承德公路隧道围岩分级与塌方机理分析

During tunnel constriction the classification of rock mass is widely used in tunnel design and construction. Moreover it offers the base information about tunnel investment and security. The quick classification of rock mass is very important for not delaying tunnel construction. Nowadays the tunnel engineers usually use initial survey files which are obtained by probe drilling to design a tunnel. It brings the problem that initial surrounding rock classification is usually much different from the real condition during the tunnel construction. Because initial surrounding rock lack credibility, it need us to make real time surrounding rock classification during the tunnel construction, and feed back the result to designers and constructors. Therefore, to find a quick wall rock classification method is very important not only for the time limit for a project but also for not delaying tunnel construction. Not all but many tunnels and underground constructions do suffer form collapse during the period of construction. Although accidental collapse in a large project in civil and geotechnical engineering sometimes appears to be a local event, if it occurred, it can bring about casualties, disrupted，production, construction delay, environmental damage, capital cost etc，therefore, it has been a difficult problem ,both in theory and in practice, establishing how to prevent underground structures form collapse and how to handle such an event in case in occurs. It is important to develop effective solutions and technical measures to prevent and control the collapse. According to the tunnel collapse occurred in Cheng De this paper analyze the main collapse mechanism leading to tunnel collapse and summon up the disposal method when collapse happened. It may be useful for tunnel construction in Cheng De in future. This paper is base on tunnel surrounding rock classification and tunnel support tasks during the tunnel construction in Cheng De area. It aims at solving 4 important problems in tunnel design and construction. 1) The relationship between rock rebound strength and rock single axle compression strength. First we go to the face wall and do rebound test on the tunnel face, then we chose some pieces of rock and do point loading test. Form the tests record we try to find the relationship between rock rebound strength and rock single axle compression strength. 2) The relationship between the value [BQ] and the value Q. First in order to obtain the information of rock character, rock strength, degree of weathering, the structure of rock mass, the joint condition, underground water condition and so on, we go to the tunnel face to do field investigation. And then we use two kinds of rock classification method to make surrounding rock classification. Base on the works above, finally we analyze the relationship between the value [BQ] and the value Q. 3) Sum up the mechanism leading to tunnel collapse and it disposal method in Cheng De area According to the tunnel collapse occurred in Cheng De this paper analyze the main reasons leading to the tunnel collapse and sum up the disposal method when collapse happened. 4) Obtain the properties of steel frame grid by numerical simulation. First we establish the 3D numeral model of steel frame grid by ADINA, and then find the mechanics properties by numerical simulation in ADINA. Second Based on the rock mass geological structure model, we established steel frame grid numeral model which is installed in the tunnel by FLAC3D and simulated the progress of tunnel construction. We hope that the support effect in tunnel can be evaluated from the numerical simulation.

松辽盆地南部腰英台区块低渗透储层整体压裂改造技术研究

The Yaoyingtai Block is located within the northeastern Changling Depression of southern Songliao Basin, where the reservoir sandstones are petrophysically characterized by very low permeability, which results in the low success probability of artificial fracturing, and the low oil yield by water injection in the course of oil production. In order to improve the situations as stated above, this research aims to work out an integral fracturing technology and strategy applicable to the low permeable reservoirs in Yaoyingtai Block. Under the guidance of geological theory, reservoir engineering and technology, the subsurface occurrences of natural and hydraulic fractures in the reservoirs are expected to be delineated, and appropriate fracturing fluids and proppants are to be optimized, based on the data of drilling, well logging, laboratory and field experiments, and geological data. These approaches lay the basis of the integral fracturing technology suitable for the low permeable reservoir in the study area. Based on core sample test, in-situ stress analysis of well logging, and forward and inversion stress field modeling, as well as fluid dynamic analysis, the maximum in-situ stress field is unraveled to be extended nearly along the E-W direction (clustering along N85-135°E) as is demonstrated by the E-W trending tensional fractures. Hydraulic fractures are distributed approximately along the E-W direction as well. Faulting activities could have exerted obvious influences on the distribution of fractures, which were preferentially developed along fault zones. Based on reservoir sensitivity analysis, integrated with studies on rock mechanics, in-situ stress, natural fracture distribution and production in injection-production pilot area, the influences of primary fractures on fracturing operation are analyzed, and a diagnostic technology for primary fractures during depressurization is accordingly developed. An appropriate fracturing fluid (hydroxypropyl guar gum) and a proppant (Yixing ceramsite, with a moderate-density, 0.45-0.9mm in size) applicable to Qingshankou Formation reservoir are worked out through extensive optimization analysis. The fracturing fluid can decrease the damage to the oil reservoir, and the friction in fracturing operation, improving the effect of fracturing operation. Some problems, such as sand-out at early stage and low success rate of fracturing operations, have been effectively solved, through pre-fracturing formation evaluation, “suspension plug” fracturing, real-time monitoring and limited-flow fracturing. Through analysis of fracture-bearing tight reservoir with variable densities and dynamic analysis of influences of well patterns on fracturing by using numerical simulation, a fracturing operation scheme for the Qingshankou Formation reservoir is proposed here as being better to compress the short factures, rather than to compress the long fractures during hydraulic fracturing. It is suggested to adopt the 450m×150m inverted 9-spot well pattern in a diamond shape with wells placed parallel to fractures and a half fracture length of 60-75m.

基于精细结构描述及数值试验的断续节理岩体力学参数智能选取

Evaluating the mechanical properties of rock masses is the base of rock engineering design and construction. It has great influence on the safety and cost of rock project. The recognition is inevitable consequence of new engineering activities in rock, including high-rise building, super bridge, complex underground installations, hydraulic project and etc. During the constructions, lots of engineering accidents happened, which bring great damage to people. According to the investigation, many failures are due to choosing improper mechanical properties. ‘Can’t give the proper properties’ becomes one of big problems for theoretic analysis and numerical simulation. Selecting the properties reasonably and effectively is very significant for the planning, design and construction of rock engineering works. A multiple method based on site investigation, theoretic analysis, model test, numerical test and back analysis by artificial neural network is conducted to determine and optimize the mechanical properties for engineering design. The following outcomes are obtained: (1) Mapping of the rock mass structure Detailed geological investigation is the soul of the fine structure description. Based on statistical window，geological sketch and digital photography，a new method for rock mass fine structure in-situ mapping is developed. It has already been taken into practice and received good comments in Baihetan Hydropower Station. (2) Theoretic analysis of rock mass containing intermittent joints The shear strength mechanisms of joint and rock bridge are analyzed respectively. And the multiple modes of failure on different stress condition are summarized and supplied. Then, through introducing deformation compatibility equation in normal direction, the direct shear strength formulation and compression shear strength formulation for coplanar intermittent joints, as well as compression shear strength formulation for ladderlike intermittent joints are deducted respectively. In order to apply the deducted formulation conveniently in the real projects, a relationship between these formulations and Mohr-Coulomb hypothesis is built up. (3) Model test of rock mass containing intermittent joints Model tests are adopted to study the mechanical mechanism of joints to rock masses. The failure modes of rock mass containing intermittent joints are summarized from the model test. Six typical failure modes are found in the test, and brittle failures are the main failure mode. The evolvement processes of shear stress, shear displacement, normal stress and normal displacement are monitored by using rigid servo test machine. And the deformation and failure character during the loading process is analyzed. According to the model test, the failure modes quite depend on the joint distribution, connectivity and stress states. According to the contrastive analysis of complete stress strain curve, different failure developing stages are found in the intact rock, across jointed rock mass and intermittent jointed rock mass. There are four typical stages in the stress strain curve of intact rock, namely shear contraction stage, linear elastic stage, failure stage and residual strength stage. There are three typical stages in the across jointed rock mass, namely linear elastic stage, transition zone and sliding failure stage. Correspondingly, five typical stages are found in the intermittent jointed rock mass, namely linear elastic stage, sliding of joint, steady growth of post-crack, joint coalescence failure, and residual strength. According to strength analysis, the failure envelopes of intact rock and across jointed rock mass are the upper bound and lower bound separately. The strength of intermittent jointed rock mass can be evaluated by reducing the bandwidth of the failure envelope with geo-mechanics analysis. (4) Numerical test of rock mass Two sets of methods, i.e. the distinct element method (DEC) based on in-situ geology mapping and the realistic failure process analysis (RFPA) based on high-definition digital imaging, are developed and introduced. The operation process and analysis results are demonstrated detailedly from the research on parameters of rock mass based on numerical test in the Jinping First Stage Hydropower Station and Baihetan Hydropower Station. By comparison，the advantages and disadvantages are discussed. Then the applicable fields are figured out respectively. (5) Intelligent evaluation based on artificial neural network (ANN) The characters of both ANN and parameter evaluation of rock mass are discussed and summarized. According to the investigations, ANN has a bright application future in the field of parameter evaluation of rock mass. Intelligent evaluation of mechanical parameters in the Jinping First Stage Hydropower Station is taken as an example to demonstrate the analysis process. The problems in five aspects, i. e. sample selection, network design, initial value selection, learning rate and expected error, are discussed detailedly.

水-岩土反应的力学与环境效应研究

The research on mechanical effects of water-rock and soil interaction on deformation and failure of rocks and soils involves three aspects of mechanics, physics and chemistry. It is the cross between geochemistry and rock mechanics and soil mechanics. To sum up, the mechanical effects of water-rock and soil interaction is related to many complex processes. Research in this respect has been being an important forward field and has broad prospects. In connection with the mechanism of the effects of the chemical action of water-rock on deformation and failure of rocks and soils, the research significance, the present state, the developments in this research domain are summarized. Author prospects the future of this research. The research of the subject should be possessed of important position in studying engineering geology and will lead directly to a new understand on geological hazard and control research. In order to investigation the macroscopic mechanics effects of chemical kinetics of water-rock interaction on the deformation and failure, calcic rock, red sandstone and grey granite reacting chemically with different aqueous solution at atmospheric temperature and atmospheric pressure are uniaxially compressed. The quantitative results concerning the changes of uniaxially compressive strength and elastic modulus under different conditions are obtained. It is found that the mechanical effects of water on rock is closely related to the chemical action of water-rock or the chemical damage in rock, and the intensity of chemical damage is direct ratio to the intensity of chemical action in water-rock system. It is also found that the hydrochemical action on rock is time-dependent through the test. The mechanism of permeation and hydrochemical action resulting in failure of loaded rock mass or propagation of fractures in rocks would be a key question in rock fracture mechanics. In this paper, the fracture mechanical effects of chemical action of water-rock and their time- and chemical environment-dependent behavior in grey granite, green granite, grey sandstone and red sandstone are analyzed by testing K_(IC) and COD of rock under different conditions. It is found that: ①the fracture mechanical effect of chemical action of water-rock is outstanding and time-dependent, and high differences exist in the influence of different aqueous solution, different rocks, different immersion ways and different velocity of cycle flow on the fracture mechanical effects in rock. ②the mechanical effects of water-rock interaction on propagation of fractures is consistent with the mechanical effects on the peak strength of rock. ③the intensity of the mechanical fracture effects increases as the intensity of chemical action of water-rock increases. ④iron and calcium ion bearing mineral or cement in rock are some key ion or chemical composition, and especially iron ion-bearing mineral resulting in chemical action of water-rock to be provided with both positive and negative mechanical effects on rock. Through the above two tests, we suggest that primary factors influencing chemical damage in rock consist of the chemical property of rock and aqueous solution, the structure or homogeneity of rocks, the flow velocity of aqueous solution passing through rock, and cause of formation or evolution of rock. The paper explores the mechanism on the mechanical effects of water-rock interaction on rock by using the theory of chemistry and rock fracture mechanics with chemical damage proposed by author, the modeling method and the energy point of view. In this paper, the concept of absorbed suction between soil grains caused by capillary response is given and expounded, and the relation and basic distinction among this absorbed suction, surface tension and capillary pressure of the soil are analyzed and established. The law of absorbed suction change and the primary factors affecting it are approached. We hold that the structure suction are changeable along with the change of the saturation state in unsaturated soils. In view of this, the concept of intrinsic structure suction and variable structure suction are given and expounded, and this paper points out: What we should study is variable structure suction when studying the effective stress. By IIIy κHH's theory of structure strength of soils, the computer method for variable structure suction is analyzed, the measure method for variable structure suction is discussed, and it reach the conclusions: ①Besides saturation state, variable structure suction is affected by grain composition and packing patter of grains. ②The internal relations are present between structure parameter N in computing structure suction and structure parameter D in computing absorbed suction. We think that some problems exit in available principle of effective stress and shear strength theory for unsaturated soil. Based on the variable structure suction and absorbed suction, the classification of saturation in soil and a principle of narrow sense effective stress are proposed for unsaturated soils. Based on generalized suction, the generalized effective stress formula and a principle of generalized effective stress are proposed for unsaturated soils. The experience parameter χ in Bishop's effective stress formula is defined, and the principal factors influencing effective stress or χ. The primary factor affecting the effective stress in unsaturated soils, and the principle classifying unsaturated soils and its mechanics methods analyzing unsaturated soils are discussed, and this paper points out: The theory on studying unsaturated soil mechanics should adopt the micromechanics method, then raise it to macromechanics and to applying. Researching the mechanical effects of chemical action of water-soil on soil is of great importance to geoenvironmental hazard control. The texture of soil and the fabric of soil mass are set forth. The tests on physical and mechanical property are performed to investigate the mechanism of the positive and negative mechanical effects of different chemical property of aqueous solution. The test results make clear that the plastic limit, liquid limit and plasticity index are changed, and there exists both positive and negative effects on specimens in this test. Based on analyzing the mechanism of the mechanical effects of water-soil interaction on soil, author thinks that hydrochemical actions being provided with mechanical effects on soil comprise three kinds of dissolution, sedimentation or crystallization. The significance of these tests lie in which it is recognized for us that we may improve, adjust and control the quality of soils, and may achieve the goal geological hazard control and prevention.The present and the significance of the research on environmental effects of water-rock and soil interaction. Various living example on geoenvironmental hazard in this field are enumerated. Following above thinking, we have approached such ideals that: ①changing the intensity and distribution of source and sink in groundwater flow system can be used to control the water-rock and soil interaction. ②the chemical action of water-rock and soil can be used to ameliorate the physical and mechanical property of rocks and soils. Lastly, the research thinking and the research methods on mechanical effects and environmental effects of water-rock and soil interaction are put forward and detailed.

基于工程地质力学的岩土工程加固理论、技术与实践

In the engineering reinforcement of-rock and soil mass, engineers must consider how to obtain better reinforcing effect at the cost of less reinforcing expense, which, in fact, is the aim of reinforcement design. In order to accomplish the purpose, they require not only researching the material used to reinforce and its structure, but also taking into account of several important geological factors, such as the structure and property of rock and soil mass. How to improve the reinforcing effect according to engineering geomechanical principle at the respect of the reinforcement of engineering soil and rock mass is studied and discussed in this paper. The author studies the theory, technology and practice of geotechnical reinforcement based on engineering geomechanics, taking example for the soil treatment of Zhengzhou Airport, the effect analysis of reinforcement to the slope on the left bank of Wuqiangxi Hydropower Station and the reinforcing design of the No. 102 Landslide and unique sand-slide slope on the Sichuan-Tibet Highway. The paper is comprised of two parts for the convenience of discussion. In the first part, from the first chapter to the fifth chapter, trying to perform the relevant research and application at the viewpoint of soil mass engineering geomechanics, the author mainly discusses the study of reinforcing soft ground soil through dynamical consolidation and its application. Then, in the second part, from the sixth chapter to the eleventh chapter, the study of new technologies in the rock slope reinforcement and their application are discussed. The author finds that not only better reinforcing effect can be gained in the research where the principle and method of rock mass engineering geomechanics is adopted, but also new reinforcing technologies can be put forward. Zhengzhou Airport is an important one in central plains. It lies on Yellow River alluvial deposit and the structure of stratum is complex and heterogeneous. The area of airport is very large, which can result in differential settlement easily, damage of airport and aircraft accident, whereas, there are no similar experiences to dispose the foundation, so the foundation treatment become a principal problem. During the process of treatment, the method of dynamic compaction was adopted after compared with other methods using the theory of synthetic integration. Dynamic compaction is an important method to consolidate foundation, which was successfully used in the foundation of Zhengzhou Airport. For fill foundation, controlling the thickness of fill so as to make the foundation treatment can reach the design demand and optimum thickness of the fill is a difficult problem. Considering this problem, the author proposed a calculation method to evaluate the thickness of fill. The method can consider not only the self-settlement of fill but also the settlement of the ground surface under applied load so as to ensure the settlement occurred during the using period can satisfy the design demand. It is proved that the method is correct after using it to choose reasonable energy of dynamic compaction to treat foundation. At the same time, in order to examine the effect of dynamic compaction, many monitor methods were adopted in the test such as static loading test, modulus of resilience test, deep pore pressure -test, static cone penetration test and the variation of the pore volume measurement. Through the tests, the author summarized the discipline of the accumulation and dissipation of pore pressure in Yellow River alluvial deposit under the action of dynamic compaction, gave a correct division of the property change of silt and clay under dynamic compaction, determined the bearing capacity of foundation after treatment and weighted the reinforcing effect of dynamic consolidation from the variation of the soil particle in microcosmic and the parameter of soil mass' density. It can be considered that the compactness of soil is in proportion to the energy of dynamic compaction. This conclusion provided a reference to the research of the "Problem of Soil Structure-the Central Problem of Soil Mechanics in 21 Century ". It is also important to strengthen rock mass for water conservancy and electric power engineering. Slip-resistance pile and anchoring adit full of reinforced concrete are usually adopted in engineering experience to strengthen rock mass and very important for engineering. But there also some deficiency such as the weakest section can't be highlighted, the monitor is inconvenient and the diameter of pile and adit is very large etc. The author and his supervisor professor Yangzhifa invented prestressed slip-resistance pile and prestressed anchoring adit full of reinforced concrete, utilizing the advantage that the prestressed structure has better anti-tensile characteristic (this invention is to be published). These inventions overcome the disadvantages of general slip-resistance pile and anchoring adit full of reinforced concrete and have the functions of engineering prospecting, strengthening, drainage and monitor simultaneous, so they have better strengthened effect and be more convenient for monitor and more economical than traditional methods. Drainage is an important factor in treatments of rock mass and slop. In view of the traditional drainage method that drainage pore often be clogged so as to resulted in incident, professor Yangzhifa invented the method and setting of guide penetration by fiber bundle. It would take good effect to use it in prestressed slip-resistance pile and anchoring adit full of reinforced concrete. In this paper, the author took example for anchoring adit full of reinforced concrete used to strengthen Wuqiangxi left bank to simulate the strengthened effect after consolidated by prestressed slip-resistance pile, took example for 102 landslide occurred along Sichuan-Tibet highway to simulate the application of slip-resistance pile and the new technology of drainage. At the same time the author proposed the treatment method of flowing sand in Sichuan-Tibet highway, which will benefit the study on strengthening similar engineering. There are five novelties in the paper with the author's theoretical study and engineering practice: 1. Summarizing the role of pore water pressure accumulation and dissipation of the Yellow River alluvial and diluvial soil under the action of dynamical consolidation, which has instructive significance in the engineering construction under the analogical engineering geological conditions in the future. It has not been researched by the predecessors. 2. Putting forward the concept of density D in microcosmic based on the microcosmical structure study of the soil sample. Adopting D to weight the reinforcing effect of dynamic consolidation is considered to be appropriate by the means of comparing the D values of Zhengzhou Airport's ground soil before with after dynamically consolidating reinforcement, so a more convenient balancing method can be provided for engineering practice. 3. According to the deep research into the soil mass engineering geology, engineering rock and soil science, soil mechanics, as well as considerable field experiments, improving the consolidating method in airport construction, from the conventional method, which is dynamically compactmg original ground surface firstly, then filling soil and dynamically layer-consolidating or layer-compacting at last to the upgraded method, which is performing dynamical consolidation after filling soil to place totally at the extent of the certain earth-filling depth. The result of the dynamical consolidation not only complies with the specifications, but also reduces the soil treatment investment by 10 million RMB. 4. Proposing the method for calculating the height of the filled soil by the means of estimating the potential displacement produced in the original ground surface and the filled earth soil under the possible load, selecting the appropriate dynamically-compacting power and determining the virtual height of the filled earth soil. The method is proved to be effective and scientific. 5. According to the thought of Engineering Geomechanics Metal-Synthetic Methodology (EGMS), patenting two inventions (to the stage of roclamation, with Professor Yang Zhi-fa, the cooperative tutor, and etc.) in which multi-functions, engineering geological investigation, reinforcement, drainage and strength remedy, are integrated all over in one body at the viewpoint of the breakage mechanism of the rock slope.

A study of a molecular mechanics field used in simulating enantiorecognition

A molecular mechanics field, Alchemy II, was utilized to model the chiral recognition between S-N-acetyl-alpha-methyl-alpha-naphthylamine and (R, S)-N-(3, 5-dinitrophrnyl)-alpha-methyl-benzeneacetamide and between beta-cyclodextrin and (R, S)-fenoprofen. Some preliminary results have: been obtained to sustain the three-point action models and the induce-fit action in enantiorecognition.

Qualitative and Quantitative Knowledge in Classical Mechanics

This thesis investigates what knowledge is necessary to solve mechanics problems. A program NEWTON is described which understands and solves problems in mechanics mini-world of objects moving on surfaces. Facts and equations such as those given in mechanics text need to be represented. However, this is far from sufficient to solve problems. Human problem solvers rely on "common sense" and "qualitative" knowledge which the physics text tacitly assumes to be present. A mechanics problem solver must embody such knowledge. Quantitative knowledge given by equations and more qualitative common sense knowledge are the major research points exposited in this thesis. The major issue in solving problems is planning. Planning involves tentatively outlining a possible path to the solution without actually solving the problem. Such a plan needs to be constructed and debugged in the process of solving the problem. Envisionment, or qualitative simulation of the event, plays a central role in this planning process.

Comprehensive assessment of alcohol-related brain damage (ARBD): gap or chasm in the evidence?

Alcohol-related brain damage (ARBD) is primarily caused by chronic alcohol misuse and thiamine deficiency, and results in a broad range of impairments. Despite the increasing incidence of ARBD in the UK in recent decades, it is currently underdiagnosed, managed inappropriately and treated inadequately. Moreover, information about assessments for individuals with ARBD is currently absent from clinical guidelines and policy documents. The aim of this paper was to review the evidence relating to the neurological, neuropsychological, psychosocial, physical and nutritional assessment of individuals with ARBD to identify appropriate assessment tools that could be used to measure and monitor the impact of ARBD over time. A systematic online database search revealed a total of 160 separate references, 133 of which were rejected and two of which could not be accessed. Twenty-five papers were included in the review, including six neuroimaging studies, 17 neuropsychological studies and two studies using psychosocial methods of assessment. A lack of evidence for nutritional and physical assessment of individuals with ARBD was found. The review findings are inconclusive; most instruments currently used in ARBD research have not specifically been validated for use within an ARBD context. Further research is required to identify comprehensive methods of ARBD assessment.

Acid damage to vegetation following the Laki Fissure eruption in 1783 - an historical review

Grattan, John and Pyatt, Brian. 'Acid damage to vegetation following the laki fissure eruption in 1783 - an historical review' The Science of the Total Environment. 26 August 1993. 151 pgs 241-247

Xanthine oxidase pathway and muscle damage: Insights from McArdle disease

The intent of this review is to summarize current body of knowledge on the potential implication of the xanthine oxidase pathway (XO) on skeletal muscle damage. The possible involvement of the XO pathway in muscle damage is exemplified by the role of XO inhibitors (e.g., allopurinol) in attenuating muscle damage. Reliance on this pathway (as well as on the purine nucleotide cycle) could be exacerbated in conditions of low muscle glycogen availability. Thus, we also summarize current hypotheses on the etiology of both baseline and exertional muscle damage in McArdle disease, a condition caused by inherited deficiency of myophosphorylase. Because myophosphorylase catalyzes the first step of muscle glycogen breakdown, patients are unable to obtain energy from their muscle glycogen stores. Finally, we provide preliminary data from our laboratory on the potential implication of the XO pathway in the muscle damage that is commonly experienced by these patients.

Active paraplegics are protected against exercise-induced oxidative damage through the induction of antioxidant enzymes

Exercise improves functional capacity in spinal cord injury (SCI). However, exhaustive exercise, especially when sporadic, is linked to the production of reactive oxygen species that may have a detrimental effect on SCI. We aimed to study the effect of a single bout of exhaustive exercise on systemic oxidative stress parameters and on the expression of antioxidant enzymes in individuals with paraplegia. The study was conducted in the Physical Therapy department and the Physical Education and Sports department of the University of Valencia. Sixteen paraplegic subjects were submitted to a graded exercise test (GET) until volitional exhaustion. They were divided into active or non-active groups. Blood samples were drawn immediately, 1 and 2 h after the GET. We determined plasma malondialdehyde (MDA) and protein carbonylation as markers of oxidative damage. Antioxidant gene expression (catalase and glutathione peroxidase-GPx) was determined in peripheral blood mononuclear cells. We found a significant increase in plasma MDA and protein carbonyls immediately after the GET (P<0.05). This increment correlated significantly with the lactate levels. Active paraplegics showed lower levels of exercise-induced oxidative damage (P<0.05) and higher exercise-induced catalase (P<0.01) and GPx (P<0.05) gene expression after the GET. These results suggest that exercise training may be useful in SCI patients to develop systemic antioxidant defenses that may protect them against exercise-induced oxidative damage.

Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology.

The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.

Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11.

Ataxia telangiectasia mutant (ATM) is an S/T-Q-directed kinase that is critical for the cellular response to double-stranded breaks (DSBs) in DNA. Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest. In cancer cells, this regulation may be faulty, and cell division may proceed even in the presence of damaged DNA. We show here that the ribosomal s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that Rsk targets loading of MRN complex components onto DNA at DSB sites. Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs. Accordingly, mutation of S676 to Ala can reverse inhibition of the response to DSBs by Rsk. Collectively, these data point to Mre11 as an important locus of Rsk-mediated checkpoint inhibition acting upstream of ATM activation.