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Mitochondria are essential for energy supply and cell signalling and may be triggers and effectors of cell death. Mitochondrial respiration is tightly controlled by the matrix Ca2+ concentration, which is beat-to-beat regulated by uptake and release mainly through the mitochondrial Ca2+ uniporter and Na+/Ca2+ exchanger, respectively. Recent studies demonstrate that mitochondrial Ca2+ uptake is more dependent on anatomo-functional microdomains established with the sarcoplasmic reticulum (SR) than on cytosolic Ca2+. This privileged communication between SR and mitochondria is not restricted to Ca2+ but may involve ATP and reactive oxygen species, which has important implications in cardiac pathophysiology. The disruption of the SR–mitochondria interaction caused by cell remodelling has been implicated in the deterioration of excitation–contraction coupling of the failing heart. The SR–mitochondria interplay has been suggested to be involved in the depressed Ca2+ transients and mitochondrial dysfunction observed in diabetic hearts as well as in the genesis of certain arrhythmias, and it may play an important role in myocardial reperfusion injury. During reperfusion, re-energization in the presence of cytosolic Ca2+ overload results in SR-driven Ca2+ oscillations that may promote mitochondrial permeability transition (MPT). The relationship between MPT and Ca2+ oscillations is bidirectional, as recent data show that the induction of MPT in Ca2+-overloaded cardiomyocytes may result in mitochondrial Ca2+ release that aggravates Ca2+ handling and favours hypercontracture. A more complete characterization of the structural arrangements responsible for SR–mitochondria interplay will allow better understanding of cardiac (patho)physiology but also, and no less important, should serve as a basis for the development of new treatments for cardiac diseases.
Mitochondria have long been recognized as critical players in eukaryotic cell metabolism and energetics, but it was not until recent years that they have re-emerged as determinants of cell death or survival, with great relevance in cardiovascular (patho)physiology. The possibility that they form local privileged communication with other cell organelles, in particular with endo(sarco)plasmic reticulum, has aroused a new area of interest among cardiovascular scientists.
Mitochondria made complexity possible
Energy suppliers and cell signalling mediators
The ability of cells to produce energy from atmospheric oxygen is possible only because of mitochondria, and this feature is in the basis of multicellular life. Electrons from dietary substrates are transferred by the respiratory complexes to the oxygen, generating an H+ electrochemical gradient (ΔΨm), whose energy is used by the F1Fo-ATP synthase to drive ATP synthesis. Remarkably, as the ΔΨm dissipates, i.e. under hypoxic conditions or when H+ influx follows an alternative route not coupled to energy production, mitochondria can act as ATP consumers by reversing the activity of ATP synthase into ATP hydrolase in an attempt to maintain their own ΔΨm.1 The endosymbiotic evolutionary origin of mitochondria may provide the clues to understanding their molecular response under this and other stressful conditions. Mitochondrial energy production requires the coordination of several sequential steps tightly interconnected and suited to cellular requirements. However, even under well-coupled respiration, up to 1% of electron flux results in an incomplete reduction of molecular oxygen and production of superoxide that is subsequently converted to hydrogen peroxide.2 Thus, mitochondria are the main source of reactive oxygen species (ROS) production within cells. Whereas a mild increase in oxidative stress acts as a cell signalling mechanism required to trigger several stress responses,3 the insidious increase in free radical production or a burst of oxidative damage may risk mitochondrial integrity and exacerbate cell damage during different processes, from ageing to ischaemia–reperfusion.2,4 Superoxide production is very sensitive to the ΔΨm, being strongly decreased by mild uncoupling. It has been proposed that the modulation of the inner membrane H+ permeability (by uncoupling proteins, mitochondrial ion channels, and fatty acids, among others) may be an important mechanism of cardioprotection due to its effect on ROS production by mitochondria.5
Contribution of mitochondria to ionic homeostasis
From the pioneering studies of Carafoli and Lehninger6 and Carafoli et al.,7 mitochondria have been recognized as organelles capable of accumulating large quantities of calcium. The physiological significance and the specific routes of mitochondrial calcium uptake pathways, however, have been much debated. Mitochondria take up calcium primarily through the calcium uniporter,8 whose isolation and purification has not yet been accomplished, in a manner that is dependent on ΔΨm at the physiological range of cytosolic calcium concentration. Calcium extrusion from the matrix may take place even after ΔΨm dissipation through the mitochondrial Na+/Ca2+ exchanger (mNCX),9 through reversal of the uniporter,10 or by permeability transition of mitochondrial membranes.11–13 Mitochondrial calcium controls the rate of energy production14 and plays an instrumental role in cell apoptosis and necrosis.15–17 Moreover, mitochondrial calcium uptake and release participates in the regulation of the amplitude and spatio-temporal pattern of intracellular calcium signals in different cell types, including contracting cardiomyocytes.8–20
Among the several mitochondrial membrane ion channels and exchangers, K channels (either ATP-sensitive or calcium-activated) have been extensively investigated for their potential cardioprotective roles. The opening of mitochondrial K-ATP channels21,22 or calcium-activated K channels23 has been shown to be beneficial for cell survival under certain stress conditions, including ischaemia–reperfusion and heart failure. The precise mechanism of this protective effect has not been elucidated, but it is postulated that the opening of these channels produces both an increase in mitochondrial volume24 and a certain degree of mitochondrial uncoupling which, in turn, reduces calcium overload.25 The regulation of matrix volume is crucial for the correct functioning of mitochondria and is accomplished indirectly by a number of specific exchangers, uniporters, and ion channels present in both membranes. Moderate matrix swelling has been shown to exert a protective function against myocardial ischaemic–reperfusion damage.24 In particular, voltage-dependent anion channel or mitochondrial porin, the most abundant protein of the outer membrane, is a large, water-filled pore that allows charged molecules to cross freely to the intermembrane space.26 In the last years, aquaporins have been found associated with mitochondrial inner membranes, where they may constitute the molecular pathway underlying osmotic movement of water to the matrix.27 Connexin 43, a protein constitutively forming sarcolemmal hemichannels and gap junction channels in ventricular myocytes, is also present at the inner mitochondrial membranes28,29 where it contributes to mitochondrial K+ influx.30 Resting intramitochondrial pH has been estimated at 7.7–8, is controlled by several inner membrane transporters and exchangers, and may influence cytosolic pH. Thus, reverse operation of FoF1 ATPase has been implicated in cytosolic acidification (concomitant with mitochondrial alkalinization), and represents a triggering event in the mitochondria-dependent pathway for caspase activation and apoptosis.31
Mitochondrial death pathways
Mitochondria are the central regulators of cell fate during exposure to stress, as they contain the specific and latent mechanisms for activating both the intrinsic apoptotic pathway and necrotic death in a variety of cell types.19,32 The intrinsic apoptotic pathway involves the activation and subsequent translocation to mitochondria of the members of the Bcl2 family (Bax, Bak, and Bid), following the canonical mechanism of programmed cell death.32,33 These pro-apoptotic proteins insert into the mitochondrial outer membrane where they can behave as death channels, allowing the release of apoptogenic proteins from the intermembrane space that are responsible for the activation of the signal cascade that eventually leads to cell death through caspase-9 and -3-dependent proteolysis. It has been described that the intrinsic and extrinsic pathways (receptor-mediated apoptosis) may be interconnected by the activation and subsequent translocation of the protein Bid (a substrate of caspase 8), eventually leading to mitochondrial permeabilization.34 An irreversible loss of mitochondrial function or the release of some mitochondrial death effectors, like apoptosis-inducing factor, may initiate a suicide programme by a caspase-independent pathway. Other cell death effectors released by mitochondria are cytochrome C, second mitochondrial-derived activator of caspase (Smac), and endonuclease G, among others.32
Mitochondria-induced cell death may also be initiated by the development of a sudden increase in the permeability of the mitochondrial inner membrane, the so-called permeability transition (MPT), which allows the passage of ions and solutes with molecular masses up to 1500 Da.35 This phenomenon leads to the dissipation of ΔΨm, uncoupling of oxidative phosphorylation (ATP depletion), and matrix swelling and is triggered by oxidative stress and matrix calcium overload. MPT is modulated by voltage, adenine nucleotide concentration and pH,35 and by pharmacological agents.36,37 The exact molecular nature of MPT remains elusive,38,39 but its contribution to the pathophysiology of multiple cardiac diseases is unequivocal and has been extensively reviewed.39
The connection between mitochondria and endoplasmic reticulum
The endoplasmic reticulum (ER) is a complex, folded membrane network composed of tubules, vesicles, and cisternae expanded within the cytoplasm of eukaryotic cells. It is divided into rough (ribosome-containing) ER, smooth ER, and nuclear membrane, and it fulfils several cellular functions, including synthesis of lipids and steroids, metabolism of carbohydrates, manufacturing and folding of proteins, regulation of calcium concentration, drug detoxification, and attachment of receptors on cell membrane proteins.40 The lumen of the ER contains the highest calcium concentration within the cell, which is due to the activity of calcium ATPases, and a very rich oxidative environment necessary for the formation of protein disulfide bonds and proper protein folding.41 As a result, the ER is particularly sensitive to disturbances in redox regulation and calcium homeostasis, which can promote the unfolded protein response, an activation of a signal transduction event aimed at accelerating degradation of defective proteins.42 Upon persistent noxious stimulus, the ER can initiate cell death via mitochondria-dependent and -independent apoptotic pathways.43 Thus, there is a close interconnection between ER stress and cell survival. The Bcl-2 family proteins, first described by their actions on mitochondrial death pathway, may also interact with ER membranes, and they have been described to modulate ER calcium44 and protect mitochondria through regulation of ER–mitochondria communication.45
Mitochondria also have an important role as intracellular reservoirs of calcium. Interestingly, there is a clear discrepancy between mitochondrial calcium kinetics observed in in vitro preparations and in intact cells. Studies with calcium microelectrodes or with fluorescent markers have established that energized, isolated mitochondria may take up significant amounts of calcium when exposed to high calcium concentrations—in the high micromolar range—through the low-affinity calcium uniporter, without suffering permeability transition.46,47 However, the cytosolic calcium concentration in resting cells is well below this level, and even maximal calcium concentrations reached after physiological stimulation (1–3 µM) appear to be insufficient for mitochondrial calcium uptake, according to the described calcium affinity of the mitochondrial calcium uniporter. The studies from Rizzuto et al.48,49 using chimeric recombinant aequorin targeted to mitochondria established that the mitochondrial calcium concentration increases rapidly and transiently upon the stimulation of ER calcium release (IP3 agonists) in different quiescent cell types, although the speed and amplitude of the rise in mitochondrial calcium levels was not accounted for by the relatively small increases in mean cytosolic calcium. These and other similar experimental approaches showed that mitochondria respond more efficiently to calcium increases in the specific sites located close to the ER calcium channels than to increases in general cytosolic calcium, and that only a fraction of mitochondria are exposed to these microanatomical sites.50 The existence of a physical coupling between ER and mitochondria has been demonstrated in experiments in which limited proteolysis with trypsin or proteinase K significantly modified mitochondrial calcium signalling evoked by IP3 receptor-mediated calcium release.51 Cross-talk between mitochondria and ER has been confirmed in many cell types, including astrocytes,18 hepatocytes,52 and cardiac myocytes53,54 and has been unequivocally established by electron microscopy using fixed samples.55 According to electronic tomography measurements, the distance between the outer mitochondrial membrane and the ER in situ has been calculated to be 10–50 nm.51 These findings agree with the existence of local calcium microdomains that allow privileged signalling between the ER and mitochondria that are responsible for the microheterogeneity of cellular calcium.56 Mitochondria would act as calcium sensors in a discrete number of functional microdomains (in close juxtaposition with the ER) and would allow the diffusion and amplification of the calcium signal following a well-coordinated pattern. This concept has been proved in experiments in which high-speed mitochondrial calcium imaging revealed propagating intramitochondrial calcium waves in intact cells that were susceptible to interruption by overexpression of the mitochondrial fission factor Drp-1.57 A handful of biochemical and functional results have implicated several proteins in sustaining ER–mitochondria coupling.58–61 The preferential communication between ER and mitochondria has emerged as a concept with great biological relevance in a variety of tissues, and more specifically in those cells with a high degree of specialized functions.62,63
The case of cardiac myocytes: communication between mitochondria and sarcoplasmic reticulum
Specific characteristics of mitochondria and sarcoplasmic reticulum in cardiac cells
Cardiac myocytes are the paradigm of highly compartmentalized cells, with a terminally differentiated morphology and extremely specialized functions. Their large size, as well as the uninterrupted mechanical work they exert throughout life, makes cardiac myocytes the most energy-demanding cells in the body. The development of contractile activity is also possible by a precise and perfectly coupled calcium oscillatory movement. These requirements have impacted on the specialization and abundance of cardiac mitochondria and sarcoplasmic reticulum (SR), the two organelles that coordinate energy production and calcium control. Cardiac mitochondria occupy as much as 40% of cell volume and are unique, in that they can be morphologically and biochemically differentiated into two subpopulations: subsarcolemmal mitochondria, located beneath the plasma membrane, and interfibrillar mitochondria, located between myofibrils.64 Morphological differences in the two types of mitochondria are subtle, but respiratory activity and the capacity to retain calcium are significantly higher in interfibrillar mitochondria.65 It has been recently described that connexin 43, a protein whose translocation to mitochondrial membranes has been associated with cardioprotection during ischaemic preconditioning,28,29 is present only in subsarcolemmal mitochondria.66 Similarly, functional decline associated with ageing is predominantly manifested in interfibrillar mitochondria,67 and diabetic interfibrillar mitochondria have been shown to display a greater propensity for undergoing apoptosis when compared with subsarcolemmal mitochondria.68 It can be speculated that biochemical differences between the two mitochondrial subpopulations may be the result of their different interaction with other intracellular organelles.
The SR shares several morphofunctional features with the ER, like the complex tubular structure and cisternae, but they differ in some biochemical characteristics and interactions with other cell structures. In striated skeletal and cardiac cells, the SR coexists with the classical ER-containing ribosomal network. The SR constitutes the main intracellular calcium store in striated muscle and plays a crucial role in excitation–contraction coupling. Owing to its high degree of functional specialization, the vast majority of SR protein content in cardiac cells corresponds to calcium transporters SERCA at the longitudinal region, and calcium release channels (ryanodine receptors, or RyR) at the region juxtaposed to T-tubules.56,69 SERCA belongs to a family of ATP-dependent calcium transporters that maintain intraluminal calcium concentration 3–4 orders of magnitude greater than cytosolic calcium,70 and it is regulated by phospholamban, a 22 kDa protein present in the longitudinal fraction of SR.71 SERCA2 is the only isoform expressed in cardiac cells. RyR mediate the release of calcium from SR to myofibrils during cell contraction. RyR channels are blocked by micromolar concentrations of ryanodine and activated by millimolar concentrations of caffeine, and they are the main components responsible for calcium-induced calcium release, a cycle of positive feedback, in cardiac cells.72 RyR2 is the only isoform expressed in myocardial tissue. RyR have a complex regulatory mechanism, and several factors have been described to modify their open probability apart of calcium, like oxidation of critical residues, phophorylation/dephosphorylation events, and protein interactions (mainly with calmodulin, FKBP12.6, and calsequestrin).3,73,74 Moreover, SR calcium storage capacity is regulated by a series of intraluminal, low-affinity calcium-binding proteins. During calcium transients, only 40–60% of total SR calcium is released.75,76 Calsequestrin, the most abundant intraluminal protein, acts as a calcium sensor capable of inhibiting RyR activity at low calcium concentrations and terminating SR calcium release during normal cell contraction.77 Several other less-represented SR proteins also participate in SR calcium regulation.78 Efficient delivery of calcium and ATP to the sarcomere is possible because of an intimate structural interaction between T-tubules, RyR channels, myofilaments, and mitochondria. Calcium uptake by mitochondria located in close proximity to SR calcium release channels participates in the modulation of the calcium transient and contraction.79
Functional microdomains between mitochondria and SR
In cardiac myocytes, mitochondria form a dynamic and continuous network surrounding myofibrils and the SR network, within which the inter-organelle distance has been estimated to be 10–50 nm.51 SR–mitochondria communication occurs through anatomical and functional cell microdomains and is in part responsible for the heterogeneous distribution of calcium across the cytosol of cardiac cells. It has been demonstrated that mitochondrial calcium uptake is more dependent on high cytosolic Ca2+ microdomains around the contact sites with SR than on the cytosolic Ca2+ concentration.54 Although it is clear that the interplay between SR and mitochondria allows a rapid exchange of molecules between both organelles,50 the mechanism of such diffusion is less well understood. According to the recent evidence, SR–mitochondrial communication is supported by a physical coupling resistant to purification procedures that cause demolition of cytoskeletal structure.50 By means of conventional transmission electron microscopy as well as electron tomography, it has been possible to visualize tethering structures (electron-dense bridges) between the terminal cisternae of the SR and mitochondria80 (Figure 1). In any case, the mitochondrial calcium uniporter is exposed to local high calcium concentrations, since RyR-mediated calcium propagation to mitochondria persists even after cytosolic calcium chelation with BAPTA in permeabilized cardiac myocytes.81
Cross-talk between mitochondria and SR is not only a determinant of calcium handling but for a proper matching of energy supply and demand and regulation of mitochondrial respiration.82,83 More recently, the concept of 'ROS microdomains' has been proposed to describe a spatially restricted ROS generation with different physiological effects, depending on their localization.84 Because mitochondria are the major producers of superoxide, it can be speculated that mitochondrial ROS production may specifically impact SR function and calcium microdomains. In fact, both SERCA pumps and RyR channels contain multiple, potentially redox-sensitive cysteine residues, and cysteine thiol oxidation has been described to increase RyR channel activity.3 Therefore, it is not surprising that photostimulation of mitochondrial ROS production is able to induce a transient increase in SR calcium sparks in rat cardiac myocytes.85 Remarkably, the relationship between ROS and calcium at the locally restricted cell domains may take place in both directions. A recent report86 has shown that local increases in cytosolic calcium concentration, initiated by calcium release from the SR, increased ROS production and favoured MPT. Thus, the existence of a mutual relationship between calcium and ROS signalling is favoured by the SR–mitochondria interface and probably represents one of the most important signalling mechanisms in cardiac cells.
Mitochondria and SR in cardiovascular pathophysiology
The interplay between SR and mitochondria has some genuine characteristics that go beyond the individual role of each organelle. Functional consequences of the close anatomical interaction between SR and mitochondria are increasingly recognized as playing important roles in the pathophysiology of several conditions. Truncation or modification of the physiological behaviour of one of the components of these microdomains may impact on the other, amplify cell injury, and even induce necrotic or apoptotic death.87,88 Defects in the intercommunication between SR and mitochondria make cardiac myocytes particularly vulnerable to problems related to ATP availability, sarcomeric calcium, and oxidative stress.
SR–mitochondria communication may amplify ischaemia–repefusion injury
Cell death secondary to transient myocardial ischaemia occurs mainly within the first minutes of restoration of blood flow in the form of necrosis. The mechanisms of reperfusion-induced cardiomyocyte death have been reviewed elsewhere.89 Although they have not been completely elucidated, calcium overload and altered calcium handling play a prominent role by inducing calpain-mediated proteolysis, hyperactivation of the contractile machinery, and MPT. The pathological hallmark of reperfusion necrosis is the presence of contraction bands, reflecting cardiomyocyte hypercontracture.90,91 Energy-dependent hypercontracture92 contributes to cell death, as demonstrated by studies in which pharmacological inhibition of contractility at the onset of reperfusion reduced infarct size.93–95 Previous studies have indicated that hypercontracture can be triggered by SR calcium cycling96,97 induced by restoration of ATP in the presence of cytosolic calcium overload. The reactivation of SERCA causes SR calcium uptake beyond maximal SR storage capacity, resulting in subsequent calcium release through RyR and an increase in the concentration of cytosolic calcium, reinitiating the process. This abnormal SR behaviour gives rise to cytosolic calcium oscillations that propagate as calcium waves and may induce arrhythmias and myofibrillar hypercontracture.96,97 The prevention or attenuation of calcium oscillations by drugs interfering with SR calcium uptake or release96,98 or reducing cytosolic calcium overload99,100 has been proved to be effective strategies to protect against hypercontracture and cell death during reperfusion.
The role of mitochondria in myocardial reperfusion injury has been the object of extensive research and has been reviewed in detail previously.101 Oxidative stress, mitochondrial Ca2+ overload, and low ATP concentration—circumstances that concur upon myocardial reperfusion after prolonged ischaemia—promote MPT in different experimental models.101–103 Pharmacological and genetic inhibition of MPT effectively reduced infarct size in several experimental models,36,37,104 and two proof-of-concept clinical trials have demonstrated that targeting MPT with postconditioning105 or cyclosporine A106 at the moment of angioplasty improves contractile function and reduces cell death in patients with acute myocardial infarction. However, hypercontracture is an energy-dependent response, whereas MPT causes energy dissipation. One interesting possibility is the coexistence within the same cell of an intact subpopulation of mitochondria, capable of sustaining ATP synthesis, with more severely damaged mitochondria undergoing membrane permeabilization. The anatomo-functional interplay between the SR and mitochondria predicts, in fact, a different tolerance to ischaemic damage of subsarcolemmal and interfibrillar mitochondria, since only the latter subpopulation is in close contact with the SR. The coexistence of damaged and intact mitochondria within the same cell during reperfusion has been tested in a model of laser-induced mitochondrial permeabilization in calcium-overloaded cadiomyocytes.107 In this study, experimental induction of MPT impaired cytosolic calcium overload, favoured SR-driven calcium oscillations, and eventually led to hypercontracture, supporting the existence of heterogeneously damaged mitochondria within the same cell. The relationship between SR-driven calcium oscillations and MPT appears to be bidirectional, and SR calcium cycling may increase the susceptibility for MPT in a fraction of mitochondria located in areas of close contact with the SR. In a recent study,108 pharmacological blockade of SR calcium load with thapsigargin/ryanodine slowed mitochondrial calcium uptake in intact cells but had no effect in isolated mitochondria where the contribution of SR is negligible. The inhibition of SR calcium uptake and release also reduced MPT, hypercontracture, and cell death during reperfusion, and this protective effect was abrogated when anatomical interaction between the SR and mitochondria was partially disrupted with colchicine108 (Figure 2). The prevention of cytosolic calcium oscillations did not reduce the total cytosolic calcium concentration during the first minutes of reperfusion, supporting the hypothesis that there is a component of cell death triggered by a local mechanism not related to total cellular calcium load.108Figure 3 illustrates the concept of the role of SR–mitochondria microdomains in reperfusion injury.
Arrhythmias may be the consequence of a defective SR–mitochondria interplay
Imbalanced SR–mitochondria communication may have important functional consequences in cardiac arrhythmias. Mitochondrial calcium is the main regulatory factor for the orchestration of mitochondrial energetics with variations in cardiac workload and excitation–contraction coupling.79,109,110 Some studies have linked mitochondrial dysfunction to certain types of cardiac arrhythmias and sudden death.111 Atrial myocyte energetics has been reported to be perturbed in patients and animal models of atrial fibrillation,112 and mitochondrial depolarization during reperfusion—secondary to calcium uptake—could facilitate mitochondrial network disruption and the occurrence of ventricular fibrillation.113 Whether mitochondrial dysfunction is the cause or consequence of SR dysfunction remains to be elucidated. It is postulated that calcium-dependent arrhythmias are generally associated with the instability of SR calcium release, whereas heart failure is related to a reduction in systolic SR calcium release.114 The pathophysiological mechanism of SR dysfunction is extremely complex and multiple molecular disturbances, like abnormal RyR2 behaviour with increased SR calcium leak115 or failure of RyR2 gating,116 have been described. Moreover, conditions causing an increase in the cytosolic calcium concentration, i.e. myocardial ischaemia/reperfusion, may lead to the generation of spontaneous SR calcium waves, which can give rise to sustained tachyarrhythmias117 and promote excessive activation of the contractile machinery, leading to hypercontracture and cell death.96,97 The SR has been pointed out as the major contributor of the contractile dysfunction in human atrial cardiomyocytes obtained from patients with atrial fibrillation by a mechanism involving hyperphosphorylation of the RyR2.118 This effect could be responsible for a continuous SR calcium leak and arrhythmogenesis. Alternatively, the increase in mitochondrial ROS production described in human atrial fibrillation119 could be in part responsible for SR dysfunction. Computer simulation studies integrating the role of excitation–contraction coupling and mitochondrial bioenergetics showed that mitochondrial ROS production triggers ΔΨm oscillations and shortens the duration of the cell action potential.120 The possibility that altered SR function may locally modify mitochondrial energetics deserves further investigation.
Disruption of mitochondria–SR interaction in the failing heart
Advanced heart failure has been consistently associated with a progressive decline in mitochondrial respiratory activity,121 reduced ATP generation,122 and mitochondrial structural abnormalities.123 These mitochondrial alterations, together with reduced amplitude of SR-driven calcium transients,124,125 are the most prominent disturbances described to contribute to cardiac contractile dysfunction. A large variety of defects in the activity of individual components of the mitochondrial respiratory chain have been proposed to participate in the pathogenesis of heart failure.126–128 It is controversial whether the reduction in the respiratory rates may be attributed to a mere decrease in mitochondrial function or to a reduced number of mitochondria.129 Studies from Rosca et al.121,130 propose that the pronounced variability of mitochondrial electron transport defects reported thus far in severe acquired cardiomyopathies may be explained by a sequential mechanistic pathway in which defects in supramolecular assembly (respirasomes)—rather than in the individual components of oxidative phosphorylation—are the primary event responsible for the progression of heart failure. Recently, it has also been suggested that changes in mitochondrial protein dynamics can contribute to the cell loss and the progression of cardiac failure.131 Moreover, in some specific conditions like heart failure secondary to diabetic cardiomyopathy, interfibrillar and subsarcolemmal mitochondria are selectively affected.68,132 Mitochondria-induced apoptotic death of cardiac myocytes has been described to play a role in the progression of cardiac dysfunction, since it is persistently activated in patients with decompensated heart failure.133
Because in cardiac cells, the matching of energy supply and demand is strongly dependent on local, metabolically active microdomains, the impairment of the local ATP/ADP ratio is one of the molecular disturbances described in failing myocardium, probably developing as a consequence of a cytoarchitectural perturbation.134,135 Indeed, heart failure is associated with structural remodelling of various subcellular organelles,136 and it has been described that local energy transfer between SR and mitochondria is affected in mice with genetically altered subcellular organization.137 Mouse hearts deficient in muscle LIM protein exhibit a defective nucleotide channelling from mitochondria to SR, despite having normal mitochondrial oxidative capacity, an effect that likely accounts for the energetic and contractile dysfunction.137 Therefore, there is a tight relationship between the disorganization of several cellular structural components and the impairment of SR–mitochondria intercommunication, with concomitant deterioration in the excitation–contraction coupling.135,137 Although the specific role of SR–mitochondria interplay in the pathogenesis of the different cardiomyopathies (dilated vs. hypertrophic) has not been elucidated, subcellular microanatomical remodelling seems to be dependent on the differences in cardiac load and cardiac failure stage.135
Disarrangement between SR and mitochondria is not the only mechanism responsible for the defective biochemical interaction among both organelles. Alterations of structural or regulatory proteins on any side of the functional unit may have consequences on its counterpart. Thus, the modification of the expression of the uncoupling protein 2 not only has an intrinsic mitochondrial effect on ΔΨm and ROS production but also exerts a deleterious influence on excitation–contraction coupling and calcium handling.138 Conversely, calcium/calmodulin-dependent protein kinase II, a protein that plays a role in regulating SR calcium release, may reduce ΔΨm and increase mitochondrial susceptibility to undergoing membrane permeabilization by a mechanism related to local rise in cytosolic calcium and stimulation of mitochondrial ROS generation.86 Overall, these studies emphasize the critical role of the disruption of functional units, particularly those established by SR and mitochondria interplay, in the progression of heart failure.
Role of mitochondria–SR microdomains in diabetes
Several lines of evidence support the notion that mitochondrial defects play a critical role in the progression of diabetes.139,140 Similarly, a number of studies have found altered SR function with disturbed calcium handling in the cardiomyopathic phenotype associated with the diabetic state.141,142 Cardiac myocytes submitted to hyperglycaemic conditions are exposed to increased oxidative stress and mitochondrial calcium overload, which can lead to a reduction in mitochondrial respiration and increased susceptibility to undergoing MPT.143 Mitochondrial perturbations have been attributed to impaired myocardial insulin signalling144 or to a fragmentation of the mitochondrial network.145 Defective nitric oxide production might also deteriorate mitochondrial biogenesis in the metabolic syndrome.146 Indirect evidence suggests an interaction between SR and mitochondrial disturbances in the progression of diabetes. Reduced insulin action promoted a rapid decline in mitochondrial fatty acid oxidative capacity.147 Interestingly, the expression levels of SERCA2 were concomitantly reduced.147 A different study148 indicated that chronic exposure to high fatty acid levels adversely affected mitochondrial function (reduced ΔΨm and stimulated ROS production), which, in turn, was associated with reduced SR calcium content and depressed cytosolic calcium transients. It cannot be ruled out that SR (or ER) stress mediates mitochondrial damage by a cell signalling mechanism rather than by a direct local effect. Miki et al.149 described a reduced threshold for MPT associated with ER stress in the myocardium of type 2 diabetic rats by an impaired phospho-GSK3β-mediated suppression of MPT, an effect that may underlie the failure of cytoprotective strategies against ischaemia–reperfusion injury in diabetic hearts. Dysregulation in the formation of ROS microdomains could play a role in the pathophysiology of diabetes due to the existence of a tight interplay between ROS and calcium, but, to date, the specific contribution of SR–mitochondria interaction in the aetiopathogenesis of diabetic disease has not yet been explicitly investigated.
Might ageing be a disease of SR–mitochondria communication?
Ageing is a complex, multifactorial process that is far from being deciphered. It is usually linked to degenerative diseases, including cardiac diseases, but the nature of this link remains speculative.150 An overwhelming amount of experimental data links mitochondrial dysfunction with cell senescence and lifespan.151 The mitochondrial theory of ageing assumes three main mediators of cell damage: increased ROS accumulation, progressive mitochondrial DNA damage, and insidious failure of respiratory complexes.151,152 However, to our knowledge, the possibility that different populations of mitochondria age at different rates depending on their interrelation with the SR, orchestrating cell senescence, has not been investigated thus far. An intriguing observation is that subsarcolemmal and interfibrillar mitochondria experience different functional decline during ageing, with a selective reduction in oxidative phosphorylation affecting interfibrillar mitochondria.153 The capacity to retain calcium before undergoing membrane permeabilization is also specifically reduced in the interfibrillar mitochondria from myocardium of old rats.154 Remarkably, interfibrillar mitochondria are exposed to continuous SR calcium oscillations throughout the life in the beating heart. This is probably the biological reason for their higher respiratory capacity and a more efficient calcium uptake system.65 Because the SR–mitochondria interaction is bidirectional, the possibility exists that progressive mitochondrial decline in oxidative phosphorylation observed in interfibrillar mitochondria deteriorates the closely juxtaposed, energy-dependent SR, providing the pathophysiological basis for the progression of age-related degenerative diseases in which calcium homeostasis is lost, i.e. heart failure. Ageing has been shown to account for an increased sensitivity to ischaemia–repefusion injury mediated in part by a higher diastolic calcium concentration, although the mechanisms leading to this persistent loss of calcium control have not been identified.155 The activity of SR calcium transporters is very sensitive to redox state,3 and functional units regulating local SR calcium release and the calcium-induced-calcium-release response in skeletal and cardiac cells have been shown to lose their plasticity during ageing.156 However, what the molecular machinery that induces such alterations might be is not clear at present, nor is the cause–consequence relationship between them, and the role of the SR–mitochondria interaction in the cellular functional decline associated with ageing is still an unexplored field of research.
The concept that mitochondria and SR behave in many respects as a functional unit has potentially important implications. First, it may allow a better understanding of the pathophysiology and evolution of cardiovascular diseases and their modulation by ageing. Secondly, and most importantly, it may help to identify and develop new therapeutic strategies. It should allow the protection of mitochondria by targeting SR molecules or treatment of SR dysfunction by mitochondrial interventions. Finally, it opens a new field of research on the potential value of strategies aimed at modifying SR–mitochondria communication itself.
Conflict of interest: none declared.
Partially supported by RECAVA-RETICS (RD060014/0025, ISCIII, Spanish Ministry of Science), FIS (PS09/02034, Spanish Ministry of Science), and SAF (2008-03067, Spanish Ministry of Education).


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3 out of 3 people found this review helpful:GREAT ANIME SHOULD CHECK IT OUTAll i can say is what a great anime! Im a gamer an addicted to RPGs so i cant help but fall in love with it! Not to mention the realistic feel of an actual RPG video game i am a continuing fan. Plan to buy once out on dvd
3 out of 3 people found this review helpful:The Perfect Combination.I'll start my review by saying this is one the greatest anime I have ever seen, and I don't say that very often ^^Read more
It can be hard to find and series that combines so neatly the genres of romance, action, and fantasy these days, but Sword Art Online manages to do the task almost perfectly, maybe one of the best points of this anime is how nicely the characters ( not only the ...
2 out of 2 people found this review helpful:Ok, it has a few issues, but lay off on the hate,Ok, yes this show has 101 problems in terms of the plot, and the story does go a bit downhill in the second half, but none of this really bothered me. The show is just very entertaining, and if you want a good fun watch, look no furtherRead more
The animation looks great, the action and soundtrack are good, and whether the plot was any good or not, I was just enjoying the ride. A second season would not ...
2 out of 2 people found this review helpful:The first half is great. the series as a whole though...not so muchThe first half of SAO was pretty good. Was a bit disappointed that so many character just got dropped and forgotten after one episode and I definitely had a problem with the pacing of the show. That said though, the show still held pretty nicely, what with the animation and a few gem episodes with interesting concepts, and i enjoyed myself a very good amount.Read more
Then the second half happened.. ...
2 out of 2 people found this review helpful:Couldn't avoid falling in love with it.This is by far the BEST anime I've ever seen. Period.
One of the best story-lines I've ever seen, excellent animations, excellent characters, pretty good graphics and design. Overall, this anime is absolutely perfect.
From what it looks, it is most likely that we will get another season possibly this year.... I hope.
2 out of 2 people found this review helpful:Takes veiw of Online MMORPG to a whole new level.I'm a gamer, honestly when i watched the first episode it pretty much describe what you will see in a typical online game. Guys pretending to be girls, girls be guys vice versa.
As the story progressed, It became either survival of the fittest or team work survival.
But Season 2, not really worth my time.
Season 1: 10/10
Season 2: 5/10
5 out of 8 people found this review helpful:Emotional and amazing storyIf you are into romance, action, and an awesome story, then look no further. This anime is absolutely amazing. Really nice design, great cast of characters that you can become attached to, and lots of awesome moments. You will not be disappointed.
6 out of 10 people found this review helpful:ALMOST PERFECT- ty for reading all of it if u did otherwise u should read all of itI have to say SAO is the best anime i have seen in a long time and i mean it. It blew my standards away, now when i see another show on i roll my eyes because i know that there nowhere near what u have accomplished with SAO. But i do hope however that u can go more in-depth this go round like how the story is in what u wrote make the series longer than 25 episodes because u could easily make it a ...Read more
6 out of 10 people found this review helpful:Very, very enjoyable anime.My favorite part about this anime would have to be the concept. I like video games, so I was drawn to the plot, where characters are trapped inside an MMO. The characters were fun to watch as well. It was enjoyable to see Kirito and Asuna bond closer as the anime progresses. However, I thought the anime progressed too quickly during the SAO portion. It would have been nice to see more of Kirito's ...Read more
6 out of 10 people found this review helpful:Great Anime Poor Plot TwistSAO is a great anime for people who are not the critiszing type of people and are free goers, the anime has a good plot, OK romance and a better then normal characters. This anime's plot is great at the beginning with a deep plot and it keeps the audience's eyes glued to the anime until the 2nd arc comes around and the anime pulls a massive dick move which sent the anime into a downward spiral ...Read more

subset: commoncrawl


text:
|» Step 1: Tell Us About Your Case
|» Step 2: Provide Contact Information & Submit
Tell us about your case so that we can connect you with the right lawyers.
Personal Injury Law Firm
Address: 130 Dudley Road Suite 195-Edgewood KY 41017
Phone: 859-261-4200
The law firm of Weisser & Wolf was founded in 1988 by Mark Weisser and Scott Wolf to provide exceptional legal counsel to injured individuals in our community.
Address: 600 Vine Street, Suite 1920 -Cincinnati OH 45202
Phone: (513) 296-5237
For serious injuries, Call the Lawyers Other Lawyers Call
Address: -Cincinnati OH
Phone: 800-792-1480
Get Cash For Your Workers' Compensation Claim - Hochman & Plunkett attorneys are skilled in the art of settling workers' compensation claims. Our Ohio workers' compensation lawyers have more than 150 years of combined experience.
Address: 810 Sycamore Street Third Floor-Cincinnati OH 45202
Phone: (937) 228-2666
My practice focuses exclusively on Ohio Workers Compensation and Social Security Disability.
Address: 225 West Court Street -Cincinnati OH 45202
Phone: 513-721-5525
Mark devotes his practice to assisting injured and disabled individuals pursue workers' compensation, social security disability, and personal injury claims. He also assists individuals and families achieve their estate planning goals.
Address: 1344 Vine Street -Cincinnati OH 45202
Phone: (513) 533-2009
The Law Offices of Kurt M. Young, along with our partners The Law Offices of Russell Gerney & The Law Offices of Emil George Gravelle is a community oriented firm offering quality legal services to the working men & women of Northwest Ohio.
Address: 1217 Jefferson Ave. -Toledo OH 43604
Phone: 419-244-7885
Columbus Workers' Compensation Attorneys .
Address: 89 East Nationwide Blvd. Suite 300-Columbus OH 43215
Phone: (614) 224-3838
Address: 55 Public Square, Suite 1200 -Cleveland OH 44113
Phone: (216) 861-1234
We help injured Ohio workers receive the compensation they deserve. If you've suffered an injury in the workplace call us today.
Address: 628 W. Market St. -Akron OH 44303
Phone: (330) 535-5757
Nager, Romaine & Schneiberg Co., L.P.A. (NRS) is an injury law firm based in northeastern Ohio with a statewide practice. Our attorneys have more than 150 years of combined legal experience in the areas of PI, WC, Medmal & SSD cases.
Heller, Maas, Moro & Magill, Co., LPA has been committed to protecting the rights of injured workers, injury victims, and the disabled since it's beginning in 1985. We have a staff of eight attorneys, four of which have practiced 25 + years.
I am a Certified Specialist in Workers' Compensation Law with 36 years of experience. No office visit is needed. All free claim and settlement reviews can be done by phone at a time convenient for you--Including Evenings and Weekends.


text:
Invaluable cannot guarantee the accuracy of translations through Google Translate and disclaims any responsibility for inaccurate translations.
ORIGINAL VINTAGE FRENCH POSTER NITROLIAN PAINT BY LEONETTO CAPPIELLO 1929(185 views)
Description: This poster done for the Nitrolian paint company is one of the most iconic and endearing posters created by the great artist Leonetto Cappiello. In this image we see that the paint dries so rapidly that the woman in white can walk down the newly painted stairs without getting a spot on her. If you can notice the paint can, you will see that Cappiello mirrors the overall image in a small caption on the paint can. To further add some whimsy, Cappiello portrayed himself as the painter with the cigar in his hand. This is an Original Vintage Poster; it is not a reproduction. This poster is conservation mounted, linen backed, and in excellent condition. We guarantee the authenticity of all of our posters.
Dimensions: 46.5 x 62.5 inches
Artist or Maker: CAPPIELLO
Date: 1929
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text:
Let's be honest, the historic winter storms that hit North Texas for Super Bowl XLV didn't leave a good impression with people that visited the area in 2011 for the Green Bay Packers-Pittsburgh Steelers contest.
On the day of the game at Cowboys Stadium, the weather was beautiful -- clear skies, not a storm cloud in the sky -- but the seating fiasco caused embarrassment and brought on a lawsuit. It raised serious questions about North Texas' chances at hosting another Super Bowl, much less Super Bowl L. Of course, North Texas can because XLV was deemed a financial success.
Fast forward to what's happening in Miami.
The Florida Speaker of the House blocked a bill giving the citizens of Miami-Dade County the ability to vote on public funding of upgrades to Sun Life Stadium.
It appears doubtful that Miami is going to be awarded one of the two upcoming Super Bowls -- L and LI -- that don't yet have a site.
Where does this leave North Texas?
Miami was poised to submit a bid for one of these two title games, but it appears Santa Clara, Calif., and Houston, are in position to get Super Bowl L and LI. With Miami having funding troubles for upgrades, maybe North Texas moves ahead of Miami for future games.
Cowboys Stadium is hosting the Final Four, college football's national title game and other major events. The seating issue seems forgotten, and maybe North Texas is back in play as a major player in hosting Super Bowls.
NFL owners will vote on May 21 on who gets Super Bowl L and LI, and North Texas isn't in the mix right now. But future NFL title games will have to seriously consider North Texas, especially with Miami having issues.


text:
|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|"Yonik Seeley (JIRA)" <j...@apache.org>
|[jira] [Commented] (SOLR-3916) fl parsing is sensitive to newlines at the end of field names
|Fri, 05 Oct 2012 20:58:03 GMT
[ https://issues.apache.org/jira/browse/SOLR-3916?page=com.atlassian.jira.plugin.system.issuetabpanels:comment-tabpanel&focusedCommentId=13470652#comment-13470652 ] Yonik Seeley commented on SOLR-3916: ------------------------------------ bq. blaming this on xml parsing doesn't really seem productive ? I'm suggesting this could be a much wider problem than just "fl", which would seem to be a very productive line of conversation. In the context of grabbing defaults from XML, we should consider trimming whitespace in the process of generating those defaults (rather than later). The only downside is if certain parameters could reasonably expect to want leading/trailing whitespace. If we want to support that, we could introduce a new type called <verbatim> or something. > fl parsing is sensitive to newlines at the end of field names > ------------------------------------------------------------- > > Key: SOLR-3916 > URL: https://issues.apache.org/jira/browse/SOLR-3916 > Project: Solr > Issue Type: Bug > Affects Versions: 4.0-BETA > Reporter: Hoss Man > Assignee: Hoss Man > Fix For: 4.0 > > Attachments: SOLR-3916.patch > > > As reported by giovanni.bricconi on the user list, there is a bug in "fl" parsing that causes solr to get confused when a field name is followed by a newline character -- eg: in a requestHandler default like... > {noformat} > <!-- newlines showing using "$" -->$ > <str name="fl">$ > sku,store_slug$ > </str>$ > {noformat} > ...this results in solr assuming it should use function parsing to evaluate the field name, which can cause missleading errors if the field name can't be used in a function (eg: "can not use FieldCache on multivalued field: store_slug") -- This message is automatically generated by JIRA. If you think it was sent incorrectly, please contact your JIRA administrators For more information on JIRA, see: http://www.atlassian.com/software/jira --------------------------------------------------------------------- To unsubscribe, e-mail: firstname.lastname@example.com For additional commands, e-mail: firstname.lastname@example.com
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Search By Vehicle
K&N Engine Cold Air Intake Performance Kit 69-7800TB (NOT LEGAL FOR SALE OR USE IN CALIFORNIA) TYPHOON (EU); RENAULT CLIO RS172, 2.0L, 16V, L4, 1
Performance Intake Kit
K&N's easy-to-install Typhoon air intake system replaces the restrictive factory air filter and air intake housing delivering a guaranteed power gain. The low-restriction aluminum intake tube comes in a blue powder coat finish.
The K&N 69-7800TB Typhoon air intake system is a free-flowing, mandrel-bent aluminum tube air induction system designed to fit some Renault Clio II models. The restrictive factory air filter and air intake housing are replaced by the K&N Typhoon air intake which is designed to dramatically reduce air flow restriction as it smoothes and straightens air flow. This allows your engine to inhale a larger amount of air than the factory air intake. More air means more usable power and acceleration throughout the engine's RPM range. The 69-7800TB air intake comes with a black rubber topped K&N high-flow air filter that installs into the previous air box space. Air is directed through the intake tube into the engine's throttle body for a guaranteed power gain. The intake tube has an attractive blue powder-coat finish that's made to last and it accommodates a replacement silicone vent hose. The oversized cone shaped air filter comes with a water repellent DryCharger filter wrap to protect the filter from moisture. The air filter can be used for up to 100,000 miles before servicing is needed depending on driving conditions. This air intake is relatively easy to install usually in 90 minutes or less using existing factory mounting points requiring commonly available tools to do the job. Some Typhoon air intakes are not legal for sale or use in California and other states adopting California emission standards while others are CARB exempt and 50 state legal. Check the K&N catalog or website for vehicle applications and specific CARB status for each vehicle and air intake.
Extended Information
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- 8421310000
- 2 Available to Order
- 24844105943
- Ships from Manufacturer Typically in 1-3 Business Days, Depending on Availability!
- New
Shipping Information
- Item Requires Shipping
- 5.2 lbs.
- W14.5000" x H8.5000" x L18.2500"
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Thesaurus: synonyms and related words
Definition of "salable" - English Dictionary
(Definition of "salable" from the Cambridge Advanced Learner's Dictionary & Thesaurus © Cambridge University Press)
(Definition of "salable" from the Cambridge Business English Dictionary © Cambridge University Press)
Translations of "salable"
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Create and share your own word lists and quizzes for free!
More meanings of "salable"
Word of the Day
can't hear yourself think
If you cannot hear yourself think, you cannot give your attention to anything because there is so much noise.


text:
Great trip...fantastic view. A bit more communication from the guides regarding when to get on and generally where to go etc would have been helpful but otherwise a great trip
Claire from , United Kingdom
From £34.94 per personBook now
Pick-up serviceYou will be picked up at your hotel in the south-west of the island, in the area between Los Cristianos and Gigantes, or at a maximum walking distance of 10 minutes.
Mount Teide cable car station (Open in Google Maps)
From £34.94 per personBook now
Product ID: 51783


text:
Chocolate, pistachio & nougat semi-freddo
Nutrition and extra info
- Freezable
Nutrition: per serving
- kcal490
- fat37g
- saturates20g
- carbs34g
- sugars34g
- fibre1g
- protein6g
- salt0.1g
Butter and line a 900g/2lb loaf tin with cling film. Bring a pan of water to a gentle simmer. Put the sugar and eggs in a heatproof bowl, then place over the simmering water and whisk until pale, thick and doubled in volume. Remove from the heat, plunge the bottom of the bowl into cold water and continue whisking until the mixture is cool.
Melt the chocolate in the microwave on Low, stir, then fold into the egg mixture. Whip the cream to soft peaks and fold into the chocolate egg mixture with the nougat and pistachios.
Pour the mixture into the loaf tin, smooth the surface with a spoon, then cover and freeze until firm. This can be done up to 2 weeks ahead. To serve, turn out onto a serving dish, remove the cling film and leave in the fridge for 15 mins to soften slightly before slicing.
Recipe Tip
TorroneTorrone is a traditional Italian hard nougat and is available in most good delis. This recipe calls for a hard nougat - rubbery pink and white bars won't work here!


text:
Friday, September 28, 2012
The 5th Annual Engineer's Ball, on Saturday, the 29th of September!
Afraid I've been quite under the weather this week (as the lack of posts would indicate), but before I take some particularly strong medications, I did want to remind those in the virtual worlds that tomorrow, the 29th of September, is the 5th Annual Engineer's Ball, which will begin at 6pm SLT. Do make a point of returning to the highlight of the Steamland's most popular social events! For more details, do visit the New Babbage homepage, located at: http://cityofnewbabbage.com/reader/node/5950
Posted by RF at 20:50
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The Station Access Collection
| |
Release Date: March 15, 2006
Sony Offers MMO Collection
February 14, 2006 - Sony Online Entertainment today announced the Station Access Collection, an anthology of the company's most popular massively-multiplayer online titles, including EverQuest II and Star Wars Galaxies.
Games You May Like
- Compilation
The Mass Effect Trilogy follows the rise of Commander Shepard from Alliance Marine to becoming the galaxy's most elite soldier -- the only…
Battle Chess Collection is a compilation of Interplay's battle/strategy game series, packaged in one box.
Once again players assume the role of Gordon Freeman, a scientist destined to save the Earth from hordes of gruesome alien attackers.
Trouble taps on your window again with this next chapter in the Grand Theft Auto universe, set in the city of Los Santos.
Taking the fundamental concepts of open-world freedom, ambient activity and mission-based gameplay of the Grand Theft Auto series and making…
The Witcher 3: Wild Hunt -- Blood and Wine is the second major story/land expansion for the massive RPG adventure The Witcher 3.


text:
Parts and Tools
Car & Truck Parts
Motorcycle Parts
Tools & Supplies
Cars & Trucks
Classics & Exotics
eBay Frontline Vehicles
By Julia JohnsonFeb 181
According to the Bureau of Labor Statistics, women make up only 2 percent of the automotive...
The 455 cubic-inch V8 under the hood fills the engine bay with American muscle.
See Listing
Seller is offering his grandfather's 1936 Ford Three-Window rumble seat with a flathead V8. Barely driven since the 1970s.
See Listing
Of all the vehicles Toyota built in the past 60 years, the FJ40 is perhaps the most iconic. Here's a very drivable example.
See Listing
This 1963 Studebaker R1 Avanti is in excellent restored condition, showing 68,000 actual miles and sporting a striking turquoise exterior.
See Listing
The Metz automobile was made from 1909 until 1921 in Waltham Mass. This one still has its friction-drive transmission.
See Listing
The seller wanted a car that remained exactly as it was when it left the Pininfarina factory and headed to America. This is it.
See Listing
This hot rod '62 Ford Falcon sports a 345-horsepower Ford performance crate motor from Summit Racing.
See Listing
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I will voice your advertisement in an American female voice over
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Tropical Fish Keeping - Aquarium fish care and resources (http://www.tropicalfishkeeping.com/forum.php)
- Beginner Planted Aquarium (http://www.tropicalfishkeeping.com/beginner-planted-aquarium/)
- - got my new light ordered! (http://www.tropicalfishkeeping.com/beginner-planted-aquarium/got-my-new-light-ordered-129699/)
got my new light ordered!
this is going to be what i start with and will have plenty of room for expansion down the road. raver reviews on its instalation dependablity and ease of use. even has a built in timer! it didnt come with liughts but i ordered x2 of the life glo tubes. should be a week or 2 untill i get them, but once i get them im going to go out and grab some plants. any reccomendations? i know most stem plants grow fast and easy but any others that will go nicely with these lights?
Nice light. The reflector is far superior than what you can get in a typical hood setup.
I expect that almost anything will grow well under those so just pick what you like the look of.
wow thats awesome. i did research on all kinds of t5's in this price range. this is by far the best fixture due to the reflector material. if you were to buyh just the reflector its like more then half the cost of the whole thing. once i get it and get some plants ill put up some pics
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Smegma (Greek smēgma, "soap"[1]) is a combination of shed skin cells, skin oils, and moisture. It occurs in both male and female mammalian genitalia. In females, it collects around the clitoris and in the folds of the labia minora; in males, smegma can collect under the foreskin.
The accumulation of sebum combined with dead skin cells forms smegma. Smegma clitoridis is defined as the secretion of the apocrine glands of the clitoris, in combination with desquamating epithelial cells.[2] Glands that are located around the clitoris and the vulva majoris secrete sebum.
In males, smegma helps keep the glans moist and facilitates sexual intercourse by acting as a lubricant.[3] [4] [5]
Smegma was originally thought to be produced by sebaceous glands near the frenulum called Tyson's glands; however, subsequent studies have failed to find these glands.[6] Wright states that smegma is produced from minute microscopic protrusions of the mucosal surface of the foreskin and that living cells constantly grow towards the surface, undergo fatty degeneration, separate off, and form smegma.[3] Parkash et al. found that smegma contains 26.6% fats and 13.3% proteins, which they judged to be consistent with necrotic epithelial debris.[6] Newly produced smegma has a smooth, moist texture. It is thought to be rich in squalene[7] and contain prostatic and seminal secretions, desquamated epithelial cells, and the mucin content of the urethral glands of Littré.[5] Smegma contains Cathepsin B, lysozymes, chymotrypsin, neutrophil elastase, and cytokines, which aid the immune system.[8]
According to Wright, little smegma is produced during childhood, although the foreskin may contain sebaceous glands. She also says that production of smegma increases from adolescence until sexual maturity when the function of smegma for lubrication assumes its full value, and from middle-age production starts to decline and in old age virtually no smegma is produced.[3] Øster reported that the incidence of smegma increased from 1% among 6- to 7-year-olds and 8- to 9-year-olds to 8% among 14- to 15-year-olds and 16- to 17-year-olds (an overall incidence of 5%).[9]
There is no evidence that smegma causes penile cancer,[4] but its presence over a long period of time may irritate and inflame the penis,[3] which may increase the risk of cancer. It may also make it harder to see very early cancers.[10]
Other mammals[edit]
In healthy animals, smegma helps clean and lubricate the genitals. In veterinary medicine, analysis of this smegma is sometimes used for detection of urogenital tract pathogens, such as Tritrichomonas foetus.[11] Accumulation of smegma in the equine preputial folds and the urethral fossa and urethral diverticulum can form large "beans" and promote the carriage of Taylorella equigenitalis, the causative agent of contagious equine metritis.[12] Some equine veterinarians have recommended periodic cleaning of male genitals to improve the health of the animal.[13]
See also[edit]
- List of cutaneous conditions
- Mycobacterium smegmatis - found in smegma
- ^ "Websters dictionary definition for smegma". Mirriam-Webster. Retrieved 2008-08-26.
- ^ "Medical Dictionary". Medilexicon.
- ^ a b c d Wright, Joyce (September 1970). "How smegma serves the penis: Nature's assurance that the uncircumcised glans penis will function smoothly is provided by smegma.". Sexology (New York). 37 (2): 50–53.
- ^ a b Van Howe, RS; FM Hodges (October 2006). "The carcinogenicity of smegma: debunking a myth". J Eur Acad Dermatol Venereol. 20 (9): 1046–1054. doi:10.1111/j.1468-3083.2006.01653.x. PMID 16987256.
- ^ a b Fleiss, P.M.; F.M. Hodges; R.S. Van Howe (October 1998). "Immunological functions of the human prepuce". Sexually transmitted infections. 74 (5): 364–367. doi:10.1136/sti.74.5.364. PMC 1758142. PMID 10195034.
- ^ a b Parkash, Satya; K. Jeyakumar; K. Subramanya; S. Chaudhuri (August 1973). "Human subpreputial collection: its nature and formation". The Journal of Urology. 110 (2): 211–212. PMID 4722614.
- ^ O'Neill, H.J.; L.L. Gershbein (1976). "Lipids of human and equine smegma". Oncology. 33 (4): 161–166. doi:10.1159/000225134. PMID 1018879.
- ^ Chukwuemeka Anyanwu, Lofty-John; Kashibu, Emmanuel; Edwin, Chinagozi Precious; Mohammad, Aminu Mohammad (2012). "Microbiology of Smegma in Boys in Kano, Nigeria". Journal of Surgical Research. 173 (1): 21–25. doi:10.1016/j.jss.2011.04.057. ISSN 0022-4804.
- ^ Øster J (April 1968). "Further fate of the foreskin. Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys". Arch. Dis. Child. 43 (228): 200–3. doi:10.1136/adc.43.228.200. PMC 2019851. PMID 5689532.
- ^ "What are the risk factors for penile cancer?". American Cancer Society. Retrieved 14 February 2014.
- ^ Chen, X.G.; J. Li (2001). "Increasing the sensitivity of PCR detection in bovine preputial smegma spiked with Tritrichomonas foetus by the addition of agar and resin". Parasitol Res. 87 (7): 556–558. doi:10.1007/s004360100401. PMID 11484853.
- ^ Primary Industries Ministerial Council of Australia and New Zealand (2002). Disease strategy: Contagious equine metritis (Version 1.0). In: Australian Veterinary Emergency Plan (AUSVETPLAN), Edition 3, PIMCANZ, Canberra, ACT.
- ^ Michael Lowder (September 1, 2001). "A Clean Sheath Is A Healthy Sheath". Horse City. Retrieved on September 4, 2008.
External links[edit]
- Media related to Smegma at Wikimedia Commons


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