standard constant-stress creep rupture tests, and (2) a sequence of two-step creep rupture tests.

Modeling of karst deformation and analysis of acoustic emission during sinkhole formation

NASA Astrophysics Data System (ADS)

Bakeev, R. A.; Stefanov, Yu. P.; Duchkov, A. A.; Myasnikov, A. V.

2017-12-01

In this paper, the fracture pattern and formation of a sinkhole are estimated depending on the rock properties. The possibility of using geophysical methods for recording and analyzing acoustic emission to monitor and predict the state of the medium is considered. The problem of deformation of the sedimentary cover over the growing karst cavity is solved on the basis of the elastoplastic Drucker-Prager-Nikolaevsky model and the equation of damage accumulation. The specified kinetics of accumulation of damages allows us to describe slow processes of degradation of the strength of the medium under stresses that are low for the development of inelastic deformations. The results are obtained for different values of the strength of karst rock; we show the influence of the kinetic parameters of damage accumulation on the shape of collapse depressions. We also model acoustic emission caused by the material fracture. One can follow different stages of the karst development by looking at patterns of cells which fail at a given time. Our observations show the relation between the intensity of material fracture and the intensity of seismic emission.

Apatite (U-Th)/He thermochronometry using a radiation damage accumulation and annealing model

NASA Astrophysics Data System (ADS)

Flowers, Rebecca M.; Ketcham, Richard A.; Shuster, David L.; Farley, Kenneth A.

2009-04-01

Helium diffusion from apatite is a sensitive function of the volume fraction of radiation damage to the crystal, a quantity that varies over the lifetime of the apatite. Using recently published laboratory data we develop and investigate a new kinetic model, the radiation damage accumulation and annealing model (RDAAM), that adopts the effective fission-track density as a proxy for accumulated radiation damage. This proxy incorporates creation of crystal damage proportional to α-production from U and Th decay, and the elimination of that damage governed by the kinetics of fission-track annealing. The RDAAM is a version of the helium trapping model (HeTM; Shuster D. L., Flowers R. M. and Farley K. A. (2006) The influence of natural radiation damage on helium diffusion kinetics in apatite. Earth Planet. Sci. Lett.249, 148-161), calibrated by helium diffusion data in natural and partially annealed apatites. The chief limitation of the HeTM, now addressed by RDAAM, is its use of He concentration as the radiation damage proxy for circumstances in which radiation damage and He are not accumulated and lost proportionately from the crystal. By incorporating the RDAAM into the HeFTy computer program, we explore its implications for apatite (U-Th)/He thermochronometry. We show how (U-Th)/He dates predicted from the model are sensitive to both effective U concentration (eU) and details of the temperature history. The RDAAM predicts an effective He closure temperature of 62 °C for a 28 ppm eU apatite of 60 μm radius that experienced a 10 °C/Ma monotonic cooling rate; this is 8 °C lower than the 70 °C effective closure temperature predicted using commonly assumed Durango diffusion kinetics. Use of the RDAAM is most important for accurate interpretation of (U-Th)/He data for apatite suites that experienced moderate to slow monotonic cooling (1-0.1 °C/Ma), prolonged residence in the helium partial retention zone, or a duration at temperatures appropriate for radiation damage accumulation followed by reheating and partial helium loss. Under common circumstances the RDAAM predicts (U-Th)/He dates that are older, sometimes much older, than corresponding fission-track dates. Nonlinear positive correlations between apatite (U-Th)/He date and eU in apatites subjected to the same temperature history are a diagnostic signature of the RDAAM for many but not all thermal histories. Observed date-eU correlations in four different localities can be explained with the RDAAM using geologically reasonable thermal histories consistent with independent fission-track datasets. The existence of date-eU correlations not only supports a radiation damage based kinetic model, but can significantly limit the range of acceptable time-temperature paths that account for the data. In contrast, these datasets are inexplicable using the Durango diffusion model. The RDAAM helps reconcile enigmatic data in which apatite (U-Th)/He dates are older than expected using the Durango model when compared with thermal histories based on apatite fission-track data or other geological constraints. It also has the potential to explain at least some cases in which (U-Th)/He dates are actually older than the corresponding fission-track dates.

Injection-Molded Long-Fiber Thermoplastic Composites: From Process Modeling to Prediction of Mechanical Properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Ba Nghiep; Kunc, Vlastimil; Jin, Xiaoshi

2013-12-18

This article illustrates the predictive capabilities for long-fiber thermoplastic (LFT) composites that first simulate the injection molding of LFT structures by Autodesk® Simulation Moldflow® Insight (ASMI) to accurately predict fiber orientation and length distributions in these structures. After validating fiber orientation and length predictions against the experimental data, the predicted results are used by ASMI to compute distributions of elastic properties in the molded structures. In addition, local stress-strain responses and damage accumulation under tensile loading are predicted by an elastic-plastic damage model of EMTA-NLA, a nonlinear analysis tool implemented in ABAQUS® via user-subroutines using an incremental Eshelby-Mori-Tanaka approach. Predictedmore » stress-strain responses up to failure and damage accumulations are compared to the experimental results to validate the model.« less

Multi-scale simulation of radiation damage accumulation and subsequent hardening in neutron-irradiated α-Fe

DOE PAGES

Dunn, Aaron; Dingreville, Remi; Capolungo, Laurent

2015-11-27

A hierarchical methodology is introduced to predict the effects of radiation damage and irradiation conditions on the yield stress and internal stress heterogeneity developments in polycrystalline α-Fe. Simulations of defect accumulation under displacement cascade damage conditions are performed using spatially resolved stochastic cluster dynamics. The resulting void and dislocation loop concentrations and average sizes are then input into a crystal plasticity formulation that accounts for the change in critical resolved shear stress due to the presence of radiation induced defects. The simulated polycrystalline tensile tests show a good match to experimental hardening data over a wide range of irradiation doses.more » With this capability, stress heterogeneity development and the effect of dose rate on hardening is investigated. The model predicts increased hardening at higher dose rates for low total doses. By contrast, at doses above 10 –2 dpa when cascade overlap becomes significant, the model does not predict significantly different hardening for different dose rates. In conclusion, the development of such a model enables simulation of radiation damage accumulation and associated hardening without relying on experimental data as an input under a wide range of irradiation conditions such as dose, dose rate, and temperature.« less

Studying damage accumulation in martensitic corrosion-resistant steel under cold radial reduction

NASA Astrophysics Data System (ADS)

Karamyshev, A. P.; Nekrasov, I. I.; Nesterenko, A. V.; Parshin, V. S.; Smirnov, S. V.; Shveikin, V. P.; Fedulov, A. A.

2017-12-01

Cold radial reduction of specimens made of the Kh17N2 corrosion-resistant martensitic steel is studied on a lever-type radial-forging machine (RFM). The mechanical properties of the deformed specimens, the "damage accumulation - strain" relation in the specimens are obtained with the application of hydrostatic and fractographic methods for fractured specimens. The damage of the Kh17N2 corrosion-resistant steel is evaluated as a result of an experimental study considering the data of simulation by a complex finite element model of cold deformation on a lever-type RFM.

Damage Tolerance of Large Shell Structures

NASA Technical Reports Server (NTRS)

Minnetyan, L.; Chamis, C. C.

1999-01-01

Progressive damage and fracture of large shell structures is investigated. A computer model is used for the assessment of structural response, progressive fracture resistance, and defect/damage tolerance characteristics. Critical locations of a stiffened conical shell segment are identified. Defective and defect-free computer models are simulated to evaluate structural damage/defect tolerance. Safe pressurization levels are assessed for the retention of structural integrity at the presence of damage/ defects. Damage initiation, growth, accumulation, and propagation to fracture are included in the simulations. Damage propagation and burst pressures for defective and defect-free shells are compared to evaluate damage tolerance. Design implications with regard to defect and damage tolerance of a large steel pressure vessel are examined.

A Combined High and Low Cycle Fatigue Model for Life Prediction of Turbine Blades

PubMed Central

Yue, Peng; Yu, Zheng-Yong; Wang, Qingyuan

2017-01-01

Combined high and low cycle fatigue (CCF) generally induces the failure of aircraft gas turbine attachments. Based on the aero-engine load spectrum, accurate assessment of fatigue damage due to the interaction of high cycle fatigue (HCF) resulting from high frequency vibrations and low cycle fatigue (LCF) from ground-air-ground engine cycles is of critical importance for ensuring structural integrity of engine components, like turbine blades. In this paper, the influence of combined damage accumulation on the expected CCF life are investigated for turbine blades. The CCF behavior of a turbine blade is usually studied by testing with four load-controlled parameters, including high cycle stress amplitude and frequency, and low cycle stress amplitude and frequency. According to this, a new damage accumulation model is proposed based on Miner’s rule to consider the coupled damage due to HCF-LCF interaction by introducing the four load parameters. Five experimental datasets of turbine blade alloys and turbine blades were introduced for model validation and comparison between the proposed Miner, Manson-Halford, and Trufyakov-Kovalchuk models. Results show that the proposed model provides more accurate predictions than others with lower mean and standard deviation values of model prediction errors. PMID:28773064

A Combined High and Low Cycle Fatigue Model for Life Prediction of Turbine Blades.

PubMed

Zhu, Shun-Peng; Yue, Peng; Yu, Zheng-Yong; Wang, Qingyuan

2017-06-26

Combined high and low cycle fatigue (CCF) generally induces the failure of aircraft gas turbine attachments. Based on the aero-engine load spectrum, accurate assessment of fatigue damage due to the interaction of high cycle fatigue (HCF) resulting from high frequency vibrations and low cycle fatigue (LCF) from ground-air-ground engine cycles is of critical importance for ensuring structural integrity of engine components, like turbine blades. In this paper, the influence of combined damage accumulation on the expected CCF life are investigated for turbine blades. The CCF behavior of a turbine blade is usually studied by testing with four load-controlled parameters, including high cycle stress amplitude and frequency, and low cycle stress amplitude and frequency. According to this, a new damage accumulation model is proposed based on Miner's rule to consider the coupled damage due to HCF-LCF interaction by introducing the four load parameters. Five experimental datasets of turbine blade alloys and turbine blades were introduced for model validation and comparison between the proposed Miner, Manson-Halford, and Trufyakov-Kovalchuk models. Results show that the proposed model provides more accurate predictions than others with lower mean and standard deviation values of model prediction errors.

EFFECTS OF LASER RADIATION ON MATTER: Laser damage behaviour of titania coatings

NASA Astrophysics Data System (ADS)

Skvortsov, L. A.

2010-01-01

A model is proposed for the generation of defects responsible for laser damage in thin titania films during repetitive exposure to nanosecond near-IR laser pulses. The model relies on the hypothesis that there is charge transfer between two point defect centres differing in photoionisation cross section, one of which has an adsorptive nature. The model's predictions agree well with the experimentally determined accumulation curve and the temperature dependence of the damage threshold at low temperatures and clarify the role of protective coatings.

Phonons, defects and optical damage in crystalline acetanilide

NASA Astrophysics Data System (ADS)

Kosic, Thomas J.; Hill, Jeffrey R.; Dlott, Dana D.

1986-04-01

Intense picosecond pulses cause accumulated optical damage in acetanilide crystals at low temperature. Catastrophic damage to the irradiated volume occurs after an incubation period where defects accumulate. The optical damage is monitored with subanosecond time resolution. The generation of defects is studied with damage-detected picosecond spectroscopy. The accumulation of defects is studied by time-resolved coherent Raman scattering, which is used to measure optical phonon scattering from the accumulating defects.

Recent Advances in Composite Damage Mechanics

NASA Technical Reports Server (NTRS)

Reifsnider, Ken; Case, Scott; Iyengar, Nirmal

1996-01-01

The state of the art and recent developments in the field of composite material damage mechanics are reviewed, with emphasis on damage accumulation. The kinetics of damage accumulation are considered with emphasis on the general accumulation of discrete local damage events such as single or multiple fiber fractures or microcrack formation. The issues addressed include: how to define strength in the presence of widely distributed damage, and how to combine mechanical representations in order to predict the damage tolerance and life of engineering components. It is shown that a damage mechanics approach can be related to the thermodynamics of the damage accumulation processes in composite laminates subjected to mechanical loading and environmental conditions over long periods of time.

A viscoelastic damage rheology and rate- and state-dependent friction

NASA Astrophysics Data System (ADS)

Lyakhovsky, Vladimir; Ben-Zion, Yehuda; Agnon, Amotz

2005-04-01

We analyse the relations between a viscoelastic damage rheology model and rate- and state-dependent (RS) friction. Both frameworks describe brittle deformation, although the former models localization zones in a deforming volume while the latter is associated with sliding on existing surfaces. The viscoelastic damage model accounts for evolving elastic properties and inelastic strain. The evolving elastic properties are related quantitatively to a damage state variable representing the local density of microcracks. Positive and negative changes of the damage variable lead, respectively, to degradation and recovery of the material in response to loading. A model configuration having an existing narrow zone with localized damage produces for appropriate loading and temperature-pressure conditions an overall cyclic stick-slip motion compatible with a frictional response. Each deformation cycle (limit cycle) can be divided into healing and weakening periods associated with decreasing and increasing damage, respectively. The direct effect of the RS friction and the magnitude of the frictional parameter a are related to material strengthening with increasing rate of loading. The strength and residence time of asperities (model elements) in the weakening stage depend on the rates of damage evolution and accumulation of irreversible strain. The evolutionary effect of the RS friction and overall change in the friction parameters (a-b) are controlled by the duration of the healing period and asperity (element) strengthening during this stage. For a model with spatially variable properties, the damage rheology reproduces the logarithmic dependency of the steady-state friction coefficient on the sliding velocity and the normal stress. The transition from a velocity strengthening regime to a velocity weakening one can be obtained by varying the rate of inelastic strain accumulation and keeping the other damage rheology parameters fixed. The developments unify previous damage rheology results on deformation localization leading to formation of new fault zones with detailed experimental results on frictional sliding. The results provide a route for extending the formulation of RS friction into a non-linear continuum mechanics framework.

Local structural change in zircon following radiation damage accumulation. Observation by 29Si nuclear magnetic resonance

NASA Astrophysics Data System (ADS)

Farnan, I.; Trachenko, K.

2003-04-01

29Si nuclear magnetic resonance (NMR) is a one of the most useful probes of the local structure of silicates. One of the results of recent studies of naturally radiation damaged zircons is that there is an evolution of the local structure in both crystalline and amorphous fractions of partially metamict zircon as a function of accumulated α-dose. We have examined the evolution of this local structure within the framework of several models of damage accumulation. The total number of displaced atoms produced per α-decay as function of accumulated dose, as measured by NMR, is not consistent with the idea of multiple overlap events being responsible for the evolution of the total damaged fraction. However, increased connectivity in the damaged region as the number of α-events increases is correlated to the degree of cascade overlap. The results of large scale atomistic (MD) simulations of heavy nuclei recoils at realistic energies (70keV) are consistent with the NMR quantification and also with TEM estimates of the diameters of damaged regions. The local heterogeneity (density and bonding) in the damaged area in the simulations is consistent with the existence of connected silicate tetrahedra. Detailed experiments on the annealing of damaged zircons at 500 and 600^oC have been performed. These show that a significant energetic barrier to the recrystallisation exists at these temperatures once a small fraction of damaged material has been recrystallised. This correlates well with the degree of cascade overlap. Indicating that the more connected SiO_4 tetrahedra present this barrier. A sample with very little cascade overlap can be annealed to ˜97% crystallinity at these temperatures.

A Geometrically Nonlinear Phase Field Theory of Brittle Fracture

DTIC Science & Technology

2014-10-01

of crack propagation. Philos Mag 91:75–95 Sun X, Khaleel M (2004) Modeling of glass fracture damage using continuum damage mechanics -static spherical...elastic fracture mechanics ). Engineering finite element (FE) simula- tions often invoke continuum damage mechanics the- ories, wherein the tangent...stiffness of a material ele- ment degrades as “damage” accumulates.Conventional continuum damage mechanics theories (Clayton and McDowell 2003, 2004; Sun and

Dynamical analysis of cellular ageing by modeling of gene regulatory network based attractor landscape.

PubMed

Chong, Ket Hing; Zhang, Xiaomeng; Zheng, Jie

2018-01-01

Ageing is a natural phenomenon that is inherently complex and remains a mystery. Conceptual model of cellular ageing landscape was proposed for computational studies of ageing. However, there is a lack of quantitative model of cellular ageing landscape. This study aims to investigate the mechanism of cellular ageing in a theoretical model using the framework of Waddington's epigenetic landscape. We construct an ageing gene regulatory network (GRN) consisting of the core cell cycle regulatory genes (including p53). A model parameter (activation rate) is used as a measure of the accumulation of DNA damage. Using the bifurcation diagrams to estimate the parameter values that lead to multi-stability, we obtained a conceptual model for capturing three distinct stable steady states (or attractors) corresponding to homeostasis, cell cycle arrest, and senescence or apoptosis. In addition, we applied a Monte Carlo computational method to quantify the potential landscape, which displays: I) one homeostasis attractor for low accumulation of DNA damage; II) two attractors for cell cycle arrest and senescence (or apoptosis) in response to high accumulation of DNA damage. Using the Waddington's epigenetic landscape framework, the process of ageing can be characterized by state transitions from landscape I to II. By in silico perturbations, we identified the potential landscape of a perturbed network (inactivation of p53), and thereby demonstrated the emergence of a cancer attractor. The simulated dynamics of the perturbed network displays a landscape with four basins of attraction: homeostasis, cell cycle arrest, senescence (or apoptosis) and cancer. Our analysis also showed that for the same perturbed network with low DNA damage, the landscape displays only the homeostasis attractor. The mechanistic model offers theoretical insights that can facilitate discovery of potential strategies for network medicine of ageing-related diseases such as cancer.

Long-term strength and damage accumulation in laminates

NASA Astrophysics Data System (ADS)

Dzenis, Yuris A.; Joshi, Shiv P.

1993-04-01

A modified version of the probabilistic model developed by authors for damage evolution analysis of laminates subjected to random loading is utilized to predict long-term strength of laminates. The model assumes that each ply in a laminate consists of a large number of mesovolumes. Probabilistic variation functions for mesovolumes stiffnesses as well as strengths are used in the analysis. Stochastic strains are calculated using the lamination theory and random function theory. Deterioration of ply stiffnesses is calculated on the basis of the probabilities of mesovolumes failures using the theory of excursions of random process beyond the limits. Long-term strength and damage accumulation in a Kevlar/epoxy laminate under tension and complex in-plane loading are investigated. Effects of the mean level and stochastic deviation of loading on damage evolution and time-to-failure of laminate are discussed. Long-term cumulative damage at the time of the final failure at low loading levels is more than at high loading levels. The effect of the deviation in loading is more pronounced at lower mean loading levels.

Acute Doxorubicin Insult in the Mouse Ovary Is Cell- and Follicle-Type Dependent

PubMed Central

Roti Roti, Elon C.; Leisman, Scott K.; Abbott, David H.; Salih, Sana M.

2012-01-01

Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampering efforts to design effective intervention therapies to protect the ovary. Utilizing doxorubicin (DXR) as a model chemotherapy agent, we defined the acute timeline for drug accumulation, induced DNA damage, and subsequent cellular and follicular demise in the mouse ovary. DXR accumulated first in the core ovarian stroma cells, then redistributed outwards into the cortex and follicles in a time-dependent manner, without further increase in total ovarian drug levels after four hours post-injection. Consistent with early drug accumulation and intimate interactions with the blood supply, stroma cell-enriched populations exhibited an earlier DNA damage response (measurable at 2 hours) than granulosa cells (measurable at 4 hours), as quantified by the comet assay. Granulosa cell-enriched populations were more sensitive however, responding with greater levels of DNA damage. The oocyte DNA damage response was delayed, and not measurable above background until 10–12 hours post-DXR injection. By 8 hours post-DXR injection and prior to the oocyte DNA damage response, the number of primary, secondary, and antral follicles exhibiting TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive granulosa cells plateaued, indicating late-stage apoptosis and suggesting damage to the oocytes is subsequent to somatic cell failure. Primordial follicles accumulate significant DXR by 4 hours post-injection, but do not exhibit TUNEL-positive granulosa cells until 48 hours post-injection, indicating delayed demise. Taken together, the data suggest effective intervention therapies designed to protect the ovary from chemotherapy accumulation and induced insult in the ovary must act almost immediately to prevent acute insult as significant damage was seen in stroma cells within the first two hours. PMID:22876313

Acoustic Emission and Damage Accumulation for Various Woven C/SiC Composites Tested in Tension at Room Temperature

NASA Technical Reports Server (NTRS)

Morscher, Gregory; Petko, Jeanne; Kiser, James D.

2002-01-01

Modal acoustic emission (AE) has proven to be an excellent technique to monitor damage accumulation in ceramic matrix composites. In this study, AE was used to monitor tensile load-unload-reload hysteresis tests for a variety of C fiber reinforced, Sic matrix composites. C/SiC composites were reinforced with T-300 and IM7 fibers, had C, multilayer, or pseudo-porous C interphases, and had chemical vapor infiltrated Sic or melt-infiltrated SiC matrices. All of the composites exhibited considerable AE during testing. The extent and nature of the AE activity will be analyzed and discussed in light of matrix cracking and the variety of composite constituents. It is hoped that understanding the nature of stress-dependent damage accumulation in these materials can be of use in life-modeling for these types of composites.

Acoustic Emission and Damage Accumulation for Various Woven C/SiC Composites Tested in Tension at Room Temperature

NASA Technical Reports Server (NTRS)

Morscher, Gregory N.; Petko, Jeanne; Kiser, James D.; Gray, Hugh R. (Technical Monitor)

2002-01-01

Modal acoustic emission (AE) has proven to be an excellent technique to monitor damage accumulation in ceramic matrix composites. In this study, AE was used to monitor tensile load-unload-reload hysteresis tests for a variety of C fiber reinforced, SiC matrix composites. C/SiC composites were reinforced with T300 and IM7 fibers, had C, multilayer, or pseudo-porous C interphases, and had chemical vapor infiltrated SiC or melt-infiltrated SiC matrices. All of the composites exhibited considerable AE during testing. The extent and nature of the AE activity will be analyzed and discussed in light of matrix cracking and the variety of composite constituents. It is hoped that understanding the nature of stress dependent damage accumulation in these materials can be of use in life modeling for these types of composites.

Isothermal Fatigue, Damage Accumulation, and Life Prediction of a Woven PMC

NASA Technical Reports Server (NTRS)

Gyekenyesi, Andrew L.

1998-01-01

This dissertation focuses on the characterization of the fully reversed fatigue behavior exhibited by a carbon fiber/polyimide resin, woven laminate at room and elevated temperatures. Nondestructive video edge view microscopy and destructive sectioning techniques were used to study the microscopic damage mechanisms that evolved. The residual elastic stiffness was monitored and recorded throughout the fatigue life of the coupon. In addition, residual compressive strength tests were conducted on fatigue coupons with various degrees of damage as quantified by stiffness reduction. Experimental results indicated that the monotonic tensile properties were only minimally influenced by temperature, while the monotonic compressive and fully reversed fatigue properties displayed noticeable reductions due to the elevated temperature. The stiffness degradation, as a function of cycles, consisted of three stages; a short-lived high degradation period, a constant degradation rate segment composing the majority of the life, and a final stage demonstrating an increasing rate of degradation up to failure. Concerning the residual compressive strength tests at room and elevated temperatures, the elevated temperature coupons appeared much more sensitive to damage. At elevated temperatures, coupons experienced a much larger loss in compressive strength when compared to room temperature coupons with equivalent damage. The fatigue damage accumulation law proposed for the model incorporates a scalar representation for damage, but admits a multiaxial, anisotropic evolutionary law. The model predicts the current damage (as quantified by residual stiffness) and remnant life of a composite that has undergone a known load at temperature. The damage/life model is dependent on the applied multiaxial stress state as well as temperature. Comparisons between the model and data showed good predictive capabilities concerning stiffness degradation and cycles to failure.

Microstructural effects on constitutive and fatigue fracture behavior of TinSilverCopper solder

NASA Astrophysics Data System (ADS)

Tucker, Jonathon P.

As microelectronic package construction becomes more diverse and complex, the need for accurate, geometry-independent material constitutive and failure models increases. Evaluations of packages based on accelerated environmental tests (such as accelerated thermal cycling or power cycling) only provide package-dependent reliability information. In addition, extrapolations of such test data to life predictions under field conditions are often empirical. Besides geometry, accelerated environmental test data must account for microstructural factors such as alloy composition or isothermal aging condition, resulting in expensive experimental variation. In this work, displacement-controlled, creep, and fatigue lap shear tests are conducted on specially designed SnAgCu test specimens with microstructures representative to those found in commercial microelectronic packages. The data are used to develop constitutive and fatigue fracture material models capable of describing deformation and fracture behavior for the relevant temperature and strain rate ranges. Furthermore, insight is provided into the microstructural variation of solder joints and the subsequent effect on material behavior. These models are appropriate for application to packages of any geometrical construction. The first focus of the thesis is on Pb-mixed SnAgCu solder alloys. During the transition from Pb-containing solders to Pb-free solders, joints composed of a mixture of SnPb and SnAgCu often result from either mixed assemblies or rework. Three alloys of 1, 5 and 20 weight percent Pb were selected so as to represent reasonable ranges of Pb contamination expected from different 63Sn37Pb components mixed with Sn3.0Ag0.5Cu. Displacement-controlled (constant strain rate) and creep tests were performed at temperatures of 25°C, 75°C, and 125°C using a double lap shear test setup that ensures a nearly homogeneous state of plastic strain at the joint interface. Rate-dependent constitutive models for Pb-contaminated SnAgCu solder alloys ranging from the traditional time-hardening creep model to the viscoplastic Anand model are described. The second focus of the thesis is on fatigue damage accumulation in SnAgCu solder alloys. While, typical fatigue fracture models are empirical, recently a non-empirical model termed Maximum Entropy Fracture Model (MEFM) was proposed. MEFM is a thermodynamically consistent and information theory inspired damage accumulation theory for ductile solids. This model has been validated recently for Sn3.8Ag0.7Cu solder alloy, and uses a single damage accumulation parameter to relate the probability of fracture to accumulated entropic dissipation. Isothermal cycling fatigue tests on Sn3.0Ag0.5Cu and mixed SnPb/Sn3.0Ag0.5Cu solder alloys at varying strain rates and temperatures are conducted using a custom-built microscale mechanical tester capable of submicron displacement resolution. MEFM is applied here in conjunction with the Anand viscoplasticity model to predict the softening occurring over successive cycles as a result of damage accumulation. The damage accumulation parameters for Sn3.0Ag0.5Cu in different aged states are related to a microstructural parameter which quantitatively describes the state of coarsening. In addition, damage accumulation parameters for the three mixed solder alloys are reported. This approach allows for a non-empirical prediction of both constitutive and fracture behavior of packages of different geometries and different microstructural states under thermo-mechanical fatigue. Approaches to solder joint reliability predictions from materials science and mechanics perspectives differ dramatically. Materials science methods identify key failure mechanisms, but most models cannot predict failure. In contrast, mechanics approaches often provide estimates of joint lifetime, but fail to provide insight into microstructural influences. This work attempts to connect the two fields by relating constitutive behavior and fatigue fracture models for different alloys and aging conditions to one or more microstructural parameters.

Damage-based life prediction model for uniaxial low-cycle stress fatigue of super-elastic NiTi shape memory alloy microtubes

NASA Astrophysics Data System (ADS)

Song, Di; Kang, Guozheng; Kan, Qianhua; Yu, Chao; Zhang, Chuanzeng

2015-08-01

Based on the experimental observations for the uniaxial low-cycle stress fatigue failure of super-elastic NiTi shape memory alloy microtubes (Song et al 2015 Smart Mater. Struct. 24 075004) and a new definition of damage variable corresponding to the variation of accumulated dissipation energy, a phenomenological damage model is proposed to describe the damage evolution of the NiTi microtubes during cyclic loading. Then, with a failure criterion of Dc = 1, the fatigue lives of the NiTi microtubes are predicted by the damage-based model, the predicted lives are in good agreement with the experimental ones, and all of the points are located within an error band of 1.5 times.

Fatigue damage mechanics of notched graphite-epoxy laminates

NASA Astrophysics Data System (ADS)

Spearing, Mark; Beaumont, Peter W. R.; Ashby, Michael F.

A modeling approach is presented that recognizes that the residual properties of composite laminates after any form of loading depend on the damage state. Therefore, in the case of cyclic loading, it is necessary to first derive a damage growth law and then relate the residual properties to the accumulated damage. The propagation of fatigue damage in notched laminates is investigated. A power law relationship between damage growth and the strain energy release rate is developed. The material constants used in the model have been determined in independent experiments and are invariant for all the layups investigated. The strain energy release rates are calculated using a simple finite element representation of the damaged specimen. The model is used to predict the effect of tension-tension cyclic loading on laminates of the T300/914C carbon-fiber epoxy system. The extent of damage propagation is successfully predicted in a number of cross-ply laminates.

Interdependence theory of tissue failure: bulk and boundary effects.

PubMed

Suma, Daniel; Acun, Aylin; Zorlutuna, Pinar; Vural, Dervis Can

2018-02-01

The mortality rate of many complex multicellular organisms increases with age, which suggests that net ageing damage is accumulative, despite remodelling processes. But how exactly do these little mishaps in the cellular level accumulate and spread to become a systemic catastrophe? To address this question we present experiments with synthetic tissues, an analytical model consistent with experiments, and a number of implications that follow the analytical model. Our theoretical framework describes how shape, curvature and density influences the propagation of failure in a tissue subjected to oxidative damage. We propose that ageing is an emergent property governed by interaction between cells, and that intercellular processes play a role that is at least as important as intracellular ones.

Interdependence theory of tissue failure: bulk and boundary effects

NASA Astrophysics Data System (ADS)

Suma, Daniel; Acun, Aylin; Zorlutuna, Pinar; Vural, Dervis Can

2018-02-01

The mortality rate of many complex multicellular organisms increases with age, which suggests that net ageing damage is accumulative, despite remodelling processes. But how exactly do these little mishaps in the cellular level accumulate and spread to become a systemic catastrophe? To address this question we present experiments with synthetic tissues, an analytical model consistent with experiments, and a number of implications that follow the analytical model. Our theoretical framework describes how shape, curvature and density influences the propagation of failure in a tissue subjected to oxidative damage. We propose that ageing is an emergent property governed by interaction between cells, and that intercellular processes play a role that is at least as important as intracellular ones.

Omega-3 fatty acid supplementation decreases DNA damage in brain of rats subjected to a chemically induced chronic model of Tyrosinemia type II.

PubMed

Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Rebelo, Joyce; Damiani, Adriani P; Pereira, Maiara; Andrade, Vanessa M; Gava, Fernanda F; Valvassori, Samira S; Schuck, Patricia F; Ferreira, Gustavo C; Streck, Emilio L

2017-08-01

Tyrosinemia type II is an inborn error of metabolism caused by a mutation in a gene encoding the enzyme tyrosine aminotransferase leading to an accumulation of tyrosine in the body, and is associated with neurologic and development difficulties in numerous patients. Because the accumulation of tyrosine promotes oxidative stress and DNA damage, the main aim of this study was to investigate the possible antioxidant and neuroprotective effects of omega-3 treatment in a chemically-induced model of Tyrosinemia type II in hippocampus, striatum and cerebral cortex of rats. Our results showed chronic administration of L-tyrosine increased the frequency and the index of DNA damage, as well as the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the hippocampus, striatum and cerebral cortex. Moreover, omega-3 fatty acid treatment totally prevented increased DNA damage in the striatum and hippocampus, and partially prevented in the cerebral cortex, whereas the increase in 8-OHdG levels was totally prevented by omega-3 fatty acid treatment in hippocampus, striatum and cerebral cortex. In conclusion, the present study demonstrated that the main accumulating metabolite in Tyrosinemia type II induce DNA damage in hippocampus, striatum and cerebral cortex, possibly mediated by free radical production, and the supplementation with omega-3 fatty acids was able to prevent this damage, suggesting that could be involved in the prevention of oxidative damage to DNA in this disease. Thus, omega-3 fatty acids supplementation to Tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the curren t treatment of this disease.

Use of QuakeSim and UAVSAR for Earthquake Damage Mitigation and Response

NASA Technical Reports Server (NTRS)

Donnellan, A.; Parker, J. W.; Bawden, G.; Hensley, S.

2009-01-01

Spaceborne, airborne, and modeling and simulation techniques are being applied to earthquake risk assessment and response for mitigation from this natural disaster. QuakeSim is a web-based portal for modeling interseismic strain accumulation using paleoseismic and crustal deformation data. The models are used for understanding strain accumulation and release from earthquakes as well as stress transfer to neighboring faults. Simulations of the fault system can be used for understanding the likelihood and patterns of earthquakes as well as the likelihood of large aftershocks from events. UAVSAR is an airborne L-band InSAR system for collecting crustal deformation data. QuakeSim, UAVSAR, and DESDynI (following launch) can be used for monitoring earthquakes, the associated rupture and damage, and postseismic motions for prediction of aftershock locations.

Failure Mechanisms and Damage Model of Ductile Cast Iron Under Low-Cycle Fatigue Conditions

NASA Astrophysics Data System (ADS)

Wu, Xijia; Quan, Guangchun; MacNeil, Ryan; Zhang, Zhong; Sloss, Clayton

2014-10-01

Strain-controlled low-cycle fatigue (LCF) tests were conducted on ductile cast iron (DCI) at strain rates of 0.02, 0.002, and 0.0002/s in the temperature range from room temperature to 1073 K (800 °C). A constitutive-damage model was developed within the integrated creep-fatigue theory (ICFT) framework on the premise of strain decomposition into rate-independent plasticity and time-dependent creep. Four major damage mechanisms: (i) plasticity-induced fatigue, (ii) intergranular embrittlement (IE), (iii) creep, and (iv) oxidation were considered in a nonlinear creep-fatigue interaction model which represents the overall damage accumulation process consisting of oxidation-assisted fatigue crack nucleation and propagation in coalescence with internally distributed damage ( e.g., IE and creep), leading to final fracture. The model was found to agree with the experimental observations of the complex DCI-LCF phenomena, for which the linear damage summation rule would fail.

Sustained water-level changes caused by damage and compaction induced by teleseismic earthquakes

NASA Astrophysics Data System (ADS)

Shalev, Eyal; Kurzon, Ittai; Doan, Mai-Linh; Lyakhovsky, Vladimir

2016-07-01

Sustained water-level increase and decrease induced by distant earthquakes were observed in two wells, Gomè 1 and Meizar 1 in Israel. The Gomè 1 well is located within a damage zone of a major fault zone, and Meizar 1 is relatively far from a fault. The monitored pressure change in both wells shows significant water-level oscillations and sustained water-level changes in response to the passage of the seismic waves. The sustained water-level changes include short-term (minutes) undrained behavior and longer-period (hours and days) drained behavior associated with groundwater flow. We model the short-term undrained response of water pressure oscillations and sustained change to the distant 2013 Mw 7.7 Balochistan earthquake by nonlinear elastic behavior of damaged rocks, accounting for small wave-induced compaction and damage accumulation. We suggest that the rocks are close to failure in both locations and strain oscillations produced by the passing seismic waves periodically push the rock above the yield cap, creating compaction when volumetric strain increases and damage when shear strain increases. Compaction increases pore pressure, whereas damage accumulation decreases pore pressure by fracture dilation. The dominant process depends on the properties of the rock. For highly damaged rocks, dilatancy is dominant and a sustained pressure decrease is expected. For low-damage rocks, compaction is the dominant process creating sustained water-level increase. We calculate damage and porosity changes associated to the Balochistan earthquake in both wells and quantify damage accumulation and compaction during the passage of the seismic waves.

A Microstructurally Inspired Damage Model for Early Venous Thrombus

PubMed Central

Rausch, Manuel K.; Humphrey, Jay D.

2015-01-01

Accumulative damage may be an important contributor to many cases of thrombotic disease progression. Thus, a complete understanding of the pathological role of thrombus requires an understanding of its mechanics and in particular mechanical consequences of damage. In the current study, we introduce a novel microstructurally inspired constitutive model for thrombus that considers a non-uniform distribution of microstructural fibers at various crimp levels and employs one of the distribution parameters to incorporate stretch-driven damage on the microscopic level. To demonstrate its ability to represent the mechanical behavior of thrombus, including a recently reported Mullins type damage phenomenon, we fit our model to uniaxial tensile test data of early venous thrombus. Our model shows an agreement with these data comparable to previous models for damage in elastomers with the added advantages of a microstructural basis and fewer model parameters. We submit that our novel approach marks another important step toward modeling the evolving mechanics of intraluminal thrombus, specifically its damage, and hope it will aid in the study of physiological and pathological thrombotic events. PMID:26523784

Axon-glial disruption: the link between vascular disease and Alzheimer's disease?

PubMed

Horsburgh, Karen; Reimer, Michell M; Holland, Philip; Chen, Guiquan; Scullion, Gillian; Fowler, Jill H

2011-08-01

Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.

An Expanded Multi-scale Monte Carlo Simulation Method for Personalized Radiobiological Effect Estimation in Radiotherapy: a feasibility study

NASA Astrophysics Data System (ADS)

Zhang, Ying; Feng, Yuanming; Wang, Wei; Yang, Chengwen; Wang, Ping

2017-03-01

A novel and versatile “bottom-up” approach is developed to estimate the radiobiological effect of clinic radiotherapy. The model consists of multi-scale Monte Carlo simulations from organ to cell levels. At cellular level, accumulated damages are computed using a spectrum-based accumulation algorithm and predefined cellular damage database. The damage repair mechanism is modeled by an expanded reaction-rate two-lesion kinetic model, which were calibrated through replicating a radiobiological experiment. Multi-scale modeling is then performed on a lung cancer patient under conventional fractionated irradiation. The cell killing effects of two representative voxels (isocenter and peripheral voxel of the tumor) are computed and compared. At microscopic level, the nucleus dose and damage yields vary among all nucleuses within the voxels. Slightly larger percentage of cDSB yield is observed for the peripheral voxel (55.0%) compared to the isocenter one (52.5%). For isocenter voxel, survival fraction increase monotonically at reduced oxygen environment. Under an extreme anoxic condition (0.001%), survival fraction is calculated to be 80% and the hypoxia reduction factor reaches a maximum value of 2.24. In conclusion, with biological-related variations, the proposed multi-scale approach is more versatile than the existing approaches for evaluating personalized radiobiological effects in radiotherapy.

Interdependence theory of tissue failure: bulk and boundary effects

PubMed Central

Suma, Daniel; Acun, Aylin; Zorlutuna, Pinar

2018-01-01

The mortality rate of many complex multicellular organisms increases with age, which suggests that net ageing damage is accumulative, despite remodelling processes. But how exactly do these little mishaps in the cellular level accumulate and spread to become a systemic catastrophe? To address this question we present experiments with synthetic tissues, an analytical model consistent with experiments, and a number of implications that follow the analytical model. Our theoretical framework describes how shape, curvature and density influences the propagation of failure in a tissue subjected to oxidative damage. We propose that ageing is an emergent property governed by interaction between cells, and that intercellular processes play a role that is at least as important as intracellular ones. PMID:29515857

A Continuum Damage Mechanics Model for the Static and Cyclic Fatigue of Cellular Composites

PubMed Central

Huber, Otto

2017-01-01

The fatigue behavior of a cellular composite with an epoxy matrix and glass foam granules is analyzed and modeled by means of continuum damage mechanics. The investigated cellular composite is a particular type of composite foam, and is very similar to syntactic foams. In contrast to conventional syntactic foams constituted by hollow spherical particles (balloons), cellular glass, mineral, or metal place holders are combined with the matrix material (metal or polymer) in the case of cellular composites. A microstructural investigation of the damage behavior is performed using scanning electron microscopy. For the modeling of the fatigue behavior, the damage is separated into pure static and pure cyclic damage and described in terms of the stiffness loss of the material using damage models for cyclic and creep damage. Both models incorporate nonlinear accumulation and interaction of damage. A cycle jumping procedure is developed, which allows for a fast and accurate calculation of the damage evolution for constant load frequencies. The damage model is applied to examine the mean stress effect for cyclic fatigue and to investigate the frequency effect and the influence of the signal form in the case of static and cyclic damage interaction. The calculated lifetimes are in very good agreement with experimental results. PMID:28809806

Viscoelastic/damage modeling of filament-wound spherical pressure vessels

NASA Technical Reports Server (NTRS)

Hackett, Robert M.; Dozier, Jan D.

1987-01-01

A model of the viscoelastic/damage response of a filament-wound spherical vessel used for long-term pressure containment is developed. The matrix material of the composite system is assumed to be linearly viscoelastic. Internal accumulated damage based upon a quadratic relationship between transverse modulus and maximum circumferential strain is postulated. The resulting nonlinear problem is solved by an iterative routine. The elastic-viscoelastic correspondence is employed to produce, in the Laplace domain, the associated elastic solution for the maximum circumferential strain which is inverted by the method of collocation to yield the time-dependent solution. Results obtained with the model are compared to experimental observations.

Characteristics of Creep Damage for 60Sn-40Pb Solder Material

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Y.; Chow, C.L.; Fang, H.E.

This paper presents a viscoplasticity model taking into account the effects of change in grain or phase size and damage on the characterization of creep damage in 60Sn-40Pb solder. Based on the theory of damage mechanics, a two-scalar damage model is developed for isotropic materials by introducing the free energy equivalence principle. The damage evolution equations are derived in terms of the damage energy release rates. In addition, a failure criterion is developed based on the postulation that a material element is said to have ruptured when the total damage accumulated in the element reaches a critical value. The damagemore » coupled viscoplasticity model is discretized and coded in a general-purpose finite element program known as ABAQUS through its user-defined material subroutine UMAT. To illustrate the application of the model, several example cases are introduced to analyze, both numerically and experimentally, the tensile creep behaviors of the material at three stress levels. The model is then applied to predict the deformation of a notched specimen under monotonic tension at room temperature (22 C). The results demonstrate that the proposed model can successfully predict the viscoplastic behavior of the solder material.« less

A Micromechanics-Based Damage Model for [+/- Theta/90n]s Composite Laminates

NASA Technical Reports Server (NTRS)

Mayugo, Joan-Andreu; Camanho, Pedro P.; Maimi, Pere; Davila, Carlos G.

2006-01-01

A new damage model based on a micromechanical analysis of cracked [+/- Theta/90n]s laminates subjected to multiaxial loads is proposed. The model predicts the onset and accumulation of transverse matrix cracks in uniformly stressed laminates, the effect of matrix cracks on the stiffness of the laminate, as well as the ultimate failure of the laminate. The model also accounts for the effect of the ply thickness on the ply strength. Predictions relating the elastic properties of several laminates and multiaxial loads are presented.

Study on Standard Fatigue Vehicle Load Model

NASA Astrophysics Data System (ADS)

Huang, H. Y.; Zhang, J. P.; Li, Y. H.

2018-02-01

Based on the measured data of truck from three artery expressways in Guangdong Province, the statistical analysis of truck weight was conducted according to axle number. The standard fatigue vehicle model applied to industrial areas in the middle and late was obtained, which adopted equivalence damage principle, Miner linear accumulation law, water discharge method and damage ratio theory. Compared with the fatigue vehicle model Specified by the current bridge design code, the proposed model has better applicability. It is of certain reference value for the fatigue design of bridge in China.

Effect law of Damage Characteristics of Rock Similar Material with Pre-Existing Cracks

NASA Astrophysics Data System (ADS)

Li, S. G.; Cheng, X. Y.; Liu, C.

2017-11-01

In order to further study the failure mechanism for rock similar materials, this study established the damage model based on accumulative AE events, investigated the damage characteristics for rock similar material samples with pre-existing cracks of varying width under uniaxial compression load. The equipment used in this study is the self-developed YYW-II strain controlled unconfined compression apparatus and the PCIE-8 acoustic emission (AE) monitoring system. The influences of the width of the pre-existing cracks to the damage characteristics of rock similar materials are analyzed. Results show that, (1) the damage model can better describe the damage characteristics of rock similar materials; (2) the tested samples have three stages during failure: initial damage stage, stable development of damage stage, and accelerated development of damage stage; (3) with the width of pre-existing cracks vary from 3mm to 5mm, the damage of rock similar materials increases gradually. The outcomes of this study provided additional values to the research of the failure mechanism for geotechnical similar material models.

Progressive failure methodologies for predicting residual strength and life of laminated composites

NASA Technical Reports Server (NTRS)

Harris, Charles E.; Allen, David H.; Obrien, T. Kevin

1991-01-01

Two progressive failure methodologies currently under development by the Mechanics of Materials Branch at NASA Langley Research Center are discussed. The damage tolerance/fail safety methodology developed by O'Brien is an engineering approach to ensuring adequate durability and damage tolerance by treating only delamination onset and the subsequent delamination accumulation through the laminate thickness. The continuum damage model developed by Allen and Harris employs continuum damage laws to predict laminate strength and life. The philosophy, mechanics framework, and current implementation status of each methodology are presented.

Effect of the state of internal boundaries on granite fracture nature under quasi-static compression

NASA Astrophysics Data System (ADS)

Damaskinskaya, E. E.; Panteleev, I. A.; Kadomtsev, A. G.; Naimark, O. B.

2017-05-01

Based on an analysis of the spatial distribution of hypocenters of acoustic emission signal sources and an analysis of the energy distributions of acoustic emission signals, the effect of the liquid phase and a weak electric field on the spatiotemporal nature of granite sample fracture is studied. Experiments on uniaxial compression of granite samples of natural moisture showed that the damage accumulation process is twostage: disperse accumulation of damages is followed by localized accumulation of damages in the formed macrofracture nucleus region. In energy distributions of acoustic emission signals, this transition is accompanied by a change in the distribution shape from exponential to power-law. Granite water saturation qualitatively changes the damage accumulation nature: the process is delocalized until macrofracture with the exponential energy distribution of acoustic emission signals. An exposure to a weak electric field results in a selective change in the damage accumulation nature in the sample volume.

Alpha-Recoil Damage Annealing Effecfs on Zircon Crystallinity and He Diffusivity: Improving Damage-Diffusivity Models

NASA Astrophysics Data System (ADS)

Thurston, O. G.; Guenthner, W.; Garver, J. I.

2017-12-01

The effects of radiation damage on He diffusion in zircon has been a major research focus in thermochronology over the past decade. In the zircon-He system, alpha-recoil damage effects He diffusivity in two ways: a decrease in He diffusivity at low radiation damage levels, and an increase in He diffusivity at high radiation damage levels. The radiation damage accumulation process within zircon is well understood; however, the kinetics of annealing of alpha-recoil damage at geologic timescales as they pertain to damage-diffusivity models, and for metamict zircon (i.e. transition from crystalline to amorphous glass via damage accumulation), has not been well constrained. This study aims to develop a more complete model that describes the annealing kinetics for zircon grains with a broad range of pre-annealing, alpha-induced radiation damage. A suite of zircon grains from the Lucerne pluton, ME were chosen for this study due to their simple thermal history (monotonic cooling), notable range of effective uranium (eU, eU = [U] +0.235*[Th]) (15 - 34,239 ppm eU), and large range of radiation damage as measured by Raman shift from crystalline (>1005 cm-1) to metamict (<1000 cm-1). The zircon grains selected represent the full range of eU and radiation damage present in the pluton. The zircon grains were first mapped for overall crystallinity using Raman spectroscopy, then annealed at different time-temperature (t-T) schedules from 1 hr to 24 hrs at temperatures ranging from 700-1100 °C, followed by remapping with Raman spectroscopy to track the total Raman shift for each t-T step. The temperature window selected is at the "roll-over" point established in prior studies (Zhang et al., 2000), at which most laboratory annealing occurs. Our data show that high radiation damage zircon grains show larger Raman shifts than low radiation damage zircon grains when exposed to the same t-T step. The high damage zircon grains typically show a Raman shift of 4 cm-1 toward crystalline, while low radiation damage grains show a shift of 2 cm-1. These shifts suggest that the annealing process occurs at a faster rate in high damage zircon grains, and slower rates in more crystalline grains. That is, the initial level of radiation damage prior to annealing must be considered in damage-diffusivity models that contain thermal histories from zircon-He dates.

A two-stage model of fracture of rocks

USGS Publications Warehouse

Kuksenko, V.; Tomilin, N.; Damaskinskaya, E.; Lockner, D.

1996-01-01

In this paper we propose a two-stage model of rock fracture. In the first stage, cracks or local regions of failure are uncorrelated occur randomly throughout the rock in response to loading of pre-existing flaws. As damage accumulates in the rock, there is a gradual increase in the probability that large clusters of closely spaced cracks or local failure sites will develop. Based on statistical arguments, a critical density of damage will occur where clusters of flaws become large enough to lead to larger-scale failure of the rock (stage two). While crack interaction and cooperative failure is expected to occur within clusters of closely spaced cracks, the initial development of clusters is predicted based on the random variation in pre-existing Saw populations. Thus the onset of the unstable second stage in the model can be computed from the generation of random, uncorrelated damage. The proposed model incorporates notions of the kinetic (and therefore time-dependent) nature of the strength of solids as well as the discrete hierarchic structure of rocks and the flaw populations that lead to damage accumulation. The advantage offered by this model is that its salient features are valid for fracture processes occurring over a wide range of scales including earthquake processes. A notion of the rank of fracture (fracture size) is introduced, and criteria are presented for both fracture nucleation and the transition of the failure process from one scale to another.

Oxidative Damage and Cellular Defense Mechanisms in Sea Urchin Models of Aging

PubMed Central

Du, Colin; Anderson, Arielle; Lortie, Mae; Parsons, Rachel; Bodnar, Andrea

2013-01-01

The free radical or oxidative stress theory of aging proposes that the accumulation of oxidative cellular damage is a major contributor to the aging process and a key determinant of species longevity. This study investigates the oxidative stress theory in a novel model for aging research, the sea urchin. Sea urchins present a unique model for the study of aging due to the existence of species with tremendously different natural life spans including some species with extraordinary longevity and negligible senescence. Cellular oxidative damage, antioxidant capacity and proteasome enzyme activities were measured in the tissues of three sea urchin species: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus and Strongylocentrotus purpuratus which has an intermediate lifespan. Levels of protein carbonyls and 4-hydroxynonenal (HNE) measured in tissues (muscle, nerve, esophagus, gonad, coelomocytes, ampullae) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) measured in cell-free coelomic fluid showed no general increase with age. The fluorescent age-pigment lipofuscin measured in muscle, nerve and esophagus, increased with age however it appeared to be predominantly extracellular. Antioxidant mechanisms (total antioxidant capacity, superoxide dismutase) and proteasome enzyme activities were maintained with age. In some instances, levels of oxidative damage were lower and antioxidant activity higher in cells or tissues of the long-lived species compared to the short-lived species, however further studies are required to determine the relationship between oxidative damage and longevity in these animals. Consistent with the predictions of the oxidative stress theory of aging, the results suggest that negligible senescence is accompanied by a lack of accumulation of cellular oxidative damage with age and maintenance of antioxidant capacity and proteasome enzyme activities may be important mechanisms to mitigate damage. PMID:23707327

Oxidative damage and cellular defense mechanisms in sea urchin models of aging.

PubMed

Du, Colin; Anderson, Arielle; Lortie, Mae; Parsons, Rachel; Bodnar, Andrea

2013-10-01

The free radical, or oxidative stress, theory of aging proposes that the accumulation of oxidative cellular damage is a major contributor to the aging process and a key determinant of species longevity. This study investigates the oxidative stress theory in a novel model for aging research, the sea urchin. Sea urchins present a unique model for the study of aging because of the existence of species with tremendously different natural life spans, including some species with extraordinary longevity and negligible senescence. Cellular oxidative damage, antioxidant capacity, and proteasome enzyme activities were measured in the tissues of three sea urchin species: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus, and Strongylocentrotus purpuratus, which has an intermediate life span. Levels of protein carbonyls and 4-hydroxynonenal measured in tissues (muscle, nerve, esophagus, gonad, coelomocytes, ampullae) and 8-hydroxy-2'-deoxyguanosine measured in cell-free coelomic fluid showed no general increase with age. The fluorescent age pigment lipofuscin, measured in muscle, nerve, and esophagus, increased with age; however, it appeared to be predominantly extracellular. Antioxidant mechanisms (total antioxidant capacity, superoxide dismutase) and proteasome enzyme activities were maintained with age. In some instances, levels of oxidative damage were lower and antioxidant activity higher in cells or tissues of the long-lived species compared to the short-lived species; however, further studies are required to determine the relationship between oxidative damage and longevity in these animals. Consistent with the predictions of the oxidative stress theory of aging, the results suggest that negligible senescence is accompanied by a lack of accumulation of cellular oxidative damage with age, and maintenance of antioxidant capacity and proteasome enzyme activities may be important mechanisms to mitigate damage. Copyright © 2013 Elsevier Inc. All rights reserved.

Investigation of Cumulative Fatigue Damage Through Sequential Low Cycle Fatigue and High Cycle Fatigue Cycling at High Temperature for a Type 316LN Stainless Steel: Life-Prediction Techniques and Associated Mechanisms

NASA Astrophysics Data System (ADS)

Sarkar, Aritra; Nagesha, A.; Parameswaran, P.; Sandhya, R.; Laha, K.; Okazaki, M.

2017-03-01

Cumulative fatigue damage under sequential low cycle fatigue (LCF) and high cycle fatigue (HCF) cycling was investigated at 923 K (650 °C) by conducting HCF tests on specimens subjected to prior LCF cycling at various strain amplitudes. Remnant HCF lives were found to decrease drastically with increase in prior fatigue exposure as a result of strong LCF-HCF interactions. The rate of decrease in remnant lives varied as a function of the applied strain amplitude. A threshold damage in terms of prior LCF life-fraction was found, below which no significant LCF-HCF interaction takes place. Similarly, a critical damage during the LCF pre-cycling marking the highest degree of LCF-HCF interaction was identified which was found to depend on the applied strain amplitude. In view of the non-linear damage accumulation behavior, Miner's linear damage rule proved to be highly non-conservative. Manson's damage curve approach, suitably modified, was found to be a better alternative for predicting the remnant HCF life. The single constant ( β) employed in the model, which reflects the damage accumulation of the material under two/multi-level loading conditions is derived from the regression analysis of the experimental results and validated further.

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

PubMed Central

Tilstra, Jeremy S.; Robinson, Andria R.; Wang, Jin; Gregg, Siobhán Q.; Clauson, Cheryl L.; Reay, Daniel P.; Nasto, Luigi A.; St Croix, Claudette M.; Usas, Arvydas; Vo, Nam; Huard, Johnny; Clemens, Paula R.; Stolz, Donna B.; Guttridge, Denis C.; Watkins, Simon C.; Garinis, George A.; Wang, Yinsheng; Niedernhofer, Laura J.; Robbins, Paul D.

2012-01-01

The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB–activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging. PMID:22706308

Characteristics of shear damage for 60Sn-40Pb solder material

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, H.E.; Chow, C.L.; Wei, Y.

This paper presents an investigation of the development of a continuum damage model capable of accurately analyzing shear damage in 60Sn-40Pb solder material. Based on the theory of damage mechanics, an internal state variable known as the damage variable is introduced to characterize material degradation caused by the change of material microstructures under load. A damage surface in stress space is proposed to quantify damage initiation and its successive expanding surfaces to represent damage hardening. With the aid of irreversible thermodynamics, the damage-coupled constitutive equations and the damage evolution equations are established. A failure criterion is proposed based on themore » accumulation of overall damage in the material. The damage model is implemented in a general purpose finite element program ABAQUS through its user-defined material subroutine UMAT. The program is applied to predict shear deformation in a notched specimen. The predicted failure mode and maximum load agree well with those measured experimentally. The effect of finite element meshing on the numerical results is also examined and discussed.« less

Life prediction modeling based on cyclic damage accumulation

NASA Technical Reports Server (NTRS)

Nelson, Richard S.

1988-01-01

A high temperature, low cycle fatigue life prediction method was developed. This method, Cyclic Damage Accumulation (CDA), was developed for use in predicting the crack initiation lifetime of gas turbine engine materials, where initiation was defined as a 0.030 inch surface length crack. A principal engineering feature of the CDA method is the minimum data base required for implementation. Model constants can be evaluated through a few simple specimen tests such as monotonic loading and rapic cycle fatigue. The method was expanded to account for the effects on creep-fatigue life of complex loadings such as thermomechanical fatigue, hold periods, waveshapes, mean stresses, multiaxiality, cumulative damage, coatings, and environmental attack. A significant data base was generated on the behavior of the cast nickel-base superalloy B1900+Hf, including hundreds of specimen tests under such loading conditions. This information is being used to refine and extend the CDA life prediction model, which is now nearing completion. The model is also being verified using additional specimen tests on wrought INCO 718, and the final version of the model is expected to be adaptable to most any high-temperature alloy. The model is currently available in the form of equations and related constants. A proposed contract addition will make the model available in the near future in the form of a computer code to potential users.

Mathematical modelling of blood-brain barrier failure and edema

NASA Astrophysics Data System (ADS)

Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

2015-11-01

Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

Development of an engineering analysis of progressive damage in composites during low velocity impact

NASA Technical Reports Server (NTRS)

Humphreys, E. A.

1981-01-01

A computerized, analytical methodology was developed to study damage accumulation during low velocity lateral impact of layered composite plates. The impact event was modeled as perfectly plastic with complete momentum transfer to the plate structure. A transient dynamic finite element approach was selected to predict the displacement time response of the plate structure. Composite ply and interlaminar stresses were computed at selected time intervals and subsequently evaluated to predict layer and interlaminar damage. The effects of damage on elemental stiffness were then incorporated back into the analysis for subsequent time steps. Damage predicted included fiber failure, matrix ply failure and interlaminar delamination.

Unusual plastic deformation and damage features in titanium: Experimental tests and constitutive modeling

NASA Astrophysics Data System (ADS)

Revil-Baudard, Benoit; Cazacu, Oana; Flater, Philip; Chandola, Nitin; Alves, J. L.

2016-03-01

In this paper, we present an experimental study on plastic deformation and damage of polycrystalline pure HCP Ti, as well as modeling of the observed behavior. Mechanical characterization data were conducted, which indicate that the material is orthotropic and displays tension-compression asymmetry. The ex-situ and in-situ X-ray tomography measurements conducted reveal that damage distribution and evolution in this HCP Ti material is markedly different than in a typical FCC material such as copper. Stewart and Cazacu (2011) anisotropic elastic/plastic damage model is used to describe the behavior. All the parameters involved in this model have a clear physical significance, being related to plastic properties, and are determined from very few simple mechanical tests. It is shown that this model predicts correctly the anisotropy in plastic deformation, and its strong influence on damage distribution and damage accumulation. Specifically, for a smooth axisymmetric specimen subject to uniaxial tension, damage initiates at the center of the specimen, and is diffuse; the level of damage close to failure being very low. On the other hand, for a notched specimen subject to the same loading the model predicts that damage initiates at the outer surface of the specimen, and further grows from the outer surface to the center of the specimen, which corroborates with the in-situ tomography data.

Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

PubMed Central

Miller, Miles A.; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer H.; Iwamoto, Yoshiko; Yang, Katherine S.; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid C.; Weissleder, Ralph

2015-01-01

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. PMID:26503691

Radiation effects in cubic zirconia: A model system for ceramic oxides

NASA Astrophysics Data System (ADS)

Thomé, L.; Moll, S.; Sattonnay, G.; Vincent, L.; Garrido, F.; Jagielski, J.

2009-06-01

Ceramics are key engineering materials for electronic, space and nuclear industry. Some of them are promising matrices for the immobilization and/or transmutation of radioactive waste. Cubic zirconia is a model system for the study of radiation effects in ceramic oxides. Ion beams are very efficient tools for the simulation of the radiations produced in nuclear reactors or in storage form. In this article, we summarize the work made by combining advanced techniques (RBS/C, XRD, TEM, AFM) to study the structural modifications produced in ion-irradiated cubic zirconia single crystals. Ions with energies in the MeV-GeV range allow exploring the nuclear collision and electronic excitation regimes. At low energy, where ballistic effects dominate, the damage exhibits a peak around the ion projected range; it accumulates with a double-step process by the formation of a dislocation network. At high energy, where electronic excitations are favored, the damage profiles are rather flat up to several micrometers; the damage accumulation is monotonous (one step) and occurs through the creation and overlap of ion tracks. These results may be generalized to many nuclear ceramics.

The influence of rock strength on erosion processes and river morphology in central Arizona: the accumulation of damage from macro-abrasion

NASA Astrophysics Data System (ADS)

Larimer, J. E.; Yanites, B.

2017-12-01

River morphology reflects the interaction between the driving forces of erosion and the resisting properties of bedrock that limit erosion. Changes in energy dissipation at the riverbed are indicated by differences in channel geometry. To erode at the same rate, stronger rocks require more energy, and thus, an adjustment in river slope or width is necessary to accomplish this work. Therefore, morphological changes should reflect differences in the rock strength properties most relevant to the dominant erosion process. We investigate this hypothesis by comparing river morphology and rock-strength properties of reaches subject to different processes. Streams in Prescott National Forest, AZ expose bedrock through a variety of lithologies, which provides a natural testing ground. Measurements include channel geometry, surface P-wave velocity, fracture spacing, and bedload grain size distribution of 150 individual reaches, as well as 260 tensile and compressive-strength tests and P-wave velocity of cores up to depths of 20 cm. Based on observations, we infer that fluvial erosion processes in this region generally fall into three domains: (1) grain by grain abrasion, (2) progressive failure by damage accumulation due to bedload impacts or `macro-abrasion', and (3) `plucking' of jointed rocks. We focus analyses on the accumulation of damage from sub-critical stresses that weakens the surface of the bedrock, potentially leading to macroscopic fractures, fatigue, and rock failure. This plays a dual role facilitating the ease with which abrasion removes material and increasing the rate of production of pluck-able particles. We estimate the `damage potential' of saltating bedload using water discharge time-series, sediment transport models and grain size distribution. To determine the resistance to damage accumulation among different rocks, we measure the evolution of damage in core samples under uniaxial loading using strain energy and inherent flaw theory. Preliminary results suggest that tensile strength is a good predictor of channel morphology in abrasion dominated reaches, morphology is better predicted through a damage perspective in macro-abrasion dominated reaches, and reduction in P-wave velocity near the surface correlates with damage susceptibility.

MTOR-driven quasi-programmed aging as a disposable soma theory

PubMed Central

2013-01-01

If life were created by intelligent design, we would indeed age from accumulation of molecular damage. Repair is costly and limited by energetic resources, and we would allocate resources rationally. But, albeit elegant, this design is fictional. Instead, nature blindly selects for short-term benefits of robust developmental growth. “Quasi-programmed” by the blind watchmaker, aging is a wasteful and aimless continuation of developmental growth, driven by nutrient-sensing, growth-promoting signaling pathways such as MTOR (mechanistic target of rapamycin). A continuous post-developmental activity of such gerogenic pathways leads to hyperfunctions (aging), loss of homeostasis, age-related diseases, non-random organ damage and death. This model is consistent with a view that (1) soma is disposable, (2) aging and menopause are not programmed and (3) accumulation of random molecular damage is not a cause of aging as we know it. PMID:23708516

MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. intelligent designer.

PubMed

Blagosklonny, Mikhail V

2013-06-15

If life were created by intelligent design, we would indeed age from accumulation of molecular damage. Repair is costly and limited by energetic resources, and we would allocate resources rationally. But, albeit elegant, this design is fictional. Instead, nature blindly selects for short-term benefits of robust developmental growth. "Quasi-programmed" by the blind watchmaker, aging is a wasteful and aimless continuation of developmental growth, driven by nutrient-sensing, growth-promoting signaling pathways such as MTOR (mechanistic target of rapamycin). A continuous post-developmental activity of such gerogenic pathways leads to hyperfunctions (aging), loss of homeostasis, age-related diseases, non-random organ damage and death. This model is consistent with a view that (1) soma is disposable, (2) aging and menopause are not programmed and (3) accumulation of random molecular damage is not a cause of aging as we know it.

Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages.

PubMed

He, Xiao-Fei; Lan, Yue; Zhang, Qun; Liu, Dong-Xu; Wang, Qinmei; Liang, Feng-Ying; Zeng, Jin-Sheng; Xu, Guang-Qing; Pei, Zhong

2016-08-01

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages. © 2016 International Society for Neurochemistry.

Stochastic damage evolution in textile laminates

NASA Technical Reports Server (NTRS)

Dzenis, Yuris A.; Bogdanovich, Alexander E.; Pastore, Christopher M.

1993-01-01

A probabilistic model utilizing random material characteristics to predict damage evolution in textile laminates is presented. Model is based on a division of each ply into two sublaminas consisting of cells. The probability of cell failure is calculated using stochastic function theory and maximal strain failure criterion. Three modes of failure, i.e. fiber breakage, matrix failure in transverse direction, as well as matrix or interface shear cracking, are taken into account. Computed failure probabilities are utilized in reducing cell stiffness based on the mesovolume concept. A numerical algorithm is developed predicting the damage evolution and deformation history of textile laminates. Effect of scatter of fiber orientation on cell properties is discussed. Weave influence on damage accumulation is illustrated with the help of an example of a Kevlar/epoxy laminate.

Multi Resolution In-Situ Testing and Multiscale Simulation for Creep Fatigue Damage Analysis of Alloy 617

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Yongming; Oskay, Caglar

This report outlines the research activities that were carried out for the integrated experimental and simulation investigation of creep-fatigue damage mechanism and life prediction of Nickel-based alloy, Inconel 617 at high temperatures (950° and 850°). First, a novel experimental design using a hybrid control technique is proposed. The newly developed experimental technique can generate different combinations of creep and fatigue damage by changing the experimental design parameters. Next, detailed imaging analysis and statistical data analysis are performed to quantify the failure mechanisms of the creep fatigue of alloy 617 at high temperatures. It is observed that the creep damage ismore » directly associated with the internal voids at the grain boundaries and the fatigue damage is directly related to the surface cracking. It is also observed that the classical time fraction approach does not has a good correlation with the experimental observed damage features. An effective time fraction parameter is seen to have an excellent correlation with the material microstructural damage. Thus, a new empirical damage interaction diagram is proposed based on the experimental observations. Following this, a macro level viscoplastic model coupled with damage is developed to simulate the stress/strain response under creep fatigue loadings. A damage rate function based on the hysteresis energy and creep energy is proposed to capture the softening behavior of the material and a good correlation with life prediction and material hysteresis behavior is observed. The simulation work is extended to include the microstructural heterogeneity. A crystal plasticity finite element model considering isothermal and large deformation conditions at the microstructural scale has been developed for fatigue, creep-fatigue as well as creep deformation and rupture at high temperature. The model considers collective dislocation glide and climb of the grains and progressive damage accumulation of the grain boundaries. The glide model incorporates a slip resistance evolution model that characterizes the solute-drag creep effects and can capture well the stress-strain and stress time response of fatigue and creep-fatigue tests at various strain ranges and hold times. In order to accurately capture the creep strains that accumulate particularly at relatively low stress levels, a dislocation climb model has been incorporated into the crystal plasticity modeling framework. The dislocation climb model parameters are calibrated and verified through experimental creep tests performed at 950°. In addition, a cohesive zone model has been fully implemented in the context of the crystal plasticity finite element model to capture the intergranular creep damage. The parameters of the cohesive zone model have been calibrated using available experimental data. The numerical simulations illustrate the capability of the proposed model in capturing damage initiation and growth under creep loads as compared to the experimental observations. The microscale analysis sheds light on the crack initiation sites and propagation patterns within the microstructure. The model is also utilized to investigate the hybrid-controlled creep-fatigue tests and has been found to capture reasonably well the stress-strain response with different hold times and hold stress magnitudes.« less

Coupling continuous damage and debris fragmentation for energy absorption prediction by cfrp structures during crushing

NASA Astrophysics Data System (ADS)

Espinosa, Christine; Lachaud, Frédéric; Limido, Jérome; Lacome, Jean-Luc; Bisson, Antoine; Charlotte, Miguel

2015-05-01

Energy absorption during crushing is evaluated using a thermodynamic based continuum damage model inspired from the Matzenmiller-Lubliner-Taylors model. It was found that for crash-worthiness applications, it is necessary to couple the progressive ruin of the material to a representation of the matter openings and debris generation. Element kill technique (erosion) and/or cohesive elements are efficient but not predictive. A technique switching finite elements into discrete particles at rupture is used to create debris and accumulated mater during the crushing of the structure. Switching criteria are evaluated using the contribution of the different ruin modes in the damage evolution, energy absorption, and reaction force generation.

Progressive Damage Analyses of Skin/Stringer Debonding

NASA Technical Reports Server (NTRS)

Daville, Carlos G.; Camanho, Pedro P.; deMoura, Marcelo F.

2004-01-01

The debonding of skin/stringer constructions is analyzed using a step-by-step simulation of material degradation based on strain softening decohesion elements and a ply degradation procedure. Decohesion elements with mixed-mode capability are placed at the interface between the skin and the flange to simulate the initiation and propagation of the delamination. In addition, the initiation and accumulation of fiber failure and matrix damage is modeled using Hashin-type failure criteria and their corresponding material degradation schedules. The debonding predictions using simplified three-dimensional models correlate well with test results.

Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function

PubMed Central

Misra, Juhi; Mohanty, Sindhu T.; Madan, Sanjeev; Fernandes, James A.; Hal Ebetino, F.; Russell, R. Graham G.

2015-01-01

Abstract Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti‐resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit. Stem Cells 2016;34:756–767 PMID:26679354

Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function.

PubMed

Misra, Juhi; Mohanty, Sindhu T; Madan, Sanjeev; Fernandes, James A; Hal Ebetino, F; Russell, R Graham G; Bellantuono, Ilaria

2016-03-01

Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti-resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit. © 2015 AlphaMed Press.

Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants.

PubMed

Roubicek, Deborah A; Souza-Pinto, Nadja C de

2017-11-01

The mitochondrial DNA (mtDNA) is a closed circular molecule that encodes, in humans, 13 polypeptides components of the oxidative phosphorylation complexes. Integrity of the mitochondrial genome is essential for mitochondrial function and cellular homeostasis, and mutations and deletions in the mtDNA lead to oxidative stress, mitochondrial dysfunction and cell death. In vitro and in situ studies suggest that when exposed to certain genotoxins, mtDNA accumulates more damage than nuclear DNA, likely owing to its organization and localization in the mitochondrial matrix, which tends to accumulate lipophilic, positively charged molecules. In that regard, several relevant environmental and occupational contaminants have physical-chemical characteristics that indicate that they might accumulate in mitochondria and target mtDNA. Nonetheless, very little is known so far about mtDNA damage and mitochondrial dysfunction due to environmental exposure, either in model organisms or in humans. In this article, we discuss some of the characteristics of mtDNA which render it a potentially relevant target for damage by environmental contaminants, as well as possible functional consequences of damage/mutation accumulation. In addition, we review the data available in the literature focusing on mitochondrial effects of the most common classes of environmental pollutants. From that, we conclude that several lines of experimental evidence support the idea that mitochondria and mtDNA are susceptible and biologically relevant targets for pollutants, and more studies, including mechanistic ones, are needed to shed more light into the contribution of mitochondrial dysfunction to the environmental and human health effects of chemical exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Ammonium Accumulation and Cell Death in a Rat 3D Brain Cell Model of Glutaric Aciduria Type I

PubMed Central

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I. PMID:23326493

Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

PubMed

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

Root Damage under Alkaline Stress Is Associated with Reactive Oxygen Species Accumulation in Rice (Oryza sativa L.)

PubMed Central

Zhang, Hui; Liu, Xiao-Long; Zhang, Rui-Xue; Yuan, Hai-Yan; Wang, Ming-Ming; Yang, Hao-Yu; Ma, Hong-Yuan; Liu, Duo; Jiang, Chang-Jie; Liang, Zheng-Wei

2017-01-01

Alkaline stress (high pH) severely damages root cells, and consequently, inhibits rice (Oryza sativa L.) seedling growth. In this study, we demonstrate the accumulation of reactive oxygen species (ROS) in root cells under alkaline stress. Seedlings of two rice cultivars with different alkaline tolerances, ‘Dongdao-4’ (moderately alkaline-tolerant) and ‘Jiudao-51’ (alkaline-sensitive), were subjected to alkaline stress simulated by 15 mM sodium carbonate (Na2CO3). Alkaline stress greatly reduced seedling survival rate, shoot and root growth, and root vigor. Moreover, severe root cell damage was observed under alkaline stress, as shown by increased membrane injury, malondialdehyde accumulation, and Evan’s Blue staining. The expression of the cell death-related genes OsKOD1, OsHsr203j, OsCP1, and OsNAC4 was consistently upregulated, while that of a cell death-suppressor gene, OsBI1, was downregulated. Analysis of the ROS contents revealed that alkaline stress induced a marked accumulation of superoxide anions (O2•-) and hydrogen peroxide (H2O2) in rice roots. The application of procyanidins (a potent antioxidant) to rice seedlings 24 h prior to alkaline treatment significantly alleviated alkalinity-induced root damage and promoted seedling growth inhibition, which were concomitant with reduced ROS accumulation. These results suggest that root cell damage, and consequently growth inhibition, of rice seedlings under alkaline stress is closely associated with ROS accumulation. The antioxidant activity of superoxide dismutase, catalase, peroxidase, and ascorbate peroxidase increased under alkaline stress in the roots, probably in response to the cellular damage induced by oxidative stress. However, this response mechanism may be overwhelmed by the excess ROS accumulation observed under stress, resulting in oxidative damage to root cells. Our findings provide physiological insights into the molecular mechanisms of alkalinity-induced damage to root cells, and will contribute to the improvement of alkaline stress tolerance in rice plants. PMID:28943882

Root Damage under Alkaline Stress Is Associated with Reactive Oxygen Species Accumulation in Rice (Oryza sativa L.).

PubMed

Zhang, Hui; Liu, Xiao-Long; Zhang, Rui-Xue; Yuan, Hai-Yan; Wang, Ming-Ming; Yang, Hao-Yu; Ma, Hong-Yuan; Liu, Duo; Jiang, Chang-Jie; Liang, Zheng-Wei

2017-01-01

Alkaline stress (high pH) severely damages root cells, and consequently, inhibits rice ( Oryza sativa L.) seedling growth. In this study, we demonstrate the accumulation of reactive oxygen species (ROS) in root cells under alkaline stress. Seedlings of two rice cultivars with different alkaline tolerances, 'Dongdao-4' (moderately alkaline-tolerant) and 'Jiudao-51' (alkaline-sensitive), were subjected to alkaline stress simulated by 15 mM sodium carbonate (Na 2 CO 3 ). Alkaline stress greatly reduced seedling survival rate, shoot and root growth, and root vigor. Moreover, severe root cell damage was observed under alkaline stress, as shown by increased membrane injury, malondialdehyde accumulation, and Evan's Blue staining. The expression of the cell death-related genes OsKOD1 , OsHsr203j , OsCP1 , and OsNAC4 was consistently upregulated, while that of a cell death-suppressor gene, OsBI1 , was downregulated. Analysis of the ROS contents revealed that alkaline stress induced a marked accumulation of superoxide anions ([Formula: see text]) and hydrogen peroxide (H 2 O 2 ) in rice roots. The application of procyanidins (a potent antioxidant) to rice seedlings 24 h prior to alkaline treatment significantly alleviated alkalinity-induced root damage and promoted seedling growth inhibition, which were concomitant with reduced ROS accumulation. These results suggest that root cell damage, and consequently growth inhibition, of rice seedlings under alkaline stress is closely associated with ROS accumulation. The antioxidant activity of superoxide dismutase, catalase, peroxidase, and ascorbate peroxidase increased under alkaline stress in the roots, probably in response to the cellular damage induced by oxidative stress. However, this response mechanism may be overwhelmed by the excess ROS accumulation observed under stress, resulting in oxidative damage to root cells. Our findings provide physiological insights into the molecular mechanisms of alkalinity-induced damage to root cells, and will contribute to the improvement of alkaline stress tolerance in rice plants.

Protective effects of resveratrol and its analogs on age-related macular degeneration in vitro.

PubMed

Kang, Jung-Hwan; Choung, Se-Young

2016-12-01

Damage of retinal pigment epithelial (RPE) cells by A2E may be critical for age-related macular degeneration (AMD) management. Accumulation and photooxidation of A2E are known to be one of the critical causes in AMD. Here, we evaluated the protective effect of resveratrol (RES), piceatannol (PIC) and RES glycones on blue-light-induced RPE cell death caused by A2E photooxidation. A2E treatment followed by blue light exposure caused significant damages on human RPE cells (ARPE-19). But the damages were attenuated by post- and pre-treatment of RES and PIC in our in vitro models. The results of cell free system and FAB-MS analysis clearly showed that the reduction of A2E by blue light exposure was significantly rescued, and that oxidized forms of A2E were significantly reduced by RES or PIC treatment. Besides, RES or PIC inhibited the intracellular accumulation of A2E. Not only RES and PIC but RES glycones showed protection of ARPE-19 cells against A2E and blue-light-induced photo-damage. These findings demonstrate that RES and its analogs may have protective effects against A2E and blue-light-induced ARPE-19 cell death through regulation of A2E accumulation as well as photooxidation of A2E. Thus RES and its analogs may be beneficial for AMD treatment.

Residual strength of GFR/POM as a function of damage

NASA Astrophysics Data System (ADS)

Zachariev, G.; Rudolph, H.-V.; Ivers, H.

2010-07-01

A relation between the residual strength and the dispersed damage accumulated in a short fiber reinforced polyoximethylene (GFR/POM) samples under tension is found. For that purpose dependencies of damage and residual strength on loading percentage are used. Damage as a function of loading percentage is known for the material under study. To find the dependency of residual strength on loading percentage a subsidiary function is introduced and a method is proposed for determination of the parameters in the dependency on the basis of the experimental data. Both damage and residual strength are measured after unloading samples that have been loaded applying different loading percentages. Damage is the accumulation of new internal surfaces that arise under mechanical loading in the whole volume of the material. They are registered by a new original method of X-ray refraction. The analytical relation between the residual strength and damage accumulated is compared to the experimental results found for the residual strength under different damage degrees.

Nondestructive Evaluation of Metal Fatigue Using Nonlinear Acoustics

NASA Technical Reports Server (NTRS)

Cantrell, John H., Jr.

2008-01-01

Safe-life and damage-tolerant design philosophies of high performance structures have driven the development of various methods to evaluate nondestructively the accumulation of damage in such structures resulting from cyclic loading. Although many techniques have proven useful, none has been able to provide an unambiguous, quantitative assessment of damage accumulation at each stage of fatigue from the virgin state to fracture. A method based on nonlinear acoustics is shown to provide such a means to assess the state of metal fatigue. The salient features of an analytical model are presented of the microelastic-plastic nonlinearities resulting from the interaction of an acoustic wave with fatigue-generated dislocation substructures and cracks that predictably evolve during the metal fatigue process. The interaction is quantified by the material (acoustic) nonlinearity parameter extracted from acoustic harmonic generation measurements. The parameters typically increase monotonically by several hundred percent over the fatigue life of the metal, thus providing a unique measure of the state of fatigue. Application of the model to aluminum alloy 2024-T4, 410Cb stainless steel, and IN100 nickel-base superalloy specimens fatigued using different loading conditions yields good agreement between theory and experiment. Application of the model and measurement technique to the on-site inspection of steam turbine blades is discussed.

Mechanism-Based Modeling for Low Cycle Fatigue of Cast Austenitic Steel

NASA Astrophysics Data System (ADS)

Wu, Xijia; Quan, Guangchun; Sloss, Clayton

2017-09-01

A mechanism-based approach—the integrated creep-fatigue theory (ICFT)—is used to model low cycle fatigue behavior of 1.4848 cast austenitic steel over the temperature range from room temperature (RT) to 1173 K (900 °C) and the strain rate range from of 2 × 10-4 to 2 × 10-2 s-1. The ICFT formulates the material's constitutive equation based on the physical strain decomposition into mechanism strains, and the associated damage accumulation consisting of crack nucleation and propagation in coalescence with internally distributed damage. At room temperature, the material behavior is controlled by plasticity, resulting in a rate-independent and cyclically stable behavior. The material exhibits significant cyclic hardening at intermediate temperatures, 673 K to 873 K (400 °C to 600 °C), with negative strain rate sensitivity, due to dynamic strain aging. At high temperatures >1073 K (800 °C), time-dependent deformation is manifested with positive rate sensitivity as commonly seen in metallic materials at high temperature. The ICFT quantitatively delineates the contribution of each mechanism in damage accumulation, and predicts the fatigue life as a result of synergistic interaction of the above identified mechanisms. The model descriptions agree well with the experimental and fractographic observations.

Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koike, Manabu, E-mail: m_koike@nirs.go.jp; Yutoku, Yasutomo; Graduate School of Science, Chiba University, Chiba 263-8522

2011-08-19

Highlights: {yields} p21 accumulated rapidly at laser-irradiated sites via its C-terminal region. {yields} p21 colocalized with the DSB marker {gamma}-H2AX and the DSB sensor Ku80. {yields} Accumulation of p21 is dependent on PCNA, but not p53 and the NHEJ core factors. {yields} Accumulation activity of p21 was conserved among human and animal cells. {yields} p21 is a useful tool as a detection marker of DNA damaged sites. -- Abstract: The cyclin-dependent kinase (CDK) inhibitor p21 plays key roles in p53-dependent DNA-damage responses, i.e., cell cycle checkpoints, senescence, or apoptosis. p21 might also play a role in DNA repair. p21 focimore » arise at heavy-ion-irradiated DNA-double-strand break (DSB) sites, which are mainly repaired by nonhomologous DNA-end-joining (NHEJ). However, no mechanisms of p21 accumulation at double-strand break (DSB) sites have been clarified in detail. Recent works indicate that Ku70 and Ku80 are essential for the accumulation of other NHEJ core factors, e.g., DNA-PKcs, XRCC4 and XLF, and other DNA damage response factors, e.g., BRCA1. Here, we show that p21 foci arise at laser-irradiated sites in cells from various tissues from various species. The accumulation of EGFP-p21 was detected in not only normal cells, but also transformed or cancer cells. Our results also showed that EGFP-p21 accumulated rapidly at irradiated sites, and colocalized with the DSB marker {gamma}-H2AX and with the DSB sensor protein Ku80. On the other hand, the accumulation occurred in Ku70-, Ku80-, or DNA-PKcs-deficient cell lines and in human papillomavirus 18-positive cells, whereas the p21 mutant without the PCNA-binding region (EGFP-p21(1-146)) failed to accumulate at the irradiated sites. These findings suggest that the accumulation of p21, but not functional p53 and the NHEJ core factors, is dependent on PCNA. These findings also suggest that the accumulation activity of p21 at DNA damaged sites is conserved among human and animal cells, and p21 is a useful tool as a detection marker of DNA damaged sites.« less

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

PubMed

Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

2014-01-01

Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

Tumor Induced Hepatic Myeloid Derived Suppressor Cells Can Cause Moderate Liver Damage

PubMed Central

Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J.; Korangy, Firouzeh; Greten, Tim F.

2014-01-01

Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage. PMID:25401795

A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions

PubMed Central

Phoenix, Chris

2007-01-01

The relative insensitivity of lifespan to environmental factors constitutes compelling evidence that the physiological decline associated with aging derives primarily from the accumulation of intrinsic molecular and cellular side-effects of metabolism. Here we model that accumulation starting from a biologically based interpretation of the way in which those side-effects interact. We first validate this model by showing that it very accurately reproduces the distribution of ages at death seen in typical populations that are well protected from age-independent causes of death. We then exploit the mechanistic basis of this model to explore the impact on lifespans of interventions that combat aging, with an emphasis on interventions that repair (rather than merely retard) the direct molecular or cellular consequences of metabolism and thus prevent them from accumulating to pathogenic levels. Our results strengthen the case that an indefinite extension of healthy and total life expectancy can be achieved by a plausible rate of progress in the development of such therapies, once a threshold level of efficacy of those therapies has been reached. PMID:19424837

DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marchetti, Francesco; Marchetti, Francesco; Wryobek, Andrew J

The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-inducedmore » heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7- 1 dbf). Analysis of chromosomalaberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.« less

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marchetti, Francesco; Marchetti, Francesco; Wyrobek, Andrew J.

The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-inducedmore » heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7-1 dbf). Analysis of chromosomal aberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.« less

Postbuckling Investigations of Piezoelectric Microdevices Considering Damage Effects

PubMed Central

Sun, Zhigang; Wang, Xianqiao

2014-01-01

Piezoelectric material has been emerging as a popular building block in MEMS devices owing to its unique mechanical and electrical material properties. However, the reliability of MEMS devices under buckling deformation environments remains elusive and needs to be further explored. Based on the Talreja's tensor valued internal state damage variables as well as the Helmhotlz free energy of piezoelectric material, a constitutive model of piezoelectric materials with damage is presented. The Kachanvo damage evolution law under in-plane compressive loads is employed. The model is applied to the specific case of the postbuckling analysis of the piezoelectric plate with damage. Then, adopting von Karman's plate theory, the nonlinear governing equations of the piezoelectric plates with initial geometric deflection including damage effects under in-plane compressive loads are established. By using the finite difference method and the Newmark scheme, the damage evolution for damage accumulation is developed and the finite difference procedure for postbuckling equilibrium path is simultaneously employed. Numerical results show the postbuckling behaviors of initial flat and deflected piezoelectric plates with damage or no damage under different sets of electrical loading conditions. The effects of applied voltage, aspect ratio of plate, thick-span ratio of plate, damage as well as initial geometric deflections on the postbuckling behaviors of the piezoelectric plate are discussed. PMID:24618774

Radiation Damage in Si Diodes from Short, Intense Ion Pulses

NASA Astrophysics Data System (ADS)

de Leon, S. J.; Ludewigt, B. A.; Persaud, A.; Seidl, P. A.; Schenkel, T.

2017-10-01

The Neutralized Drift Compression Experiment (NDCX-II) at Berkeley Lab is an induction accelerator studying the effects that concentrated ion beams have on various materials. Charged particle radiation damage was the focus of this research - we have characterized a series of Si diodes using an electrometer and calibrated the diodes response using an 241Am alpha source, both before and after exposing the diodes to 1 MeV He ions in the accelerator. The key part here is that the high intensity pulses from NDCX-II (>1010 ions/cm2 per pulse in <20 ns) enabled a systematic study of dose-rate effects. An example of a dose-rate effect in Si diodes is increased accumulation of defects due to damage from ions that bombard them in a short pulse. This accumulated damage leads to a reduction in the charge collection efficiency and an increase in leakage current. Testing dose-rate effects in Si diodes and other semiconductors is a crucial step in designing sustainable instruments that can encounter high doses of radiation, such as high intensity accelerators, fusion energy experiments and space applications and results from short pulses can inform models of radiation damage evolution. This work was supported by the Office of Science of the US Department of Energy under contract DE-AC0205CH11231.

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses

PubMed Central

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-01-01

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage. PMID:27021285

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses.

PubMed

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-03-29

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage.

A thermodynamic approach to nonlinear ultrasonics for material state awareness and prognosis

NASA Astrophysics Data System (ADS)

Chillara, Vamshi Krishna

2017-11-01

We develop a thermodynamic framework for modeling nonlinear ultrasonic damage sensing and prognosis in materials undergoing progressive damage. The framework is based on the internal variable approach and relies on the construction of a pseudo-elastic strain energy function that captures the energetics associated with the damage progression. The pseudo-elastic strain energy function is composed of two energy functions—one that describes how a material stores energy in an elastic fashion and the other describes how material dissipates energy or stores it in an inelastic fashion. Experimental motivation for the choice of the above two functionals is discussed and some specific choices pertaining to damage progression during fatigue and creep are presented. The thermodynamic framework is employed to model the nonlinear response of material undergoing stress relaxation and creep-like degradation. For each of the above cases, evolution of the nonlinearity parameter with damage as well as with macroscopic measurables like accumulated plastic strain is obtained.

Repair rather than segregation of damage is the optimal unicellular aging strategy.

PubMed

Clegg, Robert J; Dyson, Rosemary J; Kreft, Jan-Ulrich

2014-08-16

How aging, being unfavourable for the individual, can evolve is one of the fundamental problems of biology. Evidence for aging in unicellular organisms is far from conclusive. Some studies found aging even in symmetrically dividing unicellular species; others did not find aging in the same, or in different, unicellular species, or only under stress. Mathematical models suggested that segregation of non-genetic damage, as an aging strategy, would increase fitness. However, these models failed to consider repair as an alternative strategy or did not properly account for the benefits of repair. We used a new and improved individual-based model to examine rigorously the effect of a range of aging strategies on fitness in various environments. Repair of damage emerges as the best strategy despite its fitness costs, since it immediately increases growth rate. There is an optimal investment in repair that outperforms damage segregation in well-mixed, lasting and benign environments over a wide range of parameter values. Damage segregation becomes beneficial, and only in combination with repair, when three factors are combined: (i) the rate of damage accumulation is high, (ii) damage is toxic and (iii) efficiency of repair is low. In contrast to previous models, our model predicts that unicellular organisms should have active mechanisms to repair damage rather than age by segregating damage. Indeed, as predicted, all organisms have evolved active mechanisms of repair whilst aging in unicellular organisms is absent or minimal under benign conditions, apart from microorganisms with a different ecology, inhabiting short-lived environments strongly favouring early reproduction rather than longevity. Aging confers no fitness advantage for unicellular organisms in lasting environments under benign conditions, since repair of non-genetic damage is better than damage segregation.

Fatigue damage accumulation in various metal matrix composites

NASA Technical Reports Server (NTRS)

Johnson, W. S.

1987-01-01

The purpose of this paper is to review some of the latest understanding of the fatigue behavior of continuous fiber reinforced metal matrix composites. The emphasis is on the development of an understanding of different fatigue damage mechanisms and why and how they occur. The fatigue failure modes in continuous fiber reinforced metal matrix composites are controlled by the three constituents of the system: fiber, matrix, and fiber/matrix interface. The relative strains to fatigue failure of the fiber and matrix will determine the failure mode. Several examples of matrix, fiber, and self-similar damage growth dominated fatigue damage are given for several metal matrix composite systems. Composite analysis, failure modes, and damage modeling are discussed. Boron/aluminum, silicon-carbide/aluminum, FP/aluminum, and borsic/titanium metal matrix composites are discussed.

Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor

PubMed Central

Zhang, Jin; Chen, Xiangling; Kent, Michael S.; Rodriguez, Carlos O.; Chen, Xinbin

2009-01-01

Spontaneous tumors in the dog offer a unique opportunity as models to study human cancer etiology and therapy. p53, the most commonly mutated gene in human cancers, is found to be altered in dog cancers. However, little is known about the role of p53 in dog tumorigenesis. Here, we found that upon exposure to DNA damage agents or Mdm2 inhibitor nutlin-3, canine p53 is accumulated and capable of inducing its target genes, MDM2 and p21. We also found that upon DNA damage, canine p53 is accumulated in the nucleus, followed by MDM2 nuclear translocation and increased 53BP1 foci formation. In addition, we found that canine p63 and p73 are up-regulated by DNA damage agents. Furthermore, colony formation assay showed that canine tumor cells are sensitive to DNA damage agents and nutlin-3 in a p53-dependent manner. Surprisingly, canine p21 is expressed as two isoforms. Thus, we generated multiple canine p21 mutants and found that aa 129 to 142 is required, whereas aa 139 is one of the key determinants, for two p21 isoform expression. Finally, we showed that although the full-length human p21 cDNA expresses one polypeptide, aa 139 appears to play a similar role as that in canine p21 for various migration patterns. Taken together, our results indicate that canine p53 family proteins have biological activities similar to human counterparts. These similarities make the dog as an excellent out-bred spontaneous tumor model and the dog can serve as a translation model from bench-top to cage-side and then to bed-side. PMID:19147538

Editor's Highlight: Periodic Exposure to Smartphone-Mimic Low-Luminance Blue Light Induces Retina Damage Through Bcl-2/BAX-Dependent Apoptosis.

PubMed

Lin, Cheng-Hui; Wu, Man-Ru; Li, Ching-Hao; Cheng, Hui-Wen; Huang, Shih-Hsuan; Tsai, Chi-Hao; Lin, Fan-Li; Ho, Jau-Der; Kang, Jaw-Jou; Hsiao, George; Cheng, Yu-Wen

2017-05-01

Blue light-induced phototoxicity plays an important role in retinal degeneration and might cause damage as a consequence of smartphone dependency. Here, we investigated the effects of periodic exposure to blue light-emitting diode in a cell model and a rat retinal damage model. Retinal pigment epithelium (RPE) cells were subjected to blue light in vitro and the effects of blue light on activation of key apoptotic pathways were examined by measuring the levels of Bcl-2, Bax, Fas ligand (FasL), Fas-associated protein with death domain (FADD), and caspase-3 protein. Blue light treatment of RPE cells increased Bax, cleaved caspase-3, FasL, and FADD expression, inhibited Bcl-2 and Bcl-xL accumulation, and inhibited Bcl-2/Bax association. A rat model of retinal damage was developed with or without continuous or periodic exposure to blue light for 28 days. In this rat model of retinal damage, periodic blue light exposure caused fundus damage, decreased total retinal thickness, caused atrophy of photoreceptors, and injured neuron transduction in the retina. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Modelling accumulation of marine plastics in the coastal zone; what are the dominant physical processes?

NASA Astrophysics Data System (ADS)

Critchell, Kay; Lambrechts, Jonathan

2016-03-01

Anthropogenic marine debris, mainly of plastic origin, is accumulating in estuarine and coastal environments around the world causing damage to fauna, flora and habitats. Plastics also have the potential to accumulate in the food web, as well as causing economic losses to tourism and sea-going industries. If we are to manage this increasing threat, we must first understand where debris is accumulating and why these locations are different to others that do not accumulate large amounts of marine debris. This paper demonstrates an advection-diffusion model that includes beaching, settling, resuspension/re-floating, degradation and topographic effects on the wind in nearshore waters to quantify the relative importance of these physical processes governing plastic debris accumulation. The aim of this paper is to prioritise research that will improve modelling outputs in the future. We have found that the physical characteristic of the source location has by far the largest effect on the fate of the debris. The diffusivity, used to parameterise the sub-grid scale movements, and the relationship between debris resuspension/re-floating from beaches and the wind shadow created by high islands also has a dramatic impact on the modelling results. The rate of degradation of macroplastics into microplastics also have a large influence in the result of the modelling. The other processes presented (settling, wind drift velocity) also help determine the fate of debris, but to a lesser degree. These findings may help prioritise research on physical processes that affect plastic accumulation, leading to more accurate modelling, and subsequently management in the future.

Development and evaluation of an ozone deposition scheme for coupling to a terrestrial biosphere model

NASA Astrophysics Data System (ADS)

Franz, Martina; Simpson, David; Arneth, Almut; Zaehle, Sönke

2017-01-01

Ozone (O3) is a toxic air pollutant that can damage plant leaves and substantially affect the plant's gross primary production (GPP) and health. Realistic estimates of the effects of tropospheric anthropogenic O3 on GPP are thus potentially important to assess the strength of the terrestrial biosphere as a carbon sink. To better understand the impact of ozone damage on the terrestrial carbon cycle, we developed a module to estimate O3 uptake and damage of plants for a state-of-the-art global terrestrial biosphere model called OCN. Our approach accounts for ozone damage by calculating (a) O3 transport from 45 m height to leaf level, (b) O3 flux into the leaf, and (c) ozone damage of photosynthesis as a function of the accumulated O3 uptake over the lifetime of a leaf. A comparison of modelled canopy conductance, GPP, and latent heat to FLUXNET data across European forest and grassland sites shows a general good performance of OCN including ozone damage. This comparison provides a good baseline on top of which ozone damage can be evaluated. In comparison to literature values, we demonstrate that the new model version produces realistic O3 surface resistances, O3 deposition velocities, and stomatal to total O3 flux ratios. A sensitivity study reveals that key metrics of the air-to-leaf O3 transport and O3 deposition, in particular the stomatal O3 uptake, are reasonably robust against uncertainty in the underlying parameterisation of the deposition scheme. Nevertheless, correctly estimating canopy conductance plays a pivotal role in the estimate of cumulative O3 uptake. We further find that accounting for stomatal and non-stomatal uptake processes substantially affects simulated plant O3 uptake and accumulation, because aerodynamic resistance and non-stomatal O3 destruction reduce the predicted leaf-level O3 concentrations. Ozone impacts on GPP and transpiration in a Europe-wide simulation indicate that tropospheric O3 impacts the regional carbon and water cycling less than expected from previous studies. This study presents a first step towards the integration of atmospheric chemistry and ecosystem dynamics modelling, which would allow for assessing the wider feedbacks between vegetation ozone uptake and tropospheric ozone burden.

Downregulation of VRK1 by p53 in Response to DNA Damage Is Mediated by the Autophagic Pathway

PubMed Central

Valbuena, Alberto; Castro-Obregón, Susana; Lazo, Pedro A.

2011-01-01

Human VRK1 induces a stabilization and accumulation of p53 by specific phosphorylation in Thr18. This p53 accumulation is reversed by its downregulation mediated by Hdm2, requiring a dephosphorylated p53 and therefore also needs the removal of VRK1 as stabilizer. This process requires export of VRK1 to the cytosol and is inhibited by leptomycin B. We have identified that downregulation of VRK1 protein levels requires DRAM expression, a p53-induced gene. DRAM is located in the endosomal-lysosomal compartment. Induction of DNA damage by UV, IR, etoposide and doxorubicin stabilizes p53 and induces DRAM expression, followed by VRK1 downregulation and a reduction in p53 Thr18 phosphorylation. DRAM expression is induced by wild-type p53, but not by common human p53 mutants, R175H, R248W and R273H. Overexpression of DRAM induces VRK1 downregulation and the opposite effect was observed by its knockdown. LC3 and p62 were also downregulated, like VRK1, in response to UV-induced DNA damage. The implication of the autophagic pathway was confirmed by its requirement for Beclin1. We propose a model with a double regulatory loop in response to DNA damage, the accumulated p53 is removed by induction of Hdm2 and degradation in the proteasome, and the p53-stabilizer VRK1 is eliminated by the induction of DRAM that leads to its lysosomal degradation in the autophagic pathway, and thus permitting p53 degradation by Hdm2. This VRK1 downregulation is necessary to modulate the block in cell cycle progression induced by p53 as part of its DNA damage response. PMID:21386980

Rhelogical constraints on ridge formation on Icy Satellites

NASA Astrophysics Data System (ADS)

Rudolph, M. L.; Manga, M.

2010-12-01

The processes responsible for forming ridges on Europa remain poorly understood. We use a continuum damage mechanics approach to model ridge formation. The main objectives of this contribution are to constrain (1) choice of rheological parameters and (2) maximum ridge size and rate of formation. The key rheological parameters to constrain appear in the evolution equation for a damage variable (D): ˙ {D} = B <<σ >>r}(1-D){-k-α D (p)/(μ ) and in the equation relating damage accumulation to volumetric changes, Jρ 0 = δ (1-D). Similar damage evolution laws have been applied to terrestrial glaciers and to the analysis of rock mechanics experiments. However, it is reasonable to expect that, like viscosity, the rheological constants B, α , and δ depend strongly on temperature, composition, and ice grain size. In order to determine whether the damage model is appropriate for Europa’s ridges, we must find values of the unknown damage parameters that reproduce ridge topography. We perform a suite of numerical experiments to identify the region of parameter space conducive to ridge production and show the sensitivity to changes in each unknown parameter.

Dynamic modeling of photothermal interactions for laser-induced interstitial thermotherapy: parameter sensitivity analysis.

PubMed

Jiang, S C; Zhang, X X

2005-12-01

A two-dimensional model was developed to model the effects of dynamic changes in the physical properties on tissue temperature and damage to simulate laser-induced interstitial thermotherapy (LITT) treatment procedures with temperature monitoring. A modified Monte Carlo method was used to simulate photon transport in the tissue in the non-uniform optical property field with the finite volume method used to solve the Pennes bioheat equation to calculate the temperature distribution and the Arrhenius equation used to predict the thermal damage extent. The laser light transport and the heat transfer as well as the damage accumulation were calculated iteratively at each time step. The influences of different laser sources, different applicator sizes, and different irradiation modes on the final damage volume were analyzed to optimize the LITT treatment. The numerical results showed that damage volume was the smallest for the 1,064-nm laser, with much larger, similar damage volumes for the 980- and 850-nm lasers at normal blood perfusion rates. The damage volume was the largest for the 1,064-nm laser with significantly smaller, similar damage volumes for the 980- and 850-nm lasers with temporally interrupted blood perfusion. The numerical results also showed that the variations in applicator sizes, laser powers, heating durations and temperature monitoring ranges significantly affected the shapes and sizes of the thermal damage zones. The shapes and sizes of the thermal damage zones can be optimized by selecting different applicator sizes, laser powers, heating duration times, temperature monitoring ranges, etc.

A helium-based model for the effects of radiation damage annealing on helium diffusion kinetics in apatite

NASA Astrophysics Data System (ADS)

Willett, Chelsea D.; Fox, Matthew; Shuster, David L.

2017-11-01

Widely used to study surface processes and the development of topography through geologic time, (U-Th)/He thermochronometry in apatite depends on a quantitative description of the kinetics of 4He diffusion across a range of temperatures, timescales, and geologic scenarios. Empirical observations demonstrate that He diffusivity in apatite is not solely a function of temperature, but also depends on damage to the crystal structure from radioactive decay processes. Commonly-used models accounting for the influence of thermal annealing of radiation damage on He diffusivity assume the net effects evolve in proportion to the rate of fission track annealing, although the majority of radiation damage results from α-recoil. While existing models adequately quantify the net effects of damage annealing in many geologic scenarios, experimental work suggests different annealing rates for the two damage types. Here, we introduce an alpha-damage annealing model (ADAM) that is independent of fission track annealing kinetics, and directly quantifies the influence of thermal annealing on He diffusivity in apatite. We present an empirical fit to diffusion kinetics data and incorporate this fit into a model that tracks the competing effects of radiation damage accumulation and annealing on He diffusivity in apatite through geologic time. Using time-temperature paths to illustrate differences between models, we highlight the influence of damage annealing on data interpretation. In certain, but not all, geologic scenarios, the interpretation of low-temperature thermochronometric data can be strongly influenced by which model of radiation damage annealing is assumed. In particular, geologic scenarios involving 1-2 km of sedimentary burial are especially sensitive to the assumed rate of annealing and its influence on He diffusivity. In cases such as basement rocks in Grand Canyon and the Canadian Shield, (U-Th)/He ages predicted from the ADAM can differ by hundreds of Ma from those predicted by other models for a given thermal path involving extended residence between ∼40-80 °C.

Chk1 Promotes DNA Damage Response Bypass following Oxidative Stress in a Model of Hydrogen Peroxide-Associated Ulcerative Colitis through JNK Inactivation and Chromatin Binding.

PubMed

Reissig, Kathrin; Silver, Andrew; Hartig, Roland; Schinlauer, Antje; Walluscheck, Diana; Guenther, Thomas; Siedentopf, Sandra; Ross, Jochen; Vo, Diep-Khanh; Roessner, Albert; Poehlmann-Nitsche, Angela

2017-01-01

Dysregulation of c-Jun N -terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases. In both phases, Chk1 was linked to DNA damage response bypass by suppressing JNK activation following oxidative stress, promoting cell cycle progression despite DNA damage. Simultaneously, activated Chk1 was bound to chromatin. This triggered histone acetylation and the binding of histone acetyltransferases and transcription factors to chromatin. Thus, chromatin-immobilized activated Chk1 executed a dual function by suppressing DNA damage response and simultaneously inducing chromatin modulation. This caused undetected DNA damage and increased cellular proliferation through failure to transmit the appropriate DNA damage signal. Findings in vitro were corroborated by chromatin accumulation of activated Chk1, Ac-H3, Ac-H4, and c-Jun in active UC (AUC) in vivo. Targeting chromatin-bound Chk1, GCN5, PCAF, and p300/CBP could be a novel therapeutic strategy to prevent UC-related tumor progression.

Hormesis does not make sense except in the light of TOR-driven aging

PubMed Central

Blagosklonny, Mikhail V.

2011-01-01

Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. “Hormesis A” inhibits the TOR pathway. “Hormesis B” increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions. PMID:22166724

Impact of genomic damage and ageing on stem cell function

PubMed Central

Behrens, Axel; van Deursen, Jan M.; Rudolph, K. Lenhard; Schumacher, Björn

2014-01-01

Impairment of stem cell function contributes to the progressive deterioration of tissue maintenance and repair with ageing. Evidence is mounting that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment are partly responsible for stem cell dysfunction with ageing. Here, we review the impact of the various types of DNA damage that accumulate with ageing on stem cell functionality, as well as the development of cancer. We discuss DNA-damage-induced cell intrinsic and extrinsic alterations that influence these processes, and review recent advances in understanding systemic adjustments to DNA damage and how they affect stem cells. PMID:24576896

Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.

PubMed

Li, Fu-Long; Liu, Jin-Ping; Bao, Ruo-Xuan; Yan, GuoQuan; Feng, Xu; Xu, Yan-Ping; Sun, Yi-Ping; Yan, Weili; Ling, Zhi-Qiang; Xiong, Yue; Guan, Kun-Liang; Yuan, Hai-Xin

2018-02-06

Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.

Three-Dimensional Analysis of Voids in AM60B Magnesium Tensile Bars Using Computed Tomography Imagery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waters, A M

2001-05-01

In an effort to increase automobile fuel efficiency as well as decrease the output of harmful greenhouse gases, the automotive industry has recently shown increased interest in cast light metals such as magnesium alloys in an effort to increase weight savings. Currently several magnesium alloys such as AZ91 and AM60B are being used in structural applications for automobiles. However, these magnesium alloys are not as well characterized as other commonly used structural metals such as aluminum. This dissertation presents a methodology to nondestructively quantify damage accumulation due to void behavior in three dimensions in die-cast magnesium AM60B tensile bars asmore » a function of mechanical load. Computed tomography data was acquired after tensile bars were loaded up to and including failure, and analyzed to characterize void behavior as it relates to damage accumulation. Signal and image processing techniques were used along with a cluster labeling routine to nondestructively quantify damage parameters in three dimensions. Void analyses were performed including void volume distribution characterization, nearest neighbor distance calculations, shape parameters, and volumetric renderings of voids in the alloy. The processed CT data was used to generate input files for use in finite element simulations, both two- and three-dimensional. The void analyses revealed that the overwhelming source of failure in each tensile bar was a ring of porosity within each bar, possibly due to a solidification front inherent to the casting process. The measured damage parameters related to void nucleation, growth, and coalescence were shown to contribute significantly to total damage accumulation. Void volume distributions were characterized using a Weibull function, and the spatial distributions of voids were shown to be clustered. Two-dimensional finite element analyses of the tensile bars were used to fine-tune material damage models and a three-dimensional mesh of an extracted portion of one tensile bar including voids was generated from CT data and used as input to a finite element analysis.« less

Revealing ionization-induced dynamic recovery in ion-irradiated SrTiO 3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Velisa, Gihan; Wendler, Elke; Xue, Haizhou

The lack of fundamental understanding on the coupled effects of energy deposition to electrons and atomic nuclei on defect processes and irradiation response poses a significant roadblock for the design and control of material properties. In this work, SrTiO 3 has been irradiated with various ion species over a wide range of ion fluences at room temperature with a goal to deposit different amounts of energy to target electrons and atomic nuclei by varying the ratio of electronic to nuclear energy loss. Here, the results unambiguously show a dramatic difference in behavior of SrTiO 3 irradiated with light ions (Ne,more » O) compared to heavy ions (Ar). While the damage accumulation and amorphization under Ar ion irradiation are consistent with previous observations and existing models, the damage accumulation under Ne irradiation reveals a quasi-saturation state at a fractional disorder of 0.54 at the damage peak for an ion fluence corresponding to a dose of 0.5 dpa; this is followed by further increases in disorder with increasing ion fluence. In the case of O ion irradiation, the damage accumulation at the damage peak closely follows that for Ne ion irradiation up to a fluence corresponding to a dose of 0.5 dpa, where a quasi-saturation of fractional disorder level occurs at about 0.48; however, in this case, the disorder at the damage peak decreases slightly with further increases in fluence. This behavior is associated with changes in kinetics due to irradiation-enhanced diffusional processes that are dependent on electronic energy loss and the ratio of electronic to nuclear energy dissipation. Lastly, these findings are critical for advancing the fundamental understanding of ion-solid interactions and for a large number of applications in oxide electronics where SrTiO 3 is a foundational material.« less

Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage.

PubMed

Solozobova, Valeriya; Rolletschek, Alexandra; Blattner, Christine

2009-06-17

P53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial. In proliferating embryonic stem cells, p53 is localized predominantly in the cytoplasm. DNA damage-induced nuclear accumulation of p53 in embryonic stem cells activates transcription of the target genes mdm2, p21, puma and noxa. We observed bi-phasic kinetics for nuclear accumulation of p53 after ionizing radiation. During the first wave of nuclear accumulation, p53 levels were increased and the p53 target genes mdm2, p21 and puma were transcribed. Transcription of noxa correlated with the second wave of nuclear accumulation. Transcriptional activation of p53 target genes resulted in an increased amount of proteins with the exception of p21. While p21 transcripts were efficiently translated in 3T3 cells, we failed to see an increase in p21 protein levels after IR in embryonal stem cells. In embryonic stem cells where (anti-proliferative) p53 activity is not necessary, or even unfavorable, p53 is retained in the cytoplasm and prevented from activating its target genes. However, if its activity is beneficial or required, p53 is allowed to accumulate in the nucleus and activates its target genes, even in embryonic stem cells.

OBJECT KINETIC MONTE CARLO SIMULATIONS OF RADIATION DAMAGE ACCUMULATION IN TUNGSTEN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nandipati, Giridhar; Setyawan, Wahyu; Roche, Kenneth J.

2016-09-01

The objective of this work is to understand the accumulation of radiation damage created by primary knock-on atoms (PKAs) of various energies, at 300 K and for a dose rate of 10-4 dpa/s in bulk tungsten using the object kinetic Monte Carlo (OKMC) method.

Normalized spectral damage of a linear system over different spectral loading patterns

NASA Astrophysics Data System (ADS)

Kim, Chan-Jung

2017-08-01

Spectral fatigue damage is affected by different loading patterns; the damage may be accumulated in a different manner because the spectral pattern has an influence on stresses or strains. The normalization of spectral damage with respect to spectral loading acceleration is a novel solution to compare the accumulated fatigue damage over different spectral loading patterns. To evaluate the sensitivity of fatigue damage over different spectral loading cases, a simple notched specimen is used to conduct a uniaxial vibration test for two representative spectral patterns-random and harmonic-between 30 and 3000 Hz. The fatigue damage to the simple specimen is analyzed for different spectral loading cases using the normalized spectral damage from the measured response data for both acceleration and strain. The influence of spectral loading patterns is discussed based on these analyses.

Toxic Proteins in Neurodegenerative Disease

NASA Astrophysics Data System (ADS)

Taylor, J. Paul; Hardy, John; Fischbeck, Kenneth H.

2002-06-01

A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders.

Interacting damage models mapped onto ising and percolation models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toussaint, Renaud; Pride, Steven R.

The authors introduce a class of damage models on regular lattices with isotropic interactions between the broken cells of the lattice. Quasistatic fiber bundles are an example. The interactions are assumed to be weak, in the sense that the stress perturbation from a broken cell is much smaller than the mean stress in the system. The system starts intact with a surface-energy threshold required to break any cell sampled from an uncorrelated quenched-disorder distribution. The evolution of this heterogeneous system is ruled by Griffith's principle which states that a cell breaks when the release in potential (elastic) energy in themore » system exceeds the surface-energy barrier necessary to break the cell. By direct integration over all possible realizations of the quenched disorder, they obtain the probability distribution of each damage configuration at any level of the imposed external deformation. They demonstrate an isomorphism between the distributions so obtained and standard generalized Ising models, in which the coupling constants and effective temperature in the Ising model are functions of the nature of the quenched-disorder distribution and the extent of accumulated damage. In particular, they show that damage models with global load sharing are isomorphic to standard percolation theory, that damage models with local load sharing rule are isomorphic to the standard ising model, and draw consequences thereof for the universality class and behavior of the autocorrelation length of the breakdown transitions corresponding to these models. they also treat damage models having more general power-law interactions, and classify the breakdown process as a function of the power-law interaction exponent. Last, they also show that the probability distribution over configurations is a maximum of Shannon's entropy under some specific constraints related to the energetic balance of the fracture process, which firmly relates this type of quenched-disorder based damage model to standard statistical mechanics.« less

A Model of BGA Thermal Fatigue Life Prediction Considering Load Sequence Effects

PubMed Central

Hu, Weiwei; Li, Yaqiu; Sun, Yufeng; Mosleh, Ali

2016-01-01

Accurate testing history data is necessary for all fatigue life prediction approaches, but such data is always deficient especially for the microelectronic devices. Additionally, the sequence of the individual load cycle plays an important role in physical fatigue damage. However, most of the existing models based on the linear damage accumulation rule ignore the sequence effects. This paper proposes a thermal fatigue life prediction model for ball grid array (BGA) packages to take into consideration the load sequence effects. For the purpose of improving the availability and accessibility of testing data, a new failure criterion is discussed and verified by simulation and experimentation. The consequences for the fatigue underlying sequence load conditions are shown. PMID:28773980

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi

Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determinedmore » by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.« less

A coupled effect of nuclear and electronic energy loss on ion irradiation damage in lithium niobate

DOE PAGES

Liu, Peng; Zhang, Yanwen; Xue, Haizhou; ...

2016-01-09

Understanding irradiation effects induced by elastic energy loss to atomic nuclei and inelastic energy loss to electrons in a crystal, as well as the coupled effect between them, is a scientific challenge. Damage evolution in LiNbO 3 irradiated by 0.9 and 21 MeV Si ions at 300 K has been studied utilizing Rutherford backscattering spectrometry in channeling mode. During the low-energy ion irradiation process, damage accumulation produced due to elastic collisions is described utilizing a disorder accumulation model. Moreover, low electronic energy loss is shown to induce observable damage that increases with ion fluence. For the same electronic energy loss,more » the velocity of the incident ion could affect the energy and spatial distribution of excited electrons, and therefore effectively modify the diameter of the ion track. Furthermore, nonlinear additive phenomenon of irradiation damage induced by high electronic energy loss in pre-damaged LiNbO 3 has been observed. The result indicates that pre-existing damage induced from nuclear energy loss interacts synergistically with inelastic electronic energy loss to promote the formation of amorphous tracks and lead to rapid phase transformation, much more efficient than what is observed in pristine crystal solely induced by electronic energy loss. As a result, this synergistic effect is attributed to the fundamental mechanism that the defects produced by the elastic collisions result in a decrease in thermal conductivity, increase in the electron-phonon coupling, and further lead to higher intensity in thermal spike from intense electronic energy deposition along high-energy ion trajectory.« less

DNA Damage, DNA Repair, Aging, and Neurodegeneration

PubMed Central

Maynard, Scott; Fang, Evandro Fei; Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

2015-01-01

Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span. PMID:26385091

Effects of Amplitude Variations on Deformation and Damage Evolution in SnAgCu Solder in Isothermal Cycling

NASA Astrophysics Data System (ADS)

Wentlent, Luke; Alghoul, Thaer M.; Greene, Christopher M.; Borgesen, Peter

2018-02-01

Although apparently simpler than in thermal cycling, the behavior of SnAgCu (SAC) solder joints in cyclic bending or vibration is not currently well understood. The rate of damage has been shown to scale with the inelastic work per cycle, and excursions to higher amplitudes lead to an apparent softening, some of which remains so that damage accumulation is faster in subsequent cycling at lower amplitudes. This frequently leads to a dramatic breakdown of current damage accumulation rules. An empirical damage accumulation rule has been proposed to account for this, but any applicability to the extrapolation of accelerated test results to life under realistic long-term service conditions remains to be validated. This will require a better understanding of the underlying mechanisms. The present work provides experimental evidence to support recent suggestions that the observed behavior is a result of cycling-induced dislocation structures providing for increased diffusion creep. It is argued that this means that the measured work is an indicator of the instantaneous dislocation density, rather than necessarily reflecting the actual work involved in the creation of the damage.

High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter.

PubMed

Hayakawa, Kazuhide; Miyamoto, Nobukazu; Seo, Ji Hae; Pham, Loc-Duyen D; Kim, Kyu-Won; Lo, Eng H; Arai, Ken

2013-04-01

High-mobility group box 1 (HMGB1) was initially described as a damage-associated-molecular-pattern (DAMP) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell (EPC) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine (LPC) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB1 was up-regulated in GFAP-positive reactive astrocytes, along with the accumulation of Flk1/CD34-double-positive EPCs that expressed pro-recovery mediators such as brain-derived neurotrophic factor and basic fibroblast growth factor. Astrocyte-EPC signaling required the HMGB1 receptor RAGE as treatment with RAGE-neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB1 with siRNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB1 from reactive astrocytes may attract EPCs to promote recovery after white matter injury. © 2012 International Society for Neurochemistry.

Dietary antioxidants prevent age-related retinal pigment epithelium actin damage and blindness in mice lacking αvβ5 integrin

PubMed Central

Yu, Chia-Chia; Nandrot, Emeline F.; Dun, Ying; Finnemann, Silvia C.

2011-01-01

In the aging human eye, oxidative damage and accumulation of pro-oxidant lysosomal lipofuscin cause functional decline of the retinal pigment epithelium (RPE), which contributes to age-related macular degeneration. In mice with an RPE-specific phagocytosis defect due to lack of αvβ5 integrin receptors, RPE accumulation of lipofuscin suggests that the age-related blindness we previously described in this model may also result from oxidative stress. Cellular and molecular targets of oxidative stress in the eye remain poorly understood. Here we identify actin among 4-hydroxynonenal (HNE) adducts formed specifically in β5−/− RPE but not neural retina with age. HNE modification directly correlated with loss of resistance of actin to detergent extraction, suggesting cytoskeletal damage in aging RPE. Dietary enrichment with natural antioxidants grapes or marigold extract containing macular pigments lutein/zeaxanthin was sufficient to prevent HNE-adduct formation, actin solubility, lipofuscin accumulation, and age-related cone and rod photoreceptor dysfunction in β5−/− mice. Acute generation of HNE-adducts directly destabilized actin but not tubulin cytoskeletal elements of RPE cells. These findings identify destabilization of the actin cytoskeleton as a consequence of physiological, sublethal oxidative burden of RPE cells in vivo that is associated with age-related blindness and that can be prevented by consuming an antioxidant-rich diet. PMID:22178979

Dose-rate-dependent damage of cerium dioxide in the scanning transmission electron microscope.

PubMed

Johnston-Peck, Aaron C; DuChene, Joseph S; Roberts, Alan D; Wei, Wei David; Herzing, Andrew A

2016-11-01

Beam damage caused by energetic electrons in the transmission electron microscope is a fundamental constraint limiting the collection of artifact-free information. Through understanding the influence of the electron beam, experimental routines may be adjusted to improve the data collection process. Investigations of CeO 2 indicate that there is not a critical dose required for the accumulation of electron beam damage. Instead, measurements using annular dark field scanning transmission electron microscopy and electron energy loss spectroscopy demonstrate that the onset of measurable damage occurs when a critical dose rate is exceeded. The mechanism behind this phenomenon is that oxygen vacancies created by exposure to a 300keV electron beam are actively annihilated as the sample re-oxidizes in the microscope environment. As a result, only when the rate of vacancy creation exceeds the recovery rate will beam damage begin to accumulate. This observation suggests that dose-intensive experiments can be accomplished without disrupting the native structure of the sample when executed using dose rates below the appropriate threshold. Furthermore, the presence of an encapsulating carbonaceous layer inhibits processes that cause beam damage, markedly increasing the dose rate threshold for the accumulation of damage. Published by Elsevier B.V.

Dose-rate-dependent damage of cerium dioxide in the scanning transmission electron microscope

PubMed Central

Johnston-Peck, Aaron C.; DuChene, Joseph S.; Roberts, Alan D.; Wei, Wei David; Herzing, Andrew A.

2016-01-01

Beam damage caused by energetic electrons in the transmission electron microscope is a fundamental constraint limiting the collection of artifact-free information. Through understanding the influence of the electron beam, experimental routines may be adjusted to improve the data collection process. Investigations of CeO2 indicate that there is not a critical dose required for the accumulation of electron beam damage. Instead, measurements using annular dark field scanning transmission electron microscopy and electron energy loss spectroscopy demonstrate that the onset of measurable damage occurs when a critical dose rate is exceeded. The mechanism behind this phenomenon is that oxygen vacancies created by exposure to a 300 keV electron beam are actively annihilated as the sample re-oxidizes in the microscope environment. As a result, only when the rate of vacancy creation exceeds the recovery rate will beam damage begin to accumulate. This observation suggests that dose-intensive experiments can be accomplished without disrupting the native structure of the sample when executed using dose rates below the appropriate threshold. Furthermore, the presence of an encapsulating carbonaceous layer inhibits processes that cause beam damage, markedly increasing the dose rate threshold for the accumulation of damage. PMID:27469265

Delayed damage accumulation by athermal suppression of defect production in concentrated solid solution alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Velişa, G.; Wendler, E.; Zhao, S.

A combined experimental and computational evaluation of damage accumulation in ion-irradiated Ni, NiFe, and NiFeCoCr is presented. Furthermore, a suppressed damage accumulation, at early stages (low-fluence irradiation), is revealed in NiFeCoCr, with a linear dependence as a function of ion fluence, in sharp contrast with Ni and NiFe. This effect, observed at 16 K, is attributed to the complex energy landscape in these alloys that limits defect mobility and therefore enhances defect interaction and recombination. Our results, together with previous room-temperature and high-temperature investigations, suggest "self-healing" as an intrinsic property of complex alloys that is not a thermally activated process.

Delayed damage accumulation by athermal suppression of defect production in concentrated solid solution alloys

DOE PAGES

Velişa, G.; Wendler, E.; Zhao, S.; ...

2017-12-17

A combined experimental and computational evaluation of damage accumulation in ion-irradiated Ni, NiFe, and NiFeCoCr is presented. Furthermore, a suppressed damage accumulation, at early stages (low-fluence irradiation), is revealed in NiFeCoCr, with a linear dependence as a function of ion fluence, in sharp contrast with Ni and NiFe. This effect, observed at 16 K, is attributed to the complex energy landscape in these alloys that limits defect mobility and therefore enhances defect interaction and recombination. Our results, together with previous room-temperature and high-temperature investigations, suggest "self-healing" as an intrinsic property of complex alloys that is not a thermally activated process.

Damage accumulation of bovine bone under variable amplitude loads.

PubMed

Campbell, Abbey M; Cler, Michelle L; Skurla, Carolyn P; Kuehl, Joseph J

2016-12-01

Stress fractures, a painful injury, are caused by excessive fatigue in bone. This study on damage accumulation in bone sought to determine if the Palmgren-Miner rule (PMR), a well-known linear damage accumulation hypothesis, is predictive of fatigue failure in bone. An electromagnetic shaker apparatus was constructed to conduct cyclic and variable amplitude tests on bovine bone specimens. Three distinct damage regimes were observed following fracture. Fractures due to a low cyclic amplitude loading appeared ductile ( 4000 μ ϵ ), brittle due to high cyclic amplitude loading (> 9000 μ ϵ ), and a combination of ductile and brittle from mid-range cyclic amplitude loading (6500 -6750 μ ϵ ). Brittle and ductile fracture mechanisms were isolated and mixed, in a controlled way, into variable amplitude loading tests. PMR predictions of cycles to failure consistently over-predicted fatigue life when mixing isolated fracture mechanisms. However, PMR was not proven ineffective when used with a single damage mechanism.

Unraveling the non-senescence phenomenon in Hydra.

PubMed

Dańko, Maciej J; Kozłowski, Jan; Schaible, Ralf

2015-10-07

Unlike other metazoans, Hydra does not experience the distinctive rise in mortality with age known as senescence, which results from an increasing imbalance between cell damage and cell repair. We propose that the Hydra controls damage accumulation mainly through damage-dependent cell selection and cell sloughing. We examine our hypothesis with a model that combines cellular damage with stem cell renewal, differentiation, and elimination. The Hydra individual can be seen as a large single pool of three types of stem cells with some features of differentiated cells. This large stem cell community prevents "cellular damage drift," which is inevitable in complex conglomerate (differentiated) metazoans with numerous and generally isolated pools of stem cells. The process of cellular damage drift is based on changes in the distribution of damage among cells due to random events, and is thus similar to Muller's ratchet in asexual populations. Events in the model that are sources of randomness include budding, cellular death, and cellular damage and repair. Our results suggest that non-senescence is possible only in simple Hydra-like organisms which have a high proportion and number of stem cells, continuous cell divisions, an effective cell selection mechanism, and stem cells with the ability to undertake some roles of differentiated cells. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Crack surface roughness in three-dimensional random fuse networks

NASA Astrophysics Data System (ADS)

Nukala, Phani Kumar V. V.; Zapperi, Stefano; Šimunović, Srđan

2006-08-01

Using large system sizes with extensive statistical sampling, we analyze the scaling properties of crack roughness and damage profiles in the three-dimensional random fuse model. The analysis of damage profiles indicates that damage accumulates in a diffusive manner up to the peak load, and localization sets in abruptly at the peak load, starting from a uniform damage landscape. The global crack width scales as Wtilde L0.5 and is consistent with the scaling of localization length ξ˜L0.5 used in the data collapse of damage profiles in the postpeak regime. This consistency between the global crack roughness exponent and the postpeak damage profile localization length supports the idea that the postpeak damage profile is predominantly due to the localization produced by the catastrophic failure, which at the same time results in the formation of the final crack. Finally, the crack width distributions can be collapsed for different system sizes and follow a log-normal distribution.

A study of elevated temperature testing techniques for the fatigue behavior of PMCS: Application to T650-35/AMB21

NASA Technical Reports Server (NTRS)

Gyekenyesi, Andrew L.; Gastelli, Michael G.; Ellis, John R.; Burke, Christopher S.

1995-01-01

An experimental study was conducted to investigate the mechanical behavior of a T650-35/AMB21 eight-harness satin weave polymer composite system. Emphasis was placed on the development and refinement of techniques used in elevated temperature uniaxial PMC testing. Issues such as specimen design, gripping, strain measurement, and temperature control and measurement were addressed. Quasi-static tensile and fatigue properties (R(sub sigma) = 0.1) were examined at room and elevated temperatures. Stiffness degradation and strain accumulation during fatigue cycling were recorded to monitor damage progression and provide insight for future analytical modeling efforts. Accomplishments included an untabbed dog-bone specimen design which consistently failed in the gage section, accurate temperature control and assessment, and continuous in-situ strain measurement capability during fatigue loading at elevated temperatures. Finally, strain accumulation and stiffness degradation during fatigue cycling appeared to be good indicators of damage progression.

Assessment of Solder Joint Fatigue Life Under Realistic Service Conditions

NASA Astrophysics Data System (ADS)

Hamasha, Sa'd.; Jaradat, Younis; Qasaimeh, Awni; Obaidat, Mazin; Borgesen, Peter

2014-12-01

The behavior of lead-free solder alloys under complex loading scenarios is still not well understood. Common damage accumulation rules fail to account for strong effects of variations in cycling amplitude, and random vibration test results cannot be interpreted in terms of performance under realistic service conditions. This is a result of the effects of cycling parameters on materials properties. These effects are not yet fully understood or quantitatively predictable, preventing modeling based on parameters such as strain, work, or entropy. Depending on the actual spectrum of amplitudes, Miner's rule of linear damage accumulation has been shown to overestimate life by more than an order of magnitude, and greater errors are predicted for other combinations. Consequences may be particularly critical for so-called environmental stress screening. Damage accumulation has, however, been shown to scale with the inelastic work done, even if amplitudes vary. This and the observation of effects of loading history on subsequent work per cycle provide for a modified damage accumulation rule which allows for the prediction of life. Individual joints of four different Sn-Ag-Cu-based solder alloys (SAC305, SAC105, SAC-Ni, and SACXplus) were cycled in shear at room temperature, alternating between two different amplitudes while monitoring the evolution of the effective stiffness and work per cycle. This helped elucidate general trends and behaviors that are expected to occur in vibrations of microelectronics assemblies. Deviations from Miner's rule varied systematically with the combination of amplitudes, the sequences of cycles, and the strain rates in each. The severity of deviations also varied systematically with Ag content in the solder, but major effects were observed for all the alloys. A systematic analysis was conducted to assess whether scenarios might exist in which the more fatigue-resistant high-Ag alloys would fail sooner than the lower-Ag ones.

Adaptations of quaking aspen for defense against damage by herbivores and related environmental agents

Treesearch

Richard L. Lindroth

2001-01-01

Quaking aspen (Populus tremuloides) employs two major systems of defense against damage by environmental agents: chemical defense and tolerance. Aspen accumulates appreciable quantities of phenolic glycosides (salicylates) and condensed tannins in most tissues and accumulates coniferyl benzoate in flower buds. Phenolic glycosides are toxic and/or deterrent to pathogens...

Damage accumulation in ion-irradiated Ni-based concentrated solid-solution alloys

DOE PAGES

Ullah, Mohammad W.; Aidhy, Dilpuneet S.; Zhang, Yanwen; ...

2016-03-05

We investigate Irradiation-induced damage accumulation in Ni 0.8Fe 0.2 and Ni 0.8Cr 0.2 alloys by using molecular dynamics simulations to assess possible enhanced radiation-resistance in these face-centered cubic (fcc), single-phase, concentrated solid-solution alloys, as compared with pure fcc Ni.

Modelling the molecular mechanisms of aging

PubMed Central

Mc Auley, Mark T.; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M.; Morgan, Amy E.

2017-01-01

The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID:28096317

Modeling and Measuring the Effects of Radiation Damage Annealing on Helium Diffusion Kinetics in Apatite

NASA Astrophysics Data System (ADS)

Willett, C. D.; Fox, M.; Shuster, D. L.

2016-12-01

Understanding helium diffusion kinetics in apatite is critical for the accurate interpretation of (U-Th)/He thermochronometric data. This problem is complicated by the observation that helium diffusivity is not a simple function of temperature, but may evolve as a function of damage to the apatite crystal lattice resulting from alpha recoil. This `radiation damage' increases as a function of the amount of radiometric parent products, or effective uranium concentration, and time, but decreases due to thermal annealing of damage, necessitating a detailed understanding of radiation damage production and annealing in cases of burial heating over geologic timescales. Published observations [1,2] suggest that annealing rates of damage caused by alpha recoil and fission tracks in apatite differ. Existing models, however, assume the diffusion kinetics resulting from the two sources of damage are identical [3], demonstrating the need for further investigation of these damage sources. We present modeling and experimental work designed to interrogate the effects of radiation damage and its annealing on helium diffusion kinetics in apatite. Using previously published results [4] that investigated the effects of annealing temperature and duration on measured helium diffusivity, we fit a set of functions that are then integrated into a numerical model that tracks the evolution of radiation damage and apparent (U-Th)/He age. We compare the results of this model calibration to existing models [3]. In addition, we present data from two suites of diffusion experiments. The first suite, intended to test the published methodology and results, uses Durango apatite, while the second uses Sierran (CA) granite as a first test to determine if apatite of varying chemistry and age responds differently to the thermal annealing of radiation damage. Ultimately, the updated model and experimental results will benefit the interpretation of the effects of radiation damage accumulation and annealing in apatite and expand the range of geologic settings that can be studied using low-temperature thermochronology. References: [1] Fox, M., Shuster, D. (2014), EPSL 397, 174-183; [2] Gautheron, C. et al. (2013), Chem. Geol. 351, 257-267; [3] Flowers, R. et al. (2009), GCA 73, 2347-2365; [4] Shuster, D., Farley, K. (2009), GCA 73, 6183-6196.

Modelling of the Impact Response of Fibre-Reinforced Composites

DTIC Science & Technology

1990-09-30

observed under tensile loading alone, the damage accumulation process following initial tensile fracture of a fibre tow somewhere within the test specimen...results to be obtained which are not inconsistent with those observed experimentally. Sim- ilarly the delamination process is modelled assuming an...publication either in journals or in conference proceedings. 1 . J. Harding and K. Saka, "The effect of strain rate on the tensile failure of woven reinforced

Life Prediction Methodologies for Aerospace Materials Annual Report, 2003

DTIC Science & Technology

2003-06-01

peening parameters are obtained using a simplified model [Cao, et al .]. The solutions ultimately will need to be fine-tuned by simulating the...clamping stress and applied axial stress, identified from prior work [Hutson, et al .]. Accumulated damage on some samples was characterized using...defined using single fiber creep data [Wilson, et al .]. A two-level Mori-Tanaka model [Mori and Tanaka] has been used to define the effective

A Prospective Study of the Impact of Current Poverty, History of Poverty, and Exiting Poverty on Accumulation of Disease Damage in Systemic Lupus Erythematosus.

PubMed

Yelin, Edward; Trupin, Laura; Yazdany, Jinoos

2017-08-01

To estimate the effect of current poverty, number of years in poverty, and exiting poverty on disease damage accumulation in systemic lupus erythematosus (SLE). For this study, 783 patients with SLE were followed up from 2003 to 2015 through annual structured interviews. Respondents were categorized in each year by whether they had a household income of ≤125% of the US federal poverty level. Linear and logistic regression analyses were used to assess the impact of poverty in 2009, number of years in poverty between 2003 and 2009, and permanent exits from poverty as of 2009 on the extent of disease damage (according to the Brief Index of Lupus Damage [BILD] score) or accumulation of a clinically meaningful increase in disease damage (defined as a minimum 2-point increase in the BILD damage score) by 2015. After adjustment for sociodemographic features, health care characteristics, and health behaviors, poverty in 2009 was associated with an increased level of accumulated disease damage in 2015 (mean difference in BILD damage score between poor and non-poor 0.62 points, 95% confidence interval [95% CI] 0.25-0.98) and increased odds of a clinically important increase in damage (odds ratio [OR] 1.67, 95% CI 0.98-2.85). Being poor in every year between 2003 and 2009 was associated with greater damage (mean change in BILD score 2.45, 95% CI 1.88-3.01) than being poor for one-half or more of those years (mean change in BILD score 1.45, 95% CI 0.97-1.93), for fewer than one-half of those years (mean change in BILD score 1.49, 95% CI 1.10-1.88), or for none of those years (mean change in BILD score 1.34, 95% CI 1.20-1.49). Those exiting poverty permanently had similar increases in disease damage (mean change in BILD score 1.30, 95% CI 0.90-1.69) as those who were never in poverty (mean change in BILD score 1.36, 95% CI 1.23-1.50) but much less damage than those who remained in poverty (mean change in BILD score 1.98, 95% CI 1.59-2.38). The effects of current poverty, "dose" of poverty, and exiting poverty suggest that poverty plays a critical role in the accumulation of damage in patients with SLE. © 2017, American College of Rheumatology.

Increased oxidative phosphorylation in response to acute and chronic DNA damage

PubMed Central

Brace, Lear E; Vose, Sarah C; Stanya, Kristopher; Gathungu, Rose M; Marur, Vasant R; Longchamp, Alban; Treviño-Villarreal, Humberto; Mejia, Pedro; Vargas, Dorathy; Inouye, Karen; Bronson, Roderick T; Lee, Chih-Hao; Neilan, Edward; Kristal, Bruce S; Mitchell, James R

2016-01-01

Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. PMID:28721274

Chk1 Promotes DNA Damage Response Bypass following Oxidative Stress in a Model of Hydrogen Peroxide-Associated Ulcerative Colitis through JNK Inactivation and Chromatin Binding

PubMed Central

Silver, Andrew; Guenther, Thomas; Siedentopf, Sandra; Ross, Jochen; Vo, Diep-Khanh; Roessner, Albert

2017-01-01

Dysregulation of c-Jun N-terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases. In both phases, Chk1 was linked to DNA damage response bypass by suppressing JNK activation following oxidative stress, promoting cell cycle progression despite DNA damage. Simultaneously, activated Chk1 was bound to chromatin. This triggered histone acetylation and the binding of histone acetyltransferases and transcription factors to chromatin. Thus, chromatin-immobilized activated Chk1 executed a dual function by suppressing DNA damage response and simultaneously inducing chromatin modulation. This caused undetected DNA damage and increased cellular proliferation through failure to transmit the appropriate DNA damage signal. Findings in vitro were corroborated by chromatin accumulation of activated Chk1, Ac-H3, Ac-H4, and c-Jun in active UC (AUC) in vivo. Targeting chromatin-bound Chk1, GCN5, PCAF, and p300/CBP could be a novel therapeutic strategy to prevent UC-related tumor progression. PMID:28751935

Lower Length Scale Model Development for Embrittlement of Reactor Presure Vessel Steel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yongfeng; Schwen, Daniel; Chakraborty, Pritam

2016-09-01

This report summarizes the lower-length-scale effort during FY 2016 in developing mesoscale capabilities for microstructure evolution, plasticity and fracture in reactor pressure vessel steels. During operation, reactor pressure vessels are subject to hardening and embrittlement caused by irradiation induced defect accumulation and irradiation enhanced solute precipitation. Both defect production and solute precipitation start from the atomic scale, and manifest their eventual effects as degradation in engineering scale properties. To predict the property degradation, multiscale modeling and simulation are needed to deal with the microstructure evolution, and to link the microstructure feature to material properties. In this report, the development ofmore » mesoscale capabilities for defect accumulation and solute precipitation are summarized. A crystal plasticity model to capture defect-dislocation interaction and a damage model for cleavage micro-crack propagation is also provided.« less

Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

PubMed

Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

2015-01-01

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage

PubMed Central

Jin, Ya-Qiong; An, Guo-Shun; Ni, Ju-Hua; Li, Shu-Yan; Jia, Hong-Ti

2014-01-01

The nucleolus plays a major role in ribosome biogenesis. Most genotoxic agents disrupt nucleolar structure and function, which results in the stabilization/activation of p53, inducing cell cycle arrest or apoptosis. Likewise, transcription factor E2F1 as a DNA damage responsive protein also plays roles in cell cycle arrest, DNA repair, or apoptosis in response to DNA damage through transcriptional response and protein–protein interaction. Furthermore, E2F1 is known to be involved in regulating rRNA transcription. However, how E2F1 displays in coordinating DNA damage and nucleolar stress is unclear. In this study, we demonstrate that ATM-dependent E2F1 accumulation in the nucleolus is a characteristic feature of nucleolar stress in early response to DNA damage. We found that at the early stage of DNA damage, E2F1 accumulation in the nucleolus was an ATM-dependent and a common event in p53-suficient and -deficient cells. Increased nucleolar E2F1 was sequestered by the nucleolar protein p14ARF, which repressed E2F1-dependent rRNA transcription initiation, and was coupled with S phase. Our data indicate that early accumulation of E2F1 in the nucleolus is an indicator for nucleolar stress and a component of ATM pathway, which presumably buffers elevation of E2F1 in the nucleoplasm and coordinates the diversifying mechanisms of E2F1 acts in cell cycle progression and apoptosis in early response to DNA damage. PMID:24675884

ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage.

PubMed

Jin, Ya-Qiong; An, Guo-Shun; Ni, Ju-Hua; Li, Shu-Yan; Jia, Hong-Ti

2014-01-01

The nucleolus plays a major role in ribosome biogenesis. Most genotoxic agents disrupt nucleolar structure and function, which results in the stabilization/activation of p53, inducing cell cycle arrest or apoptosis. Likewise, transcription factor E2F1 as a DNA damage responsive protein also plays roles in cell cycle arrest, DNA repair, or apoptosis in response to DNA damage through transcriptional response and protein-protein interaction. Furthermore, E2F1 is known to be involved in regulating rRNA transcription. However, how E2F1 displays in coordinating DNA damage and nucleolar stress is unclear. In this study, we demonstrate that ATM-dependent E2F1 accumulation in the nucleolus is a characteristic feature of nucleolar stress in early response to DNA damage. We found that at the early stage of DNA damage, E2F1 accumulation in the nucleolus was an ATM-dependent and a common event in p53-suficient and -deficient cells. Increased nucleolar E2F1 was sequestered by the nucleolar protein p14ARF, which repressed E2F1-dependent rRNA transcription initiation, and was coupled with S phase. Our data indicate that early accumulation of E2F1 in the nucleolus is an indicator for nucleolar stress and a component of ATM pathway, which presumably buffers elevation of E2F1 in the nucleoplasm and coordinates the diversifying mechanisms of E2F1 acts in cell cycle progression and apoptosis in early response to DNA damage.

46 CFR 76.33-10 - Location and spacing of accumulators.

Code of Federal Regulations, 2012 CFR

2012-10-01

... PROTECTION EQUIPMENT Smoke Detecting System, Details § 76.33-10 Location and spacing of accumulators. (a) Smoke accumulators shall be located overhead in each compartment. Where liable to physical damage, the...

46 CFR 76.33-10 - Location and spacing of accumulators.

Code of Federal Regulations, 2014 CFR

2014-10-01

... PROTECTION EQUIPMENT Smoke Detecting System, Details § 76.33-10 Location and spacing of accumulators. (a) Smoke accumulators shall be located overhead in each compartment. Where liable to physical damage, the...

46 CFR 76.33-10 - Location and spacing of accumulators.

Code of Federal Regulations, 2013 CFR

2013-10-01

... PROTECTION EQUIPMENT Smoke Detecting System, Details § 76.33-10 Location and spacing of accumulators. (a) Smoke accumulators shall be located overhead in each compartment. Where liable to physical damage, the...

46 CFR 76.33-10 - Location and spacing of accumulators.

Code of Federal Regulations, 2010 CFR

2010-10-01

... PROTECTION EQUIPMENT Smoke Detecting System, Details § 76.33-10 Location and spacing of accumulators. (a) Smoke accumulators shall be located overhead in each compartment. Where liable to physical damage, the...

46 CFR 76.33-10 - Location and spacing of accumulators.

Code of Federal Regulations, 2011 CFR

2011-10-01

... PROTECTION EQUIPMENT Smoke Detecting System, Details § 76.33-10 Location and spacing of accumulators. (a) Smoke accumulators shall be located overhead in each compartment. Where liable to physical damage, the...

Computationally-efficient stochastic cluster dynamics method for modeling damage accumulation in irradiated materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoang, Tuan L.; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, CA 94550; Marian, Jaime, E-mail: jmarian@ucla.edu

2015-11-01

An improved version of a recently developed stochastic cluster dynamics (SCD) method (Marian and Bulatov, 2012) [6] is introduced as an alternative to rate theory (RT) methods for solving coupled ordinary differential equation (ODE) systems for irradiation damage simulations. SCD circumvents by design the curse of dimensionality of the variable space that renders traditional ODE-based RT approaches inefficient when handling complex defect population comprised of multiple (more than two) defect species. Several improvements introduced here enable efficient and accurate simulations of irradiated materials up to realistic (high) damage doses characteristic of next-generation nuclear systems. The first improvement is a proceduremore » for efficiently updating the defect reaction-network and event selection in the context of a dynamically expanding reaction-network. Next is a novel implementation of the τ-leaping method that speeds up SCD simulations by advancing the state of the reaction network in large time increments when appropriate. Lastly, a volume rescaling procedure is introduced to control the computational complexity of the expanding reaction-network through occasional reductions of the defect population while maintaining accurate statistics. The enhanced SCD method is then applied to model defect cluster accumulation in iron thin films subjected to triple ion-beam (Fe{sup 3+}, He{sup +} and H{sup +}) irradiations, for which standard RT or spatially-resolved kinetic Monte Carlo simulations are prohibitively expensive.« less

Modelling interactions of acid–base balance and respiratory status in the toxicity of metal mixtures in the American oyster Crassostrea virginica

PubMed Central

Macey, Brett M.; Jenny, Matthew J.; Williams, Heidi R.; Thibodeaux, Lindy K.; Beal, Marion; Almeida, Jonas S.; Cunningham, Charles; Mancia, Annalaura; Warr, Gregory W.; Burge, Erin J.; Holland, A. Fred; Gross, Paul S.; Hikima, Sonomi; Burnett, Karen G.; Burnett, Louis; Chapman, Robert W.

2010-01-01

Heavy metals, such as copper, zinc and cadmium, represent some of the most common and serious pollutants in coastal estuaries. In the present study, we used a combination of linear and artificial neural network (ANN) modelling to detect and explore interactions among low-dose mixtures of these heavy metals and their impacts on fundamental physiological processes in tissues of the Eastern oyster, Crassostrea virginica. Animals were exposed to Cd (0.001–0.400 µM), Zn (0.001–3.059 µM) or Cu (0.002–0.787 µM), either alone or in combination for 1 to 27 days. We measured indicators of acid–base balance (hemolymph pH and total CO2), gas exchange (Po2), immunocompetence (total hemocyte counts, numbers of invasive bacteria), antioxidant status (glutathione, GSH), oxidative damage (lipid peroxidation; LPx), and metal accumulation in the gill and the hepatopancreas. Linear analysis showed that oxidative membrane damage from tissue accumulation of environmental metals was correlated with impaired acid–base balance in oysters. ANN analysis revealed interactions of metals with hemolymph acid–base chemistry in predicting oxidative damage that were not evident from linear analyses. These results highlight the usefulness of machine learning approaches, such as ANNs, for improving our ability to recognize and understand the effects of subacute exposure to contaminant mixtures. PMID:19958840

Computationally-efficient stochastic cluster dynamics method for modeling damage accumulation in irradiated materials

NASA Astrophysics Data System (ADS)

Hoang, Tuan L.; Marian, Jaime; Bulatov, Vasily V.; Hosemann, Peter

2015-11-01

An improved version of a recently developed stochastic cluster dynamics (SCD) method (Marian and Bulatov, 2012) [6] is introduced as an alternative to rate theory (RT) methods for solving coupled ordinary differential equation (ODE) systems for irradiation damage simulations. SCD circumvents by design the curse of dimensionality of the variable space that renders traditional ODE-based RT approaches inefficient when handling complex defect population comprised of multiple (more than two) defect species. Several improvements introduced here enable efficient and accurate simulations of irradiated materials up to realistic (high) damage doses characteristic of next-generation nuclear systems. The first improvement is a procedure for efficiently updating the defect reaction-network and event selection in the context of a dynamically expanding reaction-network. Next is a novel implementation of the τ-leaping method that speeds up SCD simulations by advancing the state of the reaction network in large time increments when appropriate. Lastly, a volume rescaling procedure is introduced to control the computational complexity of the expanding reaction-network through occasional reductions of the defect population while maintaining accurate statistics. The enhanced SCD method is then applied to model defect cluster accumulation in iron thin films subjected to triple ion-beam (Fe3+, He+ and H+) irradiations, for which standard RT or spatially-resolved kinetic Monte Carlo simulations are prohibitively expensive.

Early axonal damage and progressive myelin pathology define the kinetics of CNS histopathology in a mouse model of multiple sclerosis.

PubMed

Recks, Mascha S; Stormanns, Eva R; Bader, Jonas; Arnhold, Stefan; Addicks, Klaus; Kuerten, Stefanie

2013-10-01

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies. Copyright © 2013 Elsevier Inc. All rights reserved.

A damage mechanics based approach to structural deterioration and reliability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattcharya, B.; Ellingwood, B.

1998-02-01

Structural deterioration often occurs without perceptible manifestation. Continuum damage mechanics defines structural damage in terms of the material microstructure, and relates the damage variable to the macroscopic strength or stiffness of the structure. This enables one to predict the state of damage prior to the initiation of a macroscopic flaw, and allows one to estimate residual strength/service life of an existing structure. The accumulation of damage is a dissipative process that is governed by the laws of thermodynamics. Partial differential equations for damage growth in terms of the Helmholtz free energy are derived from fundamental thermodynamical conditions. Closed-form solutions tomore » the equations are obtained under uniaxial loading for ductile deformation damage as a function of plastic strain, for creep damage as a function of time, and for fatigue damage as function of number of cycles. The proposed damage growth model is extended into the stochastic domain by considering fluctuations in the free energy, and closed-form solutions of the resulting stochastic differential equation are obtained in each of the three cases mentioned above. A reliability analysis of a ring-stiffened cylindrical steel shell subjected to corrosion, accidental pressure, and temperature is performed.« less

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury.

PubMed

Llacuna, Laura; Fernández, Anna; Montfort, Claudia Von; Matías, Núria; Martínez, Laura; Caballero, Francisco; Rimola, Antoni; Elena, Montserrat; Morales, Albert; Fernández-Checa, José C; García-Ruiz, Carmen

2011-05-01

Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage. We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury. Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury. Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Failure analysis of single-bolted joint for lightweight composite laminates and metal plate

NASA Astrophysics Data System (ADS)

Li, Linjie; Qu, Junli; Liu, Xiangdong

2018-01-01

A three-dimensional progressive damage model was developed in ANSYS to predict the damage accumulation of single bolted joint in composite laminates under in-plane tensile loading. First, we describe the formulation and algorithm of this model. Second, we calculate the failure loads of the joint in fibre reinforced epoxy laminated composite plates and compare it with the experiment results, which validates that our model can appropriately simulate the ultimate tensile strength of the joints and the whole process of failure of structure. Finally, this model is applied to study the failure process of the light-weight composite material (USN125). The study also has a great potential to provide a strong basis for bolted joints design in composite Laminates as well as a simple tool for comparing different laminate geometries and bolt arrangements.

Unrepaired clustered DNA lesions induce chromosome breakage in human cells

PubMed Central

Asaithamby, Aroumougame; Hu, Burong; Chen, David J.

2011-01-01

Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling, that the kinetics of loss of clustered DNA lesions was substantially compromised in human fibroblasts. The unique spatial distribution of different types of DNA lesions within the clustered damages, but not the physical location of these damages within the subnuclear domains, determined the cellular ability to repair the damage. We then examined checkpoint arrest mechanisms and yield of gross chromosomal aberrations. Induction of nonrepairable clustered damage affected only G2 accumulation but not the early G2/M checkpoint. Further, cells that were released from the G2/M checkpoint with unrepaired clustered damage manifested a spectrum of chromosome aberrations in mitosis. Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis. PMID:21527720

Lifestyle impacts on the aging associated expression of biomarkers of DNA damage and telomere dysfunction in human blood

PubMed Central

Song, Zhangfa; von Figura, Guido; Liu, Yan; Kraus, Johann M.; Torrice, Chad; Dillon, Patric; Rudolph-Watabe, Masami; Ju, Zhenyu; Kestler, Hans A.; Sanoff, Hanna; Rudolph, K. Lenhard

2010-01-01

Summary Cellular aging is characterised by telomere shortening, which can lead to uncapping of chromosome ends (telomere dysfunction) and that activation of DNA damage responses. There is some evidence the DNA damage accumulates during human aging and that lifestyle factors contribute to the accumulation of DNA damage. Recent studies have identified a set of serum markers that are induced by telomere dysfunction and DNA damage and these markers showed an increased expression in blood during human aging. Here, we investigated the influence of lifestyle factors (such as exercise, smoking, body mass) on the aging associated expression of serum markers of DNA damage (CRAMP, EF-1α, Stathmin, n-acetyl-glucosaminidase, and chitinase) in comparison to other described markers of cellular aging (p16INK4a upregulation and telomere shortening) in human peripheral blood. The study shows that lifestyle factors have an age-independent impact on the expression level of biomarkers of DNA damage. Smoking and increased body mass indices were associated with elevated levels of biomarkers of DNA damage independent of the age of the individuals. In contrast, exercise was associated with an age-independent reduction in the expression of biomarkers of DNA damage in human blood. The expression of biomarkers of DNA damage correlated positively with p16INK4a expression and negatively with telomere length in peripheral blood T-lymphocytes. Together, these data provide experimental evidence that both aging and lifestyle impact on the accumulation of DNA damage during human aging. PMID:20560902

Use of Acoustic Emission to Monitor Progressive Damage Accumulation in KEVLAR® 49 Composites

NASA Astrophysics Data System (ADS)

Waller, J. M.; Andrade, E.; Saulsberry, R. L.

2010-02-01

Acoustic emission (AE) data acquired during intermittent load hold tensile testing of epoxy impregnated Kevlar® 49 (K/Ep) composite strands were analyzed to monitor progressive damage during the approach to tensile failure. Insight into the progressive damage of K/Ep strands was gained by monitoring AE event rate and energy. Source location based on energy attenuation and arrival time data was used to discern between significant AE attributable to microstructural damage and spurious AE attributable to noise. One of the significant findings was the observation of increasing violation of the Kaiser effect (Felicity ratio <1.0) with damage accumulation. The efficacy of three different intermittent load hold stress schedules that allowed the Felicity ratio to be determined analytically is discussed.

77 FR 45981 - Airworthiness Directives; Bombardier, Inc. Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-02

... the affected parking brake hydraulic accumulator, and relocating the parking brake accumulator, on the... parking brake hydraulic accumulator, which could result in damage to the airplane's primary structures... (P/N) 08-60197-001 (Parking Brake Accumulator), are installed on the aeroplanes listed in the...

MECHANICAL PROPERTY CHARACTERIZATIONS AND PERFORMANCE MODELING OF SOFC SEALS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koeppel, Brian J.; Vetrano, John S.; Nguyen, Ba Nghiep

2008-03-26

This study provides modeling tools for the design of reliable seals for SOFC stacks. The work consists of 1) experimental testing to determine fundamental properties of SOFC sealing materials, and 2) numerical modeling of stacks and sealing systems. The material tests capture relevant temperature-dependent physical and mechanical data needed by the analytical models such as thermal expansion, strength, fracture toughness, and relaxation behavior for glass-ceramic seals and other materials. Testing has been performed on both homogenous specimens and multiple material assemblies to investigate the effect of interfacial reactions. A viscoelastic continuum damage model for a glass-ceramic seal was developed tomore » capture the nonlinear behavior of this material at high temperatures. This model was implemented in the MSC MARC finite element code and was used for a detailed analysis of a planar SOFC stack under thermal cycling conditions. Realistic thermal loads for the stack were obtained using PNNL’s in-house multiphysics solver. The accumulated seal damage and component stresses were evaluated for multiple thermal loading cycles, and regions of high seal damage susceptible to cracking were identified. Selected test results, numerical model development, and analysis results will be presented.« less

Platelet secretion of CXCL4 is Rac1-dependent and regulates neutrophil infiltration and tissue damage in septic lung damage.

PubMed

Hwaiz, Rundk; Rahman, Milladur; Zhang, Enming; Thorlacius, Henrik

2015-11-01

Platelets are potent regulators of neutrophil accumulation in septic lung damage. We hypothesized that platelet-derived CXCL4 might support pulmonary neutrophilia in a murine model of abdominal sepsis. Polymicrobial sepsis was triggered by coecal ligation and puncture (CLP) in C57BL/6 mice. Platelet secretion of CXCL4 was studied by using confocal microscopy. Plasma and lung levels of CXCL4, CXCL1 and CXCL2 were determined by elisa. Flow cytometry was used to examine surface expression of Mac-1 on neutrophils. CLP increased CXCL4 levels in plasma, and platelet depletion reduced plasma levels of CXCL4 in septic animals. Rac1 inhibitor NSC23766 decreased the CLP-enhanced CXCL4 in plasma by 77%. NSC23766 also abolished PAR4 agonist-induced secretion of CXCL4 from isolated platelets. Inhibition of CXCL4 reduced CLP-evoked neutrophil recruitment, oedema formation and tissue damage in the lung. However, immunoneutralization of CXCL4 had no effect on CLP-induced expression of Mac-1 on neutrophils. Targeting CXCL4 attenuated plasma and lung levels of CXCL1 and CXCL2 in septic mice. CXCL4 had no effect on neutrophil chemotaxis in vitro, indicating it has an indirect effect on pulmonary neutrophilia. Intratracheal CXCL4 enhanced infiltration of neutrophils and formation of CXCL2 in the lung. CXCR2 antagonist SB225002 markedly reduced CXCL4-provoked neutrophil accumulation in the lung. CXCL4 caused secretion of CXCL2 from isolated alveolar macrophages. Rac1 controls platelet secretion of CXCL4 and CXCL4 is a potent stimulator of neutrophil accumulation in septic lungs via generation of CXCL2 in alveolar macrophages. Platelet-derived CXCL4 plays an important role in lung inflammation and tissue damage in polymicrobial sepsis. © 2015 The British Pharmacological Society.

Platelet secretion of CXCL4 is Rac1‐dependent and regulates neutrophil infiltration and tissue damage in septic lung damage

PubMed Central

Hwaiz, Rundk; Rahman, Milladur; Zhang, Enming

2015-01-01

Background and Purpose Platelets are potent regulators of neutrophil accumulation in septic lung damage. We hypothesized that platelet‐derived CXCL4 might support pulmonary neutrophilia in a murine model of abdominal sepsis. Experimental Approach Polymicrobial sepsis was triggered by coecal ligation and puncture (CLP) in C57BL/6 mice. Platelet secretion of CXCL4 was studied by using confocal microscopy. Plasma and lung levels of CXCL4, CXCL1 and CXCL2 were determined by elisa. Flow cytometry was used to examine surface expression of Mac‐1 on neutrophils. Key Results CLP increased CXCL4 levels in plasma, and platelet depletion reduced plasma levels of CXCL4 in septic animals. Rac1 inhibitor NSC23766 decreased the CLP‐enhanced CXCL4 in plasma by 77%. NSC23766 also abolished PAR4 agonist‐induced secretion of CXCL4 from isolated platelets. Inhibition of CXCL4 reduced CLP‐evoked neutrophil recruitment, oedema formation and tissue damage in the lung. However, immunoneutralization of CXCL4 had no effect on CLP‐induced expression of Mac‐1 on neutrophils. Targeting CXCL4 attenuated plasma and lung levels of CXCL1 and CXCL2 in septic mice. CXCL4 had no effect on neutrophil chemotaxis in vitro, indicating it has an indirect effect on pulmonary neutrophilia. Intratracheal CXCL4 enhanced infiltration of neutrophils and formation of CXCL2 in the lung. CXCR2 antagonist SB225002 markedly reduced CXCL4‐provoked neutrophil accumulation in the lung. CXCL4 caused secretion of CXCL2 from isolated alveolar macrophages. Conclusions and Implications Rac1 controls platelet secretion of CXCL4 and CXCL4 is a potent stimulator of neutrophil accumulation in septic lungs via generation of CXCL2 in alveolar macrophages. Platelet‐derived CXCL4 plays an important role in lung inflammation and tissue damage in polymicrobial sepsis. PMID:26478565

Two-time scale fatigue modelling: application to damage

NASA Astrophysics Data System (ADS)

Devulder, Anne; Aubry, Denis; Puel, Guillaume

2010-05-01

A temporal multiscale modelling applied to fatigue damage evolution in cortical bone is presented. Microdamage accumulation in cortical bone, ensued from daily activities, leads to impaired mechanical properties, in particular by reducing the bone stiffness and inducing fatigue. However, bone damage is also known as a stimulus to bone remodelling, whose aim is to repair and generate new bone, adapted to its environment. This biological process by removing fatigue damage seems essential to the skeleton lifetime. As daily activities induce high frequency cycles (about 10,000 cycles a day), identifying two-time scale is very fruitful: a fast one connected with the high frequency cyclic loading and a slow one related to a quasi-static loading. A scaling parameter is defined between the intrinsic time (bone lifetime of several years) and the high frequency loading (few seconds). An asymptotic approach allows to decouple the two scales and to take into account history effects (Guennouni and Aubry in CR Acad Sci Paris Ser II 20:1765-1767, 1986). The method is here applied to a simple case of fatigue damage and a real cortical bone microstructure. A significant reduction in the amount of computation time in addition to a small computational error between time homogenized and non homogenized models are obtained. This method seems thus to give new perspectives to assess fatigue damage and, with regard to bone, to give a better understanding of bone remodelling.

Prediction of specific damage or infarction from the measurement of tissue impedance following repetitive brain ischaemia in the rat.

PubMed

Klein, H C; Krop-Van Gastel, W; Go, K G; Korf, J

1993-02-01

The development of irreversible brain damage during repetitive periods of hypoxia and normoxia was studied in anaesthetized rats with unilateral occlusion of the carotid artery (modified Levine model). Rats were exposed to 10 min hypoxia and normoxia until severe damage developed. As indices of damage, whole striatal tissue impedance (reflecting cellular water uptake), sodium/potassium contents (due to exchange with blood). Evans Blue staining (blood-brain barrier [BBB] integrity) and silver staining (increased in irreversibly damaged neurons) were used. A substantial decrease in blood pressure was observed during the hypoxic periods possibly producing severe ischaemia. Irreversibly increased impedance, massive changes in silver staining, accumulation of whole tissue Na and loss of K occurred only after a minimum of two periods of hypoxia, but there was no disruption of the BBB. Microscopic examination of tissue sections revealed that cell death was selective with reversible impedance changes, but became massive and non-specific after irreversible increase of the impedance. The development of brain infarcts could, however, not be predicted from measurements of physiological parameters in the blood. We suggest that the development of cerebral infarction during repetitive periods of hypoxia may serve as a model for the development of brain damage in a variety of clinical conditions. Furthermore, the present model allows the screening of potential therapeutic measuring of the prevention and treatment of both infarction and selective cell death.

77 FR 26158 - Airworthiness Directives; Saab AB, Saab Aerosystems Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-03

... of hydraulic accumulator failure. This AD requires replacing certain hydraulic accumulators with stainless steel hydraulic accumulators, and structural modifications in the nose landing gear bay. We are issuing this AD to prevent failure of hydraulic accumulators, which may result in damage to the airplane...

Aciculatin Induces p53-Dependent Apoptosis via MDM2 Depletion in Human Cancer Cells In Vitro and In Vivo

PubMed Central

Lai, Chin-Yu; Tsai, An-Chi; Chen, Mei-Chuan; Chang, Li-Hsun; Sun, Hui-Lung; Chang, Ya-Ling; Chen, Chien-Chih

2012-01-01

Aciculatin, a natural compound extracted from the medicinal herb Chrysopogon aciculatus, shows potent anti-cancer potency. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, dephosphorylation of Rb protein, PUMA expression, and induction of apoptotic signals such as cleavage of caspase-9, caspase-3, and PARP. We demonstrated that p53 allele-null (−/−) (p53-KO) HCT116 cells were more resistant to aciculatin than cells with wild-type p53 (+/+). The same result was achieved by knocking down p53 with siRNA in p53 wild-type cells, indicating that p53 plays a crucial role in aciculatin-induced apoptosis. Although DNA damage is the most common event leading to p53 activation, we found only weak evidence of DNA damage after aciculatin treatment. Interestingly, the aciculatin-induced downregulation of MDM2, an important negative regulator of p53, contributed to p53 accumulation. The anti-cancer activity and importance of p53 after aciculatin treatment were also confirmed in the HCT116 xenograft models. Collectively, these results indicate that aciculatin treatment induces cell cycle arrest and apoptosis via inhibition of MDM2 expression, thereby inducing p53 accumulation without significant DNA damage and genome toxicity. PMID:22912688

Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model.

PubMed

Meeker, Rick B; Poulton, Winona; Feng, Wen-hai; Hudson, Lola; Longo, Frank M

2012-06-01

Feline immunodeficiency virus (FIV) infection like human immunodeficiency virus (HIV), produces systemic and central nervous system disease in its natural host, the domestic cat, that parallels the pathogenesis seen in HIV-infected humans. The ability to culture feline nervous system tissue affords the unique opportunity to directly examine interactions of infectious virus with CNS cells for the development of models and treatments that can then be translated to a natural infectious model. To explore the therapeutic potential of a new p75 neurotrophin receptor ligand, LM11A-31, we evaluated neuronal survival, neuronal damage and calcium homeostasis in cultured feline neurons following inoculation with FIV. FIV resulted in the gradual appearance of dendritic beading, pruning of processes and shrinkage of neuronal perikarya in the neurons. Astrocytes developed a more activated appearance and there was an enhanced accumulation of microglia, particularly at longer times post-inoculation. Addition of 10 nM LM11A-31, to the cultures greatly reduced or eliminated the neuronal pathology as well as the FIV effects on astrocytes and microglia. LM11A-31 also, prevented the development of delayed calcium deregulation in feline neurons exposed to conditioned medium from FIV treated macrophages. The suppression of calcium accumulation prevented the development of foci of calcium accumulation and beading in the dendrites. FIV replication was unaffected by LM11A-31. The strong neuroprotection afforded by LM11A-31 in an infectious in vitro model indicates that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration.

[Increasing oxidative stress in aging].

PubMed

Shimosawa, Tatsuo

2005-06-01

The balance between reactive oxigen species (ROS) production and degradation is important in defining oxidative stress. In aging process, ROS production increases and degradation is impaired and thus oxidative stress is accumulated. Oxidative stress damages organs both directly and indirectly. Protein, lipid, as well as DNA are directly react with ROS, more over, ROS interact with intracellular signaling system. It is reported that several transcription factors such as NF-kappaB, AP-1 and ASK-1 and also it interferes MAPK activity. Besides these signaling, we recently showed that insulin resistance is induced by accumulated oxidative stress in aged mice. Adrenomedullin deficient mice accumulate higher oxidative stress and insulin resistance developed in aging. Oxidative stress in aging relates not only direct organ damage but also induce risk factors for vascular damage such as metabolic syndrome.

Accrual of organ damage over time in patients with systemic lupus erythematosus.

PubMed

Gladman, Dafna D; Urowitz, Murray B; Rahman, Proton; Ibañez, Dominique; Tam, Lai-Shan

2003-09-01

To determine the pattern of accumulation of damage in an inception cohort of patients with systemic lupus erythematosus (SLE) followed yearly for at least 15 years, and to identify damage items that might be related to corticosteroid therapy. An inception cohort was identified from among patients with SLE followed prospectively in the University of Toronto Lupus Clinic. Only patients who had at least yearly evaluations and were followed for at least 15 years were included. Using the SLICC/ACR damage index (SDI) accumulated damage was calculated at yearly intervals. Each new organ system involved was designated as either definitely, possibly, or not at all related to corticosteroid therapy. Of the 73 patients, 85% were women and 87.7% were Caucasian. Their mean age at diagnosis was 34.9 years. The mean (range) SLEDAI at presentation was 11.9 (0-37). Prednisone was used by 87.7% of the patients (mean maximum dose 37.7 mg/day, mean cumulative dose 36.8 g) for a mean of 117.1 months. Antimalarial drugs were used by 70% of the patients and 50% were taking immunosuppressive agents. The mean SDI for the whole cohort increased over time from 0.33 (0.89) during the first year to 1.90 (1.99) at 15 years. A significant proportion of the damage both early and late could be attributed to corticosteroid therapy, and this damage accumulated over time such that it constituted most of the damage at 15 years. While the overall accrual of damage is gradual, the specific systems demonstrate varying patterns of damage accrual.

Use of Acoustic Emission to Monitor Progressive Damage Accumulation in Kevlar (R) 49 Composites

NASA Technical Reports Server (NTRS)

Waller, Jess M.; Saulsberry, Regor L.; Andrade, Eduardo

2009-01-01

Acoustic emission (AE) data acquired during intermittent load hold tensile testing of epoxy impregnated Kevlar(Registeres TradeMark) 49 (K/Ep) composite strands were analyzed to monitor progressive damage during the approach to tensile failure. Insight into the progressive damage of K/Ep strands was gained by monitoring AE event rate and energy. Source location based on energy attenuation and arrival time data was used to discern between significant AE attributable to microstructural damage and spurious AE attributable to noise. One of the significant findings was the observation of increasing violation of the Kaiser effect (Felicity ratio < 1.0) with damage accumulation. The efficacy of three different intermittent load hold stress schedules that allowed the Felicity ratio to be determined analytically is discussed.

Modeling thermal and irradiation-induced swelling effects on the integrity of Ti3SiC2/SiC joints

NASA Astrophysics Data System (ADS)

Nguyen, Ba Nghiep; Henager, Charles H.; Kurtz, Richard J.

2017-11-01

Previously, results for CVD-SiC joined by a solid state displacement reaction to form a dual-phase SiC/MAX phase joint subsequently irradiated at 800 °C to 5 dpa indicated some cracking in the joint. This paper elucidates the cracking origin by developing a model that accounts for differential thermal expansion and irradiation-induced swelling between the substrate and joint materials by using a continuum damage mechanics approach with support from micromechanical modeling. Damage accumulation in joined specimens irradiated at four temperatures (300 °C, 400 °C, 500 °C and 800 °C) is analyzed. We assume the experimental irradiation dose is sufficient to cause saturation swelling in SiC. The analyses indicate that the SiC/MAX joint survives irradiation-induced swelling at all the irradiation temperatures considered. The joint experiences only minor damage when heated to and irradiated at 800 °C as well as cooling to room temperature. The prediction agrees with the experimental findings available for this case. However, the joint heated to 300 °C suffers severe damage during irradiation-induced swelling at this temperature, and additional damage after cooling to room temperature. Irradiation at 400 °C and subsequent cooling to room temperature produced similar damage to the irradiation 300 °C case, but to a lesser extent. The joint heated to 500 °C and irradiated at this temperature suffered only very minor damage, but further moderate damage occurred after cooling to room temperature.

Modeling thermal and irradiation-induced swelling effects on the integrity of Ti 3SiC 2/SiC joints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Ba Nghiep; Henager, Charles H.; Kurtz, Richard J.

Previously, results for CVD-SiC joined by a solid state displacement reaction to form a dual-phase SiC/MAX phase joint subsequently irradiated at 800 °C to 5 dpa indicated some cracking in the joint. Here, this paper elucidates the cracking origin by developing a model that accounts for differential thermal expansion and irradiation-induced swelling between the substrate and joint materials by using a continuum damage mechanics approach with support from micromechanical modeling. Damage accumulation in joined specimens irradiated at four temperatures (300 °C, 400 °C, 500 °C and 800 °C) is analyzed. We assume the experimental irradiation dose is sufficient to causemore » saturation swelling in SiC. The analyses indicate that the SiC/MAX joint survives irradiation-induced swelling at all the irradiation temperatures considered. The joint experiences only minor damage when heated to and irradiated at 800 °C as well as cooling to room temperature. The prediction agrees with the experimental findings available for this case. However, the joint heated to 300 °C suffers severe damage during irradiation-induced swelling at this temperature, and additional damage after cooling to room temperature. Irradiation at 400 °C and subsequent cooling to room temperature produced similar damage to the irradiation 300 °C case, but to a lesser extent. Finally, the joint heated to 500 °C and irradiated at this temperature suffered only very minor damage, but further moderate damage occurred after cooling to room temperature.« less

Modeling thermal and irradiation-induced swelling effects on the integrity of Ti 3SiC 2/SiC joints

DOE PAGES

Nguyen, Ba Nghiep; Henager, Charles H.; Kurtz, Richard J.

2017-09-08

Previously, results for CVD-SiC joined by a solid state displacement reaction to form a dual-phase SiC/MAX phase joint subsequently irradiated at 800 °C to 5 dpa indicated some cracking in the joint. Here, this paper elucidates the cracking origin by developing a model that accounts for differential thermal expansion and irradiation-induced swelling between the substrate and joint materials by using a continuum damage mechanics approach with support from micromechanical modeling. Damage accumulation in joined specimens irradiated at four temperatures (300 °C, 400 °C, 500 °C and 800 °C) is analyzed. We assume the experimental irradiation dose is sufficient to causemore » saturation swelling in SiC. The analyses indicate that the SiC/MAX joint survives irradiation-induced swelling at all the irradiation temperatures considered. The joint experiences only minor damage when heated to and irradiated at 800 °C as well as cooling to room temperature. The prediction agrees with the experimental findings available for this case. However, the joint heated to 300 °C suffers severe damage during irradiation-induced swelling at this temperature, and additional damage after cooling to room temperature. Irradiation at 400 °C and subsequent cooling to room temperature produced similar damage to the irradiation 300 °C case, but to a lesser extent. Finally, the joint heated to 500 °C and irradiated at this temperature suffered only very minor damage, but further moderate damage occurred after cooling to room temperature.« less

Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

PubMed Central

di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

2013-01-01

Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines. This model may both facilitate understanding of the events involved in neuroinflammation and aid in the development of neuroprotective therapies for the treatment of MS and other neurodegenerative diseases. PMID:23431360

Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.

PubMed

Borgesius, Nils Z; de Waard, Monique C; van der Pluijm, Ingrid; Omrani, Azar; Zondag, Gerben C M; van der Horst, Gijsbertus T J; Melton, David W; Hoeijmakers, Jan H J; Jaarsma, Dick; Elgersma, Ype

2011-08-31

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.

Probabilistic analysis of the influence of the bonding degree of the stem-cement interface in the performance of cemented hip prostheses.

PubMed

Pérez, M A; Grasa, J; García-Aznar, J M; Bea, J A; Doblaré, M

2006-01-01

The long-term behavior of the stem-cement interface is one of the most frequent topics of discussion in the design of cemented total hip replacements, especially with regards to the process of damage accumulation in the cement layer. This effect is analyzed here comparing two different situations of the interface: completely bonded and debonded with friction. This comparative analysis is performed using a probabilistic computational approach that considers the variability and uncertainty of determinant factors that directly compromise the damage accumulation in the cement mantle. This stochastic technique is based on the combination of probabilistic finite elements (PFEM) and a cumulative damage approach known as B-model. Three random variables were considered: muscle and joint contact forces at the hip (both for walking and stair climbing), cement damage and fatigue properties of the cement. The results predicted that the regions with higher failure probability in the bulk cement are completely different depending on the stem-cement interface characteristics. In a bonded interface, critical sites appeared at the distal and medial parts of the cement, while for debonded interfaces, the critical regions were found distally and proximally. In bonded interfaces, the failure probability was higher than in debonded ones. The same conclusion may be established for stair climbing in comparison with walking activity.

Development of a rocking R/C shear wall system implementing repairable structural fuses

NASA Astrophysics Data System (ADS)

Parsafar, Saeed; Moghadam, Abdolreza S.

2017-09-01

In the last decades, the concept of earthquake resilient structural systems is becoming popular in which the rocking structure is considered as a viable option for buildings in regions of high seismicity. To this end, a novel wall-base connection based on the " repairable structure" approach is proposed and evaluated. The proposed system is made of several steel plates and high strength bolts act as a friction connection. To achieve the desired rocking motion in the proposed system, short-slotted holes are used in vertical directions for connecting the steel plates to the shear wall (SW). The experimental and numerical studies were performed using a series of displacement control quasi-static cyclic tests on a reference model and four different configurations of the proposed connection installed at the wall corners. The seismic response of the proposed system is compared to the conventional SW in terms of energy dissipation and damage accumulation. In terms of energy dissipation, the proposed system depicted better performance with 95% more energy dissipation capability compared to conventional SW. In terms of damage accumulation, the proposed SW system is nearly undamaged compared to the conventional wall system, which was severely damaged at the wall-base region. Overall, the introduced concept presents a feasible solution for R/C structures when a low-damage design is targeted, which can improve the seismic performance of the structural system significantly.

Renal accumulation of pentosidine in non-diabetic proteinuria-induced renal damage in rats.

PubMed

Waanders, Femke; Greven, Wendela L; Baynes, John W; Thorpe, Suzanne R; Kramer, Andrea B; Nagai, Ryoji; Sakata, Noriyuki; van Goor, Harry; Navis, Gerjan

2005-10-01

Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking. Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry. Renal pentosidine was elevated in untreated AN (0.14+/-0.04 micromol/mol valine) vs healthy controls (0.04+/-0.01 micromol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09+/-0.02 micromol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26+/-0.10 micromol/mol valine) compared with controls (0.18+/-0.06 micromol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16+/-0.06 micromol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage. Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease.

Effects of fatigue induced damage on the longitudinal fracture resistance of cortical bone.

PubMed

Fletcher, Lloyd; Codrington, John; Parkinson, Ian

2014-07-01

As a composite material, cortical bone accumulates fatigue microdamage through the repetitive loading of everyday activity (e.g. walking). The accumulation of fatigue microdamage is thought to contribute to the occurrence of fragility fractures in older people. Therefore it is beneficial to understand the relationship between microcrack accumulation and the fracture resistance of cortical bone. Twenty longitudinally orientated compact tension fracture specimens were machined from a single bovine femur, ten specimens were assigned to both the control and fatigue damaged groups. The damaged group underwent a fatigue loading protocol to induce microdamage which was assessed via fluorescent microscopy. Following fatigue loading, non-linear fracture resistance tests were undertaken on both the control and damaged groups using the J-integral method. The interaction of the crack path with the fatigue induced damage and inherent toughening mechanisms were then observed using fluorescent microscopy. The results of this study show that fatigue induced damage reduces the initiation toughness of cortical bone and the growth toughness within the damage zone by three distinct mechanisms of fatigue-fracture interaction. Further analysis of the J-integral fracture resistance showed both the elastic and plastic component were reduced in the damaged group. For the elastic component this was attributed to a decreased number of ligament bridges in the crack wake while for the plastic component this was attributed to the presence of pre-existing fatigue microcracks preventing energy absorption by the formation of new microcracks.

Biomarkers of aging in Drosophila.

PubMed

Jacobson, Jake; Lambert, Adrian J; Portero-Otín, Manuel; Pamplona, Reinald; Magwere, Tapiwanashe; Miwa, Satomi; Driege, Yasmine; Brand, Martin D; Partridge, Linda

2010-08-01

Low environmental temperature and dietary restriction (DR) extend lifespan in diverse organisms. In the fruit fly Drosophila, switching flies between temperatures alters the rate at which mortality subsequently increases with age but does not reverse mortality rate. In contrast, DR acts acutely to lower mortality risk; flies switched between control feeding and DR show a rapid reversal of mortality rate. Dietary restriction thus does not slow accumulation of aging-related damage. Molecular species that track the effects of temperatures on mortality but are unaltered with switches in diet are therefore potential biomarkers of aging-related damage. However, molecular species that switch upon instigation or withdrawal of DR are thus potential biomarkers of mechanisms underlying risk of mortality, but not of aging-related damage. Using this approach, we assessed several commonly used biomarkers of aging-related damage. Accumulation of fluorescent advanced glycation end products (AGEs) correlated strongly with mortality rate of flies at different temperatures but was independent of diet. Hence, fluorescent AGEs are biomarkers of aging-related damage in flies. In contrast, five oxidized and glycated protein adducts accumulated with age, but were reversible with both temperature and diet, and are therefore not markers either of acute risk of dying or of aging-related damage. Our approach provides a powerful method for identification of biomarkers of aging.

Biomarkers of ageing in Drosophila

PubMed Central

Jacobson, Jake; Portero-Otín, Manuel; Pamplona, Reinald; Magwere, Tapiwanashe; Miwa, Satomi; Driege, Yasmine; Brand, Martin D.; Partridge, Linda

2015-01-01

Summary Low environmental temperature and dietary restriction (DR) extend lifespan in diverse organisms. In the fruit fly Drosophila, switching flies between temperatures alters the rate at which mortality subsequently increases with age but does not reverse mortality rate. In contrast, DR acts acutely to lower mortality risk; flies switched between control feeding and DR show a rapid reversal of mortality rate. DR thus does not slow accumulation of ageing-related damage. Molecular species that track the effects of temperatures on mortality but are unaltered with switches in diet are therefore potential biomarkers of ageing-related damage. However, molecular species that switch upon instigation or withdrawal of DR are thus potential biomarkers of mechanisms underlying risk of mortality, but not of ageing-related damage. Using this approach, we assessed several commonly used biomarkers of ageing-related damage. Accumulation of fluorescent advanced glycation end products (AGEs) correlated strongly with mortality rate of flies at different temperatures but was independent of diet. Hence fluorescent AGEs are biomarkers of ageing-related damage in flies. In contrast, five oxidised and glycated protein adducts accumulated with age, but were reversible with both temperature and diet, and are therefore not markers either of acute risk of dying or of ageing-related damage. Our approach provides a powerful method for identification of biomarkers of ageing. PMID:20367621

Microstructural evaluation of cumulative fatigue damage in a plant component sample

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukuoka, C.; Nakagawa, Y.G.; Yoshida, K.

1996-12-31

Fatigue damage accumulated in a real plant was evaluated in terms of microstructural conditioning. Microstructural damage induced in laboratory by cyclic deformation near and below the fatigue limit was also examined. A Transmission Electron Microscopy (TEM) technique called the Selected Area Diffraction (SAD) method was employed in this study. In earlier studies, it was found that the SAD value indicating a magnitude of crystallographic misorientation in the substructure (dislocation cells) was increasing with the increase of fatigue damage accumulation. Small samples removed from PWR feed water nozzle welds were examined by the SAD. It was found that the damage statemore » measured by the SAD well agreed with the morphological evidence. Cyclic stresses near or below the fatigue limit were applied to samples taken from a SA508 steel plate at various stresses. The SAD value increased even below the fatigue limit, but there was no sign of microstructural conditioning below the stresses of 50% of the fatigue limit. These results suggested that at stresses below the current design curve (below half the fatigue limit) no microstructural conditioning proceeded. It was concluded that the microstructural method was effective to evaluate damage accumulation in real plant components, and also that the current design curve was adequate in terms of microstructural conditioning state.« less

Lack of synchronization between iron uptake and cell growth leads to iron overload in Saccharomyces cerevisiae during post-exponential growth modes

PubMed Central

Park, Jinkyu; McCormick, Sean P.; Chakrabarti, Mrinmoy; Lindahl, Paul A.

2014-01-01

Fermenting cells growing exponentially on rich (YPAD) medium transitioned to a slow-growing state as glucose levels declined and their metabolism shifted to respiration. During exponential growth, Fe import and cell growth rates were matched, affording an approximately invariant cellular Fe concentration. During the transitionary period, the high-affinity Fe import rate declined slower than the cell growth rate declined, causing Fe to accumulate, initially as FeIII oxyhydroxide nanoparticles but eventually as mitochondrial and vacuolar Fe. Once in slow-growth mode, Fe import and cell growth rates were again matched, and the cellular Fe concentration was again approximately invariant. Fermenting cells grown on minimal medium (MM) grew more slowly during exponential phase and transitioned to a true stationary state as glucose levels declined. The Fe concentration of MM cells that just entered stationary state was similar to that of YPAD cells, but MM cells continued to accumulate Fe in stationary state. Fe initially accumulated as nanoparticles and high-spin FeII species, but vacuolar FeIII also eventually accumulated. Surprisingly, Fe-packed 5-day-old MM cells suffered no more ROS damage than younger cells, suggesting that Fe concentration alone does not accurately predict the extent of ROS damage. The mode and rate of growth at the time of harvesting dramatically affected cellular Fe content. A mathematical model of Fe metabolism in a growing cell was developed. The model included Fe import via a regulated high-affinity pathway and an unregulated low-affinity pathway. Fe import from the cytosol into vacuoles and mitochondria, and nanoparticle formation were also included. The model captured essential trafficking behavior, demonstrating that cells regulate Fe import in accordance with their overall growth rate and that they misregulate Fe import when nanoparticles accumulate. The lack of regulation of Fe in yeast is perhaps unique compared to the tight regulation of other cellular metabolites. This phenomenon likely derives from the unique chemistry associated with Fe nanoparticle formation. PMID:24344915

Effects of meso-2,3-dimercaptosuccinic acid, potassium iodide and chlorophyll on lead accumulation in male mice.

PubMed

Xie, Ying; Zhou, Guifeng

2017-02-21

Lead (Pb) pollution is a serious public health problem all over the world, it especially plays severe damage role in children's health. Apart from reducing lead-induced damages, the decrease of lead accumulation is also critical. This study has been the first attempt to investigate effects of meso-2,3-dimercaptosuccinic acid (DMSA), potassium iodide (KI) and chlorophyll (Chl) on lead accumulation in male mice. Eighty healthy Kunming male mice were selected and divided randomly into 8 groups. They were treated with lead acetate (PbAc) intraperitoneally, individually and in combination with the DMSA, KI or Chl once daily for 5 days. Meanwhile, the control group was treated with normal saline during the whole exposure period. On 30th day, mice were sacrificed and lead concentrations were detected in the whole blood, livers, kidneys, and testicles of mice by means of the graphite furnace atomic absorption spectrometry. In comparison with the control group, lead concentrations increased in mice treated with the PbAc and DMSA, KI and Chl diminished lead accumulation in the whole blood, livers, and kidneys. Chl had specifically the same effects on lead concentrations in the testicles of male mice. Potassium iodide and Chl, as food additives, had the same effects as the DMSA to reduce lead accumulation in male mice effectively. Our results provided experimental evidence in vivo for the preventive measures of lead poisoning. Int J Occup Med Environ Health 2017;30(1):87-93. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Ceroid lipofuscinosis in the border collie dog: retinal lesions in an animal model of juvenile Batten disease.

PubMed

Taylor, R M; Farrow, B R

1992-02-15

Ceroid lipofuscinosis, an inherited disorder of lipopigment accumulation, was identified in a group of Border Collie dogs. The dogs developed mental, motor, and visual signs between age 15 and 22 months and progressed rapidly to severe neurological disease. The principal signs were blindness and gait and behavioural abnormalities with progressive dementia. Lipopigment accumulation was severe in neurones and glial cells of the central nervous system and was present in some visceral cells. Inclusions with variable ultrastructure were common in all cells of the retina, but the pigment accumulation did not damage the retinal architecture. The cytoplasmic inclusions were granular, sudanophilic, eosinophilic, and autofluorescent. Ultrastructural morphology varied, but fingerprint and curvilinear patterns predominated. The retinal lesions in the Border Collies were similar to those in English Setters with ceroid lipofuscinosis, but were much less severe than in juvenile human ceroid lipofuscinosis. This disorder bears a close resemblance to ceroid lipofuscinosis in English Setters and is another useful model for Batten's disease.

Loss of Homogentisate 1,2-Dioxygenase Activity in Bacillus anthracis Results in Accumulation of Protective Pigment

PubMed Central

Han, Hesong; Iakovenko, Liudmyla; Wilson, Adam C.

2015-01-01

Melanin production is important to the pathogenicity and survival of some bacterial pathogens. In Bacillus anthracis, loss of hmgA, encoding homogentisate 1,2-dioxygenase, results in accumulation of a melanin-like pigment called pyomelanin. Pyomelanin is produced in the mutant as a byproduct of disrupted catabolism of L-tyrosine and L-phenylalanine. Accumulation of pyomelanin protects B. anthracis cells from UV damage but not from oxidative damage. Neither loss of hmgA nor accumulation of pyomelanin alter virulence gene expression, sporulation or germination. This is the first investigation of homogentisate 1,2-dioxygenase activity in the Gram-positive bacteria, and these results provide insight into a conserved aspect of bacterial physiology. PMID:26047497

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

PubMed Central

Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Santos, Janine Hertzog

2016-01-01

Abstract Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in ΔΨm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072–1083. PMID:26935406

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy.

PubMed

Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie; Hamill, Cecily; Chen, Yuming; Santos, Janine Hertzog; Jurkunas, Ula V

2016-06-20

Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in ΔΨm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072-1083.

Plate tectonics, damage and inheritance.

PubMed

Bercovici, David; Ricard, Yanick

2014-04-24

The initiation of plate tectonics on Earth is a critical event in our planet's history. The time lag between the first proto-subduction (about 4 billion years ago) and global tectonics (approximately 3 billion years ago) suggests that plates and plate boundaries became widespread over a period of 1 billion years. The reason for this time lag is unknown but fundamental to understanding the origin of plate tectonics. Here we suggest that when sufficient lithospheric damage (which promotes shear localization and long-lived weak zones) combines with transient mantle flow and migrating proto-subduction, it leads to the accumulation of weak plate boundaries and eventually to fully formed tectonic plates driven by subduction alone. We simulate this process using a grain evolution and damage mechanism with a composite rheology (which is compatible with field and laboratory observations of polycrystalline rocks), coupled to an idealized model of pressure-driven lithospheric flow in which a low-pressure zone is equivalent to the suction of convective downwellings. In the simplest case, for Earth-like conditions, a few successive rotations of the driving pressure field yield relic damaged weak zones that are inherited by the lithospheric flow to form a nearly perfect plate, with passive spreading and strike-slip margins that persist and localize further, even though flow is driven only by subduction. But for hotter surface conditions, such as those on Venus, accumulation and inheritance of damage is negligible; hence only subduction zones survive and plate tectonics does not spread, which corresponds to observations. After plates have developed, continued changes in driving forces, combined with inherited damage and weak zones, promote increased tectonic complexity, such as oblique subduction, strike-slip boundaries that are subparallel to plate motion, and spalling of minor plates.

The fatigue evaluation method for a structural stainless steel using the magnetic sensor composed of three pancake coils

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oka, M.; Tsuchida, Y.; Enokizono, M.

May metallic structural materials, such as stainless steels, are currently used in our surroundings. If external force is repeatedly added for many years, it is thought that fatigue damage accumulates in stainless steels. When excessive fatigue damage accumulates in these metals, there is a possibility that they are destroyed by fatigue damage accumulation. Therefore, it is important to know the amount of the fatigue damage they have suffered in order to prevent them from being destroyed. We are developing the fatigue evaluation method for stainless steels with a magnetic sensor composed of three pancake type coils. In this research, themore » inspection object is ferritic stainless steels such as SUS430. The method of fatigue evaluation for ferritic stainless steels uses the three coil type sensor, and shows a good correlation between the number of stress cycles and the output signal of the sensor, even though the correlation between the output signal and an added stress is not completely accurate. This paper describes the evaluation method of fatigue damage in ferritic stainless steel using a magnetic sensor composed of three pancake-type coils.« less

Evaluation of a Linear Cumulative Damage Failure Model for Epoxy Adhesive

NASA Technical Reports Server (NTRS)

Richardson, David E.; Batista-Rodriquez, Alicia; Macon, David; Totman, Peter; McCool, Alex (Technical Monitor)

2001-01-01

Recently a significant amount of work has been conducted to provide more complex and accurate material models for use in the evaluation of adhesive bondlines. Some of this has been prompted by recent studies into the effects of residual stresses on the integrity of bondlines. Several techniques have been developed for the analysis of bondline residual stresses. Key to these analyses is the criterion that is used for predicting failure. Residual stress loading of an adhesive bondline can occur over the life of the component. For many bonded systems, this can be several years. It is impractical to directly characterize failure of adhesive bondlines under a constant load for several years. Therefore, alternative approaches for predictions of bondline failures are required. In the past, cumulative damage failure models have been developed. These models have ranged from very simple to very complex. This paper documents the generation and evaluation of some of the most simple linear damage accumulation tensile failure models for an epoxy adhesive. This paper shows how several variations on the failure model were generated and presents an evaluation of the accuracy of these failure models in predicting creep failure of the adhesive. The paper shows that a simple failure model can be generated from short-term failure data for accurate predictions of long-term adhesive performance.

Blood-Brain Barrier Alterations Provide Evidence of Subacute Diaschisis in an Ischemic Stroke Rat Model

PubMed Central

Garbuzova-Davis, Svitlana; Rodrigues, Maria C. O.; Hernandez-Ontiveros, Diana G.; Tajiri, Naoki; Frisina-Deyo, Aric; Boffeli, Sean M.; Abraham, Jerry V.; Pabon, Mibel; Wagner, Andrew; Ishikawa, Hiroto; Shinozuka, Kazutaka; Haller, Edward; Sanberg, Paul R.; Kaneko, Yuji; Borlongan, Cesario V.

2013-01-01

Background Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. Methodology/Principal Findings In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. Conclusions/Significance These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke. PMID:23675488

Adaptive correlation filter-based video stabilization without accumulative global motion estimation

NASA Astrophysics Data System (ADS)

Koh, Eunjin; Lee, Chanyong; Jeong, Dong Gil

2014-12-01

We present a digital video stabilization approach that provides both robustness and efficiency for practical applications. In this approach, we adopt a stabilization model that maintains spatio-temporal information of past input frames efficiently and can track original stabilization position. Because of the stabilization model, the proposed method does not need accumulative global motion estimation and can recover the original position even if there is a failure in interframe motion estimation. It can also intelligently overcome the situation of damaged or interrupted video sequences. Moreover, because it is simple and suitable to parallel scheme, we implement it on a commercial field programmable gate array and a graphics processing unit board with compute unified device architecture in a breeze. Experimental results show that the proposed approach is both fast and robust.

An engineering approach to the prediction of fatigue behavior of unnotched/notched fiber reinforced composite laminates

NASA Technical Reports Server (NTRS)

Kulkarni, S. V.; Mclaughlin, P. V., Jr.

1978-01-01

An engineering approach is proposed for predicting unnotched/notched laminate fatigue behavior from basic lamina fatigue data. The fatigue analysis procedure was used to determine the laminate property (strength/stiffness) degradation as a function of fatigue cycles in uniaxial tension and in plane shear. These properties were then introduced into the failure model for a notched laminate to obtain damage growth, residual strength, and failure mode. The approach is thus essentially a combination of the cumulative damage accumulation (akin to the Miner-Palmgren hypothesis and its derivatives) and the damage growth rate (similar to the fracture mechanics approach) philosophies. An analysis/experiment correlation appears to confirm the basic postulates of material wearout and the predictability of laminate fatigue properties from lamina fatigue data.

Damage Accumulation in Advanced Metal Matrix Composites Under Thermal Cycling/Creep Loadings

DTIC Science & Technology

1993-09-01

34transformation strain" (Eshelby, 1957) or * eigenstrain " (Mura, 1987). The stress-strain relation of a ccmposite predicted by the Tanaka-Mori model is given by a0o...a short fiber MMC can be calculated if the following eigenstrains are given in the domains of fiber (0l) and of the punched region encompassing the...and Mortenson modified the above model to account for partial relaxation by dislocation punching along the fiber axis. The eigenstrains based on this

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

PubMed Central

Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun

2018-01-01

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. PMID:29717979

Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes.

PubMed

Katyal, Sachin; Lee, Youngsoo; Nitiss, Karin C; Downing, Susanna M; Li, Yang; Shimada, Mikio; Zhao, Jingfeng; Russell, Helen R; Petrini, John H J; Nitiss, John L; McKinnon, Peter J

2014-06-01

DNA damage is considered to be a prime factor in several spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. We observed the endogenous accumulation of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We found that the defective DNA damage response factors in these two diseases cooperatively modulated Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single-strand break repair factors, including tyrosyl-DNA phosphodiesterase-1 or XRCC1, resulted in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Notably, direct Top1 poisoning to elevate Top1cc levels phenocopied the neuropathology of the mouse models described above. Our results identify a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating that genome integrity is important for preventing disease in the nervous system.

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.

PubMed

Qian, Minxian; Liu, Zuojun; Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun; Liu, Baohua

2018-05-02

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans , but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. © 2018, Qian et al.

Molecular Clues to Physiological and Premature Ageing Revealed | Center for Cancer Research

Cancer.gov

There are many theories about the molecular basis of ageing. One of the most popular ones postulates that organisms age by accumulating damage to their tissues, cells, and molecules. On the cellular level, ageing is associated with progressive changes in chromatin (a combination of DNA and proteins that makes up chromosomes). These changes include loss of chromatin structure, loss and/or modification of essential proteins, and accumulation of DNA damage.

A computer program for cyclic plasticity and structural fatigue analysis

NASA Technical Reports Server (NTRS)

Kalev, I.

1980-01-01

A computerized tool for the analysis of time independent cyclic plasticity structural response, life to crack initiation prediction, and crack growth rate prediction for metallic materials is described. Three analytical items are combined: the finite element method with its associated numerical techniques for idealization of the structural component, cyclic plasticity models for idealization of the material behavior, and damage accumulation criteria for the fatigue failure.

Law of damage accumulation and fracture criteria in highly filled polymer materials

NASA Astrophysics Data System (ADS)

Bykov, D. L.; Kazakov, A. V.; Konovalov, D. N.; Mel'nikov, V. P.; Milyokhin, Yu. M.; Peleshko, V. A.; Sadovnichii, D. N.

2014-09-01

We present the results of a large series of experiments aimed at the study of laws of damage accumulation and fracture in highly filled polymer materials under loading conditions of various types: monotone, repeated, low- and high-cycle, with varying type of stress state, dynamic (in general, more than 50 programs implemented on specimens from one lot of material). The data obtained in these test allow one to make conclusions about the constitutive role of the attained maximum of strain intensity when estimating the accumulated damage in the process of uniaxial tension by various programs (in particular, an additional cyclic deformation below the preliminary attained strain maximum does not affect the limit values of strain and stress in the subsequent active extension), about the strong influence of the stress state on the deformation and fracture, about the specific features of the nonlinear behavior of the material under the shock loading conditions and its influence on the repeated deformation. All tests are described (with an accuracy acceptable in practical calculations, both with respect to stresses and strains in the process of loading and at the moment of fracture) in the framework of the same model of nonlinear viscoelasticity with the same set of constants. The constants of the proposed model are calculated according to a relatively simple algorithm by using the results of standard uniaxial tension tests with constant values of the strain rate and hydrostatic pressure (each test for 2-3 levels of these parameters chosen from the ranges proposed in applications, each loading lasts until the fracture occurs, and one of the tests contains an intermediate interval of total loading and repeated loading) and one axial shock compression test if there are dynamic problems in the applications. The model is based on the use of the criterion fracture parameter which, in the class of proportional loading processes, is the sum of partial increments of the strain intensity on active segments of the process (where the strain intensity is at its historical maximum) with the form of the stress state and the intensity of strain rates taken into account.

DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.

PubMed

Lans, H; Lindvall, J M; Thijssen, K; Karambelas, A E; Cupac, D; Fensgård, O; Jansen, G; Hoeijmakers, J H J; Nilsen, H; Vermeulen, W

2013-12-01

Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.

Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy.

PubMed

Blair, Laura J; Frauen, Haley D; Zhang, Bo; Nordhues, Bryce A; Bijan, Sara; Lin, Yen-Chi; Zamudio, Frank; Hernandez, Lidice D; Sabbagh, Jonathan J; Selenica, Maj-Linda B; Dickey, Chad A

2015-01-31

The blood-brain barrier (BBB) is damaged in tauopathies, including progressive supranuclear palsy (PSP) and Alzheimer's disease (AD), which is thought to contribute to pathogenesis later in the disease course. In AD, BBB dysfunction has been associated with amyloid beta (Aß) pathology, but the role of tau in this process is not well characterized. Since increased BBB permeability is found in tauopathies without Aß pathology, like PSP, we suspected that tau accumulation alone could not only be sufficient, but even more important than Aß for BBB damage. Longitudinal evaluation of brain tissue from the tetracycline-regulatable rTg4510 tau transgenic mouse model showed progressive IgG, T cell and red blood cell infiltration. The Evans blue (EB) dye that is excluded from the brain when the BBB is intact also permeated the brains of rTg4510 mice following peripheral administration, indicative of a bonafide BBB defect, but this was only evident later in life. Thus, despite the marked brain atrophy and inflammation that occurs earlier in this model, BBB integrity is maintained. Interestingly, BBB dysfunction emerged at the same time that perivascular tau emerged around major hippocampal blood vessels. However, when tau expression was suppressed using doxycycline, BBB integrity was preserved, suggesting that the BBB can be stabilized in a tauopathic brain by reducing tau levels. For the first time, these data demonstrate that tau alone can initiate breakdown of the BBB, but the BBB is remarkably resilient, maintaining its integrity in the face of marked brain atrophy, neuroinflammation and toxic tau accumulation. Moreover, the BBB can recover integrity when tau levels are reduced. Thus, late stage interventions targeting tau may slow the vascular contributions to cognitive impairment and dementia that occur in tauopathies.

Health-aware Model Predictive Control of Pasteurization Plant

NASA Astrophysics Data System (ADS)

Karimi Pour, Fatemeh; Puig, Vicenç; Ocampo-Martinez, Carlos

2017-01-01

In order to optimize the trade-off between components life and energy consumption, the integration of a system health management and control modules is required. This paper proposes the integration of model predictive control (MPC) with a fatigue estimation approach that minimizes the damage of the components of a pasteurization plant. The fatigue estimation is assessed with the rainflow counting algorithm. Using data from this algorithm, a simplified model that characterizes the health of the system is developed and integrated with MPC. The MPC controller objective is modified by adding an extra criterion that takes into account the accumulated damage. But, a steady-state offset is created by adding this extra criterion. Finally, by including an integral action in the MPC controller, the steady-state error for regulation purpose is eliminated. The proposed control scheme is validated in simulation using a simulator of a utility-scale pasteurization plant.

Non-local damage rheology and size effect

NASA Astrophysics Data System (ADS)

Lyakhovsky, V.

2011-12-01

We study scaling relations controlling the onset of transiently-accelerating fracturing and transition to dynamic rupture propagation in a non-local damage rheology model. The size effect is caused principally by growth of a fracture process zone, involving stress redistribution and energy release associated with a large fracture. This implies that rupture nucleation and transition to dynamic propagation are inherently scale-dependent processes. Linear elastic fracture mechanics (LEFM) and local damage mechanics are formulated in terms of dimensionless strain components and thus do not allow introducing any space scaling, except linear relations between fracture length and displacements. Generalization of Weibull theory provides scaling relations between stress and crack length at the onset of failure. A powerful extension of the LEFM formulation is the displacement-weakening model which postulates that yielding is complete when the crack wall displacement exceeds some critical value or slip-weakening distance Dc at which a transition to kinetic friction is complete. Scaling relations controlling the transition to dynamic rupture propagation in slip-weakening formulation are widely accepted in earthquake physics. Strong micro-crack interaction in a process zone may be accounted for by adopting either integral or gradient type non-local damage models. We formulate a gradient-type model with free energy depending on the scalar damage parameter and its spatial derivative. The damage-gradient term leads to structural stresses in the constitutive stress-strain relations and a damage diffusion term in the kinetic equation for damage evolution. The damage diffusion eliminates the singular localization predicted by local models. The finite width of the localization zone provides a fundamental length scale that allows numerical simulations with the model to achieve the continuum limit. A diffusive term in the damage evolution gives rise to additional damage diffusive time scale associated with the structural length scale. The ratio between two time scales associated with damage accumulation and diffusion, the damage diffusivity ratio, reflects the role of the diffusion-controlled delocalization. We demonstrate that localized fracturing occurs at the damage diffusivity ratio below certain critical value leading to a linear scaling between stress and crack length compatible with size effect for failures at crack initiation. A subseuqent quasi-static fracture growth is self-similar with increasing size of the process zone proportional to the fracture length. At a certain stage, controlled by dynamic weakening, the self-similarity breaks down and crack velocity significantly deviates from that predicted by the quasi-static regime, the size of the process zone decreases, and the rate of crack growth ceases to be controlled by the rate of damage increase. Furthermore, the crack speed approaches that predicted by the elasto-dynamic equation. The non-local damage rheology model predicts that the nucleation size of the dynamic fracture scales with fault zone thickness distance of the stress interraction.

Damage Accumulation in Cyclically-Loaded Glass-Ceramic Matrix Composites Monitored by Acoustic Emission

PubMed Central

Aggelis, D. G.; Dassios, K. G.; Kordatos, E. Z.; Matikas, T. E.

2013-01-01

Barium osumilite (BMAS) ceramic matrix composites reinforced with SiC-Tyranno fibers are tested in a cyclic loading protocol. Broadband acoustic emission (AE) sensors are used for monitoring the occurrence of different possible damage mechanisms. Improved use of AE indices is proposed by excluding low-severity signals based on waveform parameters, rather than only threshold criteria. The application of such improvements enhances the accuracy of the indices as accumulated damage descriptors. RA-value, duration, and signal energy follow the extension cycles indicating moments of maximum or minimum strain, while the frequency content of the AE signals proves very sensitive to the pull-out mechanism. PMID:24381524

High-sensitivity x-ray mask damage studies employing holographic gratings and phase-shifting interferometry

NASA Astrophysics Data System (ADS)

Hansen, Matthew E.; Cerrina, Franco

1994-05-01

A high-sensitivity holographic and interferometric metrology developed at the Center for X- ray Lithography (CXrL) has been employed to investigate in-plane distortions (IPD) produced in x-ray mask materials. This metrology has been applied to characterize damage to x-ray mask materials exposed to synchrotron radiation. X-ray mask damage and accelerated mask damage studies on silicon nitride and silicon carbide were conducted on the Aladdin ES-1 and ES-2 beamline exposure stations, respectively. Accumulated in-plane distortions due to x-ray irradiation were extracted from the incremental interferometric phase maps to yield IPD vs. dose curves for silicon nitride mask blanks. Silicon carbide mask blanks were subjected to accelerated mask damage in the high flux 2 mm X 2 mm beam of the ES-2 exposure station. An accelerated damage study of silicon carbide has shown no in-plane distortion for an accumulated dose of 800 kJ/cm2 with a measurement sensitivity of less than 5 nm.

Acoustic Emission Analysis of Damage during Compressive Deformation of Amorphous Zr-Based Foams with Aligned, Elongated Pores

NASA Astrophysics Data System (ADS)

Cox, Marie E.; Dunand, David C.

2013-07-01

Acoustic emission methods are used to investigate the evolution of internal microfractural damage during uniaxial compression of amorphous Zr-based foams with aligned, elongated pores. The foams are fabricated by means of densifying a blend of crystalline W powders and amorphous Zr-based powders with two oxygen contents (0.078 and 0.144 wt pct) by warm equal channel angular extrusion, followed by dissolution of the elongated W phase from the fully densified amorphous matrix. For the high-oxygen foams, prior powder boundaries in the amorphous struts promote damage that accumulates during compression, resulting in energy-absorbing properties comparable with the low-oxygen foams without stress-concentrating powder boundaries. The influence of pore orientation on the evolution of microfracture damage and the ability of the foams to accumulate damage without catastrophic failure is also investigated: pores oriented from 24 to 68 deg to the loading direction promote wall bending, resulting in foams with more diffuse damage and better energy-absorbing properties.

The Study of the Relationship between Probabilistic Design and Axiomatic Design Methodology. Volume 3

NASA Technical Reports Server (NTRS)

Onwubiko, Chin-Yere; Onyebueke, Landon

1996-01-01

Structural failure is rarely a "sudden death" type of event, such sudden failures may occur only under abnormal loadings like bomb or gas explosions and very strong earthquakes. In most cases, structures fail due to damage accumulated under normal loadings such as wind loads, dead and live loads. The consequence of cumulative damage will affect the reliability of surviving components and finally causes collapse of the system. The cumulative damage effects on system reliability under time-invariant loadings are of practical interest in structural design and therefore will be investigated in this study. The scope of this study is, however, restricted to the consideration of damage accumulation as the increase in the number of failed components due to the violation of their strength limits.

Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression.

PubMed

Lamitina, Todd; Huang, Chunyi George; Strange, Kevin

2006-08-08

The detection, stabilization, and repair of stress-induced damage are essential requirements for cellular life. All cells respond to osmotic stress-induced water loss with increased expression of genes that mediate accumulation of organic osmolytes, solutes that function as chemical chaperones and restore osmotic homeostasis. The signals and signaling mechanisms that regulate osmoprotective gene expression in animal cells are poorly understood. Here, we show that gpdh-1 and gpdh-2, genes that mediate the accumulation of the organic osmolyte glycerol, are essential for survival of the nematode Caenorhabditis elegans during osmotic stress. Expression of GFP driven by the gpdh-1 promoter (P(gpdh-1)::GFP) is detected only during hypertonic stress but is not induced by other stressors. Using P(gpdh-1)::GFP expression as a phenotype, we screened approximately 16,000 genes by RNAi feeding and identified 122 that cause constitutive activation of gpdh-1 expression and glycerol accumulation. Many of these genes function to regulate protein translation and cotranslational protein folding and to target and degrade denatured proteins, suggesting that the accumulation of misfolded proteins functions as a signal to activate osmoprotective gene expression and organic osmolyte accumulation in animal cells. Consistent with this hypothesis, 73% of these protein-homeostasis genes have been shown to slow age-dependent protein aggregation in C. elegans. Because diverse environmental stressors and numerous disease states result in protein misfolding, mechanisms must exist that discriminate between osmotically induced and other forms of stress-induced protein damage. Our findings provide a foundation for understanding how these damage-selectivity mechanisms function.

Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression

PubMed Central

Lamitina, Todd; Huang, Chunyi George; Strange, Kevin

2006-01-01

The detection, stabilization, and repair of stress-induced damage are essential requirements for cellular life. All cells respond to osmotic stress-induced water loss with increased expression of genes that mediate accumulation of organic osmolytes, solutes that function as chemical chaperones and restore osmotic homeostasis. The signals and signaling mechanisms that regulate osmoprotective gene expression in animal cells are poorly understood. Here, we show that gpdh-1 and gpdh-2, genes that mediate the accumulation of the organic osmolyte glycerol, are essential for survival of the nematode Caenorhabditis elegans during osmotic stress. Expression of GFP driven by the gpdh-1 promoter (Pgpdh-1::GFP) is detected only during hypertonic stress but is not induced by other stressors. Using Pgpdh-1::GFP expression as a phenotype, we screened ≈16,000 genes by RNAi feeding and identified 122 that cause constitutive activation of gpdh-1 expression and glycerol accumulation. Many of these genes function to regulate protein translation and cotranslational protein folding and to target and degrade denatured proteins, suggesting that the accumulation of misfolded proteins functions as a signal to activate osmoprotective gene expression and organic osmolyte accumulation in animal cells. Consistent with this hypothesis, 73% of these protein-homeostasis genes have been shown to slow age-dependent protein aggregation in C. elegans. Because diverse environmental stressors and numerous disease states result in protein misfolding, mechanisms must exist that discriminate between osmotically induced and other forms of stress-induced protein damage. Our findings provide a foundation for understanding how these damage-selectivity mechanisms function. PMID:16880390

Damage effect and mechanism of the GaAs high electron mobility transistor induced by high power microwave

NASA Astrophysics Data System (ADS)

Yang, Liu; Chang-Chun, Chai; Yin-Tang, Yang; Jing, Sun; Zhi-Peng, Li

2016-04-01

In this paper, we present the damage effect and mechanism of high power microwave (HPM) on AlGaAs/GaAs pseudomorphic high-electron-mobility transistor (pHEMT) of low-noise amplifier (LNA). A detailed investigation is carried out by simulation and experiment study. A two-dimensional electro-thermal model of the typical GaAs pHEMT induced by HPM is established in this paper. The simulation result reveals that avalanche breakdown, intrinsic excitation, and thermal breakdown all contribute to damage process. Heat accumulation occurs during the positive half cycle and the cylinder under the gate near the source side is most susceptible to burn-out. Experiment is carried out by injecting high power microwave into GaAs pHEMT LNA samples. It is found that the damage to LNA is because of the burn-out at first stage pHEMT. The interiors of the damaged samples are observed by scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS). Experimental results accord well with the simulation of our model. Project supported by the National Basic Research Program of China (Grant No. 2014CB339900) and the Open Fund of Key Laboratory of Complex Electromagnetic Environment Science and Technology, China Academy of Engineering Physics (Grant No. 2015-0214.XY.K).

AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington's Disease.

PubMed

Billes, Viktor; Kovács, Tibor; Hotzi, Bernadette; Manzéger, Anna; Tagscherer, Kinga; Komlós, Marcell; Tarnóci, Anna; Pádár, Zsolt; Erdős, Attila; Bjelik, Annamaria; Legradi, Adam; Gulya, Károly; Gulyás, Balázs; Vellai, Tibor

2016-05-07

Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1-3]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause various neurodegenerative pathologies, including Huntington's disease (HD). Here we examined whether enhanced autophagic activity can alleviate neurophatological features in a Drosophila model of HD (the transgenic animals express a human mutant Huntingtin protein with a long polyglutamine repeat, 128Q). We have recently identified an autophagy-enhancing small molecule, AUTEN-67 (autophagy enhancer 67), with potent neuroprotective effects [4]. AUTEN-67 was applied to induce autophagic activity in the HD model used in this study. We showed that AUTEN-67 treatment interferes with the progressive accumulation of ubiquitinated proteins in the brain of Drosophila transgenic for the pathological 128Q form of human Huntingtin protein. The compound significantly improved the climbing ability and moderately extended the mean life span of these flies. Furthermore, brain tissue samples from human patients diagnosed for HD displayed increased levels of the autophagy substrate SQSTM1/p62 protein, as compared with controls. These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD.

77 FR 65617 - Airworthiness Directives; Bombardier, Inc. Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-30

... part number and replacing the affected parking brake hydraulic accumulator, and relocating the parking brake accumulator, on the subject airplanes. We are issuing this AD to prevent failure of the screw caps and/or end caps of the parking brake hydraulic accumulator, which could result in damage to the...

DNA damage in an animal model of maple syrup urine disease.

PubMed

Scaini, Giselli; Jeremias, Isabela C; Morais, Meline O S; Borges, Gabriela D; Munhoz, Bruna P; Leffa, Daniela D; Andrade, Vanessa M; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

2012-06-01

Maple syrup urine disease is an inborn error of metabolism caused by a severe deficiency of the branched chain alpha-ketoacid dehydrogenase complex. Neurological dysfunction is a common finding in patients with maple syrup urine disease. However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly understood. In this study, we investigated whether acute or chronic administration of a branched chain amino acid pool (leucine, isoleucine and valine) causes transient DNA damage, as determined by the alkaline comet assay, in the brain and blood of rats during development and whether antioxidant treatment prevented the alterations induced by branched chain amino acids. Our results showed that the acute administration of branched chain amino acids increased the DNA damage frequency and damage index in the hippocampus. However, the chronic administration of branched chain amino acids increased the DNA damage frequency and damage index in both the hippocampus and the striatum, and the antioxidant treatment was able to prevent DNA damage in the hippocampus and striatum. The present study demonstrated that metabolite accumulation in MSUD induces DNA damage in the hippocampus and striatum and that it may be implicated in the neuropathology observed in the affected patients. We demonstrated that the effect of antioxidant treatment (N-acetylcysteine plus deferoxamine) prevented DNA damage, suggesting the involvement of oxidative stress in DNA damage. Copyright © 2012 Elsevier Inc. All rights reserved.

77 FR 35304 - Airworthiness Directives; Costruzioni Aeronautiche Tecnam srl Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-13

... the LG emergency accumulator and the LG retraction/extension system. You may obtain further... 300 hours TIS, inspect the LG emergency accumulator and the LG retraction/extension system for damage...

77 FR 56991 - Airworthiness Directives; Costruzioni Aeronautiche Tecnam srl Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-17

... as to inspect after the installation the LG emergency accumulator and the LG retraction/extension... the LG emergency accumulator and the LG retraction/extension system for damage and leakage following...

Motility and Chemotaxis Mediate the Preferential Colonization of Gastric Injury Sites by Helicobacter pylori

PubMed Central

Aihara, Eitaro; Closson, Chet; Matthis, Andrea L.; Schumacher, Michael A.; Engevik, Amy C.; Zavros, Yana; Ottemann, Karen M.; Montrose, Marshall H.

2014-01-01

Helicobacter pylori (H. pylori) is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1) significantly delayed healing of acetic-acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (ΔmotB) or chemotaxis (ΔcheY). ΔmotB (106) failed to colonize ulcerated or healthy stomach tissue. ΔcheY (106) colonized both tissues, but without preferential colonization of ulcerated tissue. However, ΔcheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori ΔcheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori ΔmotB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites, and thereby biases the injured tissue towards sustained gastric damage. PMID:25033386

Motility and chemotaxis mediate the preferential colonization of gastric injury sites by Helicobacter pylori.

PubMed

Aihara, Eitaro; Closson, Chet; Matthis, Andrea L; Schumacher, Michael A; Engevik, Amy C; Zavros, Yana; Ottemann, Karen M; Montrose, Marshall H

2014-07-01

Helicobacter pylori (H. pylori) is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1) significantly delayed healing of acetic-acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (ΔmotB) or chemotaxis (ΔcheY). ΔmotB (10(6)) failed to colonize ulcerated or healthy stomach tissue. ΔcheY (10(6)) colonized both tissues, but without preferential colonization of ulcerated tissue. However, ΔcheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori ΔcheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori ΔmotB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites, and thereby biases the injured tissue towards sustained gastric damage.

Inverted Apatite (U-Th)/He and Fission-track Dates from the Rae craton, Baffin Island, Canada and Implications for Apatite Radiation Damage-He Diffusivity Models

NASA Astrophysics Data System (ADS)

Ault, A. K.; Reiners, P. W.; Thomson, S. N.; Miller, G. H.

2015-12-01

Coupled apatite (U-Th)/He and fission-track (AFT) thermochronology data from the same sample can be used to decipher complex low temperature thermal histories and evaluate compatibility between these two methods. Existing apatite He damage-diffusivity models parameterize radiation damage annealing as fission-track annealing and yield inverted apatite He and AFT dates for samples with prolonged residence in the He partial retention zone. Apatite chemistry also impacts radiation damage and fission-track annealing, temperature sensitivity, and dates in both systems. We present inverted apatite He and AFT dates from the Rae craton, Baffin Island, Canada, that cannot be explained by apatite chemistry or existing damage-diffusivity and fission track models. Apatite He dates from 34 individual analyses from 6 samples range from 237 ± 44 Ma to 511 ± 25 Ma and collectively define a positive date-eU relationship. AFT dates from these same samples are 238 ± 15 Ma to 350 ± 20 Ma. These dates and associated track length data are inversely correlated and define the left segment of a boomerang diagram. Three of the six samples with 20-90 ppm eU apatite grains yield apatite He and AFT dates inverted by 300 million years. These samples have average apatite Cl chemistry of ≤0.02 wt.%, with no correlation between Cl content and Dpar. Thermal history simulations using geologic constraints, an apatite He radiation damage accumulation and annealing model, apatite He dates with the range of eU values, and AFT date and track length data, do not yield any viable time-temperature paths. Apatite He and AFT data modeled separately predict thermal histories with Paleozoic-Mesozoic peaks reheating temperatures differing by ≥15 °C. By modifying the parameter controlling damage annealing (Rmr0) from the canonical 0.83 to 0.5-0.6, forward models reproduce the apatite He date-eU correlation and AFT dates with a common thermal history. Results imply apatite radiation damage anneals at higher temperatures than fission-track damage and the impact on coupled apatite He and AFT dates is magnified for protracted cooling histories. Further experimental and field-based tests are important for refining radiation damage and fission-track annealing parameters for accurate interpretation of apatite He- and AFT-derived thermal histories.

Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

PubMed

Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

2012-03-01

The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. Copyright © 2010 Elsevier GmbH. All rights reserved.

Sensor Based Engine Life Calculation: A Probabilistic Perspective

NASA Technical Reports Server (NTRS)

Guo, Ten-Huei; Chen, Philip

2003-01-01

It is generally known that an engine component will accumulate damage (life usage) during its lifetime of use in a harsh operating environment. The commonly used cycle count for engine component usage monitoring has an inherent range of uncertainty which can be overly costly or potentially less safe from an operational standpoint. With the advance of computer technology, engine operation modeling, and the understanding of damage accumulation physics, it is possible (and desirable) to use the available sensor information to make a more accurate assessment of engine component usage. This paper describes a probabilistic approach to quantify the effects of engine operating parameter uncertainties on the thermomechanical fatigue (TMF) life of a selected engine part. A closed-loop engine simulation with a TMF life model is used to calculate the life consumption of different mission cycles. A Monte Carlo simulation approach is used to generate the statistical life usage profile for different operating assumptions. The probabilities of failure of different operating conditions are compared to illustrate the importance of the engine component life calculation using sensor information. The results of this study clearly show that a sensor-based life cycle calculation can greatly reduce the risk of component failure as well as extend on-wing component life by avoiding unnecessary maintenance actions.

Somatic stem cells and the kinetics of mutagenesis and carcinogenesis

PubMed Central

Cairns, John

2002-01-01

There is now strong experimental evidence that epithelial stem cells arrange their sister chromatids at mitosis such that the same template DNA strands stay together through successive divisions; DNA labeled with tritiated thymidine in infancy is still present in the stem cells of adult mice even though these cells are incorporating (and later losing) bromodeoxyuridine [Potten, C. S., Owen, G., Booth, D. & Booth, C. (2002) J. Cell Sci.115, 2381–2388]. But a cell that preserves “immortal strands” will avoid the accumulation of replication errors only if it inhibits those pathways for DNA repair that involve potentially error-prone resynthesis of damaged strands, and this appears to be a property of intestinal stem cells because they are extremely sensitive to the lethal effects of agents that damage DNA. It seems that the combination, in the stem cell, of immortal strands and the choice of death rather than error-prone repair makes epithelial stem cell systems resistant to short exposures to DNA-damaging agents, because the stem cell accumulates few if any errors, and any errors made by the daughters are destined to be discarded. This paper discusses these issues and shows that they lead to a model that explains the strange kinetics of mutagenesis and carcinogenesis in adult mammalian tissues. Coincidentally, the model also can explain why cancers arise even though the spontaneous mutation rate of differentiated mammalian cells is not high enough to generate the multiple mutations needed to form a cancer and why loss of nucleotide-excision repair does not significantly increase the frequency of the common internal cancers. PMID:12149477

A maximum entropy fracture model for low and high strain-rate fracture in TinSilverCopper alloys

NASA Astrophysics Data System (ADS)

Chan, Dennis K.

SnAgCu solder alloys exhibit significant rate-dependent constitutive behavior. Solder joints made of these alloys exhibit failure modes that are also rate-dependent. Solder joints are an integral part of microelectronic packages and are subjected to a wide variety of loading conditions which range from thermo-mechanical fatigue to impact loading. Consequently, there is a need for non-empirical rate-dependent failure theory that is able to accurately predict fracture in these solder joints. In the present thesis, various failure models are first reviewed. But, these models are typically empirical or are not valid for solder joints due to limiting assumptions such as elastic behavior. Here, the development and validation of a maximum entropy fracture model (MEFM) valid for low strain-rate fracture in SnAgCu solders is presented. To this end, work on characterizing SnAgCu solder behavior at low strain-rates using a specially designed tester to estimate parameters for constitutive models is presented. Next, the maximum entropy fracture model is reviewed. This failure model uses a single damage accumulation parameter and relates the risk of fracture to accumulated inelastic dissipation. A methodology is presented to extract this model parameter through a custom-built microscale mechanical tester for Sn3.8Ag0.7Cu solder. This single parameter is used to numerically simulate fracture in two solder joints with entirely different geometries. The simulations are compared to experimentally observed fracture in these same packages. Following the simulations of fracture at low strain rate, the constitutive behavior of solder alloys across nine decades of strain rates through MTS compression tests and split-Hopkinson bar are presented. Preliminary work on using orthogonal machining as novel technique of material characterization at high strain rates is also presented. The resultant data from the MTS compression and split-Hopkinson bar tester is used to demonstrate the localization of stress to the interface of solder joints at high strain rates. The MEFM is further extended to predict failure in brittle materials. Such an extension allows for fracture prediction within intermetallic compounds (IMCs) in solder joints. It has been experimentally observed that the failure mode shifts from bulk solder to the IMC layer with increasing loading rates. The extension of the MEFM would allow for prediction of the fracture mode within the solder joint under different loading conditions. A fracture model capable of predicting failure modes at higher strain rates is necessary, as mobile electronics are becoming ubiquitous. Mobile devices are prone to being dropped which can induce loading rates within solder joints that are much larger than experienced under thermo-mechanical fatigue. A range of possible damage accumulation parameters for Cu6Sn 5 is determined for the MEFM. A value within the aforementioned range is used to demonstrate the increasing likelihood of IMC fracture in solder joints with larger loading rates. The thesis is concluded with remarks about ongoing work that include determining a more accurate damage accumulation parameter for Cu6Sn 5 IMC, and on using machining as a technique for extracting failure parameters for the MEFM.

Fatigue life prediction modeling for turbine hot section materials

NASA Technical Reports Server (NTRS)

Halford, G. R.; Meyer, T. G.; Nelson, R. S.; Nissley, D. M.; Swanson, G. A.

1989-01-01

A major objective of the fatigue and fracture efforts under the NASA Hot Section Technology (HOST) program was to significantly improve the analytic life prediction tools used by the aeronautical gas turbine engine industry. This was achieved in the areas of high-temperature thermal and mechanical fatigue of bare and coated high-temperature superalloys. The cyclic crack initiation and propagation resistance of nominally isotropic polycrystalline and highly anisotropic single crystal alloys were addressed. Life prediction modeling efforts were devoted to creep-fatigue interaction, oxidation, coatings interactions, multiaxiality of stress-strain states, mean stress effects, cumulative damage, and thermomechanical fatigue. The fatigue crack initiation life models developed to date include the Cyclic Damage Accumulation (CDA) and the Total Strain Version of Strainrange Partitioning (TS-SRP) for nominally isotropic materials, and the Tensile Hysteretic Energy Model for anisotropic superalloys. A fatigue model is being developed based upon the concepts of Path-Independent Integrals (PII) for describing cyclic crack growth under complex nonlinear response at the crack tip due to thermomechanical loading conditions. A micromechanistic oxidation crack extension model was derived. The models are described and discussed.

Fatigue life prediction modeling for turbine hot section materials

NASA Technical Reports Server (NTRS)

Halford, G. R.; Meyer, T. G.; Nelson, R. S.; Nissley, D. M.; Swanson, G. A.

1988-01-01

A major objective of the fatigue and fracture efforts under the Hot Section Technology (HOST) program was to significantly improve the analytic life prediction tools used by the aeronautical gas turbine engine industry. This was achieved in the areas of high-temperature thermal and mechanical fatigue of bare and coated high-temperature superalloys. The cyclic crack initiation and propagation resistance of nominally isotropic polycrystalline and highly anisotropic single crystal alloys were addressed. Life prediction modeling efforts were devoted to creep-fatigue interaction, oxidation, coatings interactions, multiaxiality of stress-strain states, mean stress effects, cumulative damage, and thermomechanical fatigue. The fatigue crack initiation life models developed to date include the Cyclic Damage Accumulation (CDA) and the Total Strain Version of Strainrange Partitioning (TS-SRP) for nominally isotropic materials, and the Tensile Hysteretic Energy Model for anisotropic superalloys. A fatigue model is being developed based upon the concepts of Path-Independent Integrals (PII) for describing cyclic crack growth under complex nonlinear response at the crack tip due to thermomechanical loading conditions. A micromechanistic oxidation crack extension model was derived. The models are described and discussed.

Design and analysis of forward and reverse models for predicting defect accumulation, defect energetics, and irradiation conditions

DOE PAGES

Stewart, James A.; Kohnert, Aaron A.; Capolungo, Laurent; ...

2018-03-06

The complexity of radiation effects in a material’s microstructure makes developing predictive models a difficult task. In principle, a complete list of all possible reactions between defect species being considered can be used to elucidate damage evolution mechanisms and its associated impact on microstructure evolution. However, a central limitation is that many models use a limited and incomplete catalog of defect energetics and associated reactions. Even for a given model, estimating its input parameters remains a challenge, especially for complex material systems. Here, we present a computational analysis to identify the extent to which defect accumulation, energetics, and irradiation conditionsmore » can be determined via forward and reverse regression models constructed and trained from large data sets produced by cluster dynamics simulations. A global sensitivity analysis, via Sobol’ indices, concisely characterizes parameter sensitivity and demonstrates how this can be connected to variability in defect evolution. Based on this analysis and depending on the definition of what constitutes the input and output spaces, forward and reverse regression models are constructed and allow for the direct calculation of defect accumulation, defect energetics, and irradiation conditions. Here, this computational analysis, exercised on a simplified cluster dynamics model, demonstrates the ability to design predictive surrogate and reduced-order models, and provides guidelines for improving model predictions within the context of forward and reverse engineering of mathematical models for radiation effects in a materials’ microstructure.« less

Design and analysis of forward and reverse models for predicting defect accumulation, defect energetics, and irradiation conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stewart, James A.; Kohnert, Aaron A.; Capolungo, Laurent

The complexity of radiation effects in a material’s microstructure makes developing predictive models a difficult task. In principle, a complete list of all possible reactions between defect species being considered can be used to elucidate damage evolution mechanisms and its associated impact on microstructure evolution. However, a central limitation is that many models use a limited and incomplete catalog of defect energetics and associated reactions. Even for a given model, estimating its input parameters remains a challenge, especially for complex material systems. Here, we present a computational analysis to identify the extent to which defect accumulation, energetics, and irradiation conditionsmore » can be determined via forward and reverse regression models constructed and trained from large data sets produced by cluster dynamics simulations. A global sensitivity analysis, via Sobol’ indices, concisely characterizes parameter sensitivity and demonstrates how this can be connected to variability in defect evolution. Based on this analysis and depending on the definition of what constitutes the input and output spaces, forward and reverse regression models are constructed and allow for the direct calculation of defect accumulation, defect energetics, and irradiation conditions. Here, this computational analysis, exercised on a simplified cluster dynamics model, demonstrates the ability to design predictive surrogate and reduced-order models, and provides guidelines for improving model predictions within the context of forward and reverse engineering of mathematical models for radiation effects in a materials’ microstructure.« less

Amyloid and intracellular accumulation of BRI2.

PubMed

Garringer, Holly J; Sammeta, Neeraja; Oblak, Adrian; Ghetti, Bernardino; Vidal, Ruben

2017-04-01

Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI 2 gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI 2 protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI 2 pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI 2 protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI 2 was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI 2 may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI 2 in the pathogenesis of FBD and FDD and implicates BRI 2 as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition. Copyright © 2016 Elsevier Inc. All rights reserved.

Amyloid and intracellular accumulation of BRI2

PubMed Central

Garringer, Holly J.; Sammeta, Neeraja; Oblak, Adrian; Ghetti, Bernardino; Vidal, Ruben

2016-01-01

Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI2 protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI2 pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI2 protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI2 was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI2 may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI2 in the pathogenesis of FBD and FDD and implicates BRI2 as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition. PMID:28131015

Answering the ultimate question "what is the proximal cause of aging?".

PubMed

Blagosklonny, Mikhail V

2012-12-01

Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?

Answering the ultimate question “What is the Proximal Cause of Aging?”

PubMed Central

Blagosklonny, Mikhail V.

2012-01-01

Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging? PMID:23425777

OBJECT KINETIC MONTE CARLO SIMULATIONS OF RADIATION DAMAGE IN BULK TUNGSTEN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nandipati, Giridhar; Setyawan, Wahyu; Heinisch, Howard L.

2015-09-22

We used our recently developed lattice based OKMC code; KSOME [1] to carryout simulations of radiation damage in bulk W. We study the effect of dimensionality of self interstitial atom (SIA) diffusion i.e. 1D versus 3D on the defect accumulation during irradiation with a primary knock-on atom (PKA) energy of 100 keV at 300 K for the dose rates of 10-5 and 10-6 dpa/s. As expected 3D SIA diffusion significantly reduces damage accumulation due to increased probability of recombination events. In addition, dose rate, over the limited range examined here, appears to have no effect in both cases of SIAmore » diffusion.« less

Kinetics of Accumulation of Damage in Surface Layers of Lithium-Containing Aluminum Alloys in Fatigue Tests with Rigid Loading Cycle and Corrosive Effect of Environment

NASA Astrophysics Data System (ADS)

Morozova, L. V.; Zhegina, I. P.; Grigorenko, V. B.; Fomina, M. A.

2017-07-01

High-resolution methods of metal physics research including electron, laser and optical microscopy are used to study the kinetics of the accumulation of slip lines and bands and the corrosion damage in the plastic zone of specimens of aluminum-lithium alloys 1441 and B-1469 in rigid-cycle fatigue tests under the joint action of applied stresses and corrosive environment. The strain parameters (the density of slip bands, the sizes of plastic zones near fracture, the surface roughness in singled-out zones) and the damage parameters (the sizes of pits and the pitting area) are evaluated.

Uptake of indocyanine green by hamster sebaceous glands

NASA Astrophysics Data System (ADS)

McMillan, Kathleen; Lo, Kai-Ming; Wang, Zhi

2001-05-01

Photothermal injury to the sebaceous glands is a potential curative treatment for the common skin disease acne vulgaris. Accumulation of the exogenous chromophore indocyanine green in the sebaceous glands may be accomplished using an emulsion or liposomal formulation applied to the skin surface. An emulsion containing 0.09% by weight indocyanine green (ICG) was applied to the epidermis of hamster ears ex vivo and the flank organ in vivo. Fluorescence microscopy demonstrated selective accumulation of ICG in the underlying sebaceous glands. The concentration of ICG that may be expected to accumulate in sebaceous glands of humans was then estimated on the basis of the gland size and orifice area, for the case of topical application of a more concentrated 1% ICG liposomal formulation. Monte Carlo modeling and heat transfer calculations showed that the sebaceous glands containing the exogenous chromophore may be selectively damaged by pulsed 810 nm laser radiation in conjunction with cryogen spray cooling.

Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection.

PubMed

Spry, Malinda L; Vanover, Jillian C; Scott, Timothy; Abona-Ama, Osama; Wakamatsu, Kazumasa; Ito, Shosuke; D'Orazio, John A

2009-04-01

We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.

Damage Accumulation in SiC/SiC Composites with 3D Architectures

NASA Technical Reports Server (NTRS)

Morscher, Gregory N.; Yun, Hee-Mann; DiCarlo, James A.

2003-01-01

The formation and propagation of multiple matrix cracks in relatively dense ceramic matrix composites when subjected to increasing tensile stress is necessary for high strength and tough composites. However, the occurrence of matrix cracks at low stresses may limit the usefulness of some non-oxide composite systems when subjected to oxidizing environments for long times at stresses sufficient to cause matrix cracking. For SiC fiber-reinforced composites with two-dimensional woven architectures and chemically vapor infiltrated (CVI) SiC matrix and melt-infiltrated (MI) Si/SiC matrix composites, the matrix cracking behavior has been fairly well characterized for different fiber-types and woven architectures. It was found that the occurrence, degree, and growth of matrix cracks depends on the material properties of the composite constituents as well as other physical properties of the composite or architecture, e.g., matrix porosity and size of the fiber bundle. In this study, matrix cracking in SiC fiber reinforced, melt-infiltrated SiC composites with a 3D orthogonal architecture was determined for specimens tested in tension at room temperature. Acoustic emission (AE) was used to monitor the matrix cracking activity, which was later confirmed by microscopic examination of specimens that had failed. The determination of the exact location of AE demonstrated that initial cracking occurred in the matrix rich regions when a large z-direction fiber bundle was used. For specimens with large z-direction fiber tows, the earliest matrix cracking could occur at half the stress for standard 2D woven composites with similar constituents. Damage accumulation in 3D architecture composites will be compared to damage accumulation in 2D architecture composites and discussed with respect to modeling composite stress-strain behavior and use of these composites at elevated temperatures.

In situ X-ray monitoring of damage accumulation in SiC/RBSN tensile specimens

NASA Technical Reports Server (NTRS)

Baaklini, George Y.; Bhatt, Ramkrishna T.

1991-01-01

The room-temperature tensile testing of silicon carbide fiber reinforced reaction-bonded silicon nitride (SiC/RBSN) composite specimens was monitored by using in-situ X-ray film radiography. Radiographic evaluation before, during, and after loading provided data on the effect of preexisting volume flaws (high density impurities, and local density variations) on the fracture behavior of composites. Results from (O)1, (O)3, (O)5, and (O)8 composite specimens showed that X-ray film radiography can monitor damage accumulations during tensile loading. Matrix cracking, fiber-matrix debonding, and fiber pullout were imaged throughout the tensile loading history of the specimens. Further, in-situ film radiography was found to be a helpful and practical technique for estimating interfacial shear strength between the SiC fiber and the RBSN matrix by the matrix crack spacing method. It is concluded that pretest, in-situ, and post-test radiography can provide for a greater understanding of ceramic matrix composite mechanical behavior, a verification of related experimental procedures, and a validation and development of related analytical models.

In-situ x-ray monitoring of damage accumulation in SiC/RBSN tensile specimens

NASA Technical Reports Server (NTRS)

Baaklini, George Y.; Bhatt, Ramakrishna T.

1991-01-01

The room-temperature tensile testing of silicon carbide fiber reinforced reaction-bonded silicon nitride (SiC/RBSN) composite specimens was monitored by using in-situ x ray film radiography. Radiographic evaluation before, during, and after loading provided data on the effect of preexisting volume flaws (high density impurities, and local density variations) on the fracture behavior of composites. Results from (0)1, (0)3, (0)5, and (0)8 composite specimens, showed that x ray film radiography can monitor damage accumulations during tensile loading. Matrix cracking, fiber-matrix debonding, and fiber pullout were imaged throughout the tensile loading history of the specimens. Further, in-situ film radiography was found to be a helpful and practical technique for estimating interfacial shear strength between the SiC fiber and the RBSN matrix by the matrix crack spacing method. It is concluded that pretest, in-situ, and post-test radiography can provide for a greater understanding of ceramic matrix composite mechanical behavior, a verification of related experimental procedures, and a validation and development of related analytical models.

Environmental impact of multi-wall carbon nanotubes in a novel model of exposure: systemic distribution, macrophage accumulation, and amyloid deposition

PubMed Central

Albini, Adriana; Pagani, Arianna; Pulze, Laura; Bruno, Antonino; Principi, Elisa; Congiu, Terenzio; Gini, Elisabetta; Grimaldi, Annalisa; Bassani, Barbara; De Flora, Silvio; de Eguileor, Magda; Noonan, Douglas M

2015-01-01

Carbon nanotubes (CNTs) have been extensively investigated and employed for industrial use because of their peculiar physical properties, which make them ideal for many industrial applications. However, rapid growth of CNT employment raises concerns about the potential risks and toxicities for public health, environment, and workers associated with the manufacture and use of these new materials. Here we investigate the main routes of entry following environmental exposure to multi-wall CNTs (MWCNTs; currently the most widely used in industry). We developed a novel murine model that could represent a surrogate of a workplace exposure to MWCNTs. We traced the localization of MWCNTs and their possible role in inducing an innate immune response, inflammation, macrophage recruitment, and inflammatory conditions. Following environmental exposure of CD1 mice, we observed that MWCNTs rapidly enter and disseminate in the organism, initially accumulating in lungs and brain and later reaching the liver and kidney via the bloodstream. Since recent experimental studies show that CNTs are associated with the aggregation process of proteins associated with neurodegenerative diseases, we investigated whether MWCNTs are able to induce amyloid fibril production and accumulation. Amyloid deposits in spatial association with macrophages and MWCNT aggregates were found in the brain, liver, lungs, and kidneys of exposed animals. Our data suggest that accumulation of MWCNTs in different organs is associated with inflammation and amyloid accumulation. In the brain, where we observed rapid accumulation and amyloid fibril deposition, exposure to MWCNTs might enhance progression of neurodegenerative and other amyloid-related diseases. Our data highlight the conclusion that, in a novel rodent model of exposure, MWCNTs may induce macrophage recruitment, activation, and amyloid deposition, causing potential damage to several organs. PMID:26457053

Deterministic and Probabilistic Creep and Creep Rupture Enhancement to CARES/Creep: Multiaxial Creep Life Prediction of Ceramic Structures Using Continuum Damage Mechanics and the Finite Element Method

NASA Technical Reports Server (NTRS)

Jadaan, Osama M.; Powers, Lynn M.; Gyekenyesi, John P.

1998-01-01

High temperature and long duration applications of monolithic ceramics can place their failure mode in the creep rupture regime. A previous model advanced by the authors described a methodology by which the creep rupture life of a loaded component can be predicted. That model was based on the life fraction damage accumulation rule in association with the modified Monkman-Grant creep ripture criterion However, that model did not take into account the deteriorating state of the material due to creep damage (e.g., cavitation) as time elapsed. In addition, the material creep parameters used in that life prediction methodology, were based on uniaxial creep curves displaying primary and secondary creep behavior, with no tertiary regime. The objective of this paper is to present a creep life prediction methodology based on a modified form of the Kachanov-Rabotnov continuum damage mechanics (CDM) theory. In this theory, the uniaxial creep rate is described in terms of stress, temperature, time, and the current state of material damage. This scalar damage state parameter is basically an abstract measure of the current state of material damage due to creep deformation. The damage rate is assumed to vary with stress, temperature, time, and the current state of damage itself. Multiaxial creep and creep rupture formulations of the CDM approach are presented in this paper. Parameter estimation methodologies based on nonlinear regression analysis are also described for both, isothermal constant stress states and anisothermal variable stress conditions This creep life prediction methodology was preliminarily added to the integrated design code CARES/Creep (Ceramics Analysis and Reliability Evaluation of Structures/Creep), which is a postprocessor program to commercially available finite element analysis (FEA) packages. Two examples, showing comparisons between experimental and predicted creep lives of ceramic specimens, are used to demonstrate the viability of this methodology and the CARES/Creep program.

Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate.

PubMed

Choi, Sung Won; Ryu, Ok Hee; Choi, Sun Jin; Song, In Sun; Bleyer, Anthony J; Hart, Thomas C

2005-10-01

As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle's loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle's loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases.

THE SOURCE OF LIPID ACCUMULATION IN L CELLS

PubMed Central

Bensch, Klaus G.; King, Donald W.; Socolow, Edward L.

1961-01-01

Strain L cells accumulate lipid, concurrent with cessation of protein synthesis, in the stationary phase of growth from the extracellular medium and as a result of de novo synthesis. Cells which have been more severely damaged with an amino acid analogue also accumulate lipid from the extracellular medium, but synthesize very little lipid from labeled acetate. The possible roles which lipid accumulation may play in the cell are discussed. PMID:19866577

Accumulation of lipids and oxidatively damaged DNA in hepatocytes exposed to particles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vesterdal, Lise K.; Danielsen, Pernille H.; Folkmann, Janne K.

Exposure to particles has been suggested to generate hepatosteatosis by oxidative stress mechanisms. We investigated lipid accumulation in cultured human hepatocytes (HepG2) and rat liver after exposure to four different carbon-based particles. HepG2 cells were exposed to particles for 3 h and subsequently incubated for another 18 h to manifest lipid accumulation. In an animal model of metabolic syndrome we investigated the association between intake of carbon black (CB, 14 nm) particles and hepatic lipid accumulation, inflammation and gene expression of Srebp-1, Fasn and Scd-1 involved in lipid synthesis. There was a concentration-dependent increase in intracellular lipid content after exposuremore » to CB in HepG2 cells, which was only observed after co-exposure to oleic/palmitic acid. Similar results were observed in HepG2 cells after exposure to diesel exhaust particles, fullerenes C{sub 60} or pristine single-walled carbon nanotubes. All four types of particles also generated oxidatively damaged DNA, assessed as formamidopyrimidine DNA glycosylase (FPG) sensitive sites, in HepG2 cells after 3 h exposure. The animal model of metabolic syndrome showed increased lipid load in the liver after one oral exposure to 6.4 mg/kg of CB in lean Zucker rats. This was not associated with increased iNOS staining in the liver, indicating that the oral CB exposure was associated with hepatic steatosis rather than steatohepatitis. The lipid accumulation did not seem to be related to increased lipogenesis because there were unaltered gene expression levels in both the HepG2 cells and rat livers. Collectively, exposure to particles is associated with oxidative stress and steatosis in hepatocytes. - Highlights: • Oral exposure to nanosized carbon black was associated with hepatosteatosis in rats. • In vitro studies included carbon black, C{sub 60}, diesel exhaust particles and SWCNTs. • Exposure to particles and free fatty acids increased lipid load in HepG2 cells. • Unaltered expression of lipogenesis genes despite oxidative stress in hepatocytes • Particles evoke hepatosteatosis by increased uptake rather than synthesis of lipids.« less

Impaired tRNA nuclear export links DNA damage and cell-cycle checkpoint.

PubMed

Ghavidel, Ata; Kislinger, Thomas; Pogoutse, Oxana; Sopko, Richelle; Jurisica, Igor; Emili, Andrew

2007-11-30

In response to genotoxic stress, cells evoke a plethora of physiological responses collectively aimed at enhancing viability and maintaining the integrity of the genome. Here, we report that unspliced tRNA rapidly accumulates in the nuclei of yeast Saccharomyces cerevisiae after DNA damage. This response requires an intact MEC1- and RAD53-dependent signaling pathway that impedes the nuclear export of intron-containing tRNA via differential relocalization of the karyopherin Los1 to the cytoplasm. The accumulation of unspliced tRNA in the nucleus signals the activation of Gcn4 transcription factor, which, in turn, contributes to cell-cycle arrest in G1 in part by delaying accumulation of the cyclin Cln2. The regulated nucleocytoplasmic tRNA trafficking thus constitutes an integral physiological adaptation to DNA damage. These data further illustrate how signal-mediated crosstalk between distinct functional modules, namely, tRNA nucleocytoplasmic trafficking, protein synthesis, and checkpoint execution, allows for functional coupling of tRNA biogenesis and cell-cycle progression.

Accumulation of senescent cells in mitotic tissue of aging primates.

PubMed

Jeyapalan, Jessie C; Ferreira, Mark; Sedivy, John M; Herbig, Utz

2007-01-01

Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

PubMed

Dongiovanni, P; Stender, S; Pietrelli, A; Mancina, R M; Cespiati, A; Petta, S; Pelusi, S; Pingitore, P; Badiali, S; Maggioni, M; Mannisto, V; Grimaudo, S; Pipitone, R M; Pihlajamaki, J; Craxi, A; Taube, M; Carlsson, L M S; Fargion, S; Romeo, S; Kozlitina, J; Valenti, L

2018-04-01

Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease. © 2017 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

A multilevel approach to modeling of porous bioceramics

NASA Astrophysics Data System (ADS)

Mikushina, Valentina A.; Sidorenko, Yury N.

2015-10-01

The paper is devoted to discussion of multiscale models of heterogeneous materials using principles. The specificity of approach considered is the using of geometrical model of composites representative volume, which must be generated with taking the materials reinforcement structure into account. In framework of such model may be considered different physical processes which have influence on the effective mechanical properties of composite, in particular, the process of damage accumulation. It is shown that such approach can be used to prediction the value of composite macroscopic ultimate strength. As an example discussed the particular problem of the study the mechanical properties of biocomposite representing porous ceramics matrix filled with cortical bones tissue.

Effect of Phosphate-Buffered Solution Corrosion on the Ratcheting Fatigue Behavior of a Duplex Mg-Li-Al Alloy

NASA Astrophysics Data System (ADS)

Yuan, Xin; Yu, Dunji; Gao, Li-Lan; Gao, Hong

2016-05-01

This work reports the uniaxial ratcheting and fatigue behavior of a duplex Mg-Li-Al alloy under the influence of phosphate-buffered solution corrosion. Microstructural observations reveal pitting and filament corrosion defects, which impair the load-bearing capacity of the alloy and cause stress concentration, thus leading to an accelerated accumulation of ratcheting strain and shortened fatigue life under the same nominal loading conditions. Comparing Smith model, Smith-Watson-Topper model, and Paul-Sivaprasad-Dhar model, a ratcheting fatigue life prediction model based on the Broberg damage rule and the Paul-Sivaprasad-Dhar model was proposed, and the model yielded a superior prediction for the studied magnesium alloy.

Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma.

PubMed

Ahmad, Fahim; Patrick, Shruti; Sheikh, Touseef; Sharma, Vikas; Pathak, Pankaj; Malgulwar, Prit Benny; Kumar, Anupam; Joshi, Shanker Datt; Sarkar, Chitra; Sen, Ellora

2017-12-01

Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma. © 2017 International Society for Neurochemistry.

Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles.

PubMed

Zhao, Pengfei; Zheng, Mingbin; Yue, Caixia; Luo, Zhenyu; Gong, Ping; Gao, Guanhui; Sheng, Zonghai; Zheng, Cuifang; Cai, Lintao

2014-07-01

A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near-infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect. Copyright © 2014 Elsevier Ltd. All rights reserved.

Critical and subcritical damage monitoring of bonded composite repairs using innovative non-destructive techniques

NASA Astrophysics Data System (ADS)

Grammatikos, S. A.; Kordatos, E. Z.; Aggelis, D. G.; Matikas, T. E.; Paipetis, A. S.

2012-04-01

Infrared Thermography (IrT) has been shown to be capable of detecting and monitoring service induced damage of repair composite structures. Full-field imaging, along with portability are the primary benefits of the thermographic technique. On-line lock-in thermography has been reported to successfully monitor damage propagation or/and stress concentration in composite coupons, as mechanical stresses in structures induce heat concentration phenomena around flaws. During mechanical fatigue, cyclic loading plays the role of the heating source and this allows for critical and subcritical damage identification and monitoring using thermography. The Electrical Potential Change Technique (EPCT) is a new method for damage identification and monitoring during loading. The measurement of electrical potential changes at specific points of Carbon Fiber Reinforced Polymers (CFRPs) under load are reported to enable the monitoring of strain or/and damage accumulation. Along with the aforementioned techniques Finally, Acoustic Emission (AE) method is well known to provide information about the location and type of damage. Damage accumulation due to cyclic loading imposes differentiation of certain parameters of AE like duration and energy. Within the scope of this study, infrared thermography is employed along with AE and EPCT methods in order to assess the integrity of bonded repair patches on composite substrates and to monitor critical and subcritical damage induced by the mechanical loading. The combined methodologies were effective in identifying damage initiation and propagation of bonded composite repairs.

Estimating retinal vascular permeability using the adiabatic approximation to the tissue homogeneity model with fluorescein videoangiography

NASA Astrophysics Data System (ADS)

Tichauer, Kenneth M.; Osswald, Christian R.; Dosmar, Emily; Guthrie, Micah J.; Hones, Logan; Sinha, Lagnojita; Xu, Xiaochun; Mieler, William F.; St. Lawrence, Keith; Kang-Mieler, Jennifer J.

2015-06-01

Clinical symptoms of diabetic retinopathy are not detectable until damage to the retina reaches an irreversible stage, at least by today's treatment standards. As a result, there is a push to develop new, "sub-clinical" methods of predicting the onset of diabetic retinopathy before the onset of irreversible damage. With diabetic retinopathy being associated with the accumulation of long-term mild damage to the retinal vasculature, retinal blood vessel permeability has been proposed as a key parameter for detecting preclinical stages of retinopathy. In this study, a kinetic modeling approach used to quantify vascular permeability in dynamic contrast-enhanced medical imaging was evaluated in noise simulations and then applied to retinal videoangiography data in a diabetic rat for the first time to determine the potential for this approach to be employed clinically as an early indicator of diabetic retinopathy. Experimental levels of noise were found to introduce errors of less than 15% in estimates of blood flow and extraction fraction (a marker of vascular permeability), and fitting of rat retinal fluorescein angiography data provided stable maps of both parameters.

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

PubMed

Guo, Rui; Ren, Jun

2010-01-18

Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Modeling of thermo-mechanical fatigue and damage in shape memory alloy axial actuators

NASA Astrophysics Data System (ADS)

Wheeler, Robert W.; Hartl, Darren J.; Chemisky, Yves; Lagoudas, Dimitris C.

2015-04-01

The aerospace, automotive, and energy industries have seen the potential benefits of using shape memory alloys (SMAs) as solid state actuators. Thus far, however, these actuators are generally limited to non-critical components or over-designed due to a lack of understanding regarding how SMAs undergo thermomechanical or actuation fatigue and the inability to accurately predict failure in an actuator during use. The purpose of this study was to characterize the actuation fatigue response of Nickel-Titanium-Hafnium (NiTiHf) axial actuators and, in turn, use this characterization to predict failure and monitor damage in dogbone actuators undergoing various thermomechanical loading paths. Calibration data was collected from constant load, full cycle tests ranging from 200-600MPa. Subsequently, actuator lifetimes were predicted for four additional loading paths. These loading paths consisted of linearly varying load with full transformation (300-500MPa) and step loads which transition from zero stress to 300-400MPa at various martensitic volume fractions. Thermal cycling was achieved via resistive heating and convective cooling and was controlled via a state machine developed in LabVIEW. A previously developed fatigue damage model, which is formulated such that the damage accumulation rate is general in terms of its dependence on current and local stress and actuation strain states, was utilized. This form allows the model to be utilized for specimens undergoing complex loading paths. Agreement between experiments and simulations is discussed.

Repeated exposure of mouse dermal fibroblasts at a sub-cytotoxic dose of UVB leads to premature senescence: a robust model of cellular photoaging.

PubMed

Zeng, Ji-ping; Bi, Bo; Chen, Liang; Yang, Ping; Guo, Yu; Zhou, Yi-qun; Liu, Tian-yi

2014-01-01

Photoaging skin is due to accumulative effect of UV irradiation that mainly imposes its damage on dermal fibroblasts. To mimic the specific cellular responses invoked by long term effect of UVB, it is preferable to develop a photo-damaged model in vitro based on repeated UVB exposure instead of a single exposure. To develop a photo-damaged model of fibroblasts by repeated UVB exposure allowing for investigation of molecular mechanism underlying premature senescence and testing of potential anti-photoaging compounds. Mouse dermal fibroblasts (MDFs) at early passages (passages 1-3) were exposed to a series of 4 sub-cytotoxic dose of UVB. The senescent phenotypes were detected at 24 or 48h after the last irradiation including cell viability, ROS generation, mitochondrial membrane potential, cell cycle, production and degradation of extracellular matrix. Repeated exposure of UVB resulted in remarkable features of senescence. It effectively avoided the disadvantages of single dose such as induction of cell death rather than senescence, inadequate stress resulting in cellular self-rehabilitation. Our work confirms the possibility of detecting cellular machinery that mediates UVB damage to fibroblasts in vitro by repeated exposure, while the potential molecular mechanisms including cell surface receptors, protein kinase signal transduction pathways, and transcription factors remain to be further evaluated. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Overcoming challenges of catastrophe modelling in data poor regions

NASA Astrophysics Data System (ADS)

Grassby, L.; Millinship, I.; Breinl, K.

2012-04-01

There is an increasing demand for loss accumulation tools in expanding international insurance markets such as India, China and Thailand. This reflects the combination of an increase in exposures in these territories as industry intensifies and urban development expands, as well as several notable natural catastrophes affecting these areas over the past few years (e.g. extreme floods in Mumbai in 2006 and in Thailand in 2011). Large, global insurers and reinsurers are embracing the opportunity to underwrite these exposures but only where adequate tools are available to provide understanding of the hazards, exposures and potential losses. Unlike more developed countries, data availability in these regions is typically limited and of poor resolution, but model development is still required in order to analyse the risk. Some of the modelling challenges associated with data limitations include: (1) dealing with a lack of hydrological data which results in greater uncertainty of the flow rate and event frequency; (2) lower DTM resolution than that available across much of Europe, which underlies the hazard component of the catastrophe model; (3) limited accessibility to data that characterises the Built Environment including information on different building types and their susceptibility to damage; and (4) a lack of claims data from previous events or engineering research into the vulnerability of different building types. This is used to generate of country and structure specific vulnerability curves that explain the relationship between hazard intensity and damages. By presenting an industry specific flood model for data-poor India in collaboration with Allianz Re, we illustrate how we have overcome many of these challenges to allow loss accumulations to be made. The resulting model was successfully validated against the floods in Mumbai and Surat in 2006 and is being developed further with the availability of new data.

MAP kinase-signaling controls nuclear translocation of tripeptidyl-peptidase II in response to DNA damage and oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Preta, Giulio; Klark, Rainier de; Chakraborti, Shankhamala

2010-08-27

Research highlights: {yields} Nuclear translocation of TPPII occurs in response to different DNA damage inducers. {yields} Nuclear accumulation of TPPII is linked to ROS and anti-oxidant enzyme levels. {yields} MAPKs control nuclear accumulation of TPPII. {yields} Inhibited nuclear accumulation of TPPII decreases DNA damage-induced {gamma}-H2AX expression. -- Abstract: Reactive oxygen species (ROS) are a continuous hazard in eukaroytic cells by their ability to cause damage to biomolecules, in particular to DNA. Previous data indicated that the cytosolic serine peptidase tripeptidyl-peptidase II (TPPII) translocates into the nucleus of most tumor cell lines in response to {gamma}-irradiation and ROS production; an eventmore » that promoted p53 expression as well as caspase-activation. We here observed that nuclear translocation of TPPII was dependent on signaling by MAP kinases, including p38MAPK. Further, this was caused by several types of DNA-damaging drugs, a DNA cross-linker (cisplatinum), an inhibitor of topoisomerase II (etoposide), and to some extent also by nucleoside-analogues (5-fluorouracil, hydroxyurea). In the minority of tumor cell lines where TPPII was not translocated into the nucleus in response to DNA damage we observed reduced intracellular ROS levels, and the expression levels of redox defense systems were increased. Further, treatment with the ROS-inducer {gamma}-hexa-chloro-cyclohexane ({gamma}-HCH, lindane), an inhibitor of GAP junctions, restored nuclear translocation of TPPII in these cell lines upon {gamma}-irradiation. Moreover, blocking nuclear translocation of TPPII in etoposide-treated cells, by using a peptide-derived inhibitor (Z-Gly-Leu-Ala-OH), attenuated expression of {gamma}-H2AX in {gamma}-irradiated melanoma cells. Our results indicated a role for TPPII in MAPK-dependent DNA damage signaling.« less

Single α-particle irradiation permits real-time visualization of RNF8 accumulation at DNA damaged sites

NASA Astrophysics Data System (ADS)

Muggiolu, Giovanna; Pomorski, Michal; Claverie, Gérard; Berthet, Guillaume; Mer-Calfati, Christine; Saada, Samuel; Devès, Guillaume; Simon, Marina; Seznec, Hervé; Barberet, Philippe

2017-01-01

As well as being a significant source of environmental radiation exposure, α-particles are increasingly considered for use in targeted radiation therapy. A better understanding of α-particle induced damage at the DNA scale can be achieved by following their tracks in real-time in targeted living cells. Focused α-particle microbeams can facilitate this but, due to their low energy (up to a few MeV) and limited range, α-particles detection, delivery, and follow-up observations of radiation-induced damage remain difficult. In this study, we developed a thin Boron-doped Nano-Crystalline Diamond membrane that allows reliable single α-particles detection and single cell irradiation with negligible beam scattering. The radiation-induced responses of single 3 MeV α-particles delivered with focused microbeam are visualized in situ over thirty minutes after irradiation by the accumulation of the GFP-tagged RNF8 protein at DNA damaged sites.

Synergistic Effects of Physical Aging and Damage on Long-Term Behavior of Polymer Matrix Composites

NASA Technical Reports Server (NTRS)

Brinson, L. Cate

1999-01-01

The research consisted of two major parts, first modeling and simulation of the combined effects of aging and damage on polymer composites and secondly an experimental phase examining composite response at elevated temperatures, again activating both aging and damage. For the simulation, a damage model for polymeric composite laminates operating at elevated temperatures was developed. Viscoelastic behavior of the material is accounted for via the correspondence principle and a variational approach is adopted to compute the temporal stresses within the laminate. Also, the effect of physical aging on ply level stress and on overall laminate behavior is included. An important feature of the model is that damage evolution predictions for viscoelastic laminates can be made. This allows us to track the mechanical response of the laminate up to large load levels though within the confines of linear viscoelastic constitutive behavior. An experimental investigation of microcracking and physical aging effects in polymer matrix composites was also pursued. The goal of the study was to assess the impact of aging on damage accumulation, in ten-ns of microcracking, and the impact of damage on aging and viscoelastic behavior. The testing was performed both at room and elevated temperatures on [+/- 45/903](sub s) and [02/903](sub s) laminates, both containing a set of 90 deg plies centrally located to facilitate investigation of microcracking. Edge replication and X-ray-radiography were utilized to quantify damage. Sequenced creep tests were performed to characterize viscoelastic and aging parameters. Results indicate that while the aging times studied have limited ]Influence on damage evolution, elevated temperature and viscoelastic effects have a profound effect on the damage mode seen. Some results are counterintuitive, including the lower strain to failure for elevated temperature tests and the catastrophic failure mode observed for the [+/- 45/9O3](sub s), specimens. The fracture toughness for transverse cracks increases with increasing temperature for both systems: transverse cracking was completely absent prior to failure in [+/- 45/903](sub s), and was suppressed for [02/903](sub s). No significant effect of damage on aging or viscoelastic parameters was observed.

Chronic Oxidative Damage together with Genome Repair Deficiency in the Neurons is a Double Whammy for Neurodegeneration: Is Damage Response Signaling a Potential Therapeutic Target?

PubMed Central

Wang, Haibo; Dharmalingam, Prakash; Vasquez, Velmarini; Mitra, Joy; Boldogh, Istvan; Rao, K. S.; Kent, Thomas A.; Mitra, Sankar; Hegde, Muralidhar L.

2016-01-01

A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases. PMID:27663141

Thermal barrier coating life prediction model development, phase 1

NASA Technical Reports Server (NTRS)

Demasi, Jeanine T.; Ortiz, Milton

1989-01-01

The objective of this program was to establish a methodology to predict thermal barrier coating (TBC) life on gas turbine engine components. The approach involved experimental life measurement coupled with analytical modeling of relevant degradation modes. Evaluation of experimental and flight service components indicate the predominant failure mode to be thermomechanical spallation of the ceramic coating layer resulting from propagation of a dominant near interface crack. Examination of fractionally exposed specimens indicated that dominant crack formation results from progressive structural damage in the form of subcritical microcrack link-up. Tests conducted to isolate important life drivers have shown MCrAlY oxidation to significantly affect the rate of damage accumulation. Mechanical property testing has shown the plasma deposited ceramic to exhibit a non-linear stress-strain response, creep and fatigue. The fatigue based life prediction model developed accounts for the unusual ceramic behavior and also incorporates an experimentally determined oxide rate model. The model predicts the growth of this oxide scale to influence the intensity of the mechanic driving force, resulting from cyclic strains and stresses caused by thermally induced and externally imposed mechanical loads.

Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome.

PubMed

Pawlikowski, Bradley; Betta, Nicole Dalla; Elston, Tiffany; Williams, Darian A; Olwin, Bradley B

2018-03-09

Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies.

Genotoxin induced mutagenesis in the model plant Physcomitrella patens.

PubMed

Holá, Marcela; Kozák, Jaroslav; Vágnerová, Radka; Angelis, Karel J

2013-01-01

The moss Physcomitrella patens is unique for the high frequency of homologous recombination, haploid state, and filamentous growth during early stages of the vegetative growth, which makes it an excellent model plant to study DNA damage responses. We used single cell gel electrophoresis (comet) assay to determine kinetics of response to Bleomycin induced DNA oxidative damage and single and double strand breaks in wild type and mutant lig4 Physcomitrella lines. Moreover, APT gene when inactivated by induced mutations was used as selectable marker to ascertain mutational background at nucleotide level by sequencing of the APT locus. We show that extensive repair of DSBs occurs also in the absence of the functional LIG4, whereas repair of SSBs is seriously compromised. From analysis of induced mutations we conclude that their accumulation rather than remaining lesions in DNA and blocking progression through cell cycle is incompatible with normal plant growth and development and leads to sensitive phenotype.

Genotoxin Induced Mutagenesis in the Model Plant Physcomitrella patens

PubMed Central

Holá, Marcela; Kozák, Jaroslav; Vágnerová, Radka; Angelis, Karel J.

2013-01-01

The moss Physcomitrella patens is unique for the high frequency of homologous recombination, haploid state, and filamentous growth during early stages of the vegetative growth, which makes it an excellent model plant to study DNA damage responses. We used single cell gel electrophoresis (comet) assay to determine kinetics of response to Bleomycin induced DNA oxidative damage and single and double strand breaks in wild type and mutant lig4 Physcomitrella lines. Moreover, APT gene when inactivated by induced mutations was used as selectable marker to ascertain mutational background at nucleotide level by sequencing of the APT locus. We show that extensive repair of DSBs occurs also in the absence of the functional LIG4, whereas repair of SSBs is seriously compromised. From analysis of induced mutations we conclude that their accumulation rather than remaining lesions in DNA and blocking progression through cell cycle is incompatible with normal plant growth and development and leads to sensitive phenotype. PMID:24383055

Simulation and experiment of thermal fatigue in the CPV die attach

NASA Astrophysics Data System (ADS)

Bosco, Nick; Silverman, Timothy; Kurtz, Sarah

2012-10-01

FEM simulation and accelerated thermal cycling have been performed for the CPV die attach. Trends in fatigue damage accumulation and equivalent test time are explored and found to be most sensitive to temperature ramp rate. Die attach crack growth is measured through cycling and found to be in excellent agreement with simulations of the inelastic strain energy accumulated. Simulations of an entire year of weather data provides for the relative ranking of fatigue damage between four cities as well as their equivalent accelerated test time.

Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in patients.

PubMed

Vas, Adám; Shchukin, Yevgeni; Karrenbauer, Virginija D; Cselényi, Zsolt; Kostulas, Kosta; Hillert, Jan; Savic, Ivanka; Takano, Akihiro; Halldin, Christer; Gulyás, Balázs

2008-01-15

With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and regional brain uptake as well as regional distribution and binding potential (BP) of [(11)C]vinpocetine and [(11)C]PK11195. Both ligands showed increased uptake and BP in the regions of local brain damage. However, regional BP values for [(11)C]vinpocetine were markedly higher than those for [(11)C]PK11195. This feature of the former radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS), characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings may indicate that [(11)C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which, in turn, accumulate in the region of the damage. The present findings (i) confirm earlier observations with [(11)C]PK11195 as a potential glia marker in PET studies and (ii) support the working hypothesis that [(11)C]vinpocetine is a potentially useful PET marker of regional and global brain damage resulting in glia accumulation locally or globally in the human brain. The comparative analysis of the two ligands indicate that [(11)C]vinpocetine shows a number of characteristics favourable in comparison with [(11)C]PK11195.

Damage Assessment of Heat Resistant Steels through Electron BackScatter Diffraction Strain Analysis under Creep and Creep-Fatigue Conditions

NASA Astrophysics Data System (ADS)

Fujiyama, Kazunari; Kimachi, Hirohisa; Tsuboi, Toshiki; Hagiwara, Hiroyuki; Ogino, Shotaro; Mizutani, Yoshiki

EBSD(Electron BackScatter Diffraction) analyses were conducted for studying the quantitative microstructural metrics of creep and creep-fatigue damage for austenitic SUS304HTB boiler tube steel and ferritic Mod.9Cr piping steel. KAM(Kernel Average Misorientation) maps and GOS(Grain Orientation Spread) maps were obtained for these samples and the area averaged values KAMave and GOSave were obtained. While the increasing trends of these misorientation metrics were observed for SUS304HTB steel, the decreasing trends were observed for damaged Mod.9Cr steel with extensive recovery of subgrain structure. To establish more universal parameter representing the accumulation of damage to compensate these opposite trends, the EBSD strain parameters were introduced for converting the misorientation changes into the quantities representing accumulated permanent strains during creep and creep-fatigue damage process. As KAM values were dependent on the pixel size (inversely proportional to the observation magnification) and the permanent strain could be expressed as the shear strain which was the product of dislocation density, Burgers vector and dislocation movement distance, two KAM strain parameters MεKAMnet and MεδKAMave were introduced as the sum of product of the noise subtracted KAMnet and the absolute change from initial value δKAMave with dislocation movement distance divided by pixel size. MεδKAMave parameter showed better relationship both with creep strain in creep tests and accumulated creep strain range in creep-fatigue tests. This parameter can be used as the strain-based damage evaluation and detector of final failure.

Analyzing the effectiveness of using branchial NKA activity as a biomarker for assessing waterborne copper toxicity in tilapia (Oreochromis mossambicus): A damage-based modeling approach.

PubMed

Wu, Su-Mei; Tsai, Jeng-Wei; Tzeng, Wen-Nan; Chen, Wei-Yu; Shih, Wan-Yu

2015-06-01

Branchial Na(＋)-K(＋)-ATPase (NKA) activity has been suggested as a promising biomarker for assessing metal stress in aquatic organisms. However, studies that systematically show the effectiveness of using NKA activity to detect metal exposure and toxicity at the individual level are limited. In this study, we aimed to determine whether branchial NKA activity mechanistically responds to the accumulation of waterborne copper (Cu) and accounts for observed toxicity over time under environmentally-relevant and aquafarming Cu exposure levels (0.2, 1 and 2 mg L(-1)). Temporal trends in Cu accumulation and the corresponding responses of branchial NKA activity resulting from Cu exposure were investigated in laboratory experiments conducted on juvenile tilapia (Oreochromis mossambicus), a freshwater teleost that shows potential as a bioindicator of real-time and historical metal pollution. We used the process-based damage assessment model (DAM) to inspect the time course of Cu toxicity by integrating the compensation process between Cu-induced inhibition and repair of branchial NKA activity. NKA activity acted as a sensitive biomarker for Cu exposure and accumulation in tilapia, which showed induced impairment of osmoregulation and lethality when they were exposed to environmentally relevant levels (0.2 mg L(-1)), but not to higher exposure levels (1 and 2 mg L(-1)) in aquaculture farms or contaminated aquatic ecosystems. This study highlights the benefits and limitations of using branchial NKA activity as a sensitive biomarker to assess the health status of a fish population and its ecosystem. Copyright © 2015 Elsevier B.V. All rights reserved.

Deterministic Multiaxial Creep and Creep Rupture Enhancements for CARES/Creep Integrated Design Code

NASA Technical Reports Server (NTRS)

Jadaan, Osama M.

1998-01-01

High temperature and long duration applications of monolithic ceramics can place their failure mode in the creep rupture regime. A previous model advanced by the authors described a methodology by which the creep rupture life of a loaded component can be predicted. That model was based on the life fraction damage accumulation rule in association with the modified Monkman-Grant creep rupture criterion. However, that model did not take into account the deteriorating state of the material due to creep damage (e.g., cavitation) as time elapsed. In addition, the material creep parameters used in that life prediction methodology, were based on uniaxial creep curves displaying primary and secondary creep behavior, with no tertiary regime. The objective of this paper is to present a creep life prediction methodology based on a modified form of the Kachanov-Rabotnov continuum damage mechanics (CDM) theory. In this theory, the uniaxial creep rate is described in terms of sum, temperature, time, and the current state of material damage. This scalar damage state parameter is basically an abstract measure of the current state of material damage due to creep deformation. The damage rate is assumed to vary with stress, temperature, time, and the current state of damage itself. Multiaxial creep and creep rupture formulations of the CDM approach are presented in this paper. Parameter estimation methodologies based on nonlinear regression analysis are also described for both, isothermal constant stress states and anisothermal variable stress conditions This creep life prediction methodology was preliminarily added to the integrated design code CARES/Creep (Ceramics Analysis and Reliability Evaluation of Structures/Creep), which is a postprocessor program to commercially available finite element analysis (FEA) packages. Two examples, showing comparisons between experimental and predicted creep lives of ceramic specimens, are used to demonstrate the viability of Ns methodology and the CARES/Creep program.

Prediction of damage formation in hip arthroplasties by finite element analysis using computed tomography images.

PubMed

Abdullah, Abdul Halim; Todo, Mitsugu; Nakashima, Yasuharu

2017-06-01

Femoral bone fracture is one of the main causes for the failure of hip arthroplasties (HA). Being subjected to abrupt and high impact forces in daily activities may lead to complex loading configuration such as bending and sideway falls. The objective of this study is to predict the risk of femoral bone fractures in total hip arthroplasty (THA) and resurfacing hip arthroplasty (RHA). A computed tomography (CT) based on finite element analysis was conducted to demonstrate damage formation in a three dimensional model of HAs. The inhomogeneous model of femoral bone was constructed from a 79 year old female patient with hip osteoarthritis complication. Two different femoral components were modeled with titanium alloy and cobalt chromium and inserted into the femoral bones to present THA and RHA models respectively. The analysis included six configurations, which exhibited various loading and boundary conditions, including axial compression, torsion, lateral bending, stance and two types of falling configurations. The applied hip loadings were normalized to body weight (BW) and accumulated from 1 BW to 3 BW. Predictions of damage formation in the femoral models were discussed as the resulting tensile failure as well as the compressive yielding and failure elements. The results indicate that loading directions can forecast the pattern and location of fractures at varying magnitudes of loading. Lateral bending configuration experienced the highest damage formation in both THA and RHA models. Femoral neck and trochanteric regions were in a common location in the RHA model in most configurations, while the predicted fracture locations in THA differed as per the Vancouver classification. Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved.

Computational simulation of the creep-rupture process in filamentary composite materials

NASA Technical Reports Server (NTRS)

Slattery, Kerry T.; Hackett, Robert M.

1991-01-01

A computational simulation of the internal damage accumulation which causes the creep-rupture phenomenon in filamentary composite materials is developed. The creep-rupture process involves complex interactions between several damage mechanisms. A statistically-based computational simulation using a time-differencing approach is employed to model these progressive interactions. The finite element method is used to calculate the internal stresses. The fibers are modeled as a series of bar elements which are connected transversely by matrix elements. Flaws are distributed randomly throughout the elements in the model. Load is applied, and the properties of the individual elements are updated at the end of each time step as a function of the stress history. The simulation is continued until failure occurs. Several cases, with different initial flaw dispersions, are run to establish a statistical distribution of the time-to-failure. The calculations are performed on a supercomputer. The simulation results compare favorably with the results of creep-rupture experiments conducted at the Lawrence Livermore National Laboratory.

A Mechanistic Thermal Fatigue Model for SnAgCu Solder Joints

NASA Astrophysics Data System (ADS)

Borgesen, Peter; Wentlent, Luke; Hamasha, Sa'd.; Khasawneh, Saif; Shirazi, Sam; Schmitz, Debora; Alghoul, Thaer; Greene, Chris; Yin, Liang

2018-02-01

The present work offers both a complete, quantitative model and a conservative acceleration factor expression for the life span of SnAgCu solder joints in thermal cycling. A broad range of thermal cycling experiments, conducted over many years, has revealed a series of systematic trends that are not compatible with common damage functions or constitutive relations. Complementary mechanical testing and systematic studies of the evolution of the microstructure and damage have led to a fundamental understanding of the progression of thermal fatigue and failure. A special experiment was developed to allow the effective deconstruction of conventional thermal cycling experiments and the finalization of our model. According to this model, the evolution of damage and failure in thermal cycling is controlled by a continuous recrystallization process which is dominated by the coalescence and rotation of dislocation cell structures continuously added to during the high-temperature dwell. The dominance of this dynamic recrystallization contribution is not consistent with the common assumption of a correlation between the number of cycles to failure and the total work done on the solder joint in question in each cycle. It is, however, consistent with an apparent dependence on the work done during the high-temperature dwell. Importantly, the onset of this recrystallization is delayed by pinning on the Ag3Sn precipitates until these have coarsened sufficiently, leading to a model with two terms where one tends to dominate in service and the other in accelerated thermal cycling tests. Accumulation of damage under realistic service conditions with varying dwell temperatures and times is also addressed.

Accumulated α-synuclein affects the progression of GM2 gangliosidoses.

PubMed

Suzuki, Kyoko; Yamaguchi, Akira; Yamanaka, Shoji; Kanzaki, Seiichi; Kawashima, Masato; Togo, Takashi; Katsuse, Omi; Koumitsu, Noriko; Aoki, Naoya; Iseki, Eizo; Kosaka, Kenji; Yamaguchi, Kayoko; Hashimoto, Makoto; Aoki, Ichiro; Hirayasu, Yoshio

2016-10-01

The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

DELLAs Regulate Chlorophyll and Carotenoid Biosynthesis to Prevent Photooxidative Damage during Seedling Deetiolation in Arabidopsis[C][W

PubMed Central

Cheminant, Soizic; Wild, Michael; Bouvier, Florence; Pelletier, Sandra; Renou, Jean-Pierre; Erhardt, Mathieu; Hayes, Scott; Terry, Matthew J.; Genschik, Pascal; Achard, Patrick

2011-01-01

In plants, light represents an important environmental signal that triggers the production of photosynthetically active chloroplasts. This developmental switch is critical for plant survival because chlorophyll precursors that accumulate in darkness can be extremely destructive when illuminated. Thus, plants have evolved mechanisms to adaptively control plastid development during the transition into light. Here, we report that the gibberellin (GA)-regulated DELLA proteins play a crucial role in the formation of functional chloroplasts during deetiolation. We show that Arabidopsis thaliana DELLAs accumulating in etiolated cotyledons derepress chlorophyll and carotenoid biosynthetic pathways in the dark by repressing the transcriptional activity of the phytochrome-interacting factor proteins. Accordingly, dark-grown GA-deficient ga1-3 mutants (that accumulate DELLAs) display a similar gene expression pattern to wild-type seedlings grown in the light. Consistent with this, ga1-3 seedlings accumulate higher amounts of protochlorophyllide (a phototoxic chlorophyll precursor) in darkness but, surprisingly, are substantially more resistant to photooxidative damage following transfer into light. This is due to the DELLA-dependent upregulation of the photoprotective enzyme protochlorophyllide oxidoreductase (POR) in the dark. Our results emphasize the role of DELLAs in regulating the levels of POR, protochlorophyllide, and carotenoids in the dark and in protecting etiolated seedlings against photooxidative damage during initial light exposure. PMID:21571951

Vibration fatigue using modal decomposition

NASA Astrophysics Data System (ADS)

Mršnik, Matjaž; Slavič, Janko; Boltežar, Miha

2018-01-01

Vibration-fatigue analysis deals with the material fatigue of flexible structures operating close to natural frequencies. Based on the uniaxial stress response, calculated in the frequency domain, the high-cycle fatigue model using the S-N curve material data and the Palmgren-Miner hypothesis of damage accumulation is applied. The multiaxial criterion is used to obtain the equivalent uniaxial stress response followed by the spectral moment approach to the cycle-amplitude probability density estimation. The vibration-fatigue analysis relates the fatigue analysis in the frequency domain to the structural dynamics. However, once the stress response within a node is obtained, the physical model of the structure dictating that response is discarded and does not propagate through the fatigue-analysis procedure. The structural model can be used to evaluate how specific dynamic properties (e.g., damping, modal shapes) affect the damage intensity. A new approach based on modal decomposition is presented in this research that directly links the fatigue-damage intensity with the dynamic properties of the system. It thus offers a valuable insight into how different modes of vibration contribute to the total damage to the material. A numerical study was performed showing good agreement between results obtained using the newly presented approach with those obtained using the classical method, especially with regards to the distribution of damage intensity and critical point location. The presented approach also offers orders of magnitude faster calculation in comparison with the conventional procedure. Furthermore, it can be applied in a straightforward way to strain experimental modal analysis results, taking advantage of experimentally measured strains.

Oxidized LDL accumulation in experimental renal ischemia reperfusion injury model.

PubMed

Kulah, Eyup; Tascilar, Oge; Acikgoz, Serefden; Tekin, Ishak Ozel; Karadeniz, Guldeniz; Can, Murat; Gun, Banu; Barut, Figen; Comert, Mustafa

2007-01-01

The aim of this study was to identify oxidative damage of kidney during ischemia reperfusion injury (IRI) by evaluating changes in lipid peroxidation markers in tissue and blood by an experimental model. Oxidized LDL (ox-LDL) was used as an oxidative stress biomarker, whereas paraoxonase (PON-1) activity was used as an antioxidative biomarker. Sixty-three male Wistar rats were randomly assigned into three groups: renal IRI, sham, and control. In the renal IRI group, the right kidney was removed and the artery and vein of the left kidney were clamped for 90 minutes. The presence of ox-LDL in the kidney tissue sections was determined by using an immunofluorescent staining method. The plasma ox-LDL levels did not increase significantly at the 24th hour following IRI, made a peak at the 48th hour, and declined at the 72nd hour. Accumulation of ox-LDL was detected in the kidney tissue on the 24th, 48th, and 72nd hours of the renal IRI. Serum PON-1 levels have peaked on the 24th hour and then declined. This study demonstrates the accumulation of ox-LDL molecules in the renal tissues of the IRI model. Future strategies aimed to reduce the lipid peroxidation during the initial hours of renal IRI may be useful to prevent complications of ischemia.

ATM-activated autotaxin (ATX) propagates inflammation and DNA damage in lung epithelial cells: a new mode of action for silica-induced DNA damage?

PubMed

Zheng, Huiyuan; Högberg, Johan; Stenius, Ulla

2017-12-07

Silica exposure is a common risk factor for lung cancer. It has been claimed that key elements in cancer development are activation of inflammatory cells that indirectly induce DNA damage and proliferative stimuli in respiratory epithelial cells. We studied DNA damage induced by silica particles in respiratory epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). A549 and 16 bronchial epithelial cells (16HBE) lung epithelial cells were exposed to silica particles. Reactive oxygen species (ROS), NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activation, ATX, ataxia telangiectasia mutated (ATM), and DNA damage (γH2AX, pCHK1, pCHK2, comet assay) were end points. Low doses of silica induced NLRP3 activation, DNA damage accumulation, and ATM phosphorylation. A novel finding was that ATM induced ATX generation and secretion. Not only silica but also rotenone, camptothecin and H2O2 activated ATX via ATM, suggesting that ATX is part of a generalized ATM response to double-strand breaks (DSBs). Surprisingly, ATX inhibition mitigated DNA damage accumulation at later time points (6-16 h), and ATX transfection caused NLRP3 activation and DNA damage. Furthermore, the product of ATX enzymatic activity, lysophosphatidic acid, recapitulated the effects of ATX transfection. These data indicate an ATM-ATX-dependent loop that propagates inflammation and DSB accumulation, making low doses of silica effective inducers of DSBs in epithelial cells. We conclude that an ATM-ATX axis interconnects DSBs with silica-induced inflammation and propagates these effects in epithelial cells. Further studies of this adverse outcome pathway may give an accurate assessment of the lowest doses of silica that causes cancer. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis Concerning the Inspection Threshold for Multi-Site Damage.

DOT National Transportation Integrated Search

1993-12-01

Periodic inspections, at a prescribed interval, for Multi-Site Damage (MS) in longitudinal fuselage lap-joints start when the aircraft has accumulated a certain number of flights, the inspection threshold. The work reported here was an attempt to obt...

Creep-Fatigue Damage Investigation and Modeling of Alloy 617 at High Temperatures

NASA Astrophysics Data System (ADS)

Tahir, Fraaz

The Very High Temperature Reactor (VHTR) is one of six conceptual designs proposed for Generation IV nuclear reactors. Alloy 617, a solid solution strengthened Ni-base superalloy, is currently the primary candidate material for the tubing of the Intermediate Heat Exchanger (IHX) in the VHTR design. Steady-state operation of the nuclear power plant at elevated temperatures leads to creep deformation, whereas loading transients including startup and shutdown generate fatigue. A detailed understanding of the creep-fatigue interaction in Alloy 617 is necessary before it can be considered as a material for nuclear construction in ASME Boiler and Pressure Vessel Code. Current design codes for components undergoing creep-fatigue interaction at elevated temperatures require creep-fatigue testing data covering the entire range from fatigue-dominant to creep-dominant loading. Classical strain-controlled tests, which produce stress relaxation during the hold period, show a saturation in cycle life with increasing hold periods due to the rapid stress-relaxation of Alloy 617 at high temperatures. Therefore, applying longer hold time in these tests cannot generate creep-dominated failure. In this study, uniaxial isothermal creep-fatigue tests with non-traditional loading waveforms were designed and performed at 850 and 950°C, with an objective of generating test data in the creep-dominant regime. The new loading waveforms are hybrid strain-controlled and force-controlled testing which avoid stress relaxation during the creep hold. The experimental data showed varying proportions of creep and fatigue damage, and provided evidence for the inadequacy of the widely-used time fraction rule for estimating creep damage under creep-fatigue conditions. Micro-scale damage features in failed test specimens, such as fatigue cracks and creep voids, were quantified using a Scanning Electron Microscope (SEM) to find a correlation between creep and fatigue damage. Quantitative statistical imaging analysis showed that the microstructural damage features (cracks and voids) are correlated with a new mechanical driving force parameter. The results from this image-based damage analysis were used to develop a phenomenological life-prediction methodology called the effective time fraction approach. Finally, the constitutive creep-fatigue response of the material at 950°C was modeled using a unified viscoplastic model coupled with a damage accumulation model. The simulation results were used to validate an energy-based constitutive life-prediction model, as a mechanistic model for potential component and structure level creep-fatigue analysis.

Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

USDA-ARS?s Scientific Manuscript database

Recent evidence suggests potential benefits from phytochemicals and micronutrients in protecting against oxidative and lipid-mediated damage, but the molecular mechanisms of these actions are still unclear. Here we investigated whether the dietary polyphenol curcumin can modulate the accumulation of...

Interacting effects of early dietary conditions and reproductive effort on the oxidative costs of reproduction

PubMed Central

2017-01-01

The hypothesis that oxidative damage accumulation can mediate the trade-off between reproduction and lifespan has recently been questioned. However, in captive conditions, studies reporting no evidence in support of this hypothesis have usually provided easy access to food which may have mitigated the cost of reproduction. Here, I test the hypothesis that greater investment in reproduction should lead to oxidative damage accumulation and telomere loss in domestic zebra finches Taeniopygia guttata. Moreover, since the change or fluctuation in diet composition between early and late postnatal period can impair the ability to produce antioxidant defences in zebra finches, I also tested if early nutritional conditions (constant vs fluctuating early diet) influenced the magnitude of any subsequent costs of reproduction (e.g., oxidative damage and/or telomere shortening). In comparison to pairs with reduced broods, the birds that had to feed enlarged broods showed a higher level of oxidative DNA damage (8-OHdG), but brood size had no effect on telomeres. Fluctuating early diet composition reduced the capacity to maintain the activity of endogenous antioxidants (GPx), particularly when reproductive costs were increased (enlarged brood). The decline in GPx in birds feeding enlarged broods was accompanied by a change in bill colouration. This suggests that birds with lower endogenous antioxidant defences might have strategically increased the mobilization of antioxidants previously stored in other tissues (i.e., bill and liver) and thus, preventing an excessive accumulation of damage during reproduction. PMID:28316895

SIRT3 Links Oxidative Stress with Aging and Cancer | Center for Cancer Research

Cancer.gov

When cells produce energy, they also form reactive oxygen molecules capable of damaging proteins and DNA. Normally, these molecules are neutralized by a protein called superoxide dismutase, or SOD. However, as a cell ages, oxidative damage accumulates. The increase in oxidative cellular damage as people age may provide a mechanistic connection between aging and carcinogenesis.

Immune response is required for the control of in vivo translocation and chronic toxicity of graphene oxide

NASA Astrophysics Data System (ADS)

Wu, Qiuli; Zhao, Yunli; Fang, Jianpeng; Wang, Dayong

2014-05-01

Graphene oxide (GO) shows great promise as a nanomaterial for medical applications; however, the mechanism for its long-term adverse effects is still largely unclear. Here, we show that chronic GO exposure not only caused damage on the function of both primary and secondary targeted organs but also induced severe accumulation of pathogenic microbial food (OP50) in the intestine of Caenorhabditis elegans, a non-mammalian alternative toxicity assay system. GO accumulated in the intestine could be largely co-localized with OP50 and induced decreased immune response of animals. In contrast, feeding with UV-treated OP50 suppressed GO toxicity and accumulation in the intestine and maintained the relatively normal immune response of animals. The severe accumulation of OP50 in the intestine might be partially due to the damage by GO on the development and function of AVL and DVB neurons controlling defecation behavior. Reduction of chronic GO toxicity by PEG surface modification largely resulted from the inhibition of OP50 accumulation in the intestine and the maintenance of normal immune response. Our results highlight the key role of innate immunity in regulating in vivo chronic GO toxicity, which will be helpful for our understanding of the interactions between nanomaterials and biological systems during the long-term development of animals.Graphene oxide (GO) shows great promise as a nanomaterial for medical applications; however, the mechanism for its long-term adverse effects is still largely unclear. Here, we show that chronic GO exposure not only caused damage on the function of both primary and secondary targeted organs but also induced severe accumulation of pathogenic microbial food (OP50) in the intestine of Caenorhabditis elegans, a non-mammalian alternative toxicity assay system. GO accumulated in the intestine could be largely co-localized with OP50 and induced decreased immune response of animals. In contrast, feeding with UV-treated OP50 suppressed GO toxicity and accumulation in the intestine and maintained the relatively normal immune response of animals. The severe accumulation of OP50 in the intestine might be partially due to the damage by GO on the development and function of AVL and DVB neurons controlling defecation behavior. Reduction of chronic GO toxicity by PEG surface modification largely resulted from the inhibition of OP50 accumulation in the intestine and the maintenance of normal immune response. Our results highlight the key role of innate immunity in regulating in vivo chronic GO toxicity, which will be helpful for our understanding of the interactions between nanomaterials and biological systems during the long-term development of animals. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00699b

Accumulation of Senescent Cells in Mitotic Tissue of Aging Primates

PubMed Central

Jeyapalan, Jessie C.; Ferreira, Mark; Sedivy, John M.; Herbig, Utz

2013-01-01

Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over forty years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event. PMID:17116315

Cynanchum wilfordii Radix attenuates liver fat accumulation and damage by suppressing hepatic cyclooxygenase-2 and mitogen-activated protein kinase in mice fed with a high-fat and high-fructose diet.

PubMed

Jang, Seon-A; Lee, SungRyul; Sohn, Eun-Hwa; Yang, Jaehyuk; Park, Dae Won; Jeong, Yong Joon; Kim, Inhye; Kwon, Jung Eun; Song, Hae Seong; Cho, Young Mi; Meng, Xue; Koo, Hyun Jung; Kang, Se Chan

2016-09-01

Excessive consumption of fat and fructose augments the pathological progression of nonalcoholic fatty liver disease through hepatic fibrosis, inflammation, and hepatic de novo lipogenesis. We hypothesized that supplementation with Cynanchum wilfordii extract (CWE) decreases fat accumulation in the liver by suppressing cyclooxygenase-2 (COX-2), the nuclear translocation of nuclear factor κB (NF-κB), and p38 mitogen-activated protein kinase (MAPK). The beneficial effect of CWE was evaluated in a murine model of nonalcoholic fatty liver disease. Mice were fed either a normal diet or an atherogenic diet with fructose (ATHFR) in the presence or absence of CWE (50, 100, or 200 mg/kg; n=6/group). Treatment with ATHFR induced a hepatosplenomegaly-like condition (increased liver and spleen weight); this pathological change was attenuated in the presence of CWE. The ATHFR group exhibited impaired liver function, as evidenced by increased blood levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, fat accumulation in the liver, and lipid profiles. Supplementation of CWE (100 and 200 mg/kg, P<.05) ameliorated these impaired liver functions. Atherogenic diet with fructose increased the protein levels of COX-2 and p38 MAPK, as well as the nuclear translocation of NF-κB. These signaling pathways, which are associated with the inflammatory response, were markedly suppressed after CWE treatment (100 and 200 mg/kg). In summary, CWE supplementation reduced high-fat and high-fructose diet-induced fat accumulation and damage in the liver by suppressing COX-2, NF-κB, and p38 MAPK. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice.

PubMed

Rani, Reena; Li, Jie; Pang, Qishen

2008-12-01

Members of the Fanconi anemia (FA) protein family are involved in repair of genetic damage caused by DNA cross-linkers. It is not clear whether the FA proteins function in oxidative DNA damage and oncogenic stress response. Here, we report that deficiency in the Fanca gene in mice elicits a p53-dependent growth arrest and DNA damage response to oxidative DNA damage and oncogenic stress. Using a Fanca-/-Trp53-/- double knockout model and a functionally switchable p53 retrovirus, we define the kinetics, dependence, and persistence of p53-mediated response to oxidative and oncogenic stresses in Fanca-/- cells. Notably, oxidative stress induces persistent p53 response in Fanca-/- cells, likely due to accumulation of unrepaired DNA damage. On the other hand, whereas wild-type cells exhibit prolonged response to oncogene activation, the p53-activating signals induced by oncogenic ras are short-lived in Fanca-/- cells, suggesting that Fanca may be required for the cell to engage p53 during constitutive ras activation. We propose that the FA proteins protect cells from stress-induced proliferative arrest and tumor evolution by acting as a modulator of the signaling pathways that link FA to p53.

Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice

PubMed Central

Rani, Reena; Li, Jie; Pang, Qishen

2008-01-01

Members of the Fanconi anemia (FA) protein family are involved in repair of genetic damage caused by DNA cross-linkers. It is not clear whether the FA proteins function in oxidative DNA damage and oncogenic stress response. Here we report that deficiency in the Fanca gene in mice elicits a p53-dependent growth arrest and DNA damage response to oxidative DNA damage and oncogenic stress. Using a Fanca-/- Trp53-/- double knockout model and a functionally switchable p53 retrovirus, we define the kinetics, dependence, and persistence of p53-mediated response to oxidative and oncogenic stresses in Fanca-/- cells. Notably, oxidative stress induces persistent p53 response in Fanca-/- cells, likely due to accumulation of unrepaired DNA damage. On the other hand, whereas WT cells exhibit prolonged response to oncogene activation, the p53-activating signals induced by oncogenic ras are short-lived in Fanca-/- cells, suggesting that Fanca may be required for the cell to engage p53 during constitutive ras activation. We propose that the FA proteins protect cells from stress-induced proliferative arrest and tumor evolution by acting as a modulator of the signaling pathways that link FA to p53. PMID:19047147

DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression

PubMed Central

Barr, Alexis R.; Cooper, Samuel; Heldt, Frank S.; Butera, Francesca; Stoy, Henriette; Mansfeld, Jörg; Novák, Béla; Bakal, Chris

2017-01-01

Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. PMID:28317845

Black soybean seed coat polyphenols prevent AAPH-induced oxidative DNA-damage in HepG2 cells

PubMed Central

Yoshioka, Yasukiyo; Li, Xiu; Zhang, Tianshun; Mitani, Takakazu; Yasuda, Michiko; Nanba, Fumio; Toda, Toshiya; Yamashita, Yoko; Ashida, Hitoshi

2017-01-01

Black soybean seed coat extract (BE), which contains abundant polyphenols such as procyanidins, cyanidin 3-glucoside, (+)-catechin, and (−)­epicatechin, has been reported on health beneficial functions such as antioxidant activity, anti-inflammatory, anti-obesity, and anti-diabetic activities. In this study, we investigated that prevention of BE and its polyphenols on 2,2'-azobis(2-methylpropionamide) dihydrochloride (AAPH)-induced oxidative DNA damage, and found that these polyphenols inhibited AAPH-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a biomarker for oxidative DNA damage in HepG2 cells. Under the same conditions, these polyphenols also inhibited AAPH-induced accumulation of reactive oxygen species (ROS) in the cells. Inhibition of ROS accumulation was observed in both cytosol and nucleus. It was confirmed that these polyphenols inhibited formation of AAPH radical using oxygen radical absorbance capacity assay under the cell-free conditions. These results indicate that polyphenols in BE inhibit free radical-induced oxidative DNA damages by their potent antioxidant activity. Thus, BE is an effective food material for prevention of oxidative stress and oxidative DNA damages. PMID:28366989

Damage Evolution in Complex-Phase and Dual-Phase Steels during Edge Stretching.

PubMed

Pathak, Nikky; Butcher, Cliff; Worswick, Michael James; Bellhouse, Erika; Gao, Jeff

2017-03-27

The role of microstructural damage in controlling the edge stretchability of Complex-Phase (CP) and Dual-Phase (DP) steels was evaluated using hole tension experiments. The experiments considered a tensile specimen with a hole at the center of specimen that is either sheared (sheared edge condition) or drilled and then reamed (reamed edge condition). The damage mechanism and accumulation in the CP and DP steels were systematically characterized by interrupting the hole tension tests at different strain levels using scanning electron microscope (SEM) analysis and optical microscopy. Martensite cracking and decohesion of ferrite-martensite interfaces are the dominant nucleation mechanisms in the DP780. The primary source of void nucleation in the CP800 is nucleation at TiN particles, with secondary void formation at martensite/bainite interfaces near the failure strain. The rate of damage evolution is considerably higher for the sheared edge in contrast with the reamed edge since the shearing process alters the microstructure in the shear affected zone (SAZ) by introducing work-hardening and initial damage behind the sheared edge. The CP microstructures were shown to be less prone to shear-induced damage than the DP materials resulting in much higher sheared edge formability. Microstructural damage in the CP and DP steels was characterized to understand the interaction between microstructure, damage evolution and edge formability during edge stretching. An analytical model for void evolution and coalescence was developed and applied to predict the damage rate in these rather diverse microstructures.

Damage Evolution in Complex-Phase and Dual-Phase Steels during Edge Stretching

PubMed Central

Pathak, Nikky; Butcher, Cliff; Worswick, Michael James; Bellhouse, Erika; Gao, Jeff

2017-01-01

The role of microstructural damage in controlling the edge stretchability of Complex-Phase (CP) and Dual-Phase (DP) steels was evaluated using hole tension experiments. The experiments considered a tensile specimen with a hole at the center of specimen that is either sheared (sheared edge condition) or drilled and then reamed (reamed edge condition). The damage mechanism and accumulation in the CP and DP steels were systematically characterized by interrupting the hole tension tests at different strain levels using scanning electron microscope (SEM) analysis and optical microscopy. Martensite cracking and decohesion of ferrite-martensite interfaces are the dominant nucleation mechanisms in the DP780. The primary source of void nucleation in the CP800 is nucleation at TiN particles, with secondary void formation at martensite/bainite interfaces near the failure strain. The rate of damage evolution is considerably higher for the sheared edge in contrast with the reamed edge since the shearing process alters the microstructure in the shear affected zone (SAZ) by introducing work-hardening and initial damage behind the sheared edge. The CP microstructures were shown to be less prone to shear-induced damage than the DP materials resulting in much higher sheared edge formability. Microstructural damage in the CP and DP steels was characterized to understand the interaction between microstructure, damage evolution and edge formability during edge stretching. An analytical model for void evolution and coalescence was developed and applied to predict the damage rate in these rather diverse microstructures. PMID:28772707

Fatigue analysis of the bow structure of FPSO

NASA Astrophysics Data System (ADS)

Hu, Zhi-Qiang; Gao, Zhen; Gu, Yong-Ning

2003-06-01

The bow structure of FPSO moored by the single mooring system is rather complicated. There are many potential hot spots in connection parts of structures between the mooring support frame and the forecastle. Mooring forces, which are induced by wave excitation and transferred by the YOKE and the mooring support frame, may cause fatigue damage to the bow structure. Different from direct wave-induced-forces, the mooring force consists of wave frequency force (WF) and 2nd draft low frequency force (LF)[3], which are represented by two sets of short-term distribution respectively. Based on two sets of short-term distribution of mooring forces obtained by the model test, the fatigue damage of the bow structure of FPSO is analyzed, with emphasis on two points. One is the procedure and position selection for fatigue check, and the other is the application of new formulae for the calculation of accumulative fatigue damage caused by two sets of short-term distribution of hot spot stress range. From the results distinguished features of fatigue damage to the FPSO’s bow structure can be observed.

Proliferating Cell Nuclear Antigen-dependent Rapid Recruitment of Cdt1 and CRL4Cdt2 at DNA-damaged Sites after UV Irradiation in HeLa Cells*

PubMed Central

Ishii, Takashi; Shiomi, Yasushi; Takami, Toshihiro; Murakami, Yusuke; Ohnishi, Naho; Nishitani, Hideo

2010-01-01

The licensing factor Cdt1 is degraded by CRL4Cdt2 ubiquitin ligase dependent on proliferating cell nuclear antigen (PCNA) during S phase and when DNA damage is induced in G1 phase. Association of both Cdt2 and PCNA with chromatin was observed in S phase and after UV irradiation. Here we used a micropore UV irradiation assay to examine Cdt2 accumulation at cyclobutane pyrimidine dimer-containing DNA-damaged sites in the process of Cdt1 degradation in HeLa cells. Cdt2, present in the nucleus throughout the cell cycle, accumulated rapidly at damaged DNA sites during G1 phase. The recruitment of Cdt2 is dependent on prior PCNA chromatin binding because Cdt2 association was prevented when PCNA was silenced. Cdt1 was also recruited to damaged sites soon after UV irradiation through its PIP-box. As Cdt1 was degraded, the Cdt2 signal at damaged sites was reduced, but PCNA, cyclobutane pyrimidine dimer, and XPA (xeroderma pigmentosum, complementation group A) signals remained at the same levels. These findings suggest that Cdt1 degradation following UV irradiation occurs rapidly at damaged sites due to PCNA chromatin loading and the recruitment of Cdt1 and CRL4Cdt2, before DNA damage repair is completed. PMID:20929861

Transcriptomic Analysis of Carboxylic Acid Challenge in Escherichia coli: Beyond Membrane Damage

PubMed Central

Royce, Liam A.; Boggess, Erin; Fu, Yao; Liu, Ping; Shanks, Jacqueline V.; Dickerson, Julie; Jarboe, Laura R.

2014-01-01

Carboxylic acids are an attractive biorenewable chemical. Enormous progress has been made in engineering microbes for production of these compounds though titers remain lower than desired. Here we used transcriptome analysis of Escherichia coli during exogenous challenge with octanoic acid (C8) at pH 7.0 to probe mechanisms of toxicity. This analysis highlights the intracellular acidification and membrane damage caused by C8 challenge. Network component analysis identified transcription factors with altered activity including GadE, the activator of the glutamate-dependent acid resistance system (AR2) and Lrp, the amino acid biosynthesis regulator. The intracellular acidification was quantified during exogenous challenge, but was not observed in a carboxylic acid producing strain, though this may be due to lower titers than those used in our exogenous challenge studies. We developed a framework for predicting the proton motive force during adaptation to strong inorganic acids and carboxylic acids. This model predicts that inorganic acid challenge is mitigated by cation accumulation, but that carboxylic acid challenge inverts the proton motive force and requires anion accumulation. Utilization of native acid resistance systems was not useful in terms of supporting growth or alleviating intracellular acidification. AR2 was found to be non-functional, possibly due to membrane damage. We proposed that interaction of Lrp and C8 resulted in repression of amino acid biosynthesis. However, this hypothesis was not supported by perturbation of lrp expression or amino acid supplementation. E. coli strains were also engineered for altered cyclopropane fatty acid content in the membrane, which had a dramatic effect on membrane properties, though C8 tolerance was not increased. We conclude that achieving higher production titers requires circumventing the membrane damage. As higher titers are achieved, acidification may become problematic. PMID:24586888

Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPAR{alpha} deterioration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Kyoko; Department of Nephrology Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621; Kamijo, Yuji, E-mail: yujibeat@shinshu-u.ac.jp

2011-05-01

Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPAR{alpha}), suggesting the benefit of PPAR{alpha} activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPAR{alpha} agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPAR{alpha} agonistsmore » without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPAR{alpha} deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NF{kappa}B activation. These effects are common to other fibrates and dependent on PPAR{alpha} function. Interestingly, however, clofibrate pretreatment also exerted PPAR{alpha}-independent tubular toxicities in PPAR{alpha}-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPAR{alpha} activator that has a steady serum concentration regardless of kidney dysfunction. - Graphical Abstract: Massive proteinuria introduces free fatty acid toxicity to proximal tubular epithelial cells (PTECs). PPAR{alpha} activationvia clofibrate pretreatment maintains fatty acid catabolism and attenuates oxidative stress, apoptosis, and NF{kappa}B activation, resulting in protection of PTECs. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. Display Omitted Highlights: > Clofibrate pretreatment protects against acute FFA-induced tubular toxicity. > PPAR{alpha} activation decreases FFA influx and maintains fatty acid catabolism. > PPAR{alpha} activation attenuates oxidative stress, apoptosis, and NF{kappa}B activation. > Protective effects must outweigh PPAR{alpha}-independent tubular toxicities of fibrates.« less

Functionalization and Characterization of Magnetic Nanoparticles for the Detection of Ferritin Accumulation in Alzheimer's Disease.

PubMed

Fernández, Tamara; Martínez-Serrano, Alberto; Cussó, Lorena; Desco, Manuel; Ramos-Gómez, Milagros

2018-05-16

Early diagnosis in Alzheimer's disease (AD), prior to the appearance of marked clinical symptoms, is critical to prevent irreversible neuronal damage and neural malfunction that lead to dementia and death. Therefore, there is an urgent need to generate new contrast agents which reveal by a noninvasive method the presence of some of the pathological signs of AD. In the present study, we demonstrate for the first time a new nanoconjugate composed of magnetic nanoparticles bound to an antiferritin antibody, which has been developed based on the existence of iron deposits and high levels of the ferritin protein present in areas with a high accumulation of amyloid plaques (particularly the subiculum in the hippocampal area) in the brain of a transgenic mouse model with five familial AD mutations. Both in vitro and after intravenous injection, functionalized magnetic nanoparticles were able to recognize and bind specifically to the ferritin protein accumulated in the subiculum area of the AD transgenic mice.

Developing a Malaysia flood model

NASA Astrophysics Data System (ADS)

Haseldine, Lucy; Baxter, Stephen; Wheeler, Phil; Thomson, Tina

2014-05-01

Faced with growing exposures in Malaysia, insurers have a need for models to help them assess their exposure to flood losses. The need for an improved management of flood risks has been further highlighted by the 2011 floods in Thailand and recent events in Malaysia. The increasing demand for loss accumulation tools in Malaysia has lead to the development of the first nationwide probabilistic Malaysia flood model, which we present here. The model is multi-peril, including river flooding for thousands of kilometres of river and rainfall-driven surface water flooding in major cities, which may cause losses equivalent to river flood in some high-density urban areas. The underlying hazard maps are based on a 30m digital surface model (DSM) and 1D/2D hydraulic modelling in JFlow and RFlow. Key mitigation schemes such as the SMART tunnel and drainage capacities are also considered in the model. The probabilistic element of the model is driven by a stochastic event set based on rainfall data, hence enabling per-event and annual figures to be calculated for a specific insurance portfolio and a range of return periods. Losses are estimated via depth-damage vulnerability functions which link the insured damage to water depths for different property types in Malaysia. The model provides a unique insight into Malaysian flood risk profiles and provides insurers with return period estimates of flood damage and loss to property portfolios through loss exceedance curve outputs. It has been successfully validated against historic flood events in Malaysia and is now being successfully used by insurance companies in the Malaysian market to obtain reinsurance cover.

Photooxidative damage in retinal pigment epithelial cells via GRP78 and the protective role of grape skin polyphenols.

PubMed

Zhao, Zhao; Sun, Tao; Jiang, Yun; Wu, Lijiang; Cai, Xiangzhong; Sun, Xiaodong; Sun, Xiangjun

2014-12-01

Blue light induced oxidative damage and ER stress are related to the pathogenesis of age-related macular degeneration (AMD). However, the mechanism of blue light-induced damage remained obscure. The objective of this work is to assess the photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation-induced changes in expression of ER stress associated apoptotic proteins, and investigate the mechanism underlying the protective effects of grape skin extracts. To mimic lipofuscin-mediated photooxidation in vivo, ARPE-19 cells that accumulated A2E, one of lipofuscin fluorophores, were used as a model system to investigate the mechanism of photooxidative damage and the protective effects of grape skin polyphenols. Exposure of A2E containing ARPE-19 cells to blue light resulted in significant apoptosis and increases in levels of GRP78, CHOP, p-JNK, Bax, cleaved caspase-9, and cleaved caspase-3, indicating that photooxidative damage to RPE cells is mediated by the ER-stress-induced intrinsic apoptotic pathway. Cells in which GRP78 had been knocked down with shRNA were more vulnerable to photooxidative damage. Pre-treatment of blue-light-exposed A2E containing ARPE-19 cells, with grape skin extracts, inhibited apoptosis, in a dose dependent manner. Knockdown GRP78 blocked the protective effect of grape skin extracts.

Brief communication: predatory bird damage to the Taung type-skull of Australopithecus africanus Dart 1925.

PubMed

Berger, Lee R

2006-10-01

In this issue of the Journal, McGraw et al. ([2006] Am. J. Phys. Anthropol. 000:00-00) present new data on the taphonomic signature of bone assemblages accumulated by crowned hawk eagles (Stephanoaetus coronatus), including characteristic talon damage to the inferior orbits of primates preyed upon by these birds. Reexamination of the Taung juvenile hominin specimen (the type specimen of Australopithecus africanus Dart 1925) reveals previously undescribed damage to the orbital floors that is nearly identical to that seen in the crania of monkeys preyed upon by crowned hawk eagles (as reported by McGraw et al., this issue). This new evidence, along with previously described aspects of the nonhominin bone assemblage from Taung and damage to the neurocranium of the hominin specimen itself, strongly supports the hypothesis that a bird of prey was an accumulating agent at Taung, and that the Taung child itself was the victim of a bird of prey.

Esculin improves dyslipidemia, inflammation and renal damage in streptozotocin-induced diabetic rats.

PubMed

Wang, Yue-Hua; Liu, Yan-Hong; He, Guo-Rong; Lv, Yang; Du, Guan-Hua

2015-11-09

Increasing studies have shown that dyslipidemia and inflammatory responses play important roles in the progression of microvascular diabetic complications. Esculin (ES), a coumarin derivative, was extracted from Fraxinus rhynchophylla. The present study was to evaluate the potential effects of ES on lipid metabolism, inflammation responses and renal damage in streptozotocin (STZ)-induced experimental diabetic rats and explore the possible mechanism. Diabetic rat model was established by administration high-glucose-fat diet and intraperitoneal injection of STZ 45 mg/kg. ES was administrated to diabetic rats intragastrically at 10, 30 and 90 mg/kg for 10 weeks respectively. The levels of triglycerides (TG), total cholesterol (T-CHO), low density lipoproteins (LDL), and high-density-cholesterol (HDL-C) in serum were measured. IL-1, IL-6, ICAM-1, NO, NAGL, and AGEs level in serum were detected by ELISA assay. The accumulation of AGEs in kidney tissue was examined by immunohistochemistry assay. The results showed that ES could decrease TG, T-CHO, LDL levels in serum of diabetic rats in a dose dependent manner. ES also decreased IL-1, IL-6, ICAM-1, NO and NGAL levels in serum of diabetic rats in a dose dependent manner. Furthermore, ES at 30 and 90 mg/kg significantly decreased AGEs level in serum and alleviated AGEs accumulation in renal in diabetic rats. Our findings indicate that ES could improve dyslipidemia, inflammation responses, renal damage in STZ-induced diabetic rats and the possible mechanism might be associated with the inhibition of AGEs formation.

How Does the Macula Protect Itself from Oxidative Stress?

PubMed Central

Handa, James T.

2012-01-01

Oxidative stress has been hypothesized to contribute to the development of age-related macular degeneration (AMD), the most common cause of blindness in the United States. At present, there is no treatment for early disease. Reactive oxygen species (ROS) play a physiological role in the retinal pigment epithelium (RPE), a key cell type in this disease, but with excessive ROS, oxidative damage or excessive innate immune system activation can result. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2. Impaired Nrf2 signaling can lead to oxidative damage or activate the innate immune response, both of which can lead to RPE apoptosis, a defining change in AMD. Several mouse models simulating environmental stressors or targeting specific antioxidant enzymes such as superoxide dismutase or Nrf2, have simulated some of the features of AMD. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the innate immune system through pattern recognition receptors (PRRs). The macula accumulates a number of OSEs including carboxyethylpyrrole, malondialdehyde, 4-hydroxynonenal, and advanced glycation endproducts, as well as their respective neutralizing PRRs. Excessive accumulation of OSEs results in pathologic immune activation. For example, mice immunized with the carboxyethylpyrrole develop cardinal features of AMD. Regulating ROS in the RPE by modulating antioxidant systems or neutralizing OSEs through an appropriate innate immune response are potential modalities to treat or prevent early AMD. PMID:22503691

How does the macula protect itself from oxidative stress?

PubMed

Handa, James T

2012-08-01

Oxidative stress has been hypothesized to contribute to the development of age-related macular degeneration (AMD), the most common cause of blindness in the United States. At present, there is no treatment for early disease. Reactive oxygen species (ROS) play a physiological role in the retinal pigment epithelium (RPE), a key cell type in this disease, but with excessive ROS, oxidative damage or excessive innate immune system activation can result. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2. Impaired Nrf2 signaling can lead to oxidative damage or activate the innate immune response, both of which can lead to RPE apoptosis, a defining change in AMD. Several mouse models simulating environmental stressors or targeting specific antioxidant enzymes such as superoxide dismutase or Nrf2, have simulated some of the features of AMD. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the innate immune system through pattern recognition receptors (PRRs). The macula accumulates a number of OSEs including carboxyethylpyrrole, malondialdehyde, 4-hydroxynonenal, and advanced glycation endproducts, as well as their respective neutralizing PRRs. Excessive accumulation of OSEs results in pathologic immune activation. For example, mice immunized with the carboxyethylpyrrole develop cardinal features of AMD. Regulating ROS in the RPE by modulating antioxidant systems or neutralizing OSEs through an appropriate innate immune response are potential modalities to treat or prevent early AMD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Damage instability and Earthquake nucleation

NASA Astrophysics Data System (ADS)

Ionescu, I. R.; Gomez, Q.; Campillo, M.; Jia, X.

2017-12-01

Earthquake nucleation (initiation) is usually associated to the loss of the stability of the geological structure under a slip-weakening friction acting on the fault. The key parameters involved in the stability of the fault are the stress drop, the critical slip distance but also the elastic stiffness of the surrounding materials (rocks). We want to explore here how the nucleation phenomena are correlated to the material softening during damage accumulation by dynamic and/or quasi-static processes. Since damage models are describing micro-cracks growth, which is generally an unstable phenomenon, it is natural to expect some loss of stability on the associated micro-mechanics based models. If the model accurately captures the material behavior, then this can be due to the unstable nature of the brittle material itself. We obtained stability criteria at the microscopic scale, which are related to a large class of damage models. We show that for a given continuous strain history the quasi-static or dynamic problems are instable or ill-posed (multiplicity of material responses) and whatever the selection rule is adopted, shocks (time discontinuities) will occur. We show that the quasi-static equilibria chosen by the "perfect delay convention" is always stable. These stability criteria are used to analyze how NIC (Non Interacting Crack) effective elasticity associated to "self similar growth" model work in some special configurations (one family of micro-cracks in mode I, II and III and in plane strain or plain stress). In each case we determine a critical crack density parameter and critical micro-crack radius (length) which distinguish between stable and unstable behaviors. This critical crack density depends only on the chosen configuration and on the Poisson ratio.

Absolute cross section for low-energy-electron damage to condensed macromolecules: A case study of DNA

PubMed Central

Rezaee, Mohammad; Cloutier, Pierre; Bass, Andrew D.; Michaud, Marc; Hunting, Darel J.; Sanche, Léon

2013-01-01

Cross sections (CSs) for the interaction of low-energy electrons (LEE) with condensed macromolecules are essential parameters for accurate modeling of radiation-induced molecular decomposition and chemical synthesis. Electron irradiation of dry nanometer-scale macromolecular solid films has often been employed to measure CSs and other quantitative parameters for LEE interactions. Since such films have thicknesses comparable with electron thermalization distances, energy deposition varies throughout the film. Moreover, charge accumulation occurring inside the films shields a proportion of the macromolecules from electron irradiation. Such effects complicate the quantitative comparison of the CSs obtained in films of different thicknesses and limit the applicability of such measurements. Here, we develop a simple mathematical model, termed the molecular survival model, that employs a CS for a particular damage process together with an attenuation length related to the total CS, to investigate how a measured CS might be expected to vary with experimental conditions. As a case study, we measure the absolute CS for the formation of DNA strand breaks (SBs) by electron irradiation at 10 and 100 eV of lyophilized plasmid DNA films with thicknesses between 10 and 30 nm. The measurements are shown to depend strongly on the thickness and charging condition of the nanometer-scale films. Such behaviors are in accord with the model and support its validity. Via this analysis, the CS obtained for SB damage is nearly independent of film thickness and charging effects. In principle, this model can be adapted to provide absolute CSs for electron-induced damage or reactions occurring in other molecular solids across a wider range of experimental conditions. PMID:23030950

Platelet-derived CXCL4 regulates neutrophil infiltration and tissue damage in severe acute pancreatitis.

PubMed

Wetterholm, Erik; Linders, Johan; Merza, Mohammed; Regner, Sara; Thorlacius, Henrik

2016-10-01

Platelets are known to play an important role in acute pancreatitis (AP) via promotion of neutrophil accumulation, although mechanisms behind platelet-dependent accumulation of neutrophils in the pancreas remain elusive. Platelets contain a wide spectrum of different pro-inflammatory compounds, such as chemokines. CXCL4 (platelet factor 4) is one of the most abundant chemokine in platelets, and we hypothesized that CXCL4 might be involved in platelet-dependent accumulation of neutrophils in the inflamed pancreas. The aim of this study was to examine the role of CXCL4 in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine in C57BL/6 mice. Animals were treated with an antibody against platelets or CXCL4 before induction of pancreatitis. Plasma and lung levels of CXCL2, CXCL4, and interleukin (IL)-6 were determined by use of enzyme-linked immunosorbent assay. Flow cytometry was used to examine surface expression of macrophage-1 (Mac-1) on neutrophils. Plasma was obtained from healthy individuals (controls) and patients with AP. Challenge with taurocholate increased plasma levels of CXCL4, and depletion of platelets markedly reduced plasma levels of CXCL4 indicating that circulating levels of CXCL4 are mainly derived from platelets in AP. Inhibition of CXCL4 reduced taurocholate-induced neutrophil recruitment, IL-6 secretion, edema formation, amylase release, and tissue damage in the pancreas. However, immunoneutralization of CXCL4 had no effect on CXCL2-evoked neutrophil expression of Mac-1 or chemotaxis in vitro, suggesting an indirect effect of CXCL4 on neutrophil recruitment in AP. Targeting CXCL4 significantly attenuated plasma and lung levels of CXCL2, which is a potent neutrophil chemoattractant, and inhibition of the CXCL2 receptor attenuated neutrophil infiltration and tissue damage in the inflamed pancreas. A significant role of CXCL4 was confirmed in an alternate model of AP induced by L-arginine challenge. Moreover, patients with AP had significantly increased plasma levels of CXCL4 compared with healthy controls. These findings' results suggest that platelet-derived CXCL4 is a potent stimulator of neutrophil accumulation in AP and that this is mediated via generation of CXCL2 in the inflamed pancreas. We conclude that CXCL4 plays an important role in pancreatic inflammation and that targeting CXCL4 might be a useful way to ameliorate tissue damage in AP. Copyright © 2016 Elsevier Inc. All rights reserved.

Rescuing iron-overloaded macrophages by conservative relocation of the accumulated metal

PubMed Central

Sohn, Yang-Sung; Mitterstiller, Anna-Maria; Breuer, William; Weiss, Guenter; Cabantchik, Z Ioav

2011-01-01

BACKGROUND AND PURPOSE Systemic iron deficiency concomitant with macrophage iron retention is characteristic of iron-refractory anaemias associated with chronic disease. The systemic misdistribution of iron, which is further exacerbated by parenteral iron supplementation, is mainly attributable to iron retention exerted on resident macrophages by hepcidin-mediated down-regulation of the iron exporter ferroportin. We aimed at developing an experimental macrophage-based cell model that recapitulates pathophysiological features of iron misdistribution found in chronic disorders and use it as a screening platform for identifying agents with the potential for relocating the accumulated metal and restoring affected functions. EXPERIMENTAL APPROACH A RAW macrophage subline was selected as cell model of iron retention based on their capacity to take up polymeric iron or aged erythrocytes excessively, resulting in a demonstrable increase of cell labile iron pools and oxidative damage that are aggravated by hepcidin. KEY RESULTS This model provided a three-stage high throughput screening platform for identifying agents with the combined ability to: (i) scavenge cell iron and thereby rescue macrophage cells damaged by iron-overload; (ii) bypass the ferroportin blockade by conveying the scavenged iron to other iron-starved cells in co-culture via transferrin but (iii) without promoting utilization of the scavenged iron by intracellular pathogens. As test agents we used chelators in clinical practice and found the oral chelator deferiprone fulfilled essentially all of the three criteria. CONCLUSIONS AND IMPLICATIONS We provide a proof of principle for conservative iron relocation as complementary therapeutic approach for correcting the misdistribution of iron associated with chronic disease and exacerbated by parenteral iron supplementation. PMID:21091647

Exploring the impact of wounding and jasmonates on ascorbate metabolism

PubMed Central

Suza, Walter P.; Avila, Carlos A.; Carruthers, Kelly; Kulkarni, Shashank; Goggin, Fiona L.; Lorence, Argelia

2010-01-01

Vitamin C (ascorbate, AsA) is the most abundant water-soluble antioxidant in plants. Ascorbate provides the first line of defense against damaging reactive oxygen species (ROS), and helps protect plant cells from many factors that induce oxidative stress, including wounding, ozone, high salinity, and pathogen attack. Plant defenses against these stresses are also dependent upon jasmonates (JAs), a class of plant hormones that promote ROS accumulation. Here, we review evidence showing that wounding and JAs influence AsA accumulation in various plant species, and we report new data from Arabidopsis and tomato testing the influence of JAs on AsA levels in wounded and unwounded plants. In both species, certain mutations that impair JA metabolism and signaling influence foliar AsA levels, suggesting that endogenous JAs may regulate steady-state AsA. However, the impact of wounding on AsA accumulation was similar in JA mutants and wild type controls, indicating that this wound response does not require JAs. Our findings also indicate that the effects of wounding and JAs on AsA accumulation differ between species; these factors both enhanced AsA accumulation in Arabidopsis, but depressed AsA levels in tomato. These results underscore the importance of obtaining data from more than one model species, and demonstrate the complexity of AsA regulation. PMID:20346686

ANALYSIS OF BORON DILUTION TRANSIENTS IN PWRS.

DOE Office of Scientific and Technical Information (OSTI.GOV)

DIAMOND,D.J.BROMLEY,B.P.ARONSON,A.L.

2004-02-04

A study has been carried out with PARCS/RELAP5 to understand the consequences of hypothetical boron dilution events in pressurized water reactors. The scenarios of concern start with a small-break loss-of-coolant accident. If the event leads to boiling in the core and then the loss of natural circulation, a boron-free condensate can accumulate in the cold leg. The dilution event happens when natural circulation is re-established or a reactor coolant pump (RCP) is restarted in violation of operating procedures. This event is of particular concern in B&W reactors with a lowered-loop design and is a Generic Safety Issue for the U.S.more » Nuclear Regulatory Commission. The results of calculations with the reestablishment of natural circulation show that there is no unacceptable fuel damage. This is determined by calculating the maximum fuel pellet enthalpy, based on the three-dimensional model, and comparing it with the criterion for damage. The calculation is based on a model of a B&W reactor at beginning of the fuel cycle. If an RCP is restarted, unacceptable fuel damage may be possible in plants with sufficiently large volumes of boron-free condensate in the cold leg.« less

Electronic excitations and their effect on the interionic forces in simulations of radiation damage in metals.

PubMed

Race, C P; Mason, D R; Sutton, A P

2009-03-18

Using time-dependent tight-binding simulations of radiation damage cascades in a model metal we directly investigate the nature of the excitations of a system of quantum mechanical electrons in response to the motion of a set of classical ions. We furthermore investigate the effect of these excitations on the attractive electronic forces between the ions. We find that the electronic excitations are well described by a Fermi-Dirac distribution at some elevated temperature, even in the absence of the direct electron-electron interactions that would be required in order to thermalize a non-equilibrium distribution. We explain this result in terms of the spectrum of characteristic frequencies of the ionic motion. Decomposing the electronic force into four well-defined components within the basis of instantaneous electronic eigenstates, we find that the effect of accumulated excitations in weakening the interionic bonds is mostly (95%) accounted for by a thermal model for the electronic excitations. This result justifies the use of the simplifying assumption of a thermalized electron system in simulations of radiation damage with an electronic temperature dependence and in the development of temperature-dependent classical potentials.

A dual role of p21 in stem cell aging.

PubMed

Ju, Zhenyu; Choudhury, Aaheli Roy; Rudolph, K Lenhard

2007-04-01

A decline in adult stem cell function occurs during aging, likely contributing to the decline in organ homeostasis and regeneration with age. An emerging field in aging research is to analyze molecular pathways limiting adult stem cell function in response to macromolecular damage accumulation during aging. Current data suggest that the p21 cell cycle inhibitor has a dual role in stem cell aging: On one hand, p21 protects adult stem cells from acute genotoxic stress by preventing inappropriate cycling of acutely damaged stem cells. On the other hand, p21 activation impairs stem cell function and survival of aging telomere dysfunctional mice indicating that p21 checkpoint function is disadvantageous in the context of chronic and persistent damage, which accumulates during aging. This article focuses on these dual roles of p21 in aging stem cells.

Effect of ionizing radiation exposure on Trypanosoma cruzi ubiquitin-proteasome system.

PubMed

Cerqueira, Paula G; Passos-Silva, Danielle G; Vieira-da-Rocha, João P; Mendes, Isabela Cecilia; de Oliveira, Karla A; Oliveira, Camila F B; Vilela, Liza F F; Nagem, Ronaldo A P; Cardoso, Joseane; Nardelli, Sheila C; Krieger, Marco A; Franco, Glória R; Macedo, Andrea M; Pena, Sérgio D J; Schenkman, Sérgio; Gomes, Dawidson A; Guerra-Sá, Renata; Machado, Carlos R

2017-03-01

In recent years, proteasome involvement in the damage response induced by ionizing radiation (IR) became evident. However, whether proteasome plays a direct or indirect role in IR-induced damage response still unclear. Trypanosoma cruzi is a human parasite capable of remarkable high tolerance to IR, suggesting a highly efficient damage response system. Here, we investigate the role of T. cruzi proteasome in the damage response induced by IR. We exposed epimastigotes to high doses of gamma ray and we analyzed the expression and subcellular localization of several components of the ubiquitin-proteasome system. We show that proteasome inhibition increases IR-induced cell growth arrest and proteasome-mediated proteolysis is altered after parasite exposure. We observed nuclear accumulation of 19S and 20S proteasome subunits in response to IR treatments. Intriguingly, the dynamic of 19S particle nuclear accumulation was more similar to the dynamic observed for Rad51 nuclear translocation than the observed for 20S. In the other hand, 20S increase and nuclear translocation could be related with an increase of its regulator PA26 and high levels of proteasome-mediated proteolysis in vitro. The intersection between the opposed peaks of 19S and 20S protein levels was marked by nuclear accumulation of both 20S and 19S together with Ubiquitin, suggesting a role of ubiquitin-proteasome system in the nuclear protein turnover at the time. Our results revealed the importance of proteasome-mediated proteolysis in T. cruzi IR-induced damage response suggesting that proteasome is also involved in T. cruzi IR tolerance. Moreover, our data support the possible direct/signaling role of 19S in DNA damage repair. Based on these results, we speculate that spatial and temporal differences between the 19S particle and 20S proteasome controls proteasome multiple roles in IR damage response. Copyright © 2017 Elsevier B.V. All rights reserved.

Oxidative stress, aging, and central nervous system disease in the canine model of human brain aging.

PubMed

Head, Elizabeth; Rofina, Jaime; Zicker, Steven

2008-01-01

Decline in cognitive functions that accompany aging in dogs may have a biologic basis, and many of the disorders associated with aging in dogs may be mitigated through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of laboratory and clinical studies, antioxidants may be one class of nutraceutical that provides benefits to aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which may lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes may lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs.

Two-stage synergy of electronic energy loss with defects in LiTaO 3 under ion irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sellami, Neila; Crespillo, Miguel L.; Zhang, Yanwen

Understanding energy dissipation in electronic and atomic subsystems and subsequent defect evolution is a scientific challenge. Separate and combined effects of electronic and nuclear energy deposition in z-cut LiTaO 3 have been investigated. Irradiation of pristine LiTaO 3 samples with 2 MeV Ta ions leads to amorphization due to atomic displacement damage, described by a disorder accumulation model. Here, while 21 MeV Si ions do not produce significant damage in pristine LiTaO 3, introduction of pre-existing defects sensitizes LiTaO 3 to the formation of ion tracks from the electronic energy loss by 21 MeV Si ions that induce a synergisticmore » two-stage phase transition process.« less

Two-stage synergy of electronic energy loss with defects in LiTaO 3 under ion irradiation

DOE PAGES

Sellami, Neila; Crespillo, Miguel L.; Zhang, Yanwen; ...

2018-03-27

Understanding energy dissipation in electronic and atomic subsystems and subsequent defect evolution is a scientific challenge. Separate and combined effects of electronic and nuclear energy deposition in z-cut LiTaO 3 have been investigated. Irradiation of pristine LiTaO 3 samples with 2 MeV Ta ions leads to amorphization due to atomic displacement damage, described by a disorder accumulation model. Here, while 21 MeV Si ions do not produce significant damage in pristine LiTaO 3, introduction of pre-existing defects sensitizes LiTaO 3 to the formation of ion tracks from the electronic energy loss by 21 MeV Si ions that induce a synergisticmore » two-stage phase transition process.« less

Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates

USDA-ARS?s Scientific Manuscript database

The xanthophyll pigments lutein and zeaxanthin cross the blood-retina barrier to preferentially accumulate in the macular region of the neural retina. There they form macular pigment, protecting the retina from blue light damage and oxidative stress. Lutein and zeaxanthin also accumulate in brain t...

Trichothecene-Genotypes Play a Role in Fusarium Head Blight Disease Spread and Trichothecene Accumulation in Wheat

USDA-ARS?s Scientific Manuscript database

In the current study, we evaluated the impact of the observed North American evolutionary shift in the Fusarium graminearum complex on disease spread, kernel damage, and trichothecene accumulation in resistant and susceptible wheat genotypes. Four inocula were prepared using composites of F. gramin...

Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats

USDA-ARS?s Scientific Manuscript database

An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts...

Antioxidant enzymatic activity is linked to waterlogging stress tolerance in citrus.

PubMed

Arbona, Vicent; Hossain, Zahed; López-Climent, María F; Pérez-Clemente, Rosa M; Gómez-Cadenas, Aurelio

2008-04-01

Soil flooding constitutes a seasonal factor that negatively affects plant performance and crop yields. In this work, the relationship between oxidative damage and flooding sensitivity was addressed in three citrus genotypes with different abilities to tolerate waterlogging. We examined leaf visible damage, oxidative damage in terms of malondialdehyde (MDA) concentration, leaf proline concentration, leaf and root ascorbate and glutathione contents and the antioxidant enzyme activities superoxide dismutase (EC 1.15.1.1), ascorbate peroxidase (EC 1.11.1.11), catalase (EC 1.11.1.6) and glutathione reductase (EC 1.8.1.7). No differences in the extent of oxidative damage relative to controls were found among genotypes. However, a different ability to delay the apparition of oxidative damage was associated to a higher tolerance to waterlogging. This ability was linked to an enhanced activated oxygen species' scavenging capacity in terms of an increased antioxidant enzyme activity and higher content in polar antioxidant compounds. Therefore, the existence of a direct relationship between stress sensitivity and the early accumulation of MDA is proposed. In addition, data indicate that the protective role of proline has to be considered minimal as its accumulation was inversely correlated with tolerance to the stress. The positive antioxidant response in Carrizo citrange (Poncirus trifoliata L. Raf. x Citrus sinensis L. Osb.) and Citrumelo CPB 4475 (Poncirus trifoliata L. Raf. x Citrus paradisi L. Macf.) might be responsible for a higher tolerance to flooding stress, whereas in Cleopatra mandarin (Citrus reshni Hort. Ex Tan.), the early accumulation of MDA seems to be associated to an impaired ability for H2O2 scavenging.

Empirical constraints on the effects of radiation damage on helium diffusion in zircon

NASA Astrophysics Data System (ADS)

Anderson, Alyssa J.; Hodges, Kip V.; van Soest, Matthijs C.

2017-12-01

In this study, we empirically evaluate the impact of radiation damage on zircon (U-Th)/He closure temperatures for a suite of zircon crystals from the slowly cooled McClure Mountain syenite of south-central Colorado, USA. We present new zircon, titanite, and apatite conventional (U-Th)/He dates, zircon laser ablation (U-Th)/He and U-Pb dates, and zircon Raman spectra for crystals from the syenite. Titanite and apatite (U-Th)/He dates range from 447 to 523 Ma and 88.0 to 138.9 Ma, respectively, and display no clear correlation between (U-Th)/He date and effective uranium concentration. Conventional zircon (U-Th)/He dates range from 230.3 to 474 Ma, while laser ablation zircon (U-Th)/He dates show even greater dispersion, ranging from 5.31 to 520 Ma. Dates from both zircon (U-Th)/He datasets decrease with increasing alpha dose, indicating that most of the dispersion can be attributed to radiation damage. Alpha dose values for the dated zircon crystals range from effectively zero to 2.15 × 1019 α /g, spanning the complete damage spectrum. We use an independently constrained thermal model to empirically assign a closure temperature to each dated zircon grain. If we assume that this thermal model is robust, the zircon radiation damage accumulation and annealing model of Guenthner et al. (2013) does not accurately predict closure temperatures for many of the analyzed zircon crystals. Raman maps of the zircons dated by laser ablation document complex radiation damage zoning, sometimes revealing crystalline zones in grains with alpha dose values suggestive of amorphous material. Such zoning likely resulted in heterogeneous intra-crystalline helium diffusion and may help explain some of the discrepancies between our empirical findings and the Guenthner et al. (2013) model predictions. Because U-Th zoning is a common feature in zircon, radiation damage zoning is likely to be a concern for most ancient, slowly cooled zircon (U-Th)/He datasets. Whenever possible, multiple mineral-isotopic systems should be employed to add additional, independent constraints to a sample's thermal history.

Gold in the hills: patterns of placer gold accumulation under dynamic tectonic and climatic conditions

NASA Astrophysics Data System (ADS)

Roy, Sam; Upton, Phaedra; Craw, Dave

2018-01-01

Formation of placer accumulations in fluvial environments requires 103-106 or even greater times concentration of heavy minerals. For this to occur, regular sediment supply from erosion of adjacent topography is required, the river should remain within a single course for an extended period of time and the material must be reworked such that a high proportion of the sediment is removed while a high proportion of the heavy minerals remains. We use numerical modeling, constrained by observations of circum-Pacific placer gold deposits, to explore processes occurring in evolving river systems in dynamic tectonic environments. A fluvial erosion/transport model is used to determine the mobility of placer gold under variable uplift rate, storm intensity, and rock mass strength conditions. Gold concentration is calculated from hydraulic and bedload grain size conditions. Model results suggest that optimal gold concentration occurs in river channels that frequently approach a threshold between detachment-limited and transport-limited hydraulic conditions. Such a condition enables the accumulation of gold particles within the framework of a residual gravel lag. An increase in transport capacity, which can be triggered by faster uplift rates, more resistant bedrock, or higher intensity storm events, will strip all bedload from the channel. Conversely, a reduction in transport capacity, triggered by a reduction in uplift rate, bedrock resistance, or storm intensity, will lead to a greater accumulation of a majority of sediments and a net decrease in gold concentration. For our model parameter range, the optimal conditions for placer gold concentration are met by 103 times difference in strength between bedrock and fault, uplift rates between 1 and 5 mm a-1, and moderate storm intensities. Fault damage networks are shown to be a critical factor for high Au concentrations and should be a target for exploration.

In situ micropillar compression reveals superior strength and ductility but an absence of damage in lamellar bone

NASA Astrophysics Data System (ADS)

Schwiedrzik, Jakob; Raghavan, Rejin; Bürki, Alexander; Lenader, Victor; Wolfram, Uwe; Michler, Johann; Zysset, Philippe

2014-07-01

Ageing societies suffer from an increasing incidence of bone fractures. Bone strength depends on the amount of mineral measured by clinical densitometry, but also on the micromechanical properties of the hierarchical organization of bone. Here, we investigate the mechanical response under monotonic and cyclic compression of both single osteonal lamellae and macroscopic samples containing numerous osteons. Micropillar compression tests in a scanning electron microscope, microindentation and macroscopic compression tests were performed on dry ovine bone to identify the elastic modulus, yield stress, plastic deformation, damage accumulation and failure mechanisms. We found that isolated lamellae exhibit a plastic behaviour, with higher yield stress and ductility but no damage. In agreement with a proposed rheological model, these experiments illustrate a transition from a ductile mechanical behaviour of bone at the microscale to a quasi-brittle response driven by the growth of cracks along interfaces or in the vicinity of pores at the macroscale.

Investigation of Tapered Roller Bearing Damage Detection Using Oil Debris Analysis

NASA Technical Reports Server (NTRS)

Dempsey, Paula J.; Krieder, Gary; Fichter, Thomas

2006-01-01

A diagnostic tool was developed for detecting fatigue damage to tapered roller bearings. Tapered roller bearings are used in helicopter transmissions and have potential for use in high bypass advanced gas turbine aircraft engines. This diagnostic tool was developed and evaluated experimentally by collecting oil debris data from failure progression tests performed by The Timken Company in their Tapered Roller Bearing Health Monitoring Test Rig. Failure progression tests were performed under simulated engine load conditions. Tests were performed on one healthy bearing and three predamaged bearings. During each test, data from an on-line, in-line, inductance type oil debris sensor was monitored and recorded for the occurrence of debris generated during failure of the bearing. The bearing was removed periodically for inspection throughout the failure progression tests. Results indicate the accumulated oil debris mass is a good predictor of damage on tapered roller bearings. The use of a fuzzy logic model to enable an easily interpreted diagnostic metric was proposed and demonstrated.

A review of typical thermal fatigue failure models for solder joints of electronic components

NASA Astrophysics Data System (ADS)

Li, Xiaoyan; Sun, Ruifeng; Wang, Yongdong

2017-09-01

For electronic components, cyclic plastic strain makes it easier to accumulate fatigue damage than elastic strain. When the solder joints undertake thermal expansion or cold contraction, different thermal strain of the electronic component and its corresponding substrate is caused by the different coefficient of thermal expansion of the electronic component and its corresponding substrate, leading to the phenomenon of stress concentration. So repeatedly, cracks began to sprout and gradually extend [1]. In this paper, the typical thermal fatigue failure models of solder joints of electronic components are classified and the methods of obtaining the parameters in the model are summarized based on domestic and foreign literature research.

Cells with impaired mitochondrial H2O2 sensing generate less •OH radicals and live longer.

PubMed

Martins, Dorival; Titorenko, Vladimir I; English, Ann M

2014-10-01

Mitochondria are major sites of reactive oxygen species (ROS) generation, and adaptive mitochondrial ROS signaling extends longevity. We aim at linking the genetic manipulation of mitochondrial H2O2 sensing in live cells to mechanisms driving aging in the model organism, Saccharomyces cerevisiae. To this end, we compare in vivo ROS (O2(•-), H2O2 and (•)OH) accumulation, antioxidant enzyme activities, labile iron levels, GSH depletion, and protein oxidative damage during the chronological aging of three yeast strains: ccp1Δ that does not produce the mitochondrial H2O2 sensor protein, cytochrome c peroxidase (Ccp1); ccp1(W191F) that produces a hyperactive variant of this sensor protein (Ccp1(W191F)); and the isogenic wild-type strain. Since they possess elevated manganese superoxide dismutase (Sod2) activity, young ccp1Δ cells accumulate low mitochondrial superoxide (O2(•-)) levels but high H2O2 levels. These cells exhibit stable aconitase activity and contain low amounts of labile iron and hydroxyl radicals ((•)OH). Furthermore, they undergo late glutathione (GSH) depletion, less mitochondrial protein oxidative damage and live longer than wild-type cells. In contrast, young ccp1(W191F) cells accumulate little H2O2, possess depressed Sod2 activity, enabling their O2(•-) level to spike and deactivate aconitase, which, ultimately, leads to greater mitochondrial oxidative damage, early GSH depletion, and a shorter lifespan than wild-type cells. Modulation of mitochondrial H2O2 sensing offers a novel interventional approach to alter mitochondrial H2O2 levels in live cells and probe the pro- versus anti-aging effects of ROS. The strength of mitochondrial H2O2 sensing modulates adaptive mitochondrial ROS signaling and, hence, lifespan.

Characterization and Modeling of Asphalt Binder Fatigue

NASA Astrophysics Data System (ADS)

Safaei, Farinaz

Fatigue cracking is a primary distress in asphalt pavements caused by the accumulation of damage under repeated traffic loading. Many factors influence fatigue damage in pavements, including pavement structure, environmental conditions, and asphalt mixture volumetric properties. Asphalt binder is the weakest asphalt concrete constituent and, thus, plays a critical role in determining the fatigue resistance of pavements. Therefore, the ability to characterize and model the inherent fatigue performance of an asphalt binder is a necessary first step to design. A comprehensive understanding and prediction of asphalt binder fatigue performance require a suitable experiment coupled with a model to predict how the binder will perform under various traffic, temperature, and structural conditions encountered in the field. The simplified viscoelastic continuum damage (S-VECD) model has been used successfully by researchers to predict the damage evolution in asphalt mixtures for various traffic and climatic conditions using limited uniaxial test data. Although the literature shows promise for applying VECD modeling to asphalt binder fatigue, the past efforts have several shortcomings. It has been demonstrated that flow and adhesion loss can impede DSR fatigue test results. Thus, definition of test conditions (e.g., temperature) where cyclic DSR tests are appropriate for fatigue characterization of binders is necessary. In addition, the applicability of the model to predict fatigue performance under varying loading and thermal history has not been rigorously evaluated. Furthermore, the effects of material nonlinearity have been largely neglected in past modeling efforts for simplicity. In addition, past efforts have employed the parallel plate DSR geometry for the fatigue characterization of asphalt binders. In the parallel plate geometry, the strain depends on the radial distance from the specimen center. Therefore, the material will fail at different rates as a function of radial location. Past efforts have neglected the radial strain gradient, using the apparent shear stress at the sample edge to infer fatigue damage and derive S-VECD model parameters. Apparent edge stress is calculated using linear mapping to the total torque, which is erroneous in the presence of material or geometric nonlinearities (such as cracking). This study seeks to overcome the aforementioned shortcomings of past efforts to improve the ability to characterize and predict asphalt binder fatigue.

Dynamic Scaling of Lipofuscin Deposition in Aging Cells

NASA Astrophysics Data System (ADS)

Family, Fereydoon; Mazzitello, K. I.; Arizmendi, C. M.; Grossniklaus, H. E.

2011-07-01

Lipofuscin is a membrane-bound cellular waste that can be neither degraded nor ejected from the cell but can only be diluted through cell division and subsequent growth. The fate of postmitotic (non-dividing) cells such as neurons, cardiac myocytes, skeletal muscle fibers, and retinal pigment epithelial cells (RPE) is to accumulate lipofuscin, which as an "aging pigment" has been considered a reliable biomarker for the age of cells. Environmental stress can accelerate the accumulation of lipofuscin. For example, accumulation in brain cells appears to be an important issue connected with heavy consumption of alcohol. Lipofuscin is made of free-radical-damaged protein and fat, whose abnormal accumulation is related to a range of disorders including Type IV mucolipidosis (ML4), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson disease, and age-related macular degeneration (AMD) which is the leading cause of blindness beyond the age of 50 years. The study of lipofuscin formation and growth is important, because of their association with cellular aging. We introduce a model of non-equilibrium cluster growth and aggregation that we have developed for studying the formation and growth of lipofuscin. As an example of lipofuscin deposit in a given kind of postmitotic cell, we study the kinetics of lipofuscin growth in a RPE cell. Our results agree with a linear growth of the number of lipofuscin granules with age. We apply the dynamic scaling approach to our model and find excellent data collapse for the cluster size distribution. An unusual feature of our model is that while small particles are removed from the cell the larger ones become fixed and grow by aggregation.

Glaze Damage In 13- To 18-Year-Old, Natural, Even-Aged Stands of Loblolly Pines in Southeastern Arkansas

Treesearch

Michael D. Cain; Michael G. Shelton

2002-01-01

In late December 1998, a severe winter storm deposited 2.1 inches of precipitation on the Crossett Experimental Forest in southeastern Arkansas. Ice, in the form of glaze, accumulated on needles and branches of trees, and resulted in visual damage to sapling and pulpwood-sized pines. Within 60 days after the storm, damage was assessed within naturally regenerated,...

Creep rupture analysis of a beam resting on high temperature foundation

NASA Technical Reports Server (NTRS)

Gu, Randy J.; Cozzarelli, Francis A.

1988-01-01

A simplified uniaxial strain controlled creep damage law is deduced with the use of experimental observation from a more complex strain dependent law. This creep damage law correlates the creep damage, which is interpreted as the density variation in the material, directly with the accumulated creep strain. Based on the deduced uniaxial strain controlled creep damage law, a continuum mechanical creep rupture analysis is carried out for a beam resting on a high temperature elastic (Winkler) foundation. The analysis includes the determination of the nondimensional time for initial rupture, the propagation of the rupture front with the associated thinning of the beam, and the influence of creep damage on the deflection of the beam. Creep damage starts accumulating in the beam as soon as the load is applied, and a creep rupture front develops at and propagates from the point at which the creep damage first reaches its critical value. By introducing a series of fundamental assumptions within the framework of technical Euler-Bernoulli type beam theory, a governing set of integro-differential equations is derived in terms of the nondimensional bending moment and the deflection. These governing equations are subjected to a set of interface conditions at the propagating rupture front. A numerical technique is developed to solve the governing equations together with the interface equations, and the computed results are presented and discussed in detail.

Inhibitory effect of Piper betel leaf extracts on copper-mediated LDL oxidation and oxLDL-induced lipid accumulation via inducing reverse cholesterol transport in macrophages.

PubMed

Ma, Gwo-Chin; Wu, Pei-Fang; Tseng, Hsien-Chun; Chyau, Charng-Cherng; Lu, Hsiu-Chin; Chou, Fen-Pi

2013-12-15

Piper betel leaf (PBL) has the biological capabilities of detoxification and can work as an anti-inflammatory agent and an anti-oxidant. In this study, we evaluated the anti-oxidative activity of the extract of Piper betel leaves (PBLs) on the basis of Cu(2+)-mediated oxidation, and its ability to prevent foam cell formation in a model for oxidised low density lipoprotein (oxLDL)-induced lipid accumulation in macrophages. Our data demonstrated that PBLs were able to inhibit LDL oxidation in vitro and are able to reduce the lipid accumulation in macrophages. We showed the underlying mechanisms to be the following: PBLs up-regulated the protein levels of the class A and class B scavenger receptors, the membrane lipid transporter ABCA1, and its upstream regulator Liver X receptor (LXR) in the macrophages exposed to oxLDL. The results suggested that PBLs activated the reverse cholesterol transport mechanism to enhance the metabolism of the oxLDL that could prevent both lipid accumulation and foam cell formation and further minimise the possible damage of vessels caused by the oxLDL. Copyright © 2013 Elsevier Ltd. All rights reserved.

X ray attenuation measurements for high-temperature materials characterization and in-situ monitoring of damage accumulation. Ph.D. Thesis - Cleveland State Univ., 1991

NASA Technical Reports Server (NTRS)

Baaklini, George Y.

1992-01-01

The scope of this dissertation is to develop and apply x ray attenuation measurement systems that are capable of: (1) characterizing density variations in high-temperature materials, e.g., monolithic ceramics, ceramic and intermetallic matrix composites, and (2) noninvasively monitoring damage accumulation and failure sequences in ceramic matrix composites under room temperature tensile testing. This dissertation results in the development of: (1) a point scan digital radiography system, and (2) an in-situ x ray material testing system. Radiographic evaluation before, during, and after loading shows the effect of preexisting volume flaws on the fracture behavior of composites. Results show that x ray film radiography can monitor damage accumulation during tensile loading. Matrix cracking, fiber matrix debonding, fiber bridging, and fiber pullout are imaged throughout the tensile loading of the specimens. Further in-situ radiography is found to be a practical technique for estimating interfacial shear strength between the silicon carbide fibers and the reaction bonded silicon nitride matrix. It is concluded that pretest, in-situ, and post test x ray imaging can provide for greater understanding of ceramic matrix composite mechanical behavior.

Gray Matter Pathology in MS: Neuroimaging and Clinical Correlations

PubMed Central

Honce, Justin Morris

2013-01-01

It is abundantly clear that there is extensive gray matter pathology occurring in multiple sclerosis. While attention to gray matter pathology was initially limited to studies of autopsy specimens and biopsies, the development of new MRI techniques has allowed assessment of gray matter pathology in vivo. Current MRI techniques allow the direct visualization of gray matter demyelinating lesions, the quantification of diffuse damage to normal appearing gray matter, and the direct measurement of gray matter atrophy. Gray matter demyelination (both focal and diffuse) and gray matter atrophy are found in the very earliest stages of multiple sclerosis and are progressive over time. Accumulation of gray matter damage has substantial impact on the lives of multiple sclerosis patients; a growing body of the literature demonstrates correlations between gray matter pathology and various measures of both clinical disability and cognitive impairment. The effect of disease modifying therapies on the rate accumulation of gray matter pathology in MS has been investigated. This review focuses on the neuroimaging of gray matter pathology in MS, the effect of the accumulation of gray matter pathology on clinical and cognitive disability, and the effect of disease-modifying agents on various measures of gray matter damage. PMID:23878736

Photothermal damage is correlated to the delivery rate of time-integrated temperature

NASA Astrophysics Data System (ADS)

Denton, Michael L.; Noojin, Gary D.; Gamboa, B. Giovanna; Ahmed, Elharith M.; Rockwell, Benjamin A.

2016-03-01

Photothermal damage rate processes in biological tissues are usually characterized by a kinetics approach. This stems from experimental data that show how the transformation of a specified biological property of cells or biomolecule (plating efficiency for viability, change in birefringence, tensile strength, etc.) is dependent upon both time and temperature. However, kinetic methods require determination of kinetic rate constants and knowledge of substrate or product concentrations during the reaction. To better understand photothermal damage processes we have identified temperature histories of cultured retinal cells receiving minimum lethal thermal doses for a variety of laser and culture parameters. These "threshold" temperature histories are of interest because they inherently contain information regarding the fundamental thermal dose requirements for damage in individual cells. We introduce the notion of time-integrated temperature (Tint) as an accumulated thermal dose (ATD) with units of °C s. Damaging photothermal exposure raises the rate of ATD accumulation from that of the ambient (e.g. 37 °C) to one that correlates with cell death (e.g. 52 °C). The degree of rapid increase in ATD (ΔATD) during photothermal exposure depends strongly on the laser exposure duration and the ambient temperature.

Undulator Radiation Damage Experience at LCLS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nuhn, H. D.; Field, C.; Mao, S.

2015-01-06

The SLAC National Accelerator Laboratory has been running the Linac Coherent Light Source (LCLS), the first x-ray Free Electron Laser since 2009. Undulator magnet damage from radiation, produced by the electron beam traveling through the 133-m long straight vacuum tube, has been and is a concern. A damage measurement experiment has been performed in 2007 in order to obtain dose versus damage calibrations. Radiation reduction and detection devices have been integrated into the LCLS undulator system. The accumulated radiation dose rate was continuously monitored and recorded. In addition, undulator segments have been routinely removed from the beamline to be checkedmore » for magnetic (50 ppm, rms) and mechanic (about 0.25 µm, rms) changes. A reduction in strength of the undulator segments is being observed, at a level, which is now clearly above the noise. Recently, potential sources for the observed integrated radiation levels have been investigated. The paper discusses the results of these investigation as well as comparison between observed damage and measured dose accumulations and discusses, briefly, strategies for the new LCLS-II upgrade, which will be operating at more than 300 times larger beam rate.« less

Simulating irradiation hardening in tungsten under fast neutron irradiation including Re production by transmutation

NASA Astrophysics Data System (ADS)

Huang, Chen-Hsi; Gilbert, Mark R.; Marian, Jaime

2018-02-01

Simulations of neutron damage under fusion energy conditions must capture the effects of transmutation, both in terms of accurate chemical inventory buildup as well as the physics of the interactions between transmutation elements and irradiation defect clusters. In this work, we integrate neutronics, primary damage calculations, molecular dynamics results, Re transmutation calculations, and stochastic cluster dynamics simulations to study neutron damage in single-crystal tungsten to mimic divertor materials. To gauge the accuracy and validity of the simulations, we first study the material response under experimental conditions at the JOYO fast reactor in Japan and the High Flux Isotope Reactor at Oak Ridge National Laboratory, for which measurements of cluster densities and hardening levels up to 2 dpa exist. We then provide calculations under expected DEMO fusion conditions. Several key mechanisms involving Re atoms and defect clusters are found to govern the accumulation of irradiation damage in each case. We use established correlations to translate damage accumulation into hardening increases and compare our results to the experimental measurements. We find hardening increases in excess of 5000 MPa in all cases, which casts doubts about the integrity of W-based materials under long-term fusion exposure.

Thermomechanical Fatigue of Ductile Cast Iron and Its Life Prediction

NASA Astrophysics Data System (ADS)

Wu, Xijia; Quan, Guangchun; MacNeil, Ryan; Zhang, Zhong; Liu, Xiaoyang; Sloss, Clayton

2015-06-01

Thermomechanical fatigue (TMF) behaviors of ductile cast iron (DCI) were investigated under out-of-phase (OP), in-phase (IP), and constrained strain-control conditions with temperature hold in various temperature ranges: 573 K to 1073 K, 723 K to 1073 K, and 433 K to 873 K (300 °C to 800 °C, 450 °C to 800 °C, and 160 °C to 600 °C). The integrated creep-fatigue theory (ICFT) model was incorporated into the finite element method to simulate the hysteresis behavior and predict the TMF life of DCI under those test conditions. With the consideration of four deformation/damage mechanisms: (i) plasticity-induced fatigue, (ii) intergranular embrittlement, (iii) creep, and (iv) oxidation, as revealed from the previous study on low cycle fatigue of the material, the model delineates the contributions of these physical mechanisms in the asymmetrical hysteresis behavior and the damage accumulation process leading to final TMF failure. This study shows that the ICFT model can simulate the stress-strain response and life of DCI under complex TMF loading profiles (OP and IP, and constrained with temperature hold).

Cascades in model steels: The effect of cementite (Fe3C) and Cr23C6 particles on short-term crystal damage

NASA Astrophysics Data System (ADS)

Henriksson, K. O. E.

2015-06-01

Ferritic stainless steel can be modeled as an iron matrix containing precipitates of cementite (Fe3C) and Cr23C6. When used in nuclear power production the steels in the vicinity of the core start to accumulate damage due to neutrons. The role of the afore-mentioned carbides in this process is not well understood. In order to clarify the situation bulk cascades created by primary recoils in model steels have been carried out in the present work. Investigated configurations consisted of bulk ferrite containing spherical particles (diameter of 4 nm) of either (1) Fe3C or (2) Cr23C6. Primary recoils were initiated at different distances from the inclusions, with recoil energies varying between 100 eV and 1 keV. Results for the number of point defects such as vacancies and antisites are presented. These findings indicate that defects are also remaining when cascades are started outside the carbide inclusions. The work uses a recently developed Abell-Brenner-Tersoff potential for the Fe-Cr-C system.

The relation of microdamage to fracture and material property degradation in human cortical bone tissue

NASA Astrophysics Data System (ADS)

Akkus, Ozan

This dissertation investigates the relation of microdamage to fracture and material property degradation of human cortical bone tissue. Fracture resistance and fatigue crack growth of microcracks were examined experimentally and material property degradation was examined through theoretical modeling. To investigate the contribution of microdamage to static fracture resistance, fracture toughness tests were conducted in the transverse and longitudinal directions to the osteonal orientation of normal bone tissue. Damage accumulation was monitored by acoustic emission during testing and was spatially observed by histological observation following testing. The results suggested that the propagation of the main crack involved weakening of the tissue by diffuse damage at the fracture plane and by formation of linear microcracks away from the fracture plane for the transverse specimens. For the longitudinal specimens, growth of the main crack occurred in the form of separations at lamellar interfaces. Acoustic emission results supported the histological observations. To investigate the contribution of ultrastructure to static fracture resistance, fracture toughness tests were conducted after altering the collagen phase of the bone tissue by gamma radiation. A significant decrease in the fracture toughness, Work-to-Fracture and the amount damage was observed due to irradiation in both crack growth directions. For cortical bone irradiated at 27.5kGy, fracture toughness is reduced due to the inhibition of damage formation at and near the crack tip. Microcrack fatigue crack growth and arrest were investigated through observations of surface cracks during cyclic loading. At the applied cyclic stresses, the microcracks propagated and arrested in less than 10,000 cycles. In addition, the microcracks were observed not to grow beyond a length of 150mum and a DeltaK of 0.5MNm-3/2, supporting a microstructural barrier concept. Finally, the contribution of linear microcracks to material property degradation was examined by developing a theoretical micromechanical damage model. The model was compared to experimentally induced damage in bone tissue. The percent contribution of linear microcracks to the total degradation was predicted to be less than 5%, indicating that diffuse damage or an unidentified form of damage is primarily responsible for material property degradation in human cortical bone tissue.

mTOR Inhibition Improves Anaemia and Reduces Organ Damage in a Murine Model of Sickle Cell Disease

PubMed Central

Wang, Jintao; Tran, Jennifer; Wang, Hui; Guo, Chiao; Harro, David; Campbell, Andrew D.; Eitzman, Daniel T.

2016-01-01

Summary Mechanistic target of rapamycin (mTOR) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease (SCD), mice with SCD were treated with the dual mTORC1/2 inhibitor, INK128. 1 week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD. PMID:27030515

Cyclic plasticity models and application in fatigue analysis

NASA Technical Reports Server (NTRS)

Kalev, I.

1981-01-01

An analytical procedure for prediction of the cyclic plasticity effects on both the structural fatigue life to crack initiation and the rate of crack growth is presented. The crack initiation criterion is based on the Coffin-Manson formulae extended for multiaxial stress state and for inclusion of the mean stress effect. This criterion is also applied for the accumulated damage ahead of the existing crack tip which is assumed to be related to the crack growth rate. Three cyclic plasticity models, based on the concept of combination of several yield surfaces, are employed for computing the crack growth rate of a crack plane stress panel under several cyclic loading conditions.

Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS.

PubMed

Andoh, Tooru; Fujimoto, Takuya; Suzuki, Minoru; Sudo, Tamotsu; Sakurai, Yoshinori; Tanaka, Hiroki; Fujita, Ikuo; Fukase, Naomasa; Moritake, Hiroshi; Sugimoto, Tohru; Sakuma, Toshiko; Sasai, Hiroshi; Kawamoto, Teruya; Kirihata, Mitsunori; Fukumori, Yoshinobu; Akisue, Toshihiro; Ono, Koji; Ichikawa, Hideki

2015-12-01

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In the present study, we established a lung metastasis animal model of CCS and investigated the therapeutic effect of boron neutron capture therapy (BNCT) using p-borono-L-phenylalanine (L-BPA). Biodistribution data revealed tumor-selective accumulation of (10)B. Unlike conventional gamma-ray irradiation, BNCT significantly suppressed tumor growth without damaging normal tissues, suggesting that it may be a potential new therapeutic option to treat CCS lung metastases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Diallel analysis for aflatoxin accumulation and fall armyworm leaf feeding damage in maize

USDA-ARS?s Scientific Manuscript database

Two of the major impediments to profitable maize, Zea mays L., production in the southern United States are losses from feeding by fall armyworm, Spodoptera frugiperda (J.E. Smith), and losses from the production and accumulation of aflatoxin in maize grain. The fall armyworm feeds on all above-grou...

A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

PubMed

Niedernhofer, Laura J; Garinis, George A; Raams, Anja; Lalai, Astrid S; Robinson, Andria Rasile; Appeldoorn, Esther; Odijk, Hanny; Oostendorp, Roos; Ahmad, Anwaar; van Leeuwen, Wibeke; Theil, Arjan F; Vermeulen, Wim; van der Horst, Gijsbertus T J; Meinecke, Peter; Kleijer, Wim J; Vijg, Jan; Jaspers, Nicolaas G J; Hoeijmakers, Jan H J

2006-12-21

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Protective effects of skin permeable epidermal and fibroblast growth factor against ultraviolet-induced skin damage and human skin wrinkles.

PubMed

An, Jae Jin; Eum, Won Sik; Kwon, Hyuck Se; Koh, Jae Sook; Lee, Soo Yun; Baek, Ji Hwoon; Cho, Yong-Jun; Kim, Dae Won; Han, Kyu Huyng; Park, Jinseu; Jang, Sang Ho; Choi, Soo Young

2013-12-01

Epidermal and fibroblast growth factor (EGF and FGF1) proteins play an important role in the regeneration and proliferation of skin cells. EGF and FGF1 have considerable potential as possible therapeutic or cosmetic agents for the treatment of skin damage including wrinkles. Using protein transduction domains (PTD), we investigated whether PTD-EGF and FGF1 transduced into skin cells and tissue. Transduced proteins showed protective effects in a UV-induced skin damage model as well as against skin wrinkles. Transduced PTD-EGF and FGF1 proteins were detected by immunofluorescence and immunohistochemistry. The effects of PTD-EGF and FGF1 were examined by WST assay, Western blotting, immunohistochemistry, and skin wrinkle parameters. The PTD-EGF and FGF1 increased cell proliferation and collagen type 1 alpha 1 protein accumulation in skin tissue. Also, PTD-EGF and FGF1 inhibited UV-induced skin damage. Furthermore, topical application of PTD-EGF and FGF1 contained ampoules which were considered to improve the wrinkle parameters of human skin. These results show that PTD-EGF and FGF1 can be a potential therapeutic or cosmetic agent for skin damaged and injury including wrinkles and aging. © 2013 Wiley Periodicals, Inc.

Short and long time effects of low temperature Plasma Activated Media on 3D multicellular tumor spheroids

NASA Astrophysics Data System (ADS)

Judée, Florian; Fongia, Céline; Ducommun, Bernard; Yousfi, Mohammed; Lobjois, Valérie; Merbahi, Nofel

2016-02-01

This work investigates the regionalized antiproliferative effects of plasma-activated medium (PAM) on colon adenocarcinoma multicellular tumor spheroid (MCTS), a model that mimics 3D organization and regionalization of a microtumor region. PAM was generated by dielectric barrier plasma jet setup crossed by helium carrier gas. MCTS were transferred in PAM at various times after plasma exposure up to 48 hours and effect on MCTS growth and DNA damage were evaluated. We report the impact of plasma exposure duration and delay before transfer on MCTS growth and DNA damage. Local accumulation of DNA damage revealed by histone H2AX phosphorylation is observed on outermost layers and is dependent on plasma exposure. DNA damage is completely reverted by catalase addition indicating that H2O2 plays major role in observed genotoxic effect while growth inhibitory effect is maintained suggesting that it is due to others reactive species. SOD and D-mannitol scavengers also reduced DNA damage by 30% indicating that and OH* are involved in H2O2 formation. Finally, PAM is able to retain its cytotoxic and genotoxic activity upon storage at +4 °C or -80 °C. These results suggest that plasma activated media may be a promising new antitumor strategy for colorectal cancer tumors.

Exogenous calcium improves viability of biocontrol yeasts under heat stress by reducing ROS accumulation and oxidative damage of cellular protein.

PubMed

An, Bang; Li, Boqiang; Qin, Guozheng; Tian, Shiping

2012-08-01

In this article, we investigated the effect of exogenous calcium on improving viability of Debaryomyces hansenii and Pichia membranaefaciens under heat stress, and evaluated the role of calcium in reducing oxidant damage of proteins in the yeast cells. The results indicated that high concentration of exogenous calcium in culture medium was beneficial for enhancing the tolerance of the biocontrol yeasts to heat stress. The possible mechanism of calcium improving the viability of yeasts was attributed to enhancement of antioxidant enzyme activities, decrease in ROS accumulation and reduction of oxidative damage of intracellular protein in yeast cells under heat stress. D. hansenii is more sensitive to calcium as compared to P. membranaefaciens. Our results suggest that application of exogenous calcium combined with biocontrol yeasts is a practical approach for the control of postharvest disease in fruit.

Silicon Priming Created an Enhanced Tolerance in Alfalfa (Medicago sativa L.) Seedlings in Response to High Alkaline Stress.

PubMed

Liu, Duo; Liu, Miao; Liu, Xiao-Long; Cheng, Xian-Guo; Liang, Zheng-Wei

2018-01-01

Alkaline stress as a result of higher pH usually triggers more severe physiological damage to plants than that of saline stress with a neutral pH. In the present study, we demonstrated that silicon (Si) priming of alfalfa ( Medicago sativa L.) seedlings increased their tolerance to high alkaline stress situations. Gongnong No. 1 seedlings were subjected to alkaline stress simulated by 25 mM Na 2 CO 3 (pH 11.2). Alkaline stress greatly decreased the biomass and caused severe lodging or wilting of alfalfa seedlings. In contrast, the application of Si to alfalfa seedlings 36 h prior to the alkaline treatment significantly alleviated the damage symptoms and greatly increased the biomass and chlorophyll content. Because of being concomitant with increasing photosynthesis and water use efficiency, decreasing membrane injury and malondialdehyde content, and increasing peroxidase and catalase ascorbate activities in alfalfa leaves, thereby alleviating the triggered oxidative damage by alkaline stress to the plant. Furthermore, Si priming significantly decreased the accumulation of protein and proline content in alfalfa, thus reducing photosynthetic feedback repression. Si priming significantly accumulated more Na in the roots, but led to a decrease of Na accumulation and an increase of K accumulation in the leaves under alkaline stress. Meanwhile, Si priming decreased the accumulation of metal ions such as Mg, Fe, Mn, and Zn in the roots of alfalfa seedlings under alkaline stress. Collectively, these results suggested that Si is involved in the metabolic or physiological changes and has a potent priming effect on the alkaline tolerance of alfalfa seedlings. The present study indicated that Si priming is a new approach to improve the alkaline tolerance in alfalfa and provides increasing information for further exploration of the alkaline stress response at the molecular level in alfalfa.

Durability assessments of concrete using electrical properties and acoustic emission testing

NASA Astrophysics Data System (ADS)

Todak, Heather N.

Premature damage deterioration has been observed in pavement joints throughout the Midwestern region of the United States. Over time, severe joint damage creates a transportation safety concern and the necessary repairs can be an extreme economic burden. The deterioration is due in part to freeze-thaw damage associated with fluid accumulation at the pavement joints. This very preventable problem is an indication that current specifications and construction practices for freeze-thaw durability of concrete are inadequate. This thesis serves to create a better understanding of moisture ingress, freeze-thaw damage mechanisms, and the effect of variations in mixture properties on freeze-thaw behavior of concrete. The concepts of the nick point degree of saturation, sorptivity rates, and critical degree of saturation are discussed. These factors contribute to service life, defined in this study as the duration of time a concrete element remains below levels of critical saturation which are required for damage development to initiate. A theoretical model and a simple experimental procedure are introduced which help determine the nick point for a series of 32 concrete mixtures with unique mixture proportions and air entrainment properties. This simple experimental procedure is also presented as a method to measure important electrical properties in order to establish the formation factor, a valuable measure of concrete transport properties. The results of freeze-thaw testing with acoustic emission monitoring are presented to help understand and quantify damage development in concrete specimens when conditioned to various degrees of saturation. This procedure was used to study the relationship between air entrainment properties and the critical degree of saturation. Applying the concepts of degree of saturation and sorptivity, a performance-based model is proposed as a new approach to specifications for freeze-thaw durability. Finally, a conceptual model is presented to illustrate the effect of various changes in mixture proportions and air void properties on service life.

TEM Analyses of Itokawa Regolith Grains and Lunar Soil Grains to Directly Determine Space Weathering Rates on Airless Bodies

NASA Technical Reports Server (NTRS)

Berger, Eve L.; Keller, Lindsay P.; Christoffersen, Roy

2016-01-01

Samples returned from the moon and Asteroid Itokawa by NASA's Apollo Missions and JAXA's Hayabusa Mission, respectively, provide a unique record of their interaction with the space environment. Space weathering effects result from micrometeorite impact activity and interactions with the solar wind. While the effects of solar wind interactions, ion implantation and solar flare particle track accumulation, have been studied extensively, the rate at which these effects accumulate in samples on airless bodies has not been conclusively determined. Results of numerical modeling and experimental simulations do not converge with observations from natural samples. We measured track densities and rim thicknesses of three olivine grains from Itokawa and multiple olivine and anorthite grains from lunar soils of varying exposure ages. Samples were prepared for analysis using a Leica EM UC6 ultramicrotome and an FEI Quanta 3D dual beam focused ion beam scanning electron microscope (FIB-SEM). Transmission electron microscope (TEM) analyses were performed on the JEOL 2500SE 200kV field emission STEM. The solar wind damaged rims on lunar anorthite grains are amorphous, lack inclusions, and are compositionally similar to the host grain. The rim width increases as a smooth function of exposure age until it levels off at approximately 180 nm after approximately 20 My (Fig. 1). While solar wind ion damage can only accumulate while the grain is in a direct line of sight to the Sun, solar flare particles can penetrate to mm-depths. To assess whether the track density accurately predicts surface exposure, we measured the rim width and track density in olivine and anorthite from the surface of rock 64455, which was never buried and has a surface exposure age of 2 My based on isotopic measurements. The rim width from 64455 (60-70nm) plots within error of the well-defined trend for solar wind amorphized rims in Fig. 1. Measured solar flare track densities are accurately reflecting the surface exposure of the grains. Track densities correlate with the amorphous rim thicknesses. While the space-weathered rims of anorthite grains are amorphous, the space-weathered rims on both Itokawa and lunar olivine grains show solar wind damaged rims that are not amorphous. Instead, the rims are nanocrystalline with high dislocation densities and sparse inclusions of nanophase Fe metal. The rim thicknesses on the olivine grains also correlate with track density. The Itokawa olivine grains have track densities that indicate surface exposures of approximately 10(exp 5) years. Longer exposures (up to approximately 10(exp 7) years) do not amorphize the rims, as evidenced by lunar soil olivines with high track densities (approximately 10(exp 11) cm(exp -2)). From the combined data, shown in Fig. 1, it is clear that olivine is damaged (but not amorphized) more rapidly by the solar wind compared to anorthite. The olivine damaged rim forms quickly (in approximately 10(exp 6) y) and saturates at approximately 120nm with longer exposure time. The anorthite damaged rims form more slowly, amorphize, and grow thicker than the olivine rims. This is in agreement with numerical modeling data which predicts that solar wind damaged rims on anorthite will be thicker than olivine. However, the models predict that both olivine and anorthite rims will amorphize and reach equilibrium widths in less than 10(exp 3) y, in contrast to what is observed for natural samples. Laboratory irradiation experiments, which show rapid formation of fully amorphous and blistered surfaces from simulated solar wind exposures are also in contrast to observations of natural samples. These results suggest that there is a flux dependence on the type and extent of irradiation damage that develops in olivine. This flux dependence suggests that great caution be used in extrapolating between high-flux laboratory experiments and the natural case, as demonstrated by. We constrain the space weathering rate through analysis of returned samples. Provided that the track densities and the solar wind damaged rim widths exhibited by the Itokawa grains are typical of the fine-grained regions of Itokawa, then the space weathering rate is on the order of 10(exp 5) y. Space weathering effects in lunar soils saturate within a few My of exposure while those in Itokawa regolith grains formed in approximately 10(exp 5) y. Olivine and anorthite respond differently to solar wind irradiation. The space weathering effects in olivine are particularly difficult to reconcile with laboratory irradiation studies and numerical models. Additional measurements, experiments, and modeling are required to resolve the discrepancies among the observations and calculations involving solar wind amorphization of different minerals on airless bodies.

Towards Coupling of Macroseismic Intensity with Structural Damage Indicators

NASA Astrophysics Data System (ADS)

Kouteva, Mihaela; Boshnakov, Krasimir

2016-04-01

Knowledge on basic data of ground motion acceleration time histories during earthquakes is essential to understanding the earthquake resistant behaviour of structures. Peak and integral ground motion parameters such as peak ground motion values (acceleration, velocity and displacement), measures of the frequency content of ground motion, duration of strong shaking and various intensity measures play important roles in seismic evaluation of existing facilities and design of new systems. Macroseismic intensity is an earthquake measure related to seismic hazard and seismic risk description. Having detailed ideas on the correlations between the earthquake damage potential and macroseismic intensity is an important issue in engineering seismology and earthquake engineering. Reliable earthquake hazard estimation is the major prerequisite to successful disaster risk management. The usage of advanced earthquake engineering approaches for structural response modelling is essential for reliable evaluation of the accumulated damages in the existing buildings and structures due to the history of seismic actions, occurred during their lifetime. Full nonlinear analysis taking into account single event or series of earthquakes and the large set of elaborated damage indices are suitable contemporary tools to cope with this responsible task. This paper presents some results on the correlation between observational damage states, ground motion parameters and selected analytical damage indices. Damage indices are computed on the base of nonlinear time history analysis of test reinforced structure, characterising the building stock of the Mediterranean region designed according the earthquake resistant requirements in mid XX-th century.

The application of continuum damage mechanics to solve problems in geodynamics

NASA Astrophysics Data System (ADS)

Manaker, David Martin

Deformation within the Earth's lithosphere is largely controlled by the rheology of the rock. Ductile behavior in rocks is often associated with plasticity due to dislocation motion or diffusion under high pressures and temperatures. However, ductile behavior can also occur in brittle materials. An example would be cataclastic flow associated with folding at shallow crustal levels, steep subduction zones, and large-scale deformation at plate boundaries. Engineers utilize damage mechanics to model the continuum deformation of brittle materials. We utilize a modified form of damage mechanics where damage represents a reduction in frictional strength and includes a yield stress. We use this empirical approach to simulate the bending of the lithosphere. We use numerical simulations to obtain elastostatic solutions for plate bending and where the stress exceeds a yield stress, we apply damage to reduce the elastic moduli. Damage is calculated at each time step by a power-law relationship of the ratio of the yield stress to stress and the yield strain to the strain. To test our method, we apply our damage rheology to a plate deforming under applied shear, a constant bending moment, and a constant load. We simulate a wide range of behaviors from slow relaxation to instantaneous failure, over timescales that span six orders of magnitude. Stress relaxation produces elastic-perfectly plastic behavior in cases where failure does not occur. For cases of failure, we observe a rapid increase in damage leading to failure. The changes in the rate of damage accumulation in failure cases are similar to the changes in b-values of acoustic emissions observed in triaxial compression tests of fractured rock and b-value changes prior to some large earthquakes. Thus continuum damage mechanics can simulate ductile behavior due to brittle mechanisms as well as observations of laboratory experiments and seismicity.

The role of phospholipid oxidation products in inflammatory and autoimmune diseases: evidence from animal models and in humans.

PubMed

Leitinger, Norbert

2008-01-01

Since the discovery of oxidized phospholipids (OxPL) and their implication as modulators of inflammation in cardiovascular disease, roles for these lipid oxidation products have been suggested in many other disease settings. Lipid oxidation products accumulate in inflamed and oxidatively damaged tissue, where they are derived from oxidative modification of lipoproteins, but also from membranes of cells undergoing apoptosis. Thus, increased oxidative stress as well as decreased clearance of apoptotic cells has been implied to contribute to accumulation of OxPL in chronically inflamed tissues.A central role for OxPL in disease states associated with dyslipedemia, including atherosclerosis, diabetes and its complications, metabolic syndrome, and renal insufficiency, as well as general prothrombotic states, has been proposed. In addition, in organs which are constantly exposed to oxidative stress, including lung, skin, and eyes, increased levels of OxPL are suggested to contribute to inflammatory conditions. Moreover, accumulation of OxPL causes general immunmodulation and may lead to autoimmune diseases. Evidence is accumulating that OxPL play a role in lupus erythematosus, antiphospholipid syndrome, and rheumatoid arthritis. Last but not least, a role for OxPL in neurological disorders including multiple sclerosis (MS), Alzheimer's and Parkinson's disease has been suggested.This chapter will summarize recent findings obtained in animal models and from studies in humans that indicate that formation of OxPL represents a general mechanism that may play a major role in chronic inflammatory and autoimmune diseases.

78 FR 33206 - Airworthiness Directives; Bombardier, Inc. Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-04

... by reports of failure of a screw cap or end cap of the hydraulic system accumulator while on the ground, which resulted in loss of use of that hydraulic system and high-energy impact damage to adjacent..., resulting in loss of the associated hydraulic system and high-energy impact damage to adjacent systems and...

18 CFR 367.2282 - Account 228.2, Accumulated provision for injuries and damages.

Code of Federal Regulations, 2010 CFR

2010-04-01

... with amounts charged to account 925, Injuries and damages (§ 367.9250), or other appropriate accounts... must be charged to this account and credited to the appropriate current liability account. Details of.... (c) Recoveries or reimbursements for losses charged to this account must be credited to this account...

Interrogating the Effects of Radiation Damage Annealing on Helium Diffusion Kinetics in Apatite

NASA Astrophysics Data System (ADS)

Willett, C. D.; Fox, M.; Shuster, D. L.

2015-12-01

Apatite (U-Th)/He thermochronology is commonly used to study landscape evolution and potential links between climate, erosion and tectonics. The technique relies on a quantitative understanding of (i) helium diffusion kinetics in apatite, (ii) an evolving 4He concentration, (iii) accumulating damage to the crystal lattice caused by radioactive decay[1], and (iv) the thermal annealing of such damage[2],[3], which are each functions of both time and temperature. Uncertainty in existing models of helium diffusion kinetics has resulted in conflicting conclusions, especially in settings involving burial heating through geologic time. The effects of alpha recoil damage annealing are currently assumed to follow the kinetics of fission track annealing (e.g., reference [3]), although this assumption is difficult to fully validate. Here, we present results of modeling exercises and a suite of experiments designed to interrogate the effects of damage annealing on He diffusivity in apatite that are independent of empirical calibrations of fission track annealing. We use the existing experimental results for Durango apatite[2] to develop and calibrate a new function that predicts the effects of annealing temperature and duration on measured diffusivity. We also present a suite of experiments conducted on apatite from Sierra Nevada, CA granite to establish whether apatites with different chemical compositions have the same behavior as Durango apatite. Crystals were heated under vacuum to temperatures between 250 and 500°C for 1, 10, or 100 hours. The samples were then irradiated with ~220 MeV protons to produce spallogenic 3He, the diffusant then used in step-heating diffusion experiments. We compare the results of these experiments and model calibrations to existing models. Citations: [1]Shuster, D., Flowers R., and Farley K., (2006), EPSL 249(3-4), 148-161; [2]Shuster, D. and Farley, K., (2009), GCA 73 (1), 6183-6196; [3]Flowers, R., Ketcham, R., Shuster, D. and Farley, K., (2009), GCA 73, 2347-2365.

Moderate Thermal Stress Causes Active and Immediate Expulsion of Photosynthetically Damaged Zooxanthellae (Symbiodinium) from Corals.

PubMed

Fujise, Lisa; Yamashita, Hiroshi; Suzuki, Go; Sasaki, Kengo; Liao, Lawrence M; Koike, Kazuhiko

2014-01-01

The foundation of coral reef biology is the symbiosis between corals and zooxanthellae (dinoflagellate genus Symbiodinium). Recently, coral bleaching, which often results in mass mortality of corals and the collapse of coral reef ecosystems, has become an important issue around the world as coral reefs decrease in number year after year. To understand the mechanisms underlying coral bleaching, we maintained two species of scleractinian corals (Acroporidae) in aquaria under non-thermal stress (27°C) and moderate thermal stress conditions (30°C), and we compared the numbers and conditions of the expelled Symbiodinium from these corals. Under non-thermal stress conditions corals actively expel a degraded form of Symbiodinium, which are thought to be digested by their host coral. This response was also observed at 30°C. However, while the expulsion rates of Symbiodinium cells remained constant, the proportion of degraded cells significantly increased at 30°C. This result indicates that corals more actively digest and expel damaged Symbiodinium under thermal stress conditions, likely as a mechanism for coping with environmental change. However, the increase in digested Symbiodinium expulsion under thermal stress may not fully keep up with accumulation of the damaged cells. There are more photosynthetically damaged Symbiodinium upon prolonged exposure to thermal stress, and corals release them without digestion to prevent their accumulation. This response may be an adaptive strategy to moderate stress to ensure survival, but the accumulation of damaged Symbiodinium, which causes subsequent coral deterioration, may occur when the response cannot cope with the magnitude or duration of environmental stress, and this might be a possible mechanism underlying coral bleaching during prolonged moderate thermal stress.

Moderate Thermal Stress Causes Active and Immediate Expulsion of Photosynthetically Damaged Zooxanthellae (Symbiodinium) from Corals

PubMed Central

Fujise, Lisa; Yamashita, Hiroshi; Suzuki, Go; Sasaki, Kengo; Liao, Lawrence M.; Koike, Kazuhiko

2014-01-01

The foundation of coral reef biology is the symbiosis between corals and zooxanthellae (dinoflagellate genus Symbiodinium). Recently, coral bleaching, which often results in mass mortality of corals and the collapse of coral reef ecosystems, has become an important issue around the world as coral reefs decrease in number year after year. To understand the mechanisms underlying coral bleaching, we maintained two species of scleractinian corals (Acroporidae) in aquaria under non-thermal stress (27°C) and moderate thermal stress conditions (30°C), and we compared the numbers and conditions of the expelled Symbiodinium from these corals. Under non-thermal stress conditions corals actively expel a degraded form of Symbiodinium, which are thought to be digested by their host coral. This response was also observed at 30°C. However, while the expulsion rates of Symbiodinium cells remained constant, the proportion of degraded cells significantly increased at 30°C. This result indicates that corals more actively digest and expel damaged Symbiodinium under thermal stress conditions, likely as a mechanism for coping with environmental change. However, the increase in digested Symbiodinium expulsion under thermal stress may not fully keep up with accumulation of the damaged cells. There are more photosynthetically damaged Symbiodinium upon prolonged exposure to thermal stress, and corals release them without digestion to prevent their accumulation. This response may be an adaptive strategy to moderate stress to ensure survival, but the accumulation of damaged Symbiodinium, which causes subsequent coral deterioration, may occur when the response cannot cope with the magnitude or duration of environmental stress, and this might be a possible mechanism underlying coral bleaching during prolonged moderate thermal stress. PMID:25493938

Local strain and damage mapping in single trabeculae during three-point bending tests

PubMed Central

Jungmann, R.; Szabo, M.E.; Schitter, G.; Tang, Raymond Yue-Sing; Vashishth, D.; Hansma, P.K.; Thurner, P.J.

2012-01-01

The use of bone mineral density as a surrogate to diagnose bone fracture risk in individuals is of limited value. However, there is growing evidence that information on trabecular microarchitecture can improve the assessment of fracture risk. One current strategy is to exploit finite element analysis (FEA) applied to 3D image data of several mm-sized trabecular bone structures obtained from non-invasive imaging modalities for the prediction of apparent mechanical properties. However, there is a lack of FE damage models, based on solid experimental facts, which are needed to validate such approaches and to provide criteria marking elastic–plastic deformation transitions as well as microdamage initiation and accumulation. In this communication, we present a strategy that could elegantly lead to future damage models for FEA: direct measurements of local strains involved in microdamage initiation and plastic deformation in single trabeculae. We use digital image correlation to link stress whitening in bone, reported to be correlated to microdamage, to quantitative local strain values. Our results show that the whitening zones, i.e. damage formation, in the presented loading case of a three-point bending test correlate best with areas of elevated tensile strains oriented parallel to the long axis of the samples. The average local strains along this axis were determined to be (1.6 ± 0.9)% at whitening onset and (12 ± 4)% just prior to failure. Overall, our data suggest that damage initiation in trabecular bone is asymmetric in tension and compression, with failure originating and propagating over a large range of tensile strains. PMID:21396601

Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis.

PubMed

Vit, Jean-Philippe; Rosselli, Filippo

2003-11-27

Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.

Combined effects of radiation damage and He accumulation on bubble nucleation in Gd2Ti2O7

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, Caitlin A.; Patel, Maulik K.; Aguiar, Jeffery A.

2016-10-01

Pyrochlores have long been considered as host phases for long-term immobilization of radioactive waste nuclides that would undergo ..alpha..-decay for hundreds of thousands of years. This work utilizes ion-beam irradiations to examine the combined effects of radiation damage and He accumulation on bubble formation in Gd2Ti2O7 over relevant waste-form timescales. Helium bubbles are not observed in pre-damaged Gd2Ti2O7 implanted with 2 x 1016 He/cm2, even after post-implantation irradiations with 7 MeV Au3+ at 300, 500, and 700 K. However, He bubbles with average diameters of 1.5 nm and 2.1 nm are observed in pre-damaged (amorphous) Gd2Ti2O7 and pristine Gd2Ti2O7, respectively,more » after implantation of 2 x 1017 He/cm2. The critical He concentration for bubble nucleation in Gd2Ti2O7 is estimated to be 6 at.% He.« less

RAD18 and associated proteins are immobilized in nuclear foci in human cells entering S-phase with ultraviolet light-induced damage

PubMed Central

Watson, Nicholas B.; Nelson, Eric; Digman, Michelle; Thornburg, Joshua A.; Alphenaar, Bruce W.; McGregor, W. Glenn

2008-01-01

Proteins required for translesion DNA synthesis localize in nuclear foci of cells with replication-blocking lesions. The dynamics of this process were examined in human cells with fluorescence-based biophysical techniques. Photobleaching recovery and raster image correlation spectroscopy experiments indicated that involvement in the nuclear foci reduced the movement of RAD18 from diffusion-controlled to virtual immobility. Examination of the mobility of REV1 indicated that it is similarly immobilized when it is observed in nuclear foci. Reducing the level of RAD18 greatly reduced the focal accumulation of REV1 and reduced UV mutagenesis to background frequencies. Fluorescence lifetime measurements indicated that RAD18 and RAD6A or polη only transferred resonance energy when these proteins colocalized in damage-induced nuclear foci, indicating a close physical association only within such foci. Our data support a model in which RAD18 within damage-induced nuclear foci is immobilized and is required for recruitment of Y-family DNA polymerases and subsequent mutagenesis. In the absence of damage these proteins are not physically associated within the nucleoplasm. PMID:18926833

Physiological imaging of electrical trauma and therapeutic responses

NASA Astrophysics Data System (ADS)

Chen, Chin-Tu; Matthews, K.; Aarsvold, John N.; Mintzer, Robert A.; Yasillo, Nicholas J.; Hannig, Jurgen; Capelli-Schellpfefer, M.; Cooper, Malcolm; Lee, Raphael C.

2000-04-01

In victims of electrical trauma, electroporation of cell membrane, in which lipid bilayer is permeabilized by thermal and electrical forces, is thought to be a substantial cause of tissue damage. It has been suggested that certain mild surfactant in low concentration could induce sealing of permeabilized lipid bilayers, thus repairing cell membranes that had not been extensively damaged. With an animal model of electrically injured hind limb of rats, we have demonstrated and validated the use of radiotracer imaging technique to assess the physiology of the damaged tissues after electrical shock and of their repairs after applying surfactant as a therapeutic strategy. For example, using Tc-99m labeled pyrophosphate (PYP), which follows calcium in cellular function and is known to accumulate in damaged tissues, we have established a physiological imaging approach for assessment of the extent of tissue injury for diagnosis and surgical planning, as well as for evaluation of responses to therapy. With the use of a small, hand-held, miniature gamma camera, this physiological imaging method can be employed at patient's bedside and even in the field, for example, at accident site or during transfer for emergency care, rapid diagnosis, and prompt treatment in order to maximize the chance for tissue survival.

Bimodal regulation of p21waf1 protein as function of DNA damage levels

PubMed Central

Buscemi, G; Ricci, C; Zannini, L; Fontanella, E; Plevani, P; Delia, D

2014-01-01

Human p21Waf1 protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21Waf1 protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21Waf1 on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21Waf1 degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21Waf1 at any dose of damage. We also found that p21Waf1 ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21Waf1 protein levels in relation to cytostatic and cytotoxic doses of DNA damage. PMID:25486478

Physiological and Metabolic Effects of 5-Aminolevulinic Acid for Mitigating Salinity Stress in Creeping Bentgrass

PubMed Central

Yang, Zhimin; Chang, Zuoliang; Sun, Lihong; Yu, Jingjin; Huang, Bingru

2014-01-01

The objectives of this study were to determine whether foliar application of a chlorophyll precursor, 5-aminolevulinic acid (ALA), could mitigate salinity stress damages in perennial grass species by regulating photosynthetic activities, ion content, antioxidant metabolism, or metabolite accumulation. A salinity-sensitive perennial grass species, creeping bentgrass (Agrostis stolonifera), was irrigated daily with 200 mM NaCl for 28 d, which were foliar sprayed with water or ALA (0.5 mg L−1) weekly during the experiment in growth chamber. Foliar application of ALA was effective in mitigating physiological damage resulting from salinity stress, as manifested by increased turf quality, shoot growth rate, leaf relative water content, chlorophyll content, net photosynthetic rate, stomatal conductance and transpiration rate. Foliar application of ALA also alleviated membrane damages, as shown by lower membrane electrolyte leakage and lipid peroxidation, which was associated with increases in the activities of antioxidant enzymes. Leaf content of Na+ was reduced and the ratio of K+/Na+ was increased with ALA application under salinity stress. The positive effects of ALA for salinity tolerance were also associated with the accumulation of organic acids (α-ketoglutaric acid, succinic acid, and malic acid), amino acids (alanine, 5-oxoproline, aspartic acid, and γ -aminobutyric acid), and sugars (glucose, fructose, galactose, lyxose, allose, xylose, sucrose, and maltose). ALA-mitigation of physiological damages by salinity could be due to suppression of Na+ accumulation and enhanced physiological and metabolic activities related to photosynthesis, respiration, osmotic regulation, and antioxidant defense. PMID:25551443

Ideal sinks are not always ideal. Radiation damage accumulation in nanocomposites

DOE PAGES

Uberuaga, Blas Pedro; Choudhury, Samrat; Caro, Alfredo

2014-11-27

Designing radiation tolerant materials is one of the primary challenges associated with advanced nuclear energy systems. One attractive route that has received much attention world-wide is to introduce a high density of sinks, often in the form of interfaces or secondary phases. Here, we develop a simple model of such nanocomposites and examine the ramifications of various factors on the overall radiation stability of the material. In particular, we determine how the distribution of secondary phases, the relative sink strength of those phases, and the irradiation temperature influence the radiation tolerance of the matrix. We find that the best scenariomore » is one in which the sinks have intermediate strength, transiently trapping defects before releasing them back into the matrix.This provides new insight into the optimal properties of nanocomposites for radiation damage environments.« less

The ageing lens and cataract: a model of normal and pathological ageing

PubMed Central

Michael, R.; Bron, A. J.

2011-01-01

Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform. PMID:21402586

Femtosecond laser polishing of optical materials

NASA Astrophysics Data System (ADS)

Taylor, Lauren L.; Qiao, Jun; Qiao, Jie

2015-10-01

Technologies including magnetorheological finishing and CNC polishing are commonly used to finish optical elements, but these methods are often expensive, generate waste through the use of fluids or abrasives, and may not be suited for specific freeform substrates due to the size and shape of finishing tools. Pulsed laser polishing has been demonstrated as a technique capable of achieving nanoscale roughness while offering waste-free fabrication, material-specific processing through direct tuning of laser radiation, and access to freeform shapes using refined beam delivery and focusing techniques. Nanosecond and microsecond pulse duration radiation has been used to perform successful melting-based polishing of a variety of different materials, but this approach leads to extensive heat accumulation resulting in subsurface damage. We have experimentally investigated the ability of femtosecond laser radiation to ablate silicon carbide and silicon. By substituting ultrafast laser radiation, polishing can be performed by direct evaporation of unwanted surface asperities with minimal heating and melting, potentially offering damage-free finishing of materials. Under unoptimized laser processing conditions, thermal effects can occur leading to material oxidation. To investigate these thermal effects, simulation of the heat accumulation mechanism in ultrafast laser ablation was performed. Simulations have been extended to investigate the optimum scanning speed and pulse energy required for processing various substrates. Modeling methodologies and simulation results will be presented.

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress.

PubMed

Shi, Wei; Vu, Therese; Boucher, Didier; Biernacka, Anna; Nde, Jules; Pandita, Raj K; Straube, Jasmin; Boyle, Glen M; Al-Ejeh, Fares; Nag, Purba; Jeffery, Jessie; Harris, Janelle L; Bain, Amanda L; Grzelak, Marta; Skrzypczak, Magdalena; Mitra, Abhishek; Dojer, Norbert; Crosetto, Nicola; Cloonan, Nicole; Becherel, Olivier J; Finnie, John; Skaar, Jeffrey R; Walkley, Carl R; Pandita, Tej K; Rowicka, Maga; Ginalski, Krzysztof; Lane, Steven W; Khanna, Kum Kum

2017-05-04

Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, whereas conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of Ssb1 or Ssb2 Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of R -loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability. © 2017 by The American Society of Hematology.

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

PubMed Central

Vu, Therese; Boucher, Didier; Biernacka, Anna; Nde, Jules; Pandita, Raj K.; Straube, Jasmin; Boyle, Glen M.; Al-Ejeh, Fares; Jeffery, Jessie; Harris, Janelle L.; Bain, Amanda L.; Grzelak, Marta; Skrzypczak, Magdalena; Mitra, Abhishek; Dojer, Norbert; Crosetto, Nicola; Cloonan, Nicole; Becherel, Olivier J.; Finnie, John; Skaar, Jeffrey R.; Walkley, Carl R.; Pandita, Tej K.; Rowicka, Maga; Ginalski, Krzysztof

2017-01-01

Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, whereas conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of Ssb1 or Ssb2. Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of R-loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability. PMID:28270450

Damage buildup in Ar-ion-irradiated 3 C-SiC at elevated temperatures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wallace, J. B.; Bayu Aji, L. B.; Li, T. T.

Above room temperature, the accumulation of radiation damage in 3 C-SiC is strongly influenced by dynamic defect interaction processes and remains poorly understood. Here, we use a combination of ion channeling and transmission electron microscopy to study lattice disorder in 3 C-SiC irradiated with 500 keV Ar ions in the temperature range of 25–250 °C. Results reveal sigmoidal damage buildup for all the temperatures studied. For 150 °C and below, the damage level monotonically increases with ion dose up to amorphization. Starting at 200 °C, the shape of damage–depth profiles becomes anomalous, with the damage peak narrowing and moving tomore » larger depths and an additional shoulder forming close to the ion end of range. As a result, damage buildup curves for 200 and 250 °C exhibit an anomalous two-step shape, with a damage saturation stage followed by rapid amorphization above a critical ion dose, suggesting a nucleation-limited amorphization behavior. Despite their complexity, all damage buildup curves are well described by a phenomenological model based on an assumption of a linear dependence of the effective amorphization cross section on ion dose. Here, in contrast to the results of previous studies, 3 C-SiC can be amorphized by bombardment with 500 keV Ar ions even at 250 °C with a relatively large dose rate of ~2×10 13 cm -2 s -1, revealing a dominant role of defect interaction dynamics at elevated temperatures.« less

Damage buildup in Ar-ion-irradiated 3 C-SiC at elevated temperatures

DOE PAGES

Wallace, J. B.; Bayu Aji, L. B.; Li, T. T.; ...

2015-09-14

Above room temperature, the accumulation of radiation damage in 3 C-SiC is strongly influenced by dynamic defect interaction processes and remains poorly understood. Here, we use a combination of ion channeling and transmission electron microscopy to study lattice disorder in 3 C-SiC irradiated with 500 keV Ar ions in the temperature range of 25–250 °C. Results reveal sigmoidal damage buildup for all the temperatures studied. For 150 °C and below, the damage level monotonically increases with ion dose up to amorphization. Starting at 200 °C, the shape of damage–depth profiles becomes anomalous, with the damage peak narrowing and moving tomore » larger depths and an additional shoulder forming close to the ion end of range. As a result, damage buildup curves for 200 and 250 °C exhibit an anomalous two-step shape, with a damage saturation stage followed by rapid amorphization above a critical ion dose, suggesting a nucleation-limited amorphization behavior. Despite their complexity, all damage buildup curves are well described by a phenomenological model based on an assumption of a linear dependence of the effective amorphization cross section on ion dose. Here, in contrast to the results of previous studies, 3 C-SiC can be amorphized by bombardment with 500 keV Ar ions even at 250 °C with a relatively large dose rate of ~2×10 13 cm -2 s -1, revealing a dominant role of defect interaction dynamics at elevated temperatures.« less

DNA Damage Response, Redox Status and Hematopoiesis

PubMed Central

Weiss, Cary N.; Ito, Keisuke

2013-01-01

The ability of hematopoietic stem cells (HSCs) to self-renew and differentiate into progenitors is essential for homeostasis of the hematopoietic system. The longevity of HSCs makes them vulnerable to accumulating DNA damage, which may be leukemogenic or result in senescence and cell death. Additionally, the ability of HSCs to self-renew and differentiate allows DNA damage to spread throughout the hematologic system, leaving the organism vulnerable to disease. In this review we discuss cell fate decisions made in the face of DNA damage and other cellular stresses, and the role of reactive oxygen species in the long-term maintenance of HSCs and their DNA damage response. PMID:24041596

Progressive Fracture of Fiber Composite Build-Up Structures

NASA Technical Reports Server (NTRS)

Gotsis, Pascal K.; Chamis, C. C.; Minnetyan, Levon

1997-01-01

Damage progression and fracture of built-up composite structures is evaluated by using computational simulation. The objective is to examine the behavior and response of a stiffened composite (0/ +/- 45/90)(sub s6) laminate panel by simulating the damage initiation, growth, accumulation, progression and propagation to structural collapse. An integrated computer code, CODSTRAN, was augmented for the simulation of the progressive damage and fracture of built-up composite structures under mechanical loading. Results show that damage initiation and progression have significant effect on the structural response. Influence of the type of loading is investigated on the damage initiation, propagation and final fracture of the build-up composite panel.

Progressive Fracture of Fiber Composite Build-Up Structures

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Gotsis, Pascal K.; Chamis, C. C.

1997-01-01

Damage progression and fracture of built-up composite structures is evaluated by using computational simulation. The objective is to examine the behavior and response of a stiffened composite (0 +/-45/90)(sub s6) laminate panel by simulating the damage initiation, growth, accumulation, progression and propagation to structural collapse. An integrated computer code CODSTRAN was augmented for the simulation of the progressive damage and fracture of built-up composite structures under mechanical loading. Results show that damage initiation and progression to have significant effect on the structural response. Influence of the type of loading is investigated on the damage initiation, propagation and final fracture of the build-up composite panel.

Thermal fatigue durability for advanced propulsion materials

NASA Technical Reports Server (NTRS)

Halford, Gary R.

1989-01-01

A review is presented of thermal and thermomechanical fatigue (TMF) crack initiation life prediction and cyclic constitutive modeling efforts sponsored recently by the NASA Lewis Research Center in support of advanced aeronautical propulsion research. A brief description is provided of the more significant material durability models that were created to describe TMF fatigue resistance of both isotropic and anisotropic superalloys, with and without oxidation resistant coatings. The two most significant crack initiation models are the cyclic damage accumulation model and the total strain version of strainrange partitioning. Unified viscoplastic cyclic constitutive models are also described. A troika of industry, university, and government research organizations contributed to the generation of these analytic models. Based upon current capabilities and established requirements, an attempt is made to project which TMF research activities most likely will impact future generation propulsion systems.

Ultraviolet-B-induced DNA damage and ultraviolet-B tolerance mechanisms in species with different functional groups coexisting in subalpine moorlands.

PubMed

Wang, Qing-Wei; Kamiyama, Chiho; Hidema, Jun; Hikosaka, Kouki

2016-08-01

High doses of ultraviolet-B (UV-B; 280-315 nm) radiation can have detrimental effects on plants, and especially damage their DNA. Plants have DNA repair and protection mechanisms to prevent UV-B damage. However, it remains unclear how DNA damage and tolerance mechanisms vary among field species. We studied DNA damage and tolerance mechanisms in 26 species with different functional groups coexisting in two moorlands at two elevations. We collected current-year leaves in July and August, and determined accumulation of cyclobutane pyrimidine dimer (CPD) as UV-B damage and photorepair activity (PRA) and concentrations of UV-absorbing compounds (UACs) and carotenoids (CARs) as UV-B tolerance mechanisms. DNA damage was greater in dicot than in monocot species, and higher in herbaceous than in woody species. Evergreen species accumulated more CPDs than deciduous species. PRA was higher in Poaceae than in species of other families. UACs were significantly higher in woody than in herbaceous species. The CPD level was not explained by the mechanisms across species, but was significantly related to PRA and UACs when we ignored species with low CPD, PRA and UACs, implying the presence of another effective tolerance mechanism. UACs were correlated negatively with PRA and positively with CARs. Our results revealed that UV-induced DNA damage significantly varies among native species, and this variation is related to functional groups. DNA repair, rather than UV-B protection, dominates in UV-B tolerance in the field. Our findings also suggest that UV-B tolerance mechanisms vary among species under evolutionary trade-off and synergism.

Circadian Modulation of 8-Oxoguanine DNA Damage Repair

PubMed Central

Manzella, Nicola; Bracci, Massimo; Strafella, Elisabetta; Staffolani, Sara; Ciarapica, Veronica; Copertaro, Alfredo; Rapisarda, Venerando; Ledda, Caterina; Amati, Monica; Valentino, Matteo; Tomasetti, Marco; Stevens, Richard G.; Santarelli, Lory

2015-01-01

The DNA base excision repair pathway is the main system involved in the removal of oxidative damage to DNA such as 8-Oxoguanine (8-oxoG) primarily via the 8-Oxoguanine DNA glycosylase (OGG1). Our goal was to investigate whether the repair of 8-oxoG DNA damage follow a circadian rhythm. In a group of 15 healthy volunteers, we found a daily variation of Ogg1 expression and activity with higher levels in the morning compared to the evening hours. Consistent with this, we also found lower levels of 8-oxoG in morning hours compared to those in the evening hours. Lymphocytes exposed to oxidative damage to DNA at 8:00 AM display lower accumulation of 8-oxoG than lymphocytes exposed at 8:00 PM. Furthermore, altered levels of Ogg1 expression were also observed in a group of shift workers experiencing a deregulation of circadian clock genes compared to a control group. Moreover, BMAL1 knockdown fibroblasts with a deregulated molecular clock showed an abolishment of circadian variation of Ogg1 expression and an increase of OGG1 activity. Our results suggest that the circadian modulation of 8-oxoG DNA damage repair, according to a variation of Ogg1 expression, could render humans less susceptible to accumulate 8-oxoG DNA damage in the morning hours. PMID:26337123

Evaluation of DNA damage and mutagenicity induced by lead in tobacco plants.

PubMed

Gichner, Tomás; Znidar, Irena; Száková, Jirina

2008-04-30

Tobacco (Nicotiana tabacum L. var. xanthi) seedlings were treated with aqueous solutions of lead nitrate (Pb2+) at concentrations ranging from 0.4 mM to 2.4 mM for 24 h and from 25 microM to 200 microM for 7 days. The DNA damage measured by the comet assay was high in the root nuclei, but in the leaf nuclei a slight but significant increase in DNA damage could be demonstrated only after a 7-day treatment with 200 microM Pb2+. In tobacco plants growing for 6 weeks in soil polluted with Pb2+ severe toxic effects, expressed by the decrease in leaf area, and a slight but significant increase in DNA damage were observed. The tobacco plants with increased levels of DNA damage were severely injured and showed stunted growth, distorted leaves and brown root tips. The frequency of somatic mutations in tobacco plants growing in the Pb2+-polluted soil did not significantly increase. Analytical studies by inductively coupled plasma optical emission spectrometry demonstrate that after a 24-h treatment of tobacco with 2.4 mM Pb2+, the accumulation of the heavy metal is 40-fold higher in the roots than in the above-ground biomass. Low Pb2+ accumulation in the above-ground parts may explain the lower levels or the absence of Pb2+-induced DNA damage in leaves.

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

PubMed Central

Rulten, Stuart L.; Rotheray, Amy; Green, Ryan L.; Grundy, Gabrielle J.; Moore, Duncan A. Q.; Gómez-Herreros, Fernando; Hafezparast, Majid; Caldecott, Keith W

2014-01-01

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUSR521G, harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS. PMID:24049082

Analytical Modelling of Transverse Matrix Cracking of [plus or minus Theta/90(sub n)](sub s) Composite Laminates Under Multiaxial Loading

NASA Technical Reports Server (NTRS)

Mayugo, J A.; Camanho, P. P.; Maimi, P.; Davila, C. G.

2010-01-01

An analytical model based on the analysis of a cracked unit cell of a composite laminate subjected to multiaxial loads is proposed to predict the onset and accumulation of transverse matrix cracks in the 90(sub n) plies of uniformly stressed [plus or minus Theta/90(sub n)](sub s) laminates. The model predicts the effect of matrix cracks on the stiffness of the laminate, as well as the ultimate failure of the laminate, and it accounts for the effect of the ply thickness on the ply strength. Several examples describing the predictions of laminate response, from damage onset up to final failure under both uniaxial and multiaxial loads, are presented.

Linking ice accretion and crown structure: towards a model of the effect of freezing rain on tree canopies

PubMed Central

Nock, Charles A.; Lecigne, Bastien; Taugourdeau, Olivier; Greene, David F.; Dauzat, Jean; Delagrange, Sylvain; Messier, Christian

2016-01-01

Background and Aims Despite a longstanding interest in variation in tree species vulnerability to ice storm damage, quantitative analyses of the influence of crown structure on within-crown variation in ice accretion are rare. In particular, the effect of prior interception by higher branches on lower branch accumulation remains unstudied. The aim of this study was to test the hypothesis that intra-crown ice accretion can be predicted by a measure of the degree of sheltering by neighbouring branches. Methods Freezing rain was artificially applied to Acer platanoides L., and in situ branch-ice thickness was measured directly and from LiDAR point clouds. Two models of freezing rain interception were developed: ‘IceCube’, which uses point clouds to relate ice accretion to a voxel-based index (sheltering factor; SF) of the sheltering effect of branch elements above a measurement point; and ‘IceTree’, a simulation model for in silico evaluation of the interception pattern of freezing rain in virtual tree crowns. Key Results Intra-crown radial ice accretion varied strongly, declining from the tips to the bases of branches and from the top to the base of the crown. SF for branches varied strongly within the crown, and differences among branches were consistent for a range of model parameters. Intra-crown variation in ice accretion on branches was related to SF (R2 = 0·46), with in silico results from IceTree supporting empirical relationships from IceCube. Conclusions Empirical results and simulations confirmed a key role for crown architecture in determining intra-crown patterns of ice accretion. As suspected, the concentration of freezing rain droplets is attenuated by passage through the upper crown, and thus higher branches accumulate more ice than lower branches. This is the first step in developing a model that can provide a quantitative basis for investigating intra-crown and inter-specific variation in freezing rain damage. PMID:27107412

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.

PubMed

Duarte, Tiago L; Caldas, Carolina; Santos, Ana G; Silva-Gomes, Sandro; Santos-Gonçalves, Andreia; Martins, Maria João; Porto, Graça; Lopes, José Manuel

2017-04-01

In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe -/- mice (an established model of human HFE-hemochromatosis). Wild-type, Nrf2 -/- , Hfe -/- and double knockout (Hfe/Nrf2 -/- ) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Despite the parenchymal iron accumulation, Hfe -/- mice presented no liver injury. The combination of iron overload (Hfe -/- ) and defective antioxidant defences (Nrf2 -/- ) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe -/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

PubMed Central

Cheung, Eric C.; Lee, Pearl; Ceteci, Fatih; Nixon, Colin; Blyth, Karen; Sansom, Owen J.; Vousden, Karen H.

2016-01-01

Reactive oxygen species (ROS) participate in numerous cell responses, including proliferation, DNA damage, and cell death. Based on these disparate activities, both promotion and inhibition of ROS have been proposed for cancer therapy. However, how the ROS response is determined is not clear. We examined the activities of ROS in a model of Apc deletion, where loss of the Wnt target gene Myc both rescues APC loss and prevents ROS accumulation. Following APC loss, Myc has been shown to up-regulate RAC1 to promote proliferative ROS through NADPH oxidase (NOX). However, APC loss also increased the expression of TIGAR, which functions to limit ROS. To explore this paradox, we used three-dimensional (3D) cultures and in vivo models to show that deletion of TIGAR increased ROS damage and inhibited proliferation. These responses were suppressed by limiting damaging ROS but enhanced by lowering proproliferative NOX-derived ROS. Despite having opposing effects on ROS levels, loss of TIGAR and RAC1 cooperated to suppress intestinal proliferation following APC loss. Our results indicate that the pro- and anti-proliferative effects of ROS can be independently modulated in the same cell, with two key targets in the Wnt pathway functioning to integrate the different ROS signals for optimal cell proliferation. PMID:26679840

Impact of nutrition on the ageing process.

PubMed

Mathers, John C

2015-01-01

Human life expectancy has been increasing steadily for almost two centuries and is now approximately double what it was at the beginning of the Victorian era. This remarkable demographic change has been accompanied by a shift in disease prevalence so that age is now the major determinant of most common diseases. The challenge is to enhance healthy ageing and to reduce the financial and social burdens associated with chronic ill health in later life. Studies in model organisms have demonstrated that the ageing phenotype arises because of the accumulation of macromolecular damage within the cell and that the ageing process is plastic. Nutritional interventions that reduce such damage, or which enhance the organism's capacity to repair damage, lead to greater longevity and to reduced risk of age-related diseases. Dietary (energy) restriction increases lifespan in several model organisms, but it is uncertain whether it is effective in primates, including humans. However, excess energy storage leading to increased adiposity is a risk factor for premature mortality and for age-related diseases so that obesity prevention is likely to be a major public health route to healthy ageing. In addition, adherence to healthy eating patterns, such as the Mediterranean dietary pattern, is associated with longevity and reduced risk of age-related diseases.

Modelling the interaction between flooding events and economic growth

NASA Astrophysics Data System (ADS)

Grames, Johanna; Fürnkranz-Prskawetz, Alexia; Grass, Dieter; Viglione, Alberto; Blöschl, Günter

2016-04-01

Recently socio-hydrology models have been proposed to analyze the interplay of community risk-coping culture, flooding damage and economic growth. These models descriptively explain the feedbacks between socio-economic development and natural disasters such as floods. Complementary to these descriptive models, we develop a dynamic optimization model, where the inter-temporal decision of an economic agent interacts with the hydrological system. This interdisciplinary approach matches with the goals of Panta Rhei i.e. to understand feedbacks between hydrology and society. It enables new perspectives but also shows limitations of each discipline. Young scientists need mentors from various scientific backgrounds to learn their different research approaches and how to best combine them such that interdisciplinary scientific work is also accepted by different science communities. In our socio-hydrology model we apply a macro-economic decision framework to a long-term flood-scenario. We assume a standard macro-economic growth model where agents derive utility from consumption and output depends on physical capital that can be accumulated through investment. To this framework we add the occurrence of flooding events which will destroy part of the capital. We identify two specific periodic long term solutions and denote them rich and poor economies. Whereas rich economies can afford to invest in flood defense and therefore avoid flood damage and develop high living standards, poor economies prefer consumption instead of investing in flood defense capital and end up facing flood damages every time the water level rises. Nevertheless, they manage to sustain at least a low level of physical capital. We identify optimal investment strategies and compare simulations with more frequent and more intense high water level events.

Simulation of Micron-Sized Debris Populations in Low Earth Orbit

NASA Technical Reports Server (NTRS)

Xu, Y.-L.; Hyde, J. L.; Prior, T.; Matney, Mark

2010-01-01

The update of ORDEM2000, the NASA Orbital Debris Engineering Model, to its new version ORDEM2010, is nearly complete. As a part of the ORDEM upgrade, this paper addresses the simulation of micro-debris (greater than 10 m and smaller than 1 mm in size) populations in low Earth orbit. The principal data used in the modeling of the micron-sized debris populations are in-situ hypervelocity impact records, accumulated in post-flight damage surveys on the space-exposed surfaces of returned spacecrafts. The development of the micro-debris model populations follows the general approach to deriving other ORDEM2010-required input populations for various components and types of debris. This paper describes the key elements and major steps in the statistical inference of the ORDEM2010 micro-debris populations. A crucial step is the construction of a degradation/ejecta source model to provide prior information on the micron-sized objects (such as orbital and object-size distributions). Another critical step is to link model populations with data, which is rather involved. It demands detailed information on area-time/directionality for all the space-exposed elements of a shuttle orbiter and damage laws, which relate impact damage with the physical properties of a projectile and impact conditions such as impact angle and velocity. Also needed are model-predicted debris fluxes as a function of object size and impact velocity from all possible directions. In spite of the very limited quantity of the available shuttle impact data, the population-derivation process is satisfactorily stable. Final modeling results obtained from shuttle window and radiator impact data are reasonably convergent and consistent, especially for the debris populations with object-size thresholds at 10 and 100 m.

Simulation of Micron-Sized Debris Populations in Low Earth Orbit

NASA Technical Reports Server (NTRS)

Xu, Y.-L.; Matney, M.; Liou, J.-C.; Hyde, J. L.; Prior, T. G.

2010-01-01

The update of ORDEM2000, the NASA Orbital Debris Engineering Model, to its new version . ORDEM2010, is nearly complete. As a part of the ORDEM upgrade, this paper addresses the simulation of micro-debris (greater than 10 micron and smaller than 1 mm in size) populations in low Earth orbit. The principal data used in the modeling of the micron-sized debris populations are in-situ hypervelocity impact records, accumulated in post-flight damage surveys on the space-exposed surfaces of returned spacecrafts. The development of the micro-debris model populations follows the general approach to deriving other ORDEM2010-required input populations for various components and types of debris. This paper describes the key elements and major steps in the statistical inference of the ORDEM2010 micro-debris populations. A crucial step is the construction of a degradation/ejecta source model to provide prior information on the micron-sized objects (such as orbital and object-size distributions). Another critical step is to link model populations with data, which is rather involved. It demands detailed information on area-time/directionality for all the space-exposed elements of a shuttle orbiter and damage laws, which relate impact damage with the physical properties of a projectile and impact conditions such as impact angle and velocity. Also needed are model-predicted debris fluxes as a function of object size and impact velocity from all possible directions. In spite of the very limited quantity of the available shuttle impact data, the population-derivation process is satisfactorily stable. Final modeling results obtained from shuttle window and radiator impact data are reasonably convergent and consistent, especially for the debris populations with object-size thresholds at 10 and 100 micron.

OBJECT KINETIC MONTE CARLO SIMULATIONS OF RADIATION DAMAGE IN TUNGSTEN SUBJECTED TO NEUTRON FLUX WITH PKA SPECTRUM CORRESPONDING TO THE HFIR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nandipati, Giridhar; Setyawan, Wahyu; Heinisch, Howard L.

2015-12-31

The objective of this work is to study the damage accumulation in pure tungsten (W) subjected to neutron bombardment with a primary knock-on atom (PKA) spectrum corresponding to the High Flux Isotope Reactor (HFIR), using the object kinetic Monte Carlo (OKMC) method.

cGAS Conducts Micronuclei DNA Surveillance.

PubMed

de Oliveira Mann, Carina C; Kranzusch, Philip J

2017-10-01

DNA damage elicits a potent proinflammatory immune response. A collection of four papers now reveals that micronuclear DNA is a new cell intrinsic immunostimulatory molecule, and that accumulation of the immune sensor cyclic GMP-AMP synthase (cGAS) in micronuclei leads to a cell-cycle-dependent proinflammatory response following DNA damage. Copyright © 2017 Elsevier Ltd. All rights reserved.

Alkylation Damage by Lipid Electrophiles Targets Functional Protein Systems*

PubMed Central

Codreanu, Simona G.; Ullery, Jody C.; Zhu, Jing; Tallman, Keri A.; Beavers, William N.; Porter, Ned A.; Marnett, Lawrence J.; Zhang, Bing; Liebler, Daniel C.

2014-01-01

Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions. PMID:24429493

Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina

Tetrahydrofolate (THF) and its one-carbon derivatives, collectively termed folates, are essential cofactors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molecules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-products. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in many sequenced bacterial genomes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanBmore » has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that overexpression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxymethylpterin and other pterins in cells and medium, and—unexpectedly—to a 46% increase in total folate content. In silico modeling of the folate biosynthesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynthesis by folates or their damage products.« less

Micromechanics Based Failure Analysis of Heterogeneous Materials

NASA Astrophysics Data System (ADS)

Sertse, Hamsasew M.

In recent decades, heterogeneous materials are extensively used in various industries such as aerospace, defense, automotive and others due to their desirable specific properties and excellent capability of accumulating damage. Despite their wide use, there are numerous challenges associated with the application of these materials. One of the main challenges is lack of accurate tools to predict the initiation, progression and final failure of these materials under various thermomechanical loading conditions. Although failure is usually treated at the macro and meso-scale level, the initiation and growth of failure is a complex phenomena across multiple scales. The objective of this work is to enable the mechanics of structure genome (MSG) and its companion code SwiftComp to analyze the initial failure (also called static failure), progressive failure, and fatigue failure of heterogeneous materials using micromechanics approach. The initial failure is evaluated at each numerical integration point using pointwise and nonlocal approach for each constituent of the heterogeneous materials. The effects of imperfect interfaces among constituents of heterogeneous materials are also investigated using a linear traction-displacement model. Moreover, the progressive and fatigue damage analyses are conducted using continuum damage mechanics (CDM) approach. The various failure criteria are also applied at a material point to analyze progressive damage in each constituent. The constitutive equation of a damaged material is formulated based on a consistent irreversible thermodynamics approach. The overall tangent modulus of uncoupled elastoplastic damage for negligible back stress effect is derived. The initiation of plasticity and damage in each constituent is evaluated at each numerical integration point using a nonlocal approach. The accumulated plastic strain and anisotropic damage evolution variables are iteratively solved using an incremental algorithm. The damage analyses are performed for both brittle failure/high cycle fatigue (HCF) for negligible plastic strain and ductile failure/low cycle fatigue (LCF) for large plastic strain. The proposed approach is incorporated in SwiftComp and used to predict the initial failure envelope, stress-strain curve for various loading conditions, and fatigue life of heterogeneous materials. The combined effects of strain hardening and progressive fatigue damage on the effective properties of heterogeneous materials are also studied. The capability of the current approach is validated using several representative examples of heterogeneous materials including binary composites, continuous fiber-reinforced composites, particle-reinforced composites, discontinuous fiber-reinforced composites, and woven composites. The predictions of MSG are also compared with the predictions obtained using various micromechanics approaches such as Generalized Methods of Cells (GMC), Mori-Tanaka (MT), and Double Inclusions (DI) and Representative Volume Element (RVE) Analysis (called as 3-dimensional finite element analysis (3D FEA) in this document). This study demonstrates that a micromechanics based failure analysis has a great potential to rigorously and more accurately analyze initiation and progression of damage in heterogeneous materials. However, this approach requires material properties specific to damage analysis, which are needed to be independently calibrated for each constituent.

MDC1: The art of keeping things in focus.

PubMed

Jungmichel, Stephanie; Stucki, Manuel

2010-08-01

The chromatin structure is important for recognition and repair of DNA damage. Many DNA damage response proteins accumulate in large chromatin domains flanking sites of DNA double-strand breaks. The assembly of these structures-usually termed DNA damage foci-is primarily regulated by MDC1, a large nuclear mediator/adaptor protein that is composed of several distinct structural and functional domains. Here, we are summarizing the latest discoveries about the mechanisms by which MDC1 mediates DNA damage foci formation, and we are reviewing the considerable efforts taken to understand the functional implication of these structures.

5'-nucleotidase

MedlinePlus

... Use of a liver-damaging drug Risks Slight risks from having blood drawn may include: Excessive bleeding Fainting or feeling lightheaded Hematoma (blood accumulating under the skin) Infection ( ...

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

PubMed

Mian, Omar Y; Khattab, Mohamed H; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M; Veeraswamy, Ravi K; Brooks, James D; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G; Yegnasubramanian, Srinivasan; DeWeese, Theodore L

2016-02-01

Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. © 2015 Wiley Periodicals, Inc.

GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress

PubMed Central

Mian, Omar Y.; Khattab, Mohamed H.; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M.; Veeraswamy, Ravi K.; Brooks, James D.; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G.; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.

2016-01-01

BACKGROUND Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. PMID:26447830

Time resolved study of cell death mechanisms induced by amine-modified polystyrene nanoparticles

NASA Astrophysics Data System (ADS)

Wang, Fengjuan; Bexiga, Mariana G.; Anguissola, Sergio; Boya, Patricia; Simpson, Jeremy C.; Salvati, Anna; Dawson, Kenneth A.

2013-10-01

Positively charged polymers and nanoparticles (NPs) can be toxic to cells in various systems. Using human astrocytoma cells, we have previously shown that 50 nm amine-modified polystyrene NPs damage mitochondria and induce cell death by apoptosis. Here we provide comprehensive details of the cellular events occurring after exposure to the NPs in a time-resolved manner. We demonstrate that the accumulation of NPs in lysosomes plays a central role in the observed cell death, leading to swelling of the lysosomes and release of cathepsins into the cytosol, which ultimately propagates the damage to the mitochondria with subsequent activation of apoptosis. This is accompanied and sustained by other events, such as increasing ROS levels and autophagy. Using various inhibitors, we also show the interplay between apoptosis and autophagy as a response to NP accumulation in lysosomes.Positively charged polymers and nanoparticles (NPs) can be toxic to cells in various systems. Using human astrocytoma cells, we have previously shown that 50 nm amine-modified polystyrene NPs damage mitochondria and induce cell death by apoptosis. Here we provide comprehensive details of the cellular events occurring after exposure to the NPs in a time-resolved manner. We demonstrate that the accumulation of NPs in lysosomes plays a central role in the observed cell death, leading to swelling of the lysosomes and release of cathepsins into the cytosol, which ultimately propagates the damage to the mitochondria with subsequent activation of apoptosis. This is accompanied and sustained by other events, such as increasing ROS levels and autophagy. Using various inhibitors, we also show the interplay between apoptosis and autophagy as a response to NP accumulation in lysosomes. Electronic supplementary information (ESI) available: additional analysis of flow cytometry results, western blots and experiments with cathepsin inhibitors. See DOI: 10.1039/c3nr03249c

Creep fatigue life prediction for engine hot section materials (isotropic)

NASA Technical Reports Server (NTRS)

Moreno, Vito; Nissley, David; Lin, Li-Sen Jim

1985-01-01

The first two years of a two-phase program aimed at improving the high temperature crack initiation life prediction technology for gas turbine hot section components are discussed. In Phase 1 (baseline) effort, low cycle fatigue (LCF) models, using a data base generated for a cast nickel base gas turbine hot section alloy (B1900+Hf), were evaluated for their ability to predict the crack initiation life for relevant creep-fatigue loading conditions and to define data required for determination of model constants. The variables included strain range and rate, mean strain, strain hold times and temperature. None of the models predicted all of the life trends within reasonable data requirements. A Cycle Damage Accumulation (CDA) was therefore developed which follows an exhaustion of material ductility approach. Material ductility is estimated based on observed similarities of deformation structure between fatigue, tensile and creep tests. The cycle damage function is based on total strain range, maximum stress and stress amplitude and includes both time independent and time dependent components. The CDA model accurately predicts all of the trends in creep-fatigue life with loading conditions. In addition, all of the CDA model constants are determinable from rapid cycle, fully reversed fatigue tests and monotonic tensile and/or creep data.

Biochemical Changes in Erythrocytes as a Molecular Marker of Cell Damage during Long-Term Simvastatin Treatment.

PubMed

Mikashinovich, Z I; Belousova, E S

2016-08-01

Long-term administration of simvastatin to rats, irrespective of the baseline cholesterol levels, induced biochemical changes in erythrocytes attesting to hypoxic damage (accumulation of lactate and 2,3-diphosphoglycerate), disturbances in ATP-dependent mechanisms of ion homeostasis regulation (decrease in total ATPase and Ca(2+)-ATPase activities), and antioxidant enzymes system imbalance. These changes can be considered as a sensitive indicator and molecular basis of cell damage during long-term administration of statins.

Characterization of Thermo-Elastic Properties and Microcracking Behaviors of CFRP Laminates Using Cup-Stacked Carbon Nanotubes (CSCNT) Dispersed Resin

NASA Astrophysics Data System (ADS)

Yokozeki, Tomohiro; Iwahori, Yutaka; Ishiwata, Shin

This study investigated the thermo-elastic properties and microscopic ply cracking behaviors in carbon fiber reinforced nanotube-dispersed epoxy laminates. The nanocomposite laminates used in this study consisted of traditional carbon fibers and epoxy resin filled with cup-stacked carbon nanotubes (CSCNTs). Thermo-mechanical properties of unidirectional nanocomposite laminates were evaluated, and quasi-static and fatigue tension tests of cross-ply laminates were carried out in order to observe the damage accumulation behaviors of matrix cracks. Clear retardation of matrix crack onset and accumulation was found in composite laminates with CSCNT compared to those without CSCNT. Fracture toughness associated with matrix cracking was evaluated based on the analytical model using the experimental results. It was concluded that the dispersion of CSCNT resulted in fracture toughness improvement and residual thermal strain decrease, and specifically, the former was the main contribution to the retardation of matrix crack formation.

A Special Population of Regulatory T Cells Potentiates Muscle Repair

PubMed Central

Burzyn, Dalia; Kuswanto, Wilson; Kolodin, Dmitriy; Shadrach, Jennifer L.; Cerletti, Massimiliano; Jang, Young; Sefik, Esen; Tan, Tze Guan; Wagers, Amy J.; Benoist, Christophe; Mathis, Diane

2014-01-01

SUMMARY Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloidlineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies. PMID:24315098

Counterion accumulation effects on a suspension of DNA molecules: Equation of state and pressure-driven denaturation

NASA Astrophysics Data System (ADS)

Nicasio-Collazo, Luz Adriana; Delgado-González, Alexandra; Hernández-Lemus, Enrique; Castañeda-Priego, Ramón

2017-04-01

The study of the effects associated with the electrostatic properties of DNA is of fundamental importance to understand both its molecular properties at the single molecule level, like the rigidity of the chain, and its interaction with other charged bio-molecules, including other DNA molecules; such interactions are crucial to maintain the thermodynamic stability of the intra-cellular medium. In the present work, we combine the Poisson-Boltzmann mean-field theory with an irreversible thermodynamic approximation to analyze the effects of counterion accumulation inside DNA on both the denaturation profile of the chain and the equation of state of the suspension. To this end, we model the DNA molecule as a porous charged cylinder immersed in an aqueous solution. These thermo-electrostatic effects are explicitly studied in the particular case of some genes for which damage in their sequence is associated with diffuse large B-cell lymphoma.

Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes

PubMed Central

Salucci, Sara; Luchetti, Francesca; Falcieri, Elisabetta; Di Sario, Gianna; Palma, Fulvio; Papa, Stefano

2016-01-01

Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage. PMID:27798705

Optimizing phytoremediation of heavy metal-contaminated soil by exploiting plants' stress adaptation.

PubMed

Barocsi, Attila; Csintalan, Zsolt; Kocsanyi, Laszlo; Dushenkov, Slavik; Kuperberg, J Michael; Kucharski, Rafal; Richter, Peter I

2003-01-01

Soil phytoextraction is based on the ability of plants to extract contaminants from the soil. For less bioavailable metals, such as Pb, a chelator is added to the soil to mobilize the metal. The effect can be significant and in certain species, heavy metal accumulation can rapidly increase 10-fold. Accumulation of high levels of toxic metals may result in irreversible damage to the plant. Monitoring and controlling the phytotoxicity caused by EDTA-induced metal accumulation is crucial to optimize the remedial process, i.e. to achieve maximum uptake. We describe an EDTA-application procedure that minimizes phytotoxicity by increasing plant tolerance and allows phytoextraction of elevated levels of Pb and Cd. Brassica juncea is tested in soil with typical Pb and Cd concentrations of 500 mg kg-1 and 15 mg kg-1, respectively. Instead of a single dose treatment, the chelator is applied in multiple doses, that is, in several small increments, thus providing time for plants to initiate their adaptation mechanisms and raise their damage threshold. In situ monitoring of plant stress conditions by chlorophyll fluorescence recording allows for the identification of the saturating heavy metal accumulation process and of simultaneous plant deterioration.

Age-related pathology after adenoviral overexpression of the leucine-rich repeat kinase 2 in the mouse striatum.

PubMed

Kritzinger, Astrid; Ferger, Boris; Gillardon, Frank; Stierstorfer, Birgit; Birk, Gerald; Kochanek, Stefan; Ciossek, Thomas

2018-06-01

Mutations in leucine-rich repeat kinase 2 (LRRK2) age-dependently cause Parkinson's disease and are associated with several inflammatory diseases. So far, the potential role of LRRK2 expression in glial cells as mediators of neuroinflammation and the influence of aging have not been investigated in viral vector-based LRRK2 animal models. In this study, we compared the effect of striatal injection of high-capacity adenoviral vectors expressing either a kinase-overactive LRRK2 with the familial G2019S mutation or a kinase-inactive LRRK2 variant in young and old C57BL/6J mice. The intrinsic adenovirus tropism guided preferentially glial transduction, and the vector design led to stable expression for at least 6 months. In histopathological analysis, young mice expressing either LRRK2 variant presented with transient vacuolization of striatal white fiber tracts accompanied by accumulation of microglial cells and astrogliosis, but inflammation resolved without permanent damage. Old mice had a stronger and prolonged inflammatory reaction and experienced permanent damage in form of partial neuron loss after 3 months exclusively in case of LRRK2_G2019S expression. The autophagic receptor p62 accumulated in cells with high levels of either LRRK2 variant, even more so in old mice. We conclude that the aging mouse brain is more susceptible to LRRK2-associated pathology, and in this model, glial LRRK2 expression significantly contributed to neuroinflammation, ultimately causing neurodegeneration. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Post-dive ultrasound detection of gas in the liver of rats and scuba divers.

PubMed

L'abbate, Antonio; Marabotti, Claudio; Kusmic, Claudia; Pagliazzo, Antonino; Navari, Alessandro; Positano, Vincenzo; Palermo, Mario; Benassi, Antonio; Bedini, Remo

2011-09-01

In a previous study, we obtained histologic documentation of liver gas embolism in the rat model of rapid decompression. The aim of the study was to assess in the same model occurrence and time course of liver embolism using 2-D ultrasound imaging, and to explore by this means putative liver gas embolism in recreational scuba divers. Following 42 min compression at 7 ATA breathing air and 12 min decompression, eight surviving female rats were anesthetized and the liver imaged by ultrasound at 20 min intervals up to 120 min. A significant enhancement of echo signal was recorded from 60 to 120 min as compared to earlier post-decompression times. Enzymatic markers of liver damage (AST, ALT, and GGT) increased significantly at 24 h upon decompression. Twelve healthy experienced divers were studied basally and at 15-min intervals up to 60 min following a 30-min scuba dive at 30 msw depth. At 30 min upon surfacing echo images showed significant signal enhancement that progressed and reached plateau at 45 and 60 min. Total bilirubin at 24 h increased significantly (p = 0.02) with respect to basal values although within the reference range. In conclusion, 2-D ultrasound liver imaging allowed detection of gas embolism in the rat and defined the time course of gas accumulation. Its application to scuba divers revealed liver gas accumulation in all subjects in the absence of clear-cut evidence of liver damage or of any symptom. The clinical significance of our findings remains to be investigated.

Evolution of spent nuclear fuel in dry storage conditions for millennia and beyond

NASA Astrophysics Data System (ADS)

Wiss, Thierry; Hiernaut, Jean-Pol; Roudil, Danièle; Colle, Jean-Yves; Maugeri, Emilio; Talip, Zeynep; Janssen, Arne; Rondinella, Vincenzo; Konings, Rudy J. M.; Matzke, Hans-Joachim; Weber, William J.

2014-08-01

Significant amounts of spent uranium dioxide nuclear fuel are accumulating worldwide from decades of commercial nuclear power production. While such spent fuel is intended to be reprocessed or disposed in geologic repositories, out-of-reactor radiation damage from alpha decay can be detrimental to its structural stability. Here we report on an experimental study in which radiation damage in plutonium dioxide, uranium dioxide samples doped with short-lived alpha-emitters and urano-thorianite minerals have been characterized by XRD, transmission electron microscopy, thermal desorption spectrometry and hardness measurements to assess the long-term stability of spent nuclear fuel to substantial alpha-decay doses. Defect accumulation is predicted to result in swelling of the atomic structure and decrease in fracture toughness; whereas, the accumulation of helium will produce bubbles that result in much larger gaseous-induced swelling that substantially increases the stresses in the constrained spent fuel. Based on these results, the radiation-ageing of highly-aged spent nuclear fuel over more than 10,000 years is predicted.

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

PubMed Central

Griseri, Thibault; Arnold, Isabelle C.; Pearson, Claire; Krausgruber, Thomas; Schiering, Chris; Franchini, Fanny; Schulthess, Julie; McKenzie, Brent S.; Crocker, Paul R.; Powrie, Fiona

2015-01-01

Summary The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target. PMID:26200014

Significant accumulation of persistent organic pollutants and dysregulation in multiple DNA damage repair pathways in the electronic-waste-exposed populations

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Xiaobo; Jing, Yaqing; Wang, Jianhai

Electronic waste (e-waste) has created a worldwide environmental and health problem, by generating a diverse group of hazardous compounds such as persistent organic pollutants (POPs). Our previous studies demonstrated that populations from e-waste exposed region have a significantly higher level of chromosomal aberrancy and incidence of DNA damage. In this study, we further demonstrated that various POPs persisted at a significantly higher concentration in the exposed group than those in the unexposed group. The level of reactive oxygen species and micronucleus rate were also significantly elevated in the exposed group. RNA sequencing analysis revealed 31 genes in DNA damage responsesmore » and repair pathways that were differentially expressed between the two groups (Log 2 ratio >1 or <−1). Our data demonstrated that both females and males of the exposed group have activated a series of DNA damage response genes; however many important DNA repair pathways have been dysregulated. Expressions of NEIL1/3 and RPA3, which are critical in initiating base pair and nucleotide excision repairs respectively, have been downregulated in both females and males of the exposed group. In contrast, expression of RNF8, an E3 ligase involved in an error prone non-homologous end joining repair for DNA double strand break, was upregulated in both genders of the exposed group. The other genes appeared to be differentially expressed only when the males or females of the two groups were compared respectively. Importantly, the expression of cell cycle regulatory gene CDC25A that has been implicated in multiple kinds of malignant transformation was significantly upregulated among the exposed males while downregulated among the exposed females. In conclusion, our studies have demonstrated significant correlations between e-waste disposing and POPs accumulation, DNA lesions and dysregulation of multiple DNA damage repair mechanisms in the residents of the e-waste exposed region. - Highlights: • We compared concentration of POPs, ROS and micronucleus rate in POPs exposed area. • Significant accumulation of POPs homologous in the e-waste exposed residents. • DNA damage and DNA damage repair pathways have been differentially activated. • Females and males in the exposed group have different responses to the DNA damage. • Exposed males may be more prone to undergo malignant transformation.« less

Damage Characterization in SiC/SiC Composites using Electrical Resistance

NASA Technical Reports Server (NTRS)

Smith, Craig E.; Xia, Zhenhai

2011-01-01

SiC/SiC ceramic matrix composites (CMCs) under creep-rupture loading accumulate damage by means of local matrix cracks that typically form near a stress concentration, such as a 90o fiber tow or large matrix pore, and grow over time. Such damage is difficult to detect through conventional techniques. Electrical resistance changes can be correlated with matrix cracking to provide a means of damage detection. Sylramic-iBN fiber-reinforced SiC composites with both melt infiltrated (MI) and chemical vapor infiltrated (CVI) matrix types are compared here. Results for both systems exhibit an increase in resistance prior to fracture, which can be detected either in situ or post-damage.

Computational Simulation of Composite Structural Fatigue

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Chamis, Christos C. (Technical Monitor)

2005-01-01

Progressive damage and fracture of composite structures subjected to monotonically increasing static, tension-tension cyclic, pressurization, and flexural cyclic loading are evaluated via computational simulation. Constituent material properties, stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for composites. Damage initiation, growth, accumulation, and propagation to fracture due to monotonically increasing static and cyclic loads are included in the simulations. Results show the number of cycles to failure at different temperatures and the damage progression sequence during different degradation stages. A procedure is outlined for use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of results with insight for design decisions.

Computational Simulation of Composite Structural Fatigue

NASA Technical Reports Server (NTRS)

Minnetyan, Levon

2004-01-01

Progressive damage and fracture of composite structures subjected to monotonically increasing static, tension-tension cyclic, pressurization, and flexural cyclic loading are evaluated via computational simulation. Constituent material properties, stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for composites. Damage initiation, growth, accumulation, and propagation to fracture due to monotonically increasing static and cyclic loads are included in the simulations. Results show the number of cycles to failure at different temperatures and the damage progression sequence during different degradation stages. A procedure is outlined for use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of results with insight for design decisions.

Progressive Fracture of Fiber Composite Builtup Structures

NASA Technical Reports Server (NTRS)

Gotsis, Pascal K.; Chamis, Christos C.; Minnetyan, Levon

1996-01-01

The damage progression and fracture of builtup composite structures was evaluated by using computational simulation to examine the behavior and response of a stiffened composite (0 +/- 45/90)(sub s6) laminate panel subjected to a bending load. The damage initiation, growth, accumulation, progression, and propagation to structural collapse were simulated. An integrated computer code (CODSTRAN) was augmented for the simulation of the progressive damage and fracture of builtup composite structures under mechanical loading. Results showed that damage initiation and progression have a significant effect on the structural response. Also investigated was the influence of different types of bending load on the damage initiation, propagation, and final fracture of the builtup composite panel.

Nitric oxide alleviates oxidative damage induced by enhanced ultraviolet-B radiation in cyanobacterium.

PubMed

Xue, Lingui; Li, Shiweng; Sheng, Hongmei; Feng, Huyuan; Xu, Shijian; An, Lizhe

2007-10-01

To study the role of nitric oxide (NO) on enhanced ultraviolet-B (UV-B) radiation (280-320 nm)-induced damage of Cyanobacterium, the growth, pigment content, and antioxidative activity of Spirulina platensis-794 cells were investigated under enhanced UV-B radiation and under different chemical treatments with or without UV-B radiation for 6 h. The changes in chlorophyll-a, malondialdehyde content, and biomass confirmed that 0.5 mM: sodium nitroprusside (SNP), a donor of nitric oxide (NO), could markedly alleviate the damage caused by enhanced UV-B. Specifically, the biomass and the chlorophyll-a content in S. platensis-794 cells decreased 40% and 42%, respectively under enhanced UV-B stress alone, but they only decreased 10% and 18% in the cells treated with UV-B irradiation and 0.5 mM: SNP. Further experiments suggested that NO treatment significantly increased the activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the accumulation of O (2)(-) in enhanced UV-B-irradiated cells. SOD and CAT activity increased 0.95- and 6.73-fold, respectively. The accumulation of reduced glutathione (GSH) increased during treatment with 0.5 mM: SNP in normal S. platensis cells, but SNP treatment could inhibit the increase of GSH in enhanced UV-B-stressed S. platensis cells. Thus, these results suggest that NO can strongly alleviate oxidative damage caused by UV-B stress by increasing the activities of SOD, peroxidase, CAT, and the accumulation of GSH, and by eliminating O (2)(-) in S. platensis-794 cells. In addition, the difference of NO origin between plants and cyanobacteria are discussed.

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

PubMed Central

Abu-Odeh, Mohammad; Salah, Zaidoun; Herbel, Christoph; Hofmann, Thomas G.; Aqeilan, Rami I.

2014-01-01

Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells. PMID:25331887

On the strength of random fiber networks

NASA Astrophysics Data System (ADS)

Deogekar, S.; Picu, R. C.

2018-07-01

Damage accumulation and failure in random fiber networks is of importance in a variety of applications, from design of synthetic materials, such as paper and non-wovens, to accidental tearing of biological tissues. In this work we study these processes using three-dimensional models of athermal fiber networks, focusing attention on the modes of failure and on the relationship between network strength and network structural parameters. We consider network failure at small and large strains associated with the rupture of inter-fiber bonds. It is observed that the strength increases linearly with the network volume fraction and with the bond strength, while the stretch at peak stress is inversely related to these two parameters. A small fraction of the bonds rupture before peak stress and this fraction increases with increasing failure stretch. Rendering the bond strength stochastic causes a reduction of the network strength. However, heterogeneity retards damage localization and increases the stretch at peak stress, therefore promoting ductility.

E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells.

PubMed

Castillo, Daniela S; Campalans, Anna; Belluscio, Laura M; Carcagno, Abel L; Radicella, J Pablo; Cánepa, Eduardo T; Pregi, Nicolás

2015-01-01

E2F transcription factors regulate a wide range of biological processes, including the cellular response to DNA damage. In the present study, we examined whether E2F family members are transcriptionally induced following treatment with several genotoxic agents, and have a role on the cell DNA damage response. We show a novel mechanism, conserved among diverse species, in which E2F1 and E2F2, the latter specifically in neuronal cells, are transcriptionally induced after DNA damage. This upregulation leads to increased E2F1 and E2F2 protein levels as a consequence of de novo protein synthesis. Ectopic expression of these E2Fs in neuronal cells reduces the level of DNA damage following genotoxic treatment, while ablation of E2F1 and E2F2 leads to the accumulation of DNA lesions and increased apoptotic response. Cell viability and DNA repair capability in response to DNA damage induction are also reduced by the E2F1 and E2F2 deficiencies. Finally, E2F1 and E2F2 accumulate at sites of oxidative and UV-induced DNA damage, and interact with γH2AX DNA repair factor. As previously reported for E2F1, E2F2 promotes Rad51 foci formation, interacts with GCN5 acetyltransferase and induces histone acetylation following genotoxic insult. The results presented here unveil a new mechanism involving E2F1 and E2F2 in the maintenance of genomic stability in response to DNA damage in neuronal cells.

E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells

PubMed Central

Castillo, Daniela S; Campalans, Anna; Belluscio, Laura M; Carcagno, Abel L; Radicella, J Pablo; Cánepa, Eduardo T; Pregi, Nicolás

2015-01-01

E2F transcription factors regulate a wide range of biological processes, including the cellular response to DNA damage. In the present study, we examined whether E2F family members are transcriptionally induced following treatment with several genotoxic agents, and have a role on the cell DNA damage response. We show a novel mechanism, conserved among diverse species, in which E2F1 and E2F2, the latter specifically in neuronal cells, are transcriptionally induced after DNA damage. This upregulation leads to increased E2F1 and E2F2 protein levels as a consequence of de novo protein synthesis. Ectopic expression of these E2Fs in neuronal cells reduces the level of DNA damage following genotoxic treatment, while ablation of E2F1 and E2F2 leads to the accumulation of DNA lesions and increased apoptotic response. Cell viability and DNA repair capability in response to DNA damage induction are also reduced by the E2F1 and E2F2 deficiencies. Finally, E2F1 and E2F2 accumulate at sites of oxidative and UV-induced DNA damage, and interact with γH2AX DNA repair factor. As previously reported for E2F1, E2F2 promotes Rad51 foci formation, interacts with GCN5 acetyltransferase and induces histone acetylation following genotoxic insult. The results presented here unveil a new mechanism involving E2F1 and E2F2 in the maintenance of genomic stability in response to DNA damage in neuronal cells. PMID:25892555

Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes.

PubMed

Ansari, M Y; Khan, N M; Ahmad, I; Haqqi, T M

2017-08-08

Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions. Human chondrocytes were from the unaffected area of knee OA cartilage (n = 12) and were stimulated with IL-1β to mimic pathological conditions. Mitochondrial membrane depolarization and ROS levels were determined using specific dyes and flow cytometry. Autophagy was determined by Western blotting for ATG5, Beclin1, immunofluorescence staining and confocal microscopy. Gene expression was determined by RT-qPCR. siRNA, wild-type and mutant Parkin plasmids were transfected using Amaxa system. Apoptosis was determined by PI staining of chondrocytes and TUNEL assay. IL-1β-stimulated OA chondrocytes showed high levels of ROS generation, mitochondrial membrane damage, accumulation of damaged mitochondria and higher incidence of apoptosis. IL-1β stimulation of chondrocytes with depleted Parkin expression resulted in sustained high levels of ROS, accumulation of damaged/dysfunctional mitochondria and enhanced apoptosis. Parkin translocation to depolarized/damaged mitochondria and recruitment of p62/SQSTM1 was required for the elimination of damaged/dysfunctional mitochondria in IL-1β-stimulated OA chondrocytes. Importantly we demonstrate that Parkin elimination of depolarized/damaged mitochondria required the Parkin ubiquitin ligase activity and resulted in reduced ROS levels and inhibition of apoptosis in OA chondrocytes under pathological conditions. Our data demonstrates that Parkin functions to eliminate depolarized/damaged mitochondria in chondrocytes which is necessary for mitochondrial quality control, regulation of ROS levels and chondrocyte survival under pathological conditions. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2‐independent mechanisms, unlike muscular dystrophy

PubMed Central

Suzuki, Nobuyuki; Ohtake, Hitomi; Kamauchi, Shinya; Hashimoto, Naohiro; Kiyono, Tohru; Wakabayashi, Shigeo

2015-01-01

Abstract Background Muscle wasting during cancer cachexia contributes to patient morbidity. Cachexia‐induced muscle damage may be understood by comparing its symptoms with those of other skeletal muscle diseases, but currently available data are limited. Methods We modelled cancer cachexia in mice bearing Lewis lung carcinoma/colon adenocarcinoma and compared the associated muscle damage with that in a murine muscular dystrophy model (mdx mice). We measured biochemical and immunochemical parameters: amounts/localization of cytoskeletal proteins and/or Ca2+ signalling proteins related to muscle function and abnormality. We analysed intracellular Ca2+ mobilization and compared results between the two models. Involvement of Ca2+‐permeable channel transient receptor potential vanilloid 2 (TRPV2) was examined by inoculating Lewis lung carcinoma cells into transgenic mice expressing dominant‐negative TRPV2. Results Tumourigenesis caused loss of body and skeletal muscle weight and reduced muscle force and locomotor activity. Similar to mdx mice, cachexia muscles exhibited myolysis, reduced sarcolemmal sialic acid content, and enhanced lysosomal exocytosis and sarcolemmal localization of phosphorylated Ca2+/CaMKII. Abnormal autophagy and degradation of dystrophin also occurred. Unlike mdx muscles, cachexia muscles did not exhibit regeneration markers (centrally nucleated fibres), and levels of autophagic proteolytic pathway markers increased. While a slight accumulation of TRPV2 was observed in cachexia muscles, Ca2+ influx via TRPV2 was not elevated in cachexia‐associated myotubes, and the course of cachexia pathology was not ameliorated by dominant‐negative inhibition of TRPV2. Conclusions Thus, cancer cachexia may induce muscle damage through TRPV2‐independent mechanisms distinct from those in muscular dystrophy; this may help treat patients with tumour‐induced muscle wasting. PMID:27239414

Damage Accumulation in Silica Glass Nanofibers.

PubMed

Bonfanti, Silvia; Ferrero, Ezequiel E; Sellerio, Alessandro L; Guerra, Roberto; Zapperi, Stefano

2018-06-06

The origin of the brittle-to-ductile transition, experimentally observed in amorphous silica nanofibers as the sample size is reduced, is still debated. Here we investigate the issue by extensive molecular dynamics simulations at low and room temperatures for a broad range of sample sizes, with open and periodic boundary conditions. Our results show that small sample-size enhanced ductility is primarily due to diffuse damage accumulation, that for larger samples leads to brittle catastrophic failure. Surface effects such as boundary fluidization contribute to ductility at room temperature by promoting necking, but are not the main driver of the transition. Our results suggest that the experimentally observed size-induced ductility of silica nanofibers is a manifestation of finite-size criticality, as expected in general for quasi-brittle disordered networks.

Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone

NASA Astrophysics Data System (ADS)

Townend, John; Sutherland, Rupert; Toy, Virginia G.; Doan, Mai-Linh; Célérier, Bernard; Massiot, Cécile; Coussens, Jamie; Jeppson, Tamara; Janku-Capova, Lucie; Remaud, Léa.; Upton, Phaedra; Schmitt, Douglas R.; Pezard, Philippe; Williams, Jack; Allen, Michael John; Baratin, Laura-May; Barth, Nicolas; Becroft, Leeza; Boese, Carolin M.; Boulton, Carolyn; Broderick, Neil; Carpenter, Brett; Chamberlain, Calum J.; Cooper, Alan; Coutts, Ashley; Cox, Simon C.; Craw, Lisa; Eccles, Jennifer D.; Faulkner, Dan; Grieve, Jason; Grochowski, Julia; Gulley, Anton; Hartog, Arthur; Henry, Gilles; Howarth, Jamie; Jacobs, Katrina; Kato, Naoki; Keys, Steven; Kirilova, Martina; Kometani, Yusuke; Langridge, Rob; Lin, Weiren; Little, Tim; Lukacs, Adrienn; Mallyon, Deirdre; Mariani, Elisabetta; Mathewson, Loren; Melosh, Ben; Menzies, Catriona; Moore, Jo; Morales, Luis; Mori, Hiroshi; Niemeijer, André; Nishikawa, Osamu; Nitsch, Olivier; Paris, Jehanne; Prior, David J.; Sauer, Katrina; Savage, Martha K.; Schleicher, Anja; Shigematsu, Norio; Taylor-Offord, Sam; Teagle, Damon; Tobin, Harold; Valdez, Robert; Weaver, Konrad; Wiersberg, Thomas; Zimmer, Martin

2017-12-01

Fault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging-wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP-2). We present observational evidence for extensive fracturing and high hanging-wall hydraulic conductivity (˜10-9 to 10-7 m/s, corresponding to permeability of ˜10-16 to 10-14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP-2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging-wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off-fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation.

Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma.

PubMed

Hao, Shuyu; Song, Hua; Zhang, Wei; Seldomridge, Ashlee; Jung, Jinkyu; Giles, Amber J; Hutchinson, Marsha-Kay; Cao, Xiaoyu; Colwell, Nicole; Lita, Adrian; Larion, Mioara; Maric, Dragan; Abu-Asab, Mones; Quezado, Martha; Kramp, Tamalee; Camphausen, Kevin; Zhuang, Zhengping; Gilbert, Mark R; Park, Deric M

2018-05-18

Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma. Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and UM-Chor1. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation. PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G2/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay. Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.

February 1994 ice storm: forest resource damage assessment in northern Mississippi

Treesearch

Dennis M. Jacobs

2000-01-01

During February 8­11, 1994, a severe winter storm moved from Texas and Oklahoma to the mid-Atlantic depositing in northern Mississippi a major ice accumulation of 3 to 6 inches. An assessment of forest resource damage was initiated immediately after the storm by performing an airborne video mission to acquire aerial imagery linked to global positioning coordinates....

Use of Modal Acoustic Emission to Monitor Damage Progression in Carbon Fiber/Epoxy Tows and Implications for Composite Structures

NASA Technical Reports Server (NTRS)

Waller, Jess M.; Saulsberry, Regor L.; Nichols, Charles T.; Wentzel, Daniel J.

2010-01-01

This slide presentation reviews the use of Modal Acoustic Emission to monitor damage progression to carbon fiber/epoxy tows. There is a risk for catastrophic failure of composite overwrapped pressure vessels (COPVs) due to burst-before-leak (BBL) stress rupture (SR) failure of carbon-epoxy (C/Ep) COPVs. A lack of quantitative nondestructive evaluation (NDE) is causing problems in current and future spacecraft designs. It is therefore important to develop and demonstrate critical NDE that can be implemented during stages of the design process since the observed rupture can occur with little of no advanced warning. Therefore a program was required to develop quantitative acoustic emission (AE) procedures specific to C/Ep overwraps, but which also have utility for monitoring damage accumulation in composite structure in general, and to lay the groundwork for establishing critical thresholds for accumulated damage in composite structures, such as COPVs, so that precautionary or preemptive engineering steps can be implemented to minimize of obviate the risk of catastrophic failure. A computed Felicity Ratio (FR) coupled with fast Fourier Transform (FFT) frequency analysis shows promise as an analytical pass/fail criterion. The FR analysis and waveform and FFT analysis are reviewed

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis.

PubMed

Palekar, Rohun U; Jallouk, Andrew P; Goette, Matthew J; Chen, Junjie; Myerson, Jacob W; Allen, John S; Akk, Antonina; Yang, Lihua; Tu, Yizheng; Miller, Mark J; Pham, Christine T N; Wickline, Samuel A; Pan, Hua

2015-07-01

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200-300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [(19)F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy. © FASEB.

Citric acid improves lead (pb) phytoextraction in brassica napus L. by mitigating pb-induced morphological and biochemical damages.

PubMed

Shakoor, Muhammad Bilal; Ali, Shafaqat; Hameed, Amjad; Farid, Mujahid; Hussain, Sabir; Yasmeen, Tahira; Najeeb, Ullah; Bharwana, Saima Aslam; Abbasi, Ghulam Hasan

2014-11-01

Phytoextraction is an environmentally friendly and a cost-effective strategy for remediation of heavy metal contaminated soils. However, lower bioavailability of some of the metals in polluted environments e.g. lead (Pb) is a major constraint of phytoextraction process that could be overcome by applying organic chelators. We conducted a glasshouse experiment to evaluate the role of citric acid (CA) in enhancing Pb phytoextraction. Brassica napus L. seedlings were grown in hydroponic media and exposed to various treatments of Pb (50 and 100 μM) as alone or in combination with CA (2.5mM) for six weeks. Pb-induced damage in B. napus toxicity was evident from elevated levels of malondialdehyde (MDA) and H2O2 that significantly inhibited plant growth, biomass accumulation, leaf chlorophyll contents and gas exchange parameters. Alternatively, CA application to Pb-stressed B. napus plants arrested lipid membrane damage by limiting MDA and H2O2 production and by improving antioxidant enzyme activities. In addition, CA significantly increased the Pb accumulation in B. napus plants. The study concludes that CA has a potential to improve Pb phytoextraction without damaging plant growth. Copyright © 2014 Elsevier Inc. All rights reserved.

Blueberry (Vaccinium ashei Reade) extract ameliorates ovarian damage induced by subchronic cadmium exposure in mice: Potential δ-ALA-D involvement.

PubMed

Izaguirry, Aryele Pinto; Soares, Melina Bucco; Vargas, Laura Musacchio; Spiazzi, Cristiano Chiapinotto; Dos Santos Brum, Daniela; Noremberg, Simone; Mendez, Andreas Sebastian Loureiro; Santos, Francielli Weber

2017-01-01

Females are born with a finite number of oocyte-containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ-aminolevulinate dehydratase activity, and partially improved the viability of cadmium-disrupted follicles. This therapy was not able to restore the 17 β-hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 188-196, 2017. © 2015 Wiley Periodicals, Inc.

Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity.

PubMed

Homma-Takeda, Shino; Kitahara, Keisuke; Suzuki, Kyoko; Blyth, Benjamin J; Suya, Noriyoshi; Konishi, Teruaki; Terada, Yasuko; Shimada, Yoshiya

2015-12-01

Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high-resolution quantitative in situ measurements by high-energy synchrotron radiation X-ray fluorescence analysis in renal sections from a rat model of uranium-induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg(-1) body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g(-1) , sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g(-1) ). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50-fold above mean renal concentration) in micro-regions was found near the nuclei. These uranium levels were maintained up to 8 days post-administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100-fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site-specific accumulation of uranium in micro-regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney. Copyright © 2015 John Wiley & Sons, Ltd.

Caffeine stabilizes Cdc25 independently of Rad3 in S chizosaccharomyces pombe contributing to checkpoint override

PubMed Central

Alao, John P; Sjölander, Johanna J; Baar, Juliane; Özbaki-Yagan, Nejla; Kakoschky, Bianca; Sunnerhagen, Per

2014-01-01

Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both S chizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S . pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S . pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. PMID:24666325

Survey of four damage models for concrete.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leelavanichkul, Seubpong; Brannon, Rebecca Moss

2009-08-01

Four conventional damage plasticity models for concrete, the Karagozian and Case model (K&C), the Riedel-Hiermaier-Thoma model (RHT), the Brannon-Fossum model (BF1), and the Continuous Surface Cap Model (CSCM) are compared. The K&C and RHT models have been used in commercial finite element programs many years, whereas the BF1 and CSCM models are relatively new. All four models are essentially isotropic plasticity models for which 'plasticity' is regarded as any form of inelasticity. All of the models support nonlinear elasticity, but with different formulations. All four models employ three shear strength surfaces. The 'yield surface' bounds an evolving set of elasticallymore » obtainable stress states. The 'limit surface' bounds stress states that can be reached by any means (elastic or plastic). To model softening, it is recognized that some stress states might be reached once, but, because of irreversible damage, might not be achievable again. In other words, softening is the process of collapse of the limit surface, ultimately down to a final 'residual surface' for fully failed material. The four models being compared differ in their softening evolution equations, as well as in their equations used to degrade the elastic stiffness. For all four models, the strength surfaces are cast in stress space. For all four models, it is recognized that scale effects are important for softening, but the models differ significantly in their approaches. The K&C documentation, for example, mentions that a particular material parameter affecting the damage evolution rate must be set by the user according to the mesh size to preserve energy to failure. Similarly, the BF1 model presumes that all material parameters are set to values appropriate to the scale of the element, and automated assignment of scale-appropriate values is available only through an enhanced implementation of BF1 (called BFS) that regards scale effects to be coupled to statistical variability of material properties. The RHT model appears to similarly support optional uncertainty and automated settings for scale-dependent material parameters. The K&C, RHT, and CSCM models support rate dependence by allowing the strength to be a function of strain rate, whereas the BF1 model uses Duvaut-Lion viscoplasticity theory to give a smoother prediction of transient effects. During softening, all four models require a certain amount of strain to develop before allowing significant damage accumulation. For the K&C, RHT, and CSCM models, the strain-to-failure is tied to fracture energy release, whereas a similar effect is achieved indirectly in the BF1 model by a time-based criterion that is tied to crack propagation speed.« less

mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease.

PubMed

Wang, Jintao; Tran, Jennifer; Wang, Hui; Guo, Chiao; Harro, David; Campbell, Andrew D; Eitzman, Daniel T

2016-08-01

Mechanistic target of rapamycin (mTOR) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease (SCD), mice with SCD were treated with the dual mTORC1/2 inhibitor, INK128. One week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD. © 2016 John Wiley & Sons Ltd.

Autophagy - An Emerging Anti-Aging Mechanism

PubMed Central

Gelino, Sara; Hansen, Malene

2013-01-01

Autophagy is a cytoplasmic catabolic process that protects the cell against stressful conditions. Damaged cellular components are funneled by autophagy into the lysosomes, where they are degraded and can be re-used as alternative building blocks for protein synthesis and cellular repair. In contrast, aging is the gradual failure over time of cellular repair mechanisms that leads to the accumulation of molecular and cellular damage and loss of function. The cell’s capacity for autophagic degradation also declines with age, and this in itself may contribute to the aging process. Studies in model organisms ranging from yeast to mice have shown that single-gene mutations can extend lifespan in an evolutionarily conserved fashion, and provide evidence that the aging process can be modulated. Interestingly, autophagy is induced in a seemingly beneficial manner by many of the same perturbations that extend lifespan, including mutations in key signaling pathways such as the insulin/IGF-1 and TOR pathways. Here, we review recent progress, primarily derived from genetic studies with model organisms, in understanding the role of autophagy in aging and age-related diseases. PMID:23750326

Modeling Fatigue Damage Onset and Progression in Composites Using an Element-Based Virtual Crack Closure Technique Combined With the Floating Node Method

NASA Technical Reports Server (NTRS)

De Carvalho, Nelson V.; Krueger, Ronald

2016-01-01

A new methodology is proposed to model the onset and propagation of matrix cracks and delaminations in carbon-epoxy composites subject to fatigue loading. An extended interface element, based on the Floating Node Method, is developed to represent delaminations and matrix cracks explicitly in a mesh independent fashion. Crack propagation is determined using an element-based Virtual Crack Closure Technique approach to determine mixed-mode energy release rates, and the Paris-Law relationship to obtain crack growth rate. Crack onset is determined using a stressbased onset criterion coupled with a stress vs. cycle curve and Palmgren-Miner rule to account for fatigue damage accumulation. The approach is implemented in Abaqus/Standard® via the user subroutine functionality. Verification exercises are performed to assess the accuracy and correct implementation of the approach. Finally, it was demonstrated that this approach captured the differences in failure morphology in fatigue for two laminates of identical stiffness, but with layups containing ?deg plies that were either stacked in a single group, or distributed through the laminate thickness.

Rhesus monkey lens as an in vitro model for studying oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zigler, J.S. Jr.; Lucas, V.A.; Du, X.Y.

1989-10-01

Lenses from young rhesus monkeys were incubated in the presence of H{sub 2}O{sub 2} or oxygen radical generating systems to determine their suitability as a model for investigating lenticular oxidative stress. Additionally, direct comparisons were made between the effects found with the monkey lenses and those observed with cultured rat lenses exposed to the same oxidizing systems. As in earlier studies with rat lenses the monkey lenses exhibited impaired ability to actively accumulate from the medium radioactively labelled rubidium and choline following exposure to oxidative stress. Based on the effects of various scavengers of oxygen radicals it appeared that themore » mechanisms responsible for lens damage were the same for both rat and monkey lenses. However, rat lenses were damaged by lower concentrations of oxidants than were monkey lenses. It was concluded that oxidative stress affects both rat and monkey lenses by similar mechanisms but that lenses from monkeys, and probably other primates, are more resistant to these effects because they have better endogenous antioxidant defenses.« less

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress.

PubMed

Qi, Jinpeng; Ding, Yongsheng; Zhu, Ying; Wu, Yizhi

2011-01-01

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.

Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats.

PubMed

Zhang, Juan; Tucker, Lorelei Donovan; DongYan; Lu, Yujiao; Yang, Luodan; Wu, Chongyun; Li, Yong; Zhang, Quanguang

2018-06-01

Hypoxic-ischemic (HI) encephalopathy is a leading cause of dire mortality and morbidity in neonates. Unfortunately, no effective therapies have been developed as of yet. Oxidative stress plays a critical role in pathogenesis and progression of neonatal HI. Previously, as a Nrf2 activator, tert-butylhydroquinone (TBHQ) has been demonstrated to exert neuroprotection on brain trauma and ischemic stroke models, as well as oxidative stress-induced cytotoxicity in neurons. It is, however, still unknown whether TBHQ administration can protect against oxidative stress in neonatal HI brain injury. This study was undertaken to determine the neuroprotective effects and mechanisms of TBHQ post-treatment on neonatal HI brain damage. Using a neonatal HI rat model, we demonstrated that TBHQ markedly abated oxidative stress compared to the HI group, as evidenced by decreased oxidative stress indexes, enhanced Nrf2 nuclear accumulation and DNA binding activity, and up-regulated expression of Nrf2 downstream antioxidative genes. Administration of TBHQ likewise significantly suppressed reactive gliosis and release of inflammatory cytokines, and inhibited apoptosis and neuronal degeneration in the neonatal rat cerebral cortex. In addition, infarct size and neuronal damage were attenuated distinctly. These beneficial effects were accompanied by improved neurological reflex and motor coordination as well as amelioration of spatial learning and memory deficits. Overall, our results provide the first documentation of the beneficial effects of TBHQ in neonatal HI model, in part conferred by activation of Nrf2 mediated antioxidative signaling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Damage Progression in Bolted Composites

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Chamis, Christos C.; Gotsis, Pascal K.

1998-01-01

Structural durability, damage tolerance, and progressive fracture characteristics of bolted graphite/epoxy composite laminates are evaluated via computational simulation. Constituent material properties and stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for bolted composites. Single and double bolted composite specimens with various widths and bolt spacings are evaluated. The effect of bolt spacing is investigated with regard to the structural durability of a bolted joint. Damage initiation, growth, accumulation, and propagation to fracture are included in the simulations. Results show the damage progression sequence and structural fracture resistance during different degradation stages. A procedure is outlined for the use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of experimental results with insight for design decisions.

Damage Progression in Bolted Composites

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Chamis, Christos; Gotsis, Pascal K.

1998-01-01

Structural durability,damage tolerance,and progressive fracture characteristics of bolted graphite/epoxy composite laminates are evaluated via computational simulation. Constituent material properties and stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for bolted composites. Single and double bolted composite specimens with various widths and bolt spacings are evaluated. The effect of bolt spacing is investigated with regard to the structural durability of a bolted joint. Damage initiation, growth, accumulation, and propagation to fracture are included in the simulations. Results show the damage progression sequence and structural fracture resistance during different degradation stages. A procedure is outlined for the use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of experimental results with insight for design decisions.

Arsenite-induced autophagy is associated with proteotoxicity in human lymphoblastoid cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolt, Alicia M.; Zhao, Fei; Pacheco, Samantha

2012-10-15

Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examinedmore » the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation. -- Highlights: ► Arsenite induces endoplasmic reticulum stress and the unfolded protein response. ► Arsenite induces the formation of protein aggregates that contain p62 and LC3-II. ► Time-course data suggests that arsenite-induced autophagy precedes ER stress.« less

Carbon storage and long-term rate of accumulation in high-altitude Andean peatlands of Bolivia

Treesearch

J.A. Hribljan; D.J. Cooper; J. Sueltenfuss; E.C. Wolf; K.A. Heckman; Erik Lilleskov; R.A. Chimner

2015-01-01

The high-altitude (4,500+ m) Andean mountain range of north-western Bolivia contains many peatlands. Despite heavy grazing pressure and potential damage from climate change, little is known about these peatlands. Our objective was to quantify carbon pools, basal ages and long-term peat accumulation rates in peatlands in two areas of the arid puna ecoregion of Bolivia:...

Antimicrobial metallic copper surfaces kill Staphylococcus haemolyticus via membrane damage.

PubMed

Santo, Christophe Espírito; Quaranta, Davide; Grass, Gregor

2012-03-01

Recently, copper (Cu) in its metallic form has regained interest for its antimicrobial properties. Use of metallic Cu surfaces in worldwide hospital trials resulted in remarkable reductions in surface contaminations. Yet, our understanding of why microbes are killed upon contact to the metal is still limited and different modes of action have been proposed. This knowledge, however, is crucial for sustained use of such surfaces in hospitals and other hygiene-sensitive areas. Here, we report on the molecular mechanisms by which the Gram-positive Staphylococcus haemolyticus is inactivated by metallic Cu. Staphylococcus haemolyticus was killed within minutes on Cu but not on stainless steel demonstrating the antimicrobial efficacy of metallic Cu. Inductively coupled plasma mass spectroscopy (ICP-MS) analysis and in vivo staining with Coppersensor-1 indicated that cells accumulated large amounts of Cu ions from metallic Cu surfaces contributing to lethal damage. Mutation rates of Cu- or steel-exposed cells were similarly low. Instead, live/dead staining indicated cell membrane damage in Cu- but not steel-exposed cells. These findings support a model of the cellular targets of metallic Cu toxicity in bacteria, which suggests that metallic Cu is not genotoxic and does not kill via DNA damage. In contrast, membranes constitute the likely Achilles' heel of Cu surface-exposed cells.

Antimicrobial metallic copper surfaces kill Staphylococcus haemolyticus via membrane damage

PubMed Central

Santo, Christophe Espírito; Quaranta, Davide; Grass, Gregor

2012-01-01

Recently, copper (Cu) in its metallic form has regained interest for its antimicrobial properties. Use of metallic Cu surfaces in worldwide hospital trials resulted in remarkable reductions in surface contaminations. Yet, our understanding of why microbes are killed upon contact to the metal is still limited and different modes of action have been proposed. This knowledge, however, is crucial for sustained use of such surfaces in hospitals and other hygiene-sensitive areas. Here, we report on the molecular mechanisms by which the Gram-positive Staphylococcus haemolyticus is inactivated by metallic Cu. Staphylococcus haemolyticus was killed within minutes on Cu but not on stainless steel demonstrating the antimicrobial efficacy of metallic Cu. Inductively coupled plasma mass spectroscopy (ICP-MS) analysis and in vivo staining with Coppersensor-1 indicated that cells accumulated large amounts of Cu ions from metallic Cu surfaces contributing to lethal damage. Mutation rates of Cu- or steel-exposed cells were similarly low. Instead, live/dead staining indicated cell membrane damage in Cu- but not steel-exposed cells. These findings support a model of the cellular targets of metallic Cu toxicity in bacteria, which suggests that metallic Cu is not genotoxic and does not kill via DNA damage. In contrast, membranes constitute the likely Achilles’ heel of Cu surface-exposed cells. PMID:22950011

Novel self-sensing carbon nanotube-based composites for rehabilitation of structural steel members

NASA Astrophysics Data System (ADS)

Ahmed, Shafique; Doshi, Sagar; Schumacher, Thomas; Thostenson, Erik T.; McConnell, Jennifer

2016-02-01

Fatigue and fracture are among the most critical forms of damage in metal structures. Fatigue damage can initiate from microscopic defects (e.g., surface scratches, voids in welds, and internal defects) and initiate a crack. Under cyclic loading, these cracks can grow and reach a critical level to trigger fracture of the member which leads to compromised structural integrity and, in some cases, catastrophic failure of the entire structure. In our research, we are investigating a solution using carbon nanotube-based sensing composites, which have the potential to simultaneously rehabilitate and monitor fatigue-cracked structural members. These composites consist of a fiber-reinforced polymer (FRP) layer and a carbon nanotube-based sensing layer, which are integrated to form a novel structural self-sensing material. The sensing layer is composed of a non-woven aramid fabric that is coated with carbon nanotubes (CNT) to form an electrically conductive network that is extremely sensitive to detecting deformation as well as damage accumulation via changes in the resistance of the CNT network. In this paper, we introduce the sensing concept, describe the manufacturing of a model sensing prototype, and discuss a set of small-scale laboratory experiments to examine the load-carrying capacity and damage sensing response.

Epigenomic maintenance through dietary intervention can facilitate DNA repair process to slow down the progress of premature aging.

PubMed

Ghosh, Shampa; Sinha, Jitendra Kumar; Raghunath, Manchala

2016-09-01

DNA damage caused by various sources remains one of the most researched topics in the area of aging and neurodegeneration. Increased DNA damage causes premature aging. Aging is plastic and is characterised by the decline in the ability of a cell/organism to maintain genomic stability. Lifespan can be modulated by various interventions like calorie restriction, a balanced diet of macro and micronutrients or supplementation with nutrients/nutrient formulations such as Amalaki rasayana, docosahexaenoic acid, resveratrol, curcumin, etc. Increased levels of DNA damage in the form of double stranded and single stranded breaks are associated with decreased longevity in animal models like WNIN/Ob obese rats. Erroneous DNA repair can result in accumulation of DNA damage products, which in turn result in premature aging disorders such as Hutchinson-Gilford progeria syndrome. Epigenomic studies of the aging process have opened a completely new arena for research and development of drugs and therapeutic agents. We propose here that agents or interventions that can maintain epigenomic stability and facilitate the DNA repair process can slow down the progress of premature aging, if not completely prevent it. © 2016 IUBMB Life, 68(9):717-721, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

Crystallographic evolution of MAX phases in proton irradiating environments

NASA Astrophysics Data System (ADS)

Ward, Joseph; Middleburgh, Simon; Topping, Matthew; Garner, Alistair; Stewart, David; Barsoum, Michel W.; Preuss, Michael; Frankel, Philipp

2018-04-01

This work represents the first use of proton irradiation to simulate in-core radiation damage in Ti3SiC2 and Ti3AlC2 MAX phases. Irradiation experiments were performed to 0.1 dpa at 350 °C, with a damage rate of 4.57 × 10-6 dpa s-1. The MAX phases displayed significant dimensional instabilities at the crystal level during irradiation leading to large anisotropic changes in lattice parameter, even at low damage levels. The instabilities were accompanied by a decomposition of the Ti-based MAX phases to their binary constituents, TiC. Experimentally observed changes in lattice parameter have been correlated with density functional theory modelling. The most energetically favourable and/or most difficult to recombine defects considered were an M-A antisite ({MA:AM}), and carbon Frenkel ({VC:Ci}). It is proposed that antisite defects, {MA:AM}, are the main contributor to the observed changes in lattice parameter. The proposed mechanism reported in this work potentially enables to design MAX phase compositions, which do not favour antisite defect accumulation. In addition, comparison between the experimental results and theoretical calculations shows that a greater amount of residual damage remains in Ti3AlC2 when compared to Ti3SiC2 after the same irradiation treatment.

Silicon Priming Created an Enhanced Tolerance in Alfalfa (Medicago sativa L.) Seedlings in Response to High Alkaline Stress

PubMed Central

Liu, Duo; Liu, Miao; Liu, Xiao-Long; Cheng, Xian-Guo; Liang, Zheng-Wei

2018-01-01

Alkaline stress as a result of higher pH usually triggers more severe physiological damage to plants than that of saline stress with a neutral pH. In the present study, we demonstrated that silicon (Si) priming of alfalfa (Medicago sativa L.) seedlings increased their tolerance to high alkaline stress situations. Gongnong No. 1 seedlings were subjected to alkaline stress simulated by 25 mM Na2CO3 (pH 11.2). Alkaline stress greatly decreased the biomass and caused severe lodging or wilting of alfalfa seedlings. In contrast, the application of Si to alfalfa seedlings 36 h prior to the alkaline treatment significantly alleviated the damage symptoms and greatly increased the biomass and chlorophyll content. Because of being concomitant with increasing photosynthesis and water use efficiency, decreasing membrane injury and malondialdehyde content, and increasing peroxidase and catalase ascorbate activities in alfalfa leaves, thereby alleviating the triggered oxidative damage by alkaline stress to the plant. Furthermore, Si priming significantly decreased the accumulation of protein and proline content in alfalfa, thus reducing photosynthetic feedback repression. Si priming significantly accumulated more Na in the roots, but led to a decrease of Na accumulation and an increase of K accumulation in the leaves under alkaline stress. Meanwhile, Si priming decreased the accumulation of metal ions such as Mg, Fe, Mn, and Zn in the roots of alfalfa seedlings under alkaline stress. Collectively, these results suggested that Si is involved in the metabolic or physiological changes and has a potent priming effect on the alkaline tolerance of alfalfa seedlings. The present study indicated that Si priming is a new approach to improve the alkaline tolerance in alfalfa and provides increasing information for further exploration of the alkaline stress response at the molecular level in alfalfa. PMID:29896213

A developmental perspective on high power laser facility technology for ICF

NASA Astrophysics Data System (ADS)

Zhu, Jianqiang; Sun, Mingying; Liu, Chong; Guo, Yajing; Yang, Lin; Yang, Pengqian; Zhang, Yanli; Wang, Bingyan; Liu, Cheng; Li, Yangshuai; Ren, Zhiyuan; Liu, Dean; Liu, Zhigang; Jiao, Zhaoyang; Ren, Lei; Zhang, Guowen; Fan, Quantang; Feng, Tao; Lin, Zunqi

2018-02-01

The latest progress on high power laser facilities in NLHPLP was reported. Based on a high power laser prototype, damage behavior of 3ω optics was experimentally tested, and the key influencing factors contributed to laser-induced damage in optics were deeply analyzed. The latest experimental results of advanced precision measurement for optical quality applied in the high power laser facility were introduced. At last, based on the accumulated works of 3ω elements damage behavior status in our laboratory, beam expanding scheme was presented to increase the total maximum output 3ω energy properly and decrease the laser induced damage risking of ω optics simultaneously.

Limestone characterization to model damage from acidic precipitation: Effect of pore structure on mass transfer

USGS Publications Warehouse

Leith, S.D.; Reddy, M.M.; Irez, W.F.; Heymans, M.J.

1996-01-01

The pore structure of Salem limestone is investigated, and conclusions regarding the effect of the pore geometry on modeling moisture and contaminant transport are discussed based on thin section petrography, scanning electron microscopy, mercury intrusion porosimetry, and nitrogen adsorption analyses. These investigations are compared to and shown to compliment permeability and capillary pressure measurements for this common building stone. Salem limestone exhibits a bimodal pore size distribution in which the larger pores provide routes for convective mass transfer of contaminants into the material and the smaller pores lead to high surface area adsorption and reaction sites. Relative permeability and capillary pressure measurements of the air/water system indicate that Salem limestone exhibits high capillarity end low effective permeability to water. Based on stone characterization, aqueous diffusion and convection are believed to be the primary transport mechanisms for pollutants in this stone. The extent of contaminant accumulation in the stone depends on the mechanism of partitioning between the aqueous and solid phases. The described characterization techniques and modeling approach can be applied to many systems of interest such as acidic damage to limestone, mass transfer of contaminants in concrete and other porous building materials, and modeling pollutant transport in subsurface moisture zones.

Changes in circulating cytokines and markers of muscle damage in elite cyclists during a multi-stage competition.

PubMed

Córdova Martínez, Alfredo; Martorell Pons, Miquel; Sureda Gomila, Antoni; Tur Marí, Josep A; Pons Biescas, Antoni

2015-09-01

The purpose of this study was to determine the changes in the basal and post-exercise plasma markers of muscular damage, lipid peroxidation and cytokines in eight male well-trained semiprofessional cyclists, in response to a three consecutive-day cycling competition. Serum markers of oxidative and muscular damage - creatine kinase activity, lactate dehydrogenase activity, myoglobin and malondialdehyde (MDA), creatinine and nitrite levels - followed a sawtooth-type representation throughout the competition. MDA showed an accumulative pattern, evidenced in the post-race values of the third stage which were significantly higher with respect to the values of the first stage. Cortisol levels were significantly influenced by an interaction between the exercise and the stage factors, with higher values on the 4th day. Plasma cytokine levels were only determined before the first stage and post-race, after the third stage. The exercise increased TNFα, IL6, IL2 and IFNγ levels, whereas IL1β was unchanged. In conclusion, cyclist stages induced oxidative and cellular muscle damage which is partially recovered to basal values by the next morning. Repetitive stages during the cycling competition accumulated plasma muscular damage and lipid peroxidation markers and pro-inflammatory cytokines, probably as a result of local inflammatory responses. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Photoinhibition and photoinhibition-like damage to the photosynthetic apparatus in tobacco leaves induced by pseudomonas syringae pv. Tabaci under light and dark conditions.

PubMed

Cheng, Dan-Dan; Zhang, Zi-Shan; Sun, Xing-Bin; Zhao, Min; Sun, Guang-Yu; Chow, Wah Soon

2016-01-25

Pseudomonas syringae pv. tabaci (Pst), which is the pathogen responsible for tobacco wildfire disease, has received considerable attention in recent years. The objective of this study was to clarify the responses of photosystem I (PSI) and photosystem II (PSII) to Pst infection in tobacco leaves. The net photosynthetic rate (Pn) and carboxylation efficiency (CE) were inhibited by Pst infection. The normalized relative variable fluorescence at the K step (W k) and the relative variable fluorescence at the J step (V J) increased while the maximal quantum yield of PSII (F v/F m) and the density of Q A-reducing PSII reaction centers per cross section (RC/CSm) decreased, indicating that the reaction centers, and the donor and acceptor sides of PSII were all severely damaged after Pst infection. The PSI activity decreased as the infection progressed. Furthermore, we observed a considerable overall degradation of PsbO, D1, PsaA proteins and an over-accumulation of reactive oxygen species (ROS). Photoinhibition and photoinhibition-like damage were observed under light and dark conditions, respectively, after Pst infection of tobacco leaves. The damage was greater in the dark. ROS over-accumulation was not the primary cause of the photoinhibition and photoinhibition-like damage. The PsbO, D1 and PsaA proteins appear to be the targets during Pst infection under light and dark conditions.

Staying young at heart: autophagy and adaptation to cardiac aging.

PubMed

Leon, Leonardo J; Gustafsson, Åsa B

2016-06-01

Aging is a predominant risk factor for developing cardiovascular disease. Therefore, the cellular processes that contribute to aging are attractive targets for therapeutic interventions that can delay or prevent the development of age-related diseases. Our understanding of the underlying mechanisms that contribute to the decline in cell and tissue functions with age has greatly advanced over the past decade. Classical hallmarks of aging cells include increased levels of reactive oxygen species, DNA damage, accumulation of dysfunctional organelles, oxidized proteins and lipids. These all contribute to a progressive decline in the normal physiological function of the cell and to the onset of age-related conditions. A major cause of the aging process is progressive loss of cellular quality control. Autophagy is an important quality control pathway and is necessary to maintain cardiac homeostasis and to adapt to stress. A reduction in autophagy has been observed in a number of aging models and there is compelling evidence that enhanced autophagy delays aging and extends life span. Enhancing autophagy counteracts age-associated accumulation of protein aggregates and damaged organelles in cells. In this review, we discuss the functional role of autophagy in maintaining homeostasis in the heart, and how a decline is associated with accelerated cardiac aging. We also evaluate therapeutic approaches being researched in an effort to maintain a healthy young heart. Copyright © 2015 Elsevier Ltd. All rights reserved.

Irradiation-induced defect formation and damage accumulation in single crystal CeO 2

DOE PAGES

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

2017-11-15

Here, the accumulation of irradiation-induced disorder in single crystal CeO 2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO 2 thin films using 2 MeV Au 2+ ions were carried out up to a total fluence of 1.3 x 10 16 cm –2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes inmore » correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.« less

Yeast MRX deletions have short chronological life span and more triacylglycerols.

PubMed

Kanagavijayan, Dhanabalan; Rajasekharan, Ram; Srinivasan, Malathi

2016-02-01

Saccharomyces cerevisiae is an excellent model organism for lipid research. Here, we have used yeast haploid RAdiation Damage (RAD) deletion strains to study life span and lipid storage patterns. RAD genes are mainly involved in DNA repair mechanism and hence, their deletions have resulted in shorter life span. Viable RAD mutants were screened for non-polar lipid content, and some of the mutants showed significantly high amounts of triacylglycerol (TAG) and steryl ester, besides short chronological life span. Among these, RAD50, MRE11 and XRS2 form a complex, MRX that is involved in homologous recombination that showed an increase in the amount of TAG. Microarray data of single MRX deletions revealed that besides DNA damage signature genes, lipid metabolism genes are also differentially expressed. Lipid biosynthetic genes (LPP1, SLC1) were upregulated and lipid hydrolytic gene (TGL3) was downregulated. We observed that rad50Δ, mre11Δ, xrs2Δ and mrxΔ strains have high number of lipid droplets (LDs) with fragmented mitochondria. These mutants have a short chronological life span compared to wild type. Aged wild-type cells also accumulated TAG with LDs of ∼2.0 μm in diameter. These results suggest that TAG accumulation and big size LDs could be possible markers for premature or normal aging. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Irradiation-induced defect formation and damage accumulation in single crystal CeO2

NASA Astrophysics Data System (ADS)

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

2018-01-01

The accumulation of irradiation-induced disorder in single crystal CeO2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO2 thin films using 2 MeV Au2+ ions were carried out up to a total fluence of 1.3 ×1016 cm-2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes in correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.

Effects of chemical alternation on damage accumulation in concentrated solid-solution alloys

DOE PAGES

Ullah, Mohammad W.; Xue, Haizhou; Velisa, Gihan; ...

2017-06-23

Single-phase concentrated solid-solution alloys (SP-CSAs) have recently gained unprecedented attention due to their promising properties. To understand effects of alloying elements on irradiation-induced defect production, recombination and evolution, an integrated study of ion irradiation, ion beam analysis and atomistic simulations are carried out on a unique set of model crystals with increasing chemical complexity, from pure Ni to Ni 80Fe 20, Ni 50Fe 50, and Ni 80Cr 20 binaries, and to a more complex Ni 40Fe 40Cr 20 alloy. Both experimental and simulation results suggest that the binary and ternary alloys exhibit higher radiation resistance than elemental Ni. The modelingmore » work predicts that Ni 40Fe 40Cr 20 has the best radiation tolerance, with the number of surviving Frenkel pairs being factors of 2.0 and 1.4 lower than pure Ni and the 80:20 binary alloys, respectively. While the reduced defect mobility in SP-CSAs is identified as a general mechanism leading to slower growth of large defect clusters, the effect of specific alloying elements on suppression of damage accumulation is clearly demonstrated. This work suggests that concentrated solid-solution provides an effective way to enhance radiation tolerance by creating elemental alternation at the atomic level. The demonstrated chemical effects on defect dynamics may inspire new design principles of radiation-tolerant structural alloys for advanced energy systems.« less

Irradiation-induced defect formation and damage accumulation in single crystal CeO 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graham, Joseph T.; Zhang, Yanwen; Weber, William J.

Here, the accumulation of irradiation-induced disorder in single crystal CeO 2 has been investigated over a wide range of ion fluences. Room temperature irradiations of epitaxial CeO 2 thin films using 2 MeV Au 2+ ions were carried out up to a total fluence of 1.3 x 10 16 cm –2 Post-irradiation disorder was characterized using ion channeling Rutherford backscattering spectrometry (RBS/C) and confocal Raman spectroscopy. The Raman measurements were interpreted by means of a phonon confinement model, which employed rigid ion calculations to determine the phonon correlation length in the irradiated material. Comparison between the dose dependent changes inmore » correlation length of the Raman measurements and the Ce disorder fraction from RBS/C provides complementary quantitative details on the rate of point and extended defect formation on the Ce and O sub-lattices over a broad range of ion fluences. Raman measurements, which are significantly more sensitive than RBS/C at low doses, reveal that the nucleation rate of defects is highest below 0.1 displacements per atom (dpa). Comparison between Raman and RBS/C measurements suggests that between 0.1 and 10 dpa the damage evolution is characterized by modest growth of point defects and/or small clusters, while above 10 dpa the preexisting defects rapidly grow into extended clusters and/or loops.« less

Analysis of DNA double-strand break response and chromatin structure in mitosis using laser microirradiation

PubMed Central

Gomez-Godinez, Veronica; Wu, Tao; Sherman, Adria J.; Lee, Christopher S.; Liaw, Lih-Huei; Zhongsheng, You; Yokomori, Kyoko; Berns, Michael W.

2010-01-01

In this study the femtosecond near-IR and nanosecond green lasers are used to induce alterations in mitotic chromosomes. The subsequent double-strand break responses are studied. We show that both lasers are capable of creating comparable chromosomal alterations and that a phase paling observed within 1–2 s of laser exposure is associated with an alteration of chromatin as confirmed by serial section electron microscopy, DAPI, γH2AX and phospho-H3 staining. Additionally, the accumulation of dark material observed using phase contrast light microscopy (indicative of a change in refractive index of the chromatin) ∼34 s post-laser exposure corresponds spatially to the accumulation of Nbs1, Ku and ubiquitin. This study demonstrates that chromosomes selectively altered in mitosis initiate the DNA damage response within 30 s and that the accumulation of proteins are visually represented by phase-dark material at the irradiation site, allowing us to determine the fate of the damage as cells enter G1. These results occur with two widely different laser systems, making this approach to study DNA damage responses in the mitotic phase generally available to many different labs. Additionally, we present a summary of most of the published laser studies on chromosomes in order to provide a general guide of the lasers and operating parameters used by other laboratories. PMID:20923785

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

PubMed Central

Guo, Yan-xia; Lin, Zhao-min; Wang, Mei-juan; Dong, Yi-wen; Niu, Huan-min; Young, Charles YF; Lou, Hong-xiang; Yuan, Hui-qing

2016-01-01

Aim: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. Methods: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Results: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. Conclusion: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest. PMID:27133304

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro.

PubMed

Guo, Yan-Xia; Lin, Zhao-Min; Wang, Mei-Juan; Dong, Yi-Wen; Niu, Huan-Min; Young, Charles Yf; Lou, Hong-Xiang; Yuan, Hui-Qing

2016-06-01

Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest.

Progressive Damage and Fracture of Unstiffened and Stiffened Composite Pressure Vessels

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Gotsis, Pascal K.; Chamis, Christos C.

1997-01-01

Structural durability and damage tolerance characteristics of pressurized graphite/epoxy laminated thin composite cylinders are investigated via computational simulation. Both unstiffened and integral hoop stiffened cylinders are considered. A computer code is utilized for the simulation of composite structural degradation under loading. Damage initiation, growth, accumulation, and propagation to structural fracture are included in the simulation. The increase of burst pressure due to hoop stiffening is quantified. Results demonstrate the significance of the type and size of local defects on the structural durability of pressurized composite cylindrical shells.

Integrated approach for stress based lifing of aero gas turbine blades

NASA Astrophysics Data System (ADS)

Abu, Abdullahi Obonyegba

In order to analyse the turbine blade life, the damage due to the combined thermal and mechanical loads should be adequately accounted for. This is more challenging when detailed component geometry is limited. Therefore, a compromise between the level of geometric detail and the complexity of the lifing method to be implemented would be necessary. This research focuses on how the life assessment of aero engine turbine blades can be done, considering the balance between available design inputs and adequate level of fidelity. Accordingly, the thesis contributes to developing a generic turbine blade lifing method that is based on the engine thermodynamic cycle; as well as integrating critical design/technological factors and operational parameters that influence the aero engine blade life. To this end, thermo-mechanical fatigue was identified as the critical damage phenomenon driving the life of the turbine blade.. The developed approach integrates software tools and numerical models created using the minimum design information typically available at the early design stages. Using finite element analysis of an idealised blade geometry, the approach captures relevant impacts of thermal gradients and thermal stresses that contribute to the thermo-mechanical fatigue damage on the gas turbine blade. The blade life is evaluated using the Neu/Sehitoglu thermo-mechanical fatigue model that considers damage accumulation due to fatigue, oxidation, and creep. The leading edge is examined as a critical part of the blade to estimate the damage severity for different design factors and operational parameters. The outputs of the research can be used to better understand how the environment and the operating conditions of the aircraft affect the blade life consumption and therefore what is the impact on the maintenance cost and the availability of the propulsion system. This research also finds that the environmental (oxidation) effect drives the blade life and the blade coolant side was the critical location. Furthermore, a parametric and sensitivity study of the Neu/Sehitoglu model parameters suggests that in addition to four previously reported parameters, the sensitivity of the phasing to oxidation damage would be critical to overall blade life..

Grain-damage hysteresis and plate tectonic states

NASA Astrophysics Data System (ADS)

Bercovici, David; Ricard, Yanick

2016-04-01

Shear localization in the lithosphere is an essential ingredient for understanding how and why plate tectonics is generated from mantle convection on terrestrial planets. The theoretical model for grain-damage and pinning in two-phase polycrystalline rocks provides a frame-work for understanding lithospheric shear weakening and plate-generation, and is consistent with laboratory and field observations of mylonites. Grain size evolves through the competition between coarsening, which drives grain-growth, and damage, which drives grain reduction. The interface between crystalline phases controls Zener pinning, which impedes grain growth. Damage to the interface enhances the Zener pinning effect, which then reduces grain-size, forcing the rheology into the grain-size-dependent diffusion creep regime. This process thus allows damage and rheological weakening to co-exist, providing a necessary positive self-weakening feedback. Moreover, because pinning inhibits grain-growth it promotes shear-zone longevity and plate-boundary inheritance. However, the suppression of interface damage at low interface curvature (wherein inter-grain mixing is inefficient and other energy sinks of deformational work are potentially more facile) causes a hysteresis effect, in which three possible equilibrium grain-sizes for a given stress coexist: (1) a stable, large-grain, weakly-deforming state, (2) a stable, small-grain, rapidly-deforming state analogous to ultramylonites, and (3) an unstable, intermediate grain-size state perhaps comparable to protomylonites. A comparison of the model to field data suggests that shear-localized zones of small-grain mylonites and ultra-mylonites exist at a lower stress than the co-existing large-grain porphyroclasts, rather than, as predicted by paleopiezometers or paleowattmeters, at a much higher stress; this interpretation of field data thus allows localization to relieve instead of accumulate stress. The model also predicts that a lithosphere that deforms at a given stress can acquire two stable deformation regimes indicative of plate-like flows, i.e., it permits the coexistence of both slowly deforming plate interiors, and rapidly deforming plate boundaries. Earth seems to exist squarely inside the hysteresis loop and thus can have coexisting deformation states, while Venus appears to straddle the end of the loop where only the weakly deforming branch exists.

DNA Damage Repair Factors have a Tumor Promoting Role in MLL-fusion Leukemia | Center for Cancer Research

Cancer.gov

Cancers develop when cells accumulate DNA mutations that allow them to grow and divide inappropriately. Thus, proteins involved in repairing DNA damage are generally suppressors of cancer formation, and their expression is often lost in the early stages of cancer initiation. In contrast, cancer stem cells, like their normal counterparts, must retain their ability to

Nonlinear attenuation of S-waves and Love waves within ambient rock

NASA Astrophysics Data System (ADS)

Sleep, Norman H.; Erickson, Brittany A.

2014-04-01

obtain scaling relationships for nonlinear attenuation of S-waves and Love waves within sedimentary basins to assist numerical modeling. These relationships constrain the past peak ground velocity (PGV) of strong 3-4 s Love waves from San Andreas events within Greater Los Angeles, as well as the maximum PGV of future waves that can propagate without strong nonlinear attenuation. During each event, the shaking episode cracks the stiff, shallow rock. Over multiple events, this repeated damage in the upper few hundred meters leads to self-organization of the shear modulus. Dynamic strain is PGV divided by phase velocity, and dynamic stress is strain times the shear modulus. The frictional yield stress is proportional to depth times the effective coefficient of friction. At the eventual quasi-steady self-organized state, the shear modulus increases linearly with depth allowing inference of past typical PGV where rock over the damaged depth range barely reaches frictional failure. Still greater future PGV would cause frictional failure throughout the damaged zone, nonlinearly attenuating the wave. Assuming self-organization has taken place, estimated maximum past PGV within Greater Los Angeles Basins is 0.4-2.6 m s-1. The upper part of this range includes regions of accumulating sediments with low S-wave velocity that may have not yet compacted, rather than having been damaged by strong shaking. Published numerical models indicate that strong Love waves from the San Andreas Fault pass through Whittier Narrows. Within this corridor, deep drawdown of the water table from its currently shallow and preindustrial levels would nearly double PGV of Love waves reaching Downtown Los Angeles.

Mesoscale modeling of solute precipitation and radiation damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yongfeng; Schwen, Daniel; Ke, Huibin

2015-09-01

This report summarizes the low length scale effort during FY 2014 in developing mesoscale capabilities for microstructure evolution in reactor pressure vessels. During operation, reactor pressure vessels are subject to hardening and embrittlement caused by irradiation-induced defect accumulation and irradiation-enhanced solute precipitation. Both defect production and solute precipitation start from the atomic scale, and manifest their eventual effects as degradation in engineering-scale properties. To predict the property degradation, multiscale modeling and simulation are needed to deal with the microstructure evolution, and to link the microstructure feature to material properties. In this report, the development of mesoscale capabilities for defect accumulationmore » and solute precipitation are summarized. Atomic-scale efforts that supply information for the mesoscale capabilities are also included.« less

Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota

PubMed Central

van den Hoogen, Ward J.; Laman, Jon D.; ’t Hart, Bert A.

2017-01-01

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research. PMID:28928747

Investigating the Fundamentals of Molecular Depth Profiling Using Strong-field Photoionization of Sputtered Neutrals

PubMed Central

Willingham, D.; Brenes, D. A.; Winograd, N.; Wucher, A.

2010-01-01

Molecular depth profiles of model organic thin films were performed using a 40 keV C60+ cluster ion source in concert with TOF-SIMS. Strong-field photoionization of intact neutral molecules sputtered by 40 keV C60+ primary ions was used to analyze changes in the chemical environment of the guanine thin films as a function of ion fluence. Direct comparison of the secondary ion and neutral components of the molecular depth profiles yields valuable information about chemical damage accumulation as well as changes in the molecular ionization probability. An analytical protocol based on the erosion dynamics model is developed and evaluated using guanine and trehalose molecular secondary ion signals with and without comparable laser photoionization data. PMID:26269660

Durability of bends in high-temperature steam lines under the conditions of long-term operation

NASA Astrophysics Data System (ADS)

Katanakha, N. A.; Semenov, A. S.; Getsov, L. B.

2015-04-01

The article presents the results of stress-strain state computations and durability of bent and steeply curved branches of high-temperature steam lines carried out on the basis of the finite element method using the modified Soderberg formula for describing unsteady creep processes with taking the accumulation of damage into account. The computations were carried out for bends made of steel grades that are most widely used for manufacturing steam lines (12Kh1MF, 15Kh1M1F, and 10Kh9MFB) and operating at different levels of inner pressure and temperature. The solutions obtained using the developed creep model are compared with those obtained using the models widely used in practice.

Mitochondria drive autophagy pathology via microtubule disassembly

PubMed Central

Arduíno, Daniela M.; Esteves, A. Raquel; Cardoso, Sandra Morais

2013-01-01

Neurons are exquisitely dependent on quality control systems to maintain a healthy intracellular environment. A permanent assessment of protein and organelle “quality” allows a coordinated action between repair and clearance of damage proteins and dysfunctional organelles. Impairments in the intracellular clearance mechanisms in long-lived postmitotic cells, like neurons, result in the progressive accumulation of damaged organelles and aggregates of aberrant proteins. Using cells bearing Parkinson disease (PD) patients’ mitochondria, we demonstrated that aberrant accumulation of autophagosomes in PD, commonly interpreted as an abnormal induction of autophagy, is instead due to defective autophagic clearance. This defect is a consequence of alterations in the microtubule network driven by mitochondrial dysfunction that hinder mitochondria and autophagosome trafficking. We uncover mitochondria and microtubule-directed traffic as main players in the regulation of autophagy in PD. PMID:23075854

Activity and task of the saveMLAK and aid for library

NASA Astrophysics Data System (ADS)

Okamoto, Makoto

We report the activities of saveMLAK, an organization dedicated to supporting museums, libraries, archives, and kominkans damaged by the Great East Japan Earthquake, focusing on the activities for libraries. saveMLAK provides a website using MediaWiki collaborative editing software for accumulating information regarding damage and support activities, offering information support, indirect support, and intermediary support. We also report the collaboration with Miyagi Prefectural Library based on the accumulated, shared information as an example of support for libraries in the disaster area. We describe the process of the activities of saveMLAK and problems emerging so far, and provide constructive criticism and proposals to other support activities for libraries. In conclusion, we suggest establishment of permanent organizations/functions to prepare for emergencies and to cope with disasters in the future.

Effects of foliar applied nickel on tomato plants. [Lycopersicon esculentum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cash, R.C.; Leone, I.A.

Shoot-applied nickel (Ni) treatments produced symptomatology, foliar Ni accumulation, and cytological changes in tomato (Lycopersicon esculentum Mill.) similar to those caused by treatments with root-applied nickel (Ni). Leaf damage resulting from 100 ..mu..g/ml foliar Ni-treatments consisted of interveinal chlorosis and spotting necrosis which appeared histologically as tissue collapse, cell clumping, and chloroplast disintegration. Shoot-treated plants accumulated more Ni in leaves than in roots; whereas the reverse was true in root-treated plants. Interference with root-to-shoot manganese translocation was attributed to attenuated vascular tissue and phloem blockage. Evidence of reduced nutrient transport and inhibited meristem activity due to Ni toxicity presents amore » potential for crop damage from excessive Ni in the atmosphere as well as in the soil environment.« less

Phospho-Bcl-x(L)(Ser62) plays a key role at DNA damage-induced G(2) checkpoint.

PubMed

Wang, Jianfang; Beauchemin, Myriam; Bertrand, Richard

2012-06-01

Accumulating evidence suggests that Bcl-xL, an anti-apoptotic member of the Bcl-2 family, also functions in cell cycle progression and cell cycle checkpoints. Analysis of a series of phosphorylation site mutants reveals that cells expressing Bcl-xL(Ser62Ala) mutant are less stable at the G 2 checkpoint and enter mitosis more rapidly than cells expressing wild-type Bcl-xL or Bcl-xL phosphorylation site mutants, including Thr41Ala, Ser43Ala, Thr47Ala, Ser56Ala and Thr115Ala. Analysis of the dynamic phosphorylation and location of phospho-Bcl-xL(Ser62) in unperturbed, synchronized cells and during DNA damage-induced G 2 arrest discloses that a pool of phospho-Bcl-xL(Ser62) accumulates into nucleolar structures in etoposide-exposed cells during G 2 arrest. In a series of in vitro kinase assays, pharmacological inhibitors and specific siRNAs experiments, we found that Polo kinase 1 and MAPK9/JNK2 are major protein kinases involved in Bcl-xL(Ser62) phosphorylation and accumulation into nucleolar structures during the G 2 checkpoint. In nucleoli, phospho-Bcl-xL(Ser62) binds to and co-localizes with Cdk1(cdc2), the key cyclin-dependent kinase required for entry into mitosis. These data indicate that during G 2 checkpoint, phospho-Bcl-xL(Ser62) stabilizes G 2 arrest by timely trapping of Cdk1(cdc2) in nucleolar structures to slow mitotic entry. It also highlights that DNA damage affects the dynamic composition of the nucleolus, which now emerges as a piece of the DNA damage response.

Radiation Effect on Human Tissue

NASA Technical Reports Server (NTRS)

Richmond, Robert C.; Cruz, Angela; Bors, Karen; Curreri, Peter A. (Technical Monitor)

2002-01-01

Predicting the occurrence of human cancer following exposure of an epidemiologic population to any agent causing genetic damage is a difficult task. To an approximation, this is because the uncertainty of uniform exposure to the damaging agent, and the uncertainty of uniform processing of that damage within a complex set of biological variables, degrade the confidence of predicting the delayed expression of cancer as a relatively rare event within clinically normal individuals. This situation begs the need for alternate controlled experimental models that are predictive for the development of human cancer following exposures to agents causing genetic damage. Such models historically have not been of substantial proven value. It is more recently encouraging, however, that developments in molecular and cell biology have led to an expanded knowledge of human carcinogenesis, and of molecular markers associated with that process. It is therefore appropriate to consider new laboratory models developed to accomodate that expanded knowledge in order to assess the cancer risks associated with exposures to genotoxic agents. When ionizing radiation of space is the genotoxic agent, then a series of additional considerations for human cancer risk assessment must also be applied. These include the dose of radiation absorbed by tissue at different locations in the body, the quality of the absorbed radiation, the rate at which absorbed dose accumulates in tissue, the way in which absorbed dose is measured and calculated, and the alterations in incident radiation caused by shielding materials. It is clear that human cancer risk assessment for damage caused by ionizing radiation is a multidisciplinary responsibility, and that within this responsibility no single discipline can hold disproportionate sway if a risk assessment model of radiation-induced human cancer is to be developed that has proven value. Biomolecular and cellular markers from the work reported here are considered for use in assessing human cancer risk related to exposure to space radiation. This potential use must be integrated within the specified multidisciplinary context in order to create a new tool of molecular epidemiology that can hopefully then realistically assess this cancer risk.

Increasing the rate of drying reduces metabolic imbalance, lipid peroxidation and critical water content in radicles of garden pea (Pisum sativum L.).

PubMed

Ntuli, Tobias M; Pammenter, Norman W; Berjak, Patricia

2013-01-01

Orthodox seeds become desiccation-sensitive as they undergo germination. As a result, germinating seeds serve as a model to study desiccation sensitivity in plant tissues. The effects of the rate of drying on the viability, respiratory metabolism and free radical processes were thus studied during dehydration and wet storage of radicles of Pisum sativum. For both drying regimes desiccation could be described by exponential and inverse modified functions. Viability, as assessed by germination capacity and tetrazolium staining, remained at 100% during rapid (< 24 h) desiccation. However, it declined sharply at c. 0.26 g g¹ dm following slow (c. 5 days) drying. Increasing the rate of dehydration thus lowered the critical water content for survival. Rapid desiccation was also associated with higher activities and levels of malate dehydrogenase and the oxidized form of nicotinamide adenine dinucleotide. It was also accompanied by lower hydroperoxide levels and membrane damage. In addition, the activitiy of glutathione reductase was greater during rapid drying. Ageing may have contributed to increased damage during slow dehydration, since viability declined even in wet storage after two weeks. The results presented are consistent with rapid desiccation reducing the accumulation of damage resulting from desiccation-induced aqueous-based deleterious reactions. In addition, they show that radicles are a useful model to study desiccation sensitivity in plant tissues.

Proline accumulation in baker's yeast enhances high-sucrose stress tolerance and fermentation ability in sweet dough.

PubMed

Sasano, Yu; Haitani, Yutaka; Ohtsu, Iwao; Shima, Jun; Takagi, Hiroshi

2012-01-03

During bread-making processes, yeast cells are exposed to various baking-associated stresses. High-sucrose concentrations exert severe osmotic stress that seriously damages cellular components by generation of reactive oxygen species (ROS). Previously, we found that the accumulation of proline conferred freeze-thaw stress tolerance and the baker's yeast strain that accumulated proline retained higher-level fermentation abilities in frozen doughs than the wild-type strain. In this study, we constructed self-cloning diploid baker's yeast strains that accumulate proline. These resultant strains showed higher cell viability and lower intracellular oxidation levels than that observed in the wild-type strain under high-sucrose stress condition. Proline accumulation also enhanced the fermentation ability in high-sucrose-containing dough. These results demonstrate the usefulness of proline-accumulating baker's yeast for sweet dough baking. Copyright © 2011 Elsevier B.V. All rights reserved.

ACCUMULATION OF M1DG DNA ADDUCTS AFTER CHRONIC EXPOSURE TO PCBS, BUT NOT FROM ACUTE EXPOSURE TO DIOXIN-LIKE COMPOUNDS

EPA Science Inventory

ABSTRACT: Oxidative DNA damage is one of the key events leading to mutation and cancer. The present study examined the accumulation of M1dG DNA adducts, 3-(2’-deoxy-β-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, after single or yearly exposur...

Sod1 Loss Induces Intrinsic Superoxide Accumulation Leading to p53-Mediated Growth Arrest and Apoptosis

PubMed Central

Watanabe, Kenji; Shibuya, Shuichi; Koyama, Hirofumi; Ozawa, Yusuke; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

2013-01-01

Oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a major role in the antioxidant system and they also catalyze superoxide radicals (O2•−). Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of mouse tissue, SOD1 is essential for the maintenance of tissue homeostasis. To clarify the cellular function of SOD1, we investigated the cellular phenotypes of Sod1-deficient fibroblasts. We demonstrated that Sod1 deficiency impaired proliferation and induced apoptosis associated with O2•− accumulation in the cytoplasm and mitochondria in fibroblasts. Sod1 loss also decreased the mitochondrial membrane potential and led to DNA damage-mediated p53 activation. Antioxidant treatments effectively improved the cellular phenotypes through suppression of both intracellular O2•− accumulation and p53 activation in Sod1-deficient fibroblasts. In vivo experiments revealed that transdermal treatment with a vitamin C derivative significantly reversed the skin thinning commonly associated with the upregulated p53 action in the skin. Our findings revealed that intrinsic O2•− accumulation promoted p53-mediated growth arrest and apoptosis as well as mitochondrial disfunction in the fibroblasts. PMID:23708100

FY16 Status Report on Development of Integrated EPP and SMT Design Methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jetter, R. I.; Sham, T. -L.; Wang, Y.

2016-08-01

The goal of the Elastic-Perfectly Plastic (EPP) combined integrated creep-fatigue damage evaluation approach is to incorporate a Simplified Model Test (SMT) data based approach for creep-fatigue damage evaluation into the EPP methodology to avoid the separate evaluation of creep and fatigue damage and eliminate the requirement for stress classification in current methods; thus greatly simplifying evaluation of elevated temperature cyclic service. The EPP methodology is based on the idea that creep damage and strain accumulation can be bounded by a properly chosen “pseudo” yield strength used in an elastic-perfectly plastic analysis, thus avoiding the need for stress classification. The originalmore » SMT approach is based on the use of elastic analysis. The experimental data, cycles to failure, is correlated using the elastically calculated strain range in the test specimen and the corresponding component strain is also calculated elastically. The advantage of this approach is that it is no longer necessary to use the damage interaction, or D-diagram, because the damage due to the combined effects of creep and fatigue are accounted in the test data by means of a specimen that is designed to replicate or bound the stress and strain redistribution that occurs in actual components when loaded in the creep regime. The reference approach to combining the two methodologies and the corresponding uncertainties and validation plans are presented. Results from recent key feature tests are discussed to illustrate the applicability of the EPP methodology and the behavior of materials at elevated temperature when undergoing stress and strain redistribution due to plasticity and creep.« less

Damage-Mitigating Control of Space Propulsion Systems for High Performance and Extended Life

NASA Technical Reports Server (NTRS)

Ray, Asok; Wu, Min-Kuang

1994-01-01

A major goal in the control of complex mechanical system such as spacecraft rocket engine's advanced aircraft, and power plants is to achieve high performance with increased reliability, component durability, and maintainability. The current practice of decision and control systems synthesis focuses on improving performance and diagnostic capabilities under constraints that often do not adequately represent the materials degradation. In view of the high performance requirements of the system and availability of improved materials, the lack of appropriate knowledge about the properties of these materials will lead to either less than achievable performance due to overly conservative design, or over-straining of the structure leading to unexpected failures and drastic reduction of the service life. The key idea in this report is that a significant improvement in service life could be achieved by a small reduction in the system dynamic performance. The major task is to characterize the damage generation process, and then utilize this information in a mathematical form to synthesize a control law that would meet the system requirements and simultaneously satisfy the constraints that are imposed by the material and structural properties of the critical components. The concept of damage mitigation is introduced for control of mechanical systems to achieve high performance with a prolonged life span. A model of fatigue damage dynamics is formulated in the continuous-time setting, instead of a cycle-based representation, for direct application to control systems synthesis. An optimal control policy is then formulated via nonlinear programming under specified constraints of the damage rate and accumulated damage. The results of simulation experiments for the transient upthrust of a bipropellant rocket engine are presented to demonstrate efficacy of the damage-mitigating control concept.

Involvement of DNA polymerase beta in repairing oxidative damages induced by antitumor drug adriamycin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Shukun; Wu Mei; Zhang Zunzhen, E-mail: zhangzunzhen@163.co

2010-08-01

Adriamycin (ADM) is a widely used antineoplastic drug. However, the increasing cellular resistance has become a serious limitation to ADM clinical application. The most important mechanism related to ADM-induced cell death is oxidative DNA damage mediated by reactive oxygen species (ROS). Base excision repair (BER) is a major pathway in the repair of DNA single strand break (SSB) and oxidized base. In this study, we firstly applied the murine embryo fibroblasts wild-type (pol {beta} +/+) and homozygous pol {beta} null cell (pol {beta} -/-) as a model to investigate ADM DNA-damaging effects and the molecular basis underlying these effects. Here,more » cellular sensitivity to ADM was examined using colorimetric assay and colony forming assay. ADM-induced cellular ROS level and the alteration of superoxide dismutase (SOD) activity were measured by commercial kits. Further, DNA strand break, chromosomal damage and gene mutation were assessed by comet assay, micronucleus test and hprt gene mutation assay, respectively. The results showed that pol {beta} -/- cells were more sensitive to ADM compared with pol {beta} +/+ cells and more severe SSB and chromosomal damage as well as higher hprt gene mutation frequency were observed in pol {beta} -/- cells. ROS level in pol {beta} -/- cells increased along with decreased activity of SOD. These results demonstrated that pol {beta} deficiency could enable ROS accumulation with SOD activity decrease, further elevate oxidative DNA damage, and subsequently result in SSB, chromosome cleavage as well as gene mutation, which may be partly responsible for the cytotoxicity of ADM and the hypersensitivity of pol {beta} -/- cells to ADM. These findings suggested that pol {beta} is vital for repairing oxidative damage induced by ADM.« less

Ecotoxicological damage from zinc smelting at Palmerton, Pennsylvania

USGS Publications Warehouse

Beyer, W. Nelson; Storm, Gerald L.; Hoffman, David J.; Rattner, Barnett A.; Burton, G. Allen; Cairns, John

1995-01-01

The two zinc smelters at Palmerton, PA emitted huge amounts of contaminants ( 260,000 t of Zn, 3,300 t of Cd, 6,800 t of Pb) to the air and severely damaged the forest on Blue Mountain. The high Zn concentrations in soil killed tree seedlings by inhibiting root elongation. The result was a forest with too few young trees. When natural stresses such as fire challenged the forest, the forest failed to regenerate, and the exposed soil eroded down the steep slopes. Tree species that could sprout were favored over those that developed from seeds. As a result of high zinc concentrations, the lichen and moss communities were depauperate for at least 20 km along Blue Mountain. The denuded areas are in the process of being reclaimed with the addition of a mixture of fly ash and sewage sludge, which is seeded with grasses tolerant to the harsh conditions. In preliminary experiments, the fly ash and sewage sludge mixture was stable, despite the steepness of the slopes of the reclaimed sites on Blue Mountain. Zinc emissions reduced the decomposition rate of plant material on Blue Mountain. The partially decomposed litter, in particular, accumulated on the surface of the mineral soil. The populations of both microorganisms and arthropods were greatly reduced in soils near the smelters. Samples of litter collected from sites spanning 30 km were toxic to woodlice, and Zn was shown to be the toxic factor. A white-tailed deer examined had a very high renal Zn concentration and an articular lesion in one of its hind legs that closely resembled the lesions reported in Zn-poisoned horses. Zinc concentrations were regulated in wildlife tissues and were not reliable indicators of exposure, except in extreme cases. Two songbirds, a shrew, and several rabbits contained Pb concentrations that were suggested to be toxic. Shrews and ground-feeding songbirds accumulated relatively high concentrations of Pb. Exposure to Pb seemed to be related to the amount of soil that an animal ingests. Some white-tailed deer and cottontails had renal Cd concentrations near 600 ppm w.w., which is associated with renal damage in other mammals. The accumulation of Cd was greatest in wildlife that lived longest. The destruction of the habitat for wildlife on Blue Mountain decreased wildlife populations. Populations of insectivorous birds, however, were depressed well beyond the area of obvious damage to the forest. Forest-floor salamanders were completely absent from study sites spanning 18 km along Blue Mountain. Actual reductions in wildlife populations were much greater than would have been predicted from habitat suitability models alone.

Rapid intraplate strain accumulation in the New Madrid seismic zone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, L.; Zoback, M.D.; Segall, P.

1992-09-01

Remeasurement of a triangulation network in the southern part of the New Madrid seismic zone with the Global Positioning System has revealed rapid crustal strain accumulation since the 1950s. This area experienced three large (moment magnitudes greater than 8) earthquakes in 1811 to 1812. The orientation and sense of shear is consistent with right-lateral strike slip motion along a northeast-trending fault zone (as indicated by current seismicity). Detection of crustal strain accumulation may be a useful discriminant for identifying areas where potentially damaging intraplate earthquakes may occur despite the absence of large earthquakes during historic time. 34 refs.