Manganese Superoxide Dismutase: Guardian of the Powerhouse

The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial metabolic function, leading to the development and progression of numerous diseases. A better understanding of the mechanisms by which MnSOD protects cells from the harmful effects of overproduction of ROS, in particular, the effects of ROS on mitochondrial metabolic enzymes, may contribute to the development of novel treatments for various diseases in which ROS are an important component

Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling

Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role

The Connection Behavior of Precast Prestressed Piles to Cast-In-Place Bent Caps

The state of South Carolina employs a unique connection detail between precast prestressed piles to cast in place bent caps. This detail is constructed by plainly embedding piles to a specified depth into bent caps. Typically in regions of high seismicity such as South Carolina connections between these two elements require special detailing which increases both the time and cost of construction. Although connection behavior between piles and bent caps has been studied significantly, a low amount of this effort has focused on the plain pile embedment detail. In an effort to better understand the connection behavior as well as to provide damage assessment tools a series of studies was conducted. The first study investigated the behavior of the plain pile embedment detail at exterior connections using cast in place (CIP) bent caps. During seismic events, exterior connections are subjected to both axial compressive and axial tensile loads. Prior to this study the behavior of these connections under the loading scheme described had not been studied and design engineers have to date typically considered these locations to perform as a hinged connection. In this study, four full-scale specimens were constructed and tested an analytical model that considers confinement was also created. The results showed that the current SCDOT state of practice performed inadequately with an undesired failure mechanism. Two design methodologies are presented which allow for full development of the embedded pile and thus moment transfer between the pile and bent cap elements. An alternative idealized hinge design is also presented. The second investigation discusses the results of a test specimen constructed at full scale which was comprised of three piles connected to a single bent cap. This specimen was tested as a means of validation of eight single pile specimens tested previously. The connection detail of a plain pile embedment is shown again to behave favorably under different loading conditions. The results of the specimen provided a direct comparison of the two design methodologies for exterior connections presented in the previous study, and further proved the ability of the simple connection to withstand seismic loading while performing as expected given the requirements set forth by the SCDOT. In the third study, the behavior of plain embedment connection between piles and precast bent caps was examined. It has been documented that the use of precast bent caps may save significant amount of time during the construction process while improving worker safety and environmental impact. However, prior to this study, the behavior of this connection had not been studied. Therefore, two single piles were plainly embedded in an interior and an exterior precast bent caps and tested at full-scale. The results of this study showed that the connection detail is a possible connection method when using precast bent caps subjected to seismic loading. The performance of the tested systems not only met the design requirements and expectations but also performed better than similar CIP bent cap specimens. The last of the investigations presented uses Acoustic Emission (AE) as a means of non-destructive evaluation (NDE) of the test specimens presented in the previous works. In this work three previously proposed AE analysis techniques are examined. Two damage evaluation models are created based on the results of single pile specimens and validated with the results of the three pile specimen. These models are able to assess sustained damage in the specimens and predict remaining capacity. The outcomes of these studies showed that a plain pile embedment is a viable solution in areas of seismic activity when proper design considerations are considered. This is shown to be true of both CIP and precast bent cap specimens. Additionally, AE is shown to be an effective method of damage evaluation for these systems where multiple evaluation models are presented

Behavior of Prestressed Pile to Bent Cap Connections and Damage Evaluation with Acoustic Emission

The state of South Carolina employs a unique connection detail between precast prestressed piles to cast in place bent caps. This detail is constructed by plainly embedding piles to a specified depth into bent caps. Typically in regions of high seismicity such as South Carolina connections between these two elements require special detailing which increases both the time and cost of construction. Although connection behavior between piles and bent caps has been studied significantly, a low amount of this effort has focused on the plain pile embedment detail. In an effort to better understand the connection behavior as well as to provide damage assessment tools a series of studies was conducted. The first study investigated the behavior of the plain pile embedment detail at exterior connections using cast in place (CIP) bent caps. During seismic events, exterior connections are subjected to both axial compressive and axial tensile loads. Prior to this study the behavior of these connections under the loading scheme described had not been studied and design engineers have to date typically considered these locations to perform as a hinged connection. In this study, four full-scale specimens were constructed and tested an analytical model that considers confinement was also created. The results showed that the current SCDOT state of practice performed inadequately with an undesired failure mechanism. Two design methodologies are presented which allow for full development of the embedded pile and thus moment transfer between the pile and bent cap elements. An alternative idealized hinge design is also presented. The second investigation discusses the results of a test specimen constructed at full scale which was comprised of three piles connected to a single bent cap. This specimen was tested as a means of validation of eight single pile specimens tested previously. The connection detail of a plain pile embedment is shown again to behave favorably under different loading conditions. The results of the specimen provided a direct comparison of the two design methodologies for exterior connections presented in the previous study, and further proved the ability of the simple connection to withstand seismic loading while performing as expected given the requirements set forth by the SCDOT. In the third study, the behavior of plain embedment connection between piles and precast bent caps was examined. It has been documented that the use of precast bent caps may save significant amount of time during the construction process while improving worker safety and environmental impact. However, prior to this study, the behavior of this connection had not been studied. Therefore, two single piles were plainly embedded in an interior and an exterior precast bent caps and tested at full-scale. The results of this study showed that the connection detail is a possible connection method when using precast bent caps subjected to seismic loading. The performance of the tested systems not only met the design requirements and expectations but also performed better than similar CIP bent cap specimens. The last of the investigations presented uses Acoustic Emission (AE) as a means of non-destructive evaluation (NDE) of the test specimens presented in the previous works. In this work three previously proposed AE analysis techniques are examined. Two damage evaluation models are created based on the results of single pile specimens and validated with the results of the three pile specimen. These models are able to assess sustained damage in the specimens and predict remaining capacity. The outcomes of these studies showed that a plain pile embedment is a viable solution in areas of seismic activity when proper design considerations are considered. This is shown to be true of both CIP and precast bent cap specimens. Additionally, AE is shown to be an effective method of damage evaluation for these systems where multiple evaluation models are presented

Rôle des mitochondries dans l'hépatotoxicité induite par le tamoxifène

PARIS-BIUP (751062107) / SudocSudocFranceF

Altérations du génome mitochondrial et des fonctions mitochondriales induites par l'alcool et le tamoxifène

De nombreux xénobiotiques induisent des altérations des fonctions mitochondriales et de l ADN mitochondrial (ADNmt), participant ainsi au développement des maladies hépatiques. L'objectif de ce travail est d étudier les effets du tamoxifène et de l alcool sur les mitochondries hépatiques ainsi que l effet modulateur d une surexpression de la superoxyde dismutase à manganèse (MnSOD) sur la toxicité mitochondriale de l alcool : - Le tamoxifène s accumule dans les mitochondries, inhibe les topoisomérases et altère la réplication de l ADNmt. La déplétion progressive de l ADNmt qui s en suit est associée à une diminution de la respiration mitochondriale, à une inhibition de la b-oxydation et à la stéatose hépatique. - Les souris surexprimant la MnSOD sont plus sensibles aux altérations des fonctions mitochondriales et de l ADNmt induites par l alcool, probablement en raison des fortes concentrations d H202, du radical hydroxyle et des produits de la peroxydation lipidique. Ces travaux ont mis en évidence les altérations mitochondriales provoquées par le tamoxifène ainsi que le rôle délétère d une surexpression de la MnSOD lors d une alcoolisation chronique.Mitochondrial impairment and mitochondrial DNA (mtDNA) lesions contribute to xenobiotic-induced liver lesions. The aim of this study was to evaluate the toxic effects of tamoxifen and alcohol on hepatic mitochondria and to assess the modulating role of manganese superoxide dismutase overexpression (MnSOD) on ethanol-induced mitochondrial damage. We showed that tamoxifen accumulates inside mitochondria, inhibits topoisomérases and alters mtDNA replication leading to a progressive depletion of mtDNA. This decrease in mtDNA levels was associated with the inhibition of mitochondrial respiration and b-oxidation of fatty acids and the development of hepatic steatosis. In the second part, we showed that transgenic mice overexpressing MnSOD are more prone to alcohol-induced mitochondrial damage than wild type mice, probably because of enhanced formation of H202, hydroxyl radical and lipid peroxidation products. Our results show the implications of mitochondrial lesions in tamoxifen-induced steatosis as well as the negative effect of MnSOD overexpression on mitochondrial functions during chronic alcohol consumption.PARIS-BIUP (751062107) / SudocSudocFranceF

Load testing techniques for the strength evaluation of existing reinforced concrete structures

Evaluating the condition of existing reinforced concrete structures is generally undertaken if the integrity of a structure is in question or if there is concern regarding the structure meeting the safety requirements. Strength evaluation may be undertaken, for example, after extreme events (such as earthquakes) or if the structure will be used for a new function. In situ load testing may play a role in the evaluation process. Currently, the American Concrete Institute (ACI) covers in situ load testing in two separate standards: (a) ACI 318 "Building Code Requirements for Structural Concrete, and (b) ACI 437 "Code Requirements for Load Testing of Existing Concrete Structures. The latter is referenced by ACI 562 "Code Requirements for Evaluation, Repair, and Rehabilitation of Concrete Buildings". In situ load testing methods include the application of a pre-determined load in combination with response measurements of the structure. The main response measurement is deflection, but rotation, strain, crack width, acoustic emission, and other measurements may be included. In this paper, the two aforementioned load testing approaches are compared and evaluated in terms of load test procedure, load magnitude, loading criteria, and acceptance criteria. © 2016 ASCE