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|Table of Contents
|Vol. 51, No. 3, 2014
Issue release date: August 2014
|Section title: Review
Mitochondrial Mechanisms in Cerebral Vascular Control: Shared Signaling Pathways with PreconditioningBusija D.W. · Katakam P.V.
Department of Pharmacology, Tulane University School of Medicine, New Orleans, La., USA Corresponding Author
Prof. David W. Busija
Department of Pharmacology, Tulane University School of Medicine
1430 Tulane Avenue, SL 83
New Orleans, LA 70112-2632 (USA)
E-Mail email@example.com
Mitochondrial-initiated events protect the neurovascular unit against lethal stress via a process called preconditioning, which independently promotes changes in cerebrovascular tone through shared signaling pathways. Activation of adenosine triphosphate (ATP)-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels) is a specific and dependable way to induce protection of neurons, astroglia, and cerebral vascular endothelium. Through the opening of mitoKATP channels, mitochondrial depolarization leads to activation of protein kinases and transient increases in cytosolic calcium (Ca2+) levels that activate terminal mechanisms that protect the neurovascular unit against lethal stress. The release of reactive oxygen species from mitochondria has similar protective effects. Signaling elements of the preconditioning pathways also are involved in the regulation of vascular tone. Activation of mitoKATP channels in cerebral arteries causes vasodilation, with cell-specific contributions from the endothelium, vascular smooth muscles, and nerves. Preexisting chronic conditions, such as insulin resistance and/or diabetes, prevent preconditioning and impair relaxation to mitochondrial-centered responses in cerebral arteries. Surprisingly, mitochondrial activation after anoxic or ischemic stress appears to protect cerebral vascular endothelium and promotes the restoration of blood flow; therefore, mitochondria may represent an important, but underutilized target in attenuating vascular dysfunction and brain injury in stroke patients.
© 2014 S. Karger AG, Basel
Anoxia Adenosine triphosphate-sensitive potassium channels Calcium sparks Cerebral arteries Endothelium Ischemia Neurons Nitric oxide synthase Postconditioning Vascular smooth muscle
The neurovascular unit is an integrated system of vascular and parenchymal cells and their environment working together to match blood flow to metabolic demand and to maintain brain homeostasis. Mitochondria are double membrane organelles which generate chemical energy in the form of adenosine triphosphate (ATP), which is distributed within cells and promotes the varied activities of the diverse cell types comprising the neurovascular unit [endothelium, vascular smooth muscle (VSM), astroglia, perivascular neurons, parenchymal neurons, pericytes, and microglia]. Although traditionally understood solely as energy producers and relegated to that role, we now appreciate that mitochondria are involved in diverse adaptive activities, such as promotion of basal cellular functions, cellular protection, and regulation of vascular tone. Evidence also shows that mitochondrial morphology and function show plasticity and adaptability and can be affected by many factors [1,2,3,4,5]; on the other hand, mitochondrial-centered mechanisms can promote apoptotic and necrotic cell death [6,7]. The purpose of this review is to critically examine the role of mitochondrial-based mechanisms on the tone of cerebral resistance vessels. Specifically, we will examine how the selective targeting of mitochondria in the several cell types comprising the neurovascular unit leads to changes in cerebral vascular tone. The studies on cerebral vascular control in our laboratory originated from studies of pre- and postconditioning mechanisms in the neurovascular unit when we realized that identical pathways are involved and effects may be interactive. This discussion is limited to the systemic circulation; mitochondrial mechanisms in the pulmonary circulation are different [8]. We will show that even relatively mild metabolic stress, such as that which occurs with insulin resistance (IR), a prediabetic condition that impairs preconditioning, can dramatically affect mitochondrial-related events in the cerebral vasculature. Ultimately, we will present evidence suggesting that mitochondrial activation may unexpectedly benefit the cerebral vasculature after ischemia/anoxia and thus decrease morbidity and mortality in stroke patients. Several excellent reviews which focus primarily on peripheral endothelium [9,10,11] or VSM [12] have been published recently and emphasize the importance of this emerging research area. However, this is the first review to show the similarities between the preconditioning and vascular control pathways and to explore the integration of mitochondrial-based signals arising from multiple cell types into the final vascular response in normal and disease states.
Important structural features of mitochondria are an outer, relatively permeable membrane, a relatively impermeable inner membrane, the intermembrane space, extensions of the inner membrane called cristae, and the intracristae spaces referred to as the matrix [13,14]. Each anatomical component has a specific function which, when integrated, is essential for the optimal production and transfer of energy throughout the mitochondria and into the cytosol. The Krebs cycle is located in the matrix and the complexes associated with the electron transport chain are embedded in the inner mitochondrial membrane. The mitochondrial membrane potential (Δψm) across the inner membrane, which is normally maintained at approximately -180 mV, provides the proton difference used to drive the synthesis of ATP by the electron transport chain. Several diagnostic and therapeutic approaches take advantage of this negative membrane potential to target positively charged agents specifically to the mitochondria [14,15,16,17]. Detailed descriptions of ATP production by non-mitochondrial glycolysis as well as the mitochondrial electron transport chain are widely available [18,19].
Individual mitochondria are not static entities, rather they are dynamic and can move from one location to another within cells, form networks with other mitochondria or cellular structures (fig. 1, 2), and undergo replication and fission/fusion in response to physiological and pathological stimuli [5,15,20,21,22]. Because the number and length of cristae are positively related to the ATP-generating potential, it appears that changes in the location, number, size, and shape of mitochondria under physiological conditions are determined by the energy needs within a cell [23]. Mitochondria in VSM appear to be particularly mobile during cellular migration following vascular damage [24]. In addition to individual mitochondria forming networks within cells (fig. 1, 2), the mitochondrial outer membranes are often connected or closely juxtaposed with the membranes of the endoplasmic/sarcoplasmic reticulum (SR; fig. 2), i.e. cellular structures which are involved in calcium storage and release [20]. The complex interplay among mitochondrial, endoplasmic reticulum/SR, and cytosolic calcium has been described in several recent reviews [25,26,27]. In VSM, some populations of mitochondria and SR appear to be 'bundled' together and this structural feature may restrict movement of certain populations of mitochondria under normal conditions in this vascular cell type (fig. 2) as well as promote the tight functional interactions between mitochondria and SR. However, we are unaware of any systematic studies comparing the mitochondrial morphology and function in the various cell types within the neurovascular unit.
Mitochondria have their own DNA, which is distinct from nuclear DNA, and also possess a protein-synthesizing machinery which produces approximately one half of their proteins while the other half are encoded by nuclear DNA and imported into mitochondria via several different transport mechanisms. The cytochrome c oxidase complex (complex IV), which is the last major component of the electron transport chain and is localized to the inner membrane, is a good example of the dual origins of the proteins present in mitochondria since ten subunits are nuclear in origin and three are synthesized within the mitochondria [28,29].
Although it has been suggested that mitochondria contain a variant of nitric oxide synthase (NOS), and thus could produce NO via this enzymatic pathway, there is significant evidence against this view [30,31,32]. Nonetheless, diffusible NO from non-mitochondrial sources in endothelial cells and neurons [32,33], or NO arising from mitochondria via non-NOS pathways [34], could affect the functioning of the electron transport chain as well as other mitochondrial functions and could combine with superoxide anion to form peroxynitrite [11,35]. On the other hand, we have shown that NO production from cytosolic NOS occurs due to endothelial NOS phosphorylation and increased cytosolic calcium following activation of mitochondria with diazoxide or BMS-191095 [32].
Mitochondria are constant producers of reactive oxygen species (ROS) which have access to locations throughout the cell as well as to adjacent cells. Although generally thought to be an efficient system, a substantial amount of superoxide anion is continuously 'lost' or released by the electron transport chain at different sites under normal conditions [11,18]. For example, there is continuous release of superoxide anion in quiescent neurons, astroglia, VSM, and cerebral vascular endothelium [3,36,37,38]. Mitochondrial ROS can promote preconditioning as well as directly or indirectly affect cerebral vascular tone, as well as influence other cellular functions.
Superoxide anion from mitochondrial and other cellular locations appears to be an important, if not essential, signaling agent involved in the maintenance of basal cell functions such that prolonged suppression of ROS availability is detrimental to cell viability [39]. Superoxide anion acting at sites within the mitochondria or following transport across the inner mitochondrial membrane can influence events throughout the cell. It has been suggested that superoxide anion can leave the mitochondria via voltage-dependent anion channels [40,41]. However, these channels are located in the outer, more porous mitochondrial membrane and it is not clear how superoxide anion would transverse the inner mitochondrial membrane. Alternatively, superoxide anion formed at complex III may be released into either the matrix or the intermembrane space during certain conditions and then may be transported across the outer mitochondrial membrane by voltage-dependent anion channels [27,42]. Superoxide anion can also leave the matrix [43] following enzymatic conversion to hydrogen peroxide through aquaporin-like channels in the inner mitochondrial membrane [44,45,46]. Hydrogen peroxide is considered to be less reactive and has a longer half-life than superoxide anion [47] and can be produced directly by mitochondria under certain conditions [47,48]. A number of factors, such as substrate availability, status of the electron transport chain complexes, and the composition of the local environment, are able to affect mitochondrial production of ROS [47]. In addition, physical distortion of the relationship between the two mitochondrial membranes caused by increased shear stress in the endothelium leads to enhanced ROS release by mitochondria [11]. It has generally been accepted that mitochondrial depolarization is always accompanied by enhanced ROS release. However, as described in detail below, mitochondrial depolarization and enhanced ROS production are not necessarily linked and can occur separately under a variety of conditions.
The primary sites of superoxide anion production and release are complex I (NADH-ubiquinone oxidoreductase), complex II (succinate dehydrogenase, SDH), and complex III (ubiquinol-cyctochrome c oxidoreductase). Complexes I and II accept electrons from NADH + H+ and FADH2, respectively, which are transferred to complex III and finally to complex IV (cytochrome c oxidase), where the final electron acceptor is oxygen and the final product is water [48,49]. Superoxide anion from these three complexes is released into the matrix. A number of metabolic poisons are available, which inhibit one or more of the respiratory chain complexes: rotenone: complex I; 3-nitropropionic acid (3-NPA): complex II; antimycin A: complex III; cyanide: complex IV; and oligomycin: complex V. The result of inhibition, especially of complexes I-III, is enhanced ROS release.
Although 'normal' continuous release of ROS from mitochondria appears to play a positive role in the maintenance of basal cellular function, transiently elevated ROS levels can promote selective protein synthesis, preconditioning, and changes in vascular tone. However, chronically but modestly elevated ROS production by mitochondria can lead to cellular dysfunction. For example, we have shown that a mutation in the inner mitochondrial membrane peptidase 2-like (Immp2l) gene leads to chronically enhanced ROS release by mitochondria and subsequently causes reduced vascular dilation to carbachol in mesenteric arteries [50]. Similarly, chronically elevated mitochondrial ROS production due to the metabolic syndrome impairs cerebral vascular function through multiple mechanisms [51,52]. It also has been reported that a genetic deficiency in MnSOD in mice increases basal superoxide levels in cerebral arteries and aorta [53]. Additionally, chronic inhibition of complex I by rotenone blocks ischemia-induced collateral artery growth in the coronary circulation via activation of adenosine monophosphate (AMP)-activated kinase and the subsequent inhibition of mTOR and p70 ribosomal S6 kinase [54]. Higher levels of cellular ROS, which occur during injury, can lead to cell death via both mitochondrial and non-mitochondrial pathways, especially in metabolically compromised conditions [7,55].
Production of ROS by mitochondria appears to be an organelle-independent process under most basal conditions, but recent reports indicate that ROS production by mitochondria can either promote ROS production by the extramitochondrial NADPH oxidase system or, vice versa, via a positive feedback system [27,56,57]. Thus, the interaction between the mitochondria and the cytosolic NADPH oxidase axis leads to cellular damage due to excessive production of ROS. The best example of this interaction occurs with the exposure of vascular and nonvascular cells to angiotensin II [56,58]. Deficiency in MnSOD leads to cerebral vascular endothelial dysfunction, especially in aged mice, to angiotensin II [59,60].
The most reproducible and robust approach to depolarizing mitochondria experimentally can be achieved by targeting the mitochondrial ATP-sensitive potassium (mitoKATP) channel on the inner mitochondrial membrane with drugs such as BMS-191095 or diazoxide. The physical structure of mitoKATP channels is not yet known with certainty but appears to differ substantially from the previously described plasmalemmal KATP channels [61,62,63,64,65]. Nonetheless, the pharmacological identification and selectivity to agonists of the mitoKATP channels are convincing to the majority of investigators. Recent evidence indicates that the renal outer medullary potassium channel (ROMK) is a component of the K+ channel of the cardiac mitoKATP[62.] The same researchers also showed that overexpression and suppression of ROMK promoted or reduced preconditioning, respectively. SDH might also be involved in either the assembly or function of the mitoKATP channel [66,67]. Nonetheless, additional studies are needed to define completely the structure of the mitoKATP channels.
Isolated mitochondria and mitochondria in situ in cultured cells, tissue slices, and in isolated pressurized cerebral arteries depolarize in a dose-dependent manner to selective mitoKATP channel openers such as diazoxide and BMS-191095 [36,38], and mitoKATP channel activity is affected by endogenous factors such as the adenosine diphosphate (ADP)/ATP ratio [61], peroxynitrite [64,65], superoxide anion [7,65], and cytosolic protein kinase C (PKC) ε [68,69]. Nonetheless, we expect that other, yet unidentified, physiological and pathological factors will be able to directly or indirectly activate mitochondria, including the mitoKATP channel. The classical KATP channel antagonists glibenclamide and 5-hydroxydecanoic acid, which needs to be metabolized before becoming active [70], block the actions of diazoxide, BMS-191095, and/or PKCε [36,68,71]. Diazoxide, a drug previously used against acute hypertension or hypoglycemia, is the most commonly used mitoKATP channel opener [72], but it has the additional effect of inhibiting SDH (complex II), especially at high doses [73,74]. Diazoxide also readily crosses the blood-brain barrier (BBB) and thus is effective in the brain when given intravenously [75]. Although applications of diazoxide or BMS-191095 depolarize mitochondria, diazoxide, but not BMS-191095, also causes the liberation of ROS [76], an event secondary to SDH inhibition according to our findings. This view is supported by examination of the effects of the specific inhibitor of SDH, 3-NPA, which increases ROS production by mitochondria [71] and also induces preconditioning [77] and changes in vascular tone [52]. Nonetheless, the primary actions of diazoxide on the cells of the neurovascular unit are still specific to mitochondria [74,76], and the associated ROS increase appears to enhance the degree of depolarization [64,65]. In contrast, BMS-191095 is very selective for mitoKATP channels and has no known nonspecific effects to complicate the interpretation of the results [76,78,79].
A potential role for mitochondrial calcium-activated potassium (mitoKCa) channels in depolarizing mitochondria has been suggested based primarily on the use of the multiple target drug NS1619 [80]. Although NS1619 results in mitochondrial depolarization, it seems likely that, at least in neurons, effects are due to other factors, such as inhibition of complex I and subsequent increased release of ROS [81,82]. Given the multiple potential sites of action of NS1619 within various cell types, it is also possible that mitochondrial effects of this drug are secondary to non-mitochondrial events. Nonetheless, more research in this area is warranted and the development of more specific agonists would aid these efforts.
The use of BMS-191095 has led to findings which challenge accepted views concerning the linkage between mitochondrial depolarization and enhanced mitochondrial ROS release. The selectivity of BMS-191095 for mitoKATP channels and the failure to detect nonspecific effects [76,78,79], which complicate the interpretation of results, have shown that it is possible to depolarize mitochondria without eliciting the enhanced release of ROS in a variety of cells, including neurons, cerebral vascular endothelium, and cerebral VSM. The previous concept linking mitochondrial membrane potential and ROS release was developed using inhibitors of the electron transport chain which, in addition to increasing ROS release from complexes I-III, probably depolarized mitochondria via reduced ATP availability necessary for maintaining the negative transmembrane potential. The recent findings with BMS-191095, which allow dissociation between mitochondrial depolarization and mitochondrial ROS production, are supported by other laboratories [40,83] as well as other experimental approaches in our laboratory [84]. The dissociation between mitochondrial membrane potential and ROS release is not absolute, however, but probably occurs within a limited range of depolarization. The relative independence of the mitochondrial membrane potential from ROS production and release, with the subsequent induction of different signaling pathways, underscores the versatility of mitochondria to initiate appropriate and selective cellular responses to varied stimuli.
Preconditioning represents the condition in which transient exposure of cells to an initiating event leads to protection against subsequent, potentially lethal stimuli (fig. 3) by limiting ROS availability, suppressing large increases in cytosolic levels of free calcium, and/or by other mechanisms which promote cell survivability (fig. 4). The acute signaling mechanisms promoting preconditioning also affect cerebral vascular tone (fig. 5), and the chronic changes in vascular cells following preconditioning, involving altered cellular calcium and ROS dynamics, probably affect subsequent cerebral artery responses to changing conditions. However, this possibility has not been tested.
Beginning with our original observation [85], a number of independent studies by other laboratories have established that mitochondrial-centered mechanisms are important initiators of the pre- and postconditioning response in neurons, astroglia, and cerebral endothelial cells [1,49,72,75,76,85,86,87,88,89,90,91,92,93,94]. Mitochondrial-centered preconditioning also occurs in tissues such as the myocardium [51], skeletal muscle [79], and peripheral endothelium [90,95]. Important mitochondrial-specific targets for inducing preconditioning by pharmacological approaches include: (1) potassium channels located on the inner mitochondrial membrane; (2) respiratory chain enzymes, and (3) metabolic substrate restriction.
Although the mitochondrial-initiated mechanisms involved in preconditioning are not fully understood, the activation of protein kinases, transient but modest calcium fluxes, and/or ROS production appear to be essential signaling events leading to preconditioning (fig. 4). There are two general types of preconditioning: immediate and delayed. Immediate preconditioning occurs within minutes of the initiating stimulus and lasts for several hours before disappearing, whereas delayed preconditioning takes several hours to develop and persists for several days [96,97]. Given these temporal aspects, it seems probable that immediate preconditioning primarily involves changes in the activity or function of enzymes, second messengers, and ion channels already present, whereas delayed preconditioning is principally due to de novo protein synthesis, such as increased catalase levels [76]. Many subsequent signaling events not only induce preconditioning but also promote changes in vascular tone. Postconditioning, in which the initiating event occurs following the onset of the potentially lethal event [93,98], has also been reported, and its mechanisms, especially those involving mitochondria and the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, appear to be similar to those that promote preconditioning. In cultures of primary rat brain microvascular endothelium, we found that postconditioning was as effective as preconditioning against oxygen-glucose deprivation (OGD; fig. 3), and that activation of the PI3K/Akt signaling pathway was essential in both types of cellular protection (fig. 3, 4). The ability of mitochondria from cerebral vascular endothelium to function at the end of OGD, where almost 50% of cells would eventually die without treatment, indicates that mitochondria remain a potentially useful target in stroke patients.
Although some authors have presented a case for a role of mitoKCa channels in promoting preconditioning based primarily on the use of NS1619 [99,100], experimental evidence is not convincing due to the lack of a specific mitoKCa channel opener and the numerous nonspecific effects of NS1619. We were the first to show that NS1619 is both neuroprotective [101] and vasoactive in cerebral arteries [102], and that preconditioning of neurons by this agent was likely due to inhibition of complex I or other mechanisms rather than a mitoKCa channel-specific effect [81,82,103,104]. Administration of NS1619 dilates other peripheral arteries [105].
Removal or reductions in key metabolic substrates, such as glucose and oxygen, can induce preconditioning and changes in cerebral vascular tone. For example, transient withdrawal of glucose, the major energy substrate for neurons, as well as removal of amino acids, results in mitochondrial depolarization and reduced ATP production, and in delayed tolerance against various insults, such as OGD, glutamate excitotoxicity, and exogenous hydrogen peroxide toxicity [106]. Adenosine, AMP, ADP, and ATP are vasoactive stimuli in cerebral arteries [107,108].
Our studies of preconditioning indicated that many of the signaling events associated with the induction of mitochondrial-targeted cellular protection also affect cerebrovascular tone (fig. 4, 5). Although it is known that ATP, from either glycolysis or oxidative phosphorylation, as well as the metabolites adenosine, AMP, and ADP [92,109] can alter cerebrovascular tone via plasmalemmal purinergic receptors [110], only a few studies have examined direct mitochondrial influences on the diameter of cerebral resistance vessels [2,32,52,111,112]. Thus, the study of mitochondrial effects on the cerebral vasculature is a relatively unexplored field. Only a few studies have examined mitochondrial influences on the cerebral vasculature during disease states, but increasing amounts of information are rapidly becoming available in other systemic circulations [10,11,78] and VSM [12]. Although the majority of studies involving mitochondrial influences on the cerebral vasculature have used pharmacological agents, a few studies have used genetically altered mice in which a deficiency in MnSOD has resulted in increased basal levels of superoxide anion and endothelial dysfunction in cerebral arteries, especially with exposure to angiotensin II and aging in male rats [59].
Cheranov and Jaggar [113] and Xi et al. [111] were the first to show that activation of mitochondria by diazoxide promoted relaxation of VSM cells in endothelium-denuded cerebral arteries or freshly dissociated VSM via a mechanism primarily involving ROS. Thus, diazoxide application enhanced the generation of ROS from mitochondria, which sequentially caused the activation of ryanodine-sensitive Ca2+ channels on the SR, the generation of Ca2+ transients called 'Ca2+ sparks', and the opening of adjacent large-conductance Ca2+-activated K+ (BKCa) channels on the plasma membrane. The resulting K+ efflux led to VSM hyperpolarization, decreased global intracellular Ca2+, and vasodilation. We have reported similar findings in endothelium-denuded arteries with diazoxide [3,32,52]. The role of mitochondrial ROS resulting from inhibition of SDH in promoting VSM relaxation in cerebral arteries is also shown by application of 3-NPA [52]. However, BMS-191095 has a similar effect in VSM without the involvement of ROS [3,32] (fig. 5). Thus, BMS-191095 does not increase vascular cytosolic or mitochondrial levels of ROS in any of the cell types that we have examined, and dilation to BMS-191095 is not affected by ROS scavengers; nonetheless, calcium spark activity increases with BMS-191095 application. The reasons for these differences in findings are unclear but taken together underscore the importance and robustness of mitochondrial mechanisms in promoting relaxation of VSM. We speculate that there is direct electrophysiological coupling between mitochondria and SR in VSM and/or that microdomains involving the outer mitochondrial and SR membranes link functional interactions between these two organelles. The close physical association and thus the possibility of direct coupling of mitochondria and SR are clearly seen with electron microscopy in cerebral VSM (fig. 2).
Mitochondrial content in the cerebrovascular endothelium is higher than in the endothelium of other peripheral circulations, probably due to the transport requirements of the BBB [114]. We investigated the contribution of mitochondrial factors arising within the endothelium on the integrated response of intact cerebral arteries using several approaches. First, removal of the endothelium altered the vasodilation to diazoxide and BMS-191095, implying that traditional endothelium-derived factors such as NO and prostaglandins contribute to changes in vascular tone [32,52]. However, the endothelial effects are complex. In intact blood vessels, inhibition of NOS with L-NAME administration reduced relaxation to diazoxide indicating a dilator role of NO. In contrast, inhibition of cyclooxygenase with indomethacin enhanced dilation in diazoxide-treated arteries, implying a role for constrictor prostanoids. Indomethacin did not affect vasodilation in endothelium-denuded arteries. Similar results were obtained with BMS-191095 with respect to L-NAME administration [32]. However, unlike diazoxide, indomethacin administration did not enhance dilation to BMS-191095, suggesting that an ROS-mediated mechanism leading to cyclooxygenase activation may account for these differences. Fluorescence and electron spin resonance measurements of NO in intact arteries or cultured cerebral microvascular endothelial cells confirmed the production of NO in response to diazoxide and BMS-191095. In addition, fluorescence measurements showed that a global increase in free cytosolic calcium rather than calcium sparks was temporally associated with increased NO production. We have demonstrated that NO arises from cytosolic rather than mitochondrial sites during normal conditions [30,31,32]. Thus, BMS-191095 and diazoxide application led to mitochondrial depolarization, activation of eNOS by calcium- and phosphorylation-specific mechanisms, production of NO, and relaxation of VSM (fig. 5). Zhang and Gutterman [48] showed that a physiological stimulus such as increased shear stress is able to directly activate mitochondria in coronary endothelial cells via filamentous connections and dilate coronary arteries via effects of hydrogen peroxide. Whether this endothelium-specific mechanism operates in response to increases in flow or shear stress in cerebral arteries is unclear, since alternative mechanisms promoting either dilation or constriction in cerebral resistance vessels of different sizes and locations have been proposed by Koller and Toth [115]. Mitochondrial depolarization by the protonophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone in endothelial tubes from mesenteric arteries has also been shown to activate calcium-activated K+ channels presumably by elevation of endothelial Ca2+[116]. Even though precise mechanisms may be different in cerebral and coronary arteries, the common feature is that stimulation of mitochondria is able to liberate substances by the endothelium which can affect VSM tone.
Mitochondrial numbers and composition in the cerebral vascular endothelium are affected by factors such as ischemic stress [unpubl. observations] and hormones such as estrogen [112,117]. Administration of 17β-estradiol profoundly affects mitochondrial function in cerebral blood vessels via estrogen receptor α, thereby enhancing efficiency of energy production and suppressing mitochondrial oxidative stress. These results indicate that ovarian hormones normally act through a distinctive regulatory pathway involving peroxisome proliferator-activated receptor γ coactivator 1 to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS protection. An interesting observation is that female mice with MnSOD deficiency are largely protected from cerebrovascular dysfunction compared with male mice [59]. The basis for this gender difference is unclear at this time but may reflect yet unknown compensatory mechanisms in the vascular mitochondria of female mice.
The potential for mitochondrial influences from perivascular nerves or parenchymal neurons on cerebral vascular responses has never been specifically investigated. However, there are a number of factors suggesting an important neuronal contribution from both sources. Mitochondrial density is relatively high in perivascular nerves observed under confocal imaging [unpubl. observations] and as seen in our preconditioning studies, mitochondria in neurons are responsive to both diazoxide and BMS-191095 [36]. Cerebral arteries receive innervation from sympathetic, parasympathetic, and nitroxidergic nerves [118,119,120]. These speculations are supported by our preliminary studies. Specific inhibition of neuronal NOS with 7-nitroindazole in perivascular nerves, or blockade of perivascular nerves with tetrodotoxin, inhibits dilation in both intact and denuded cerebral arteries to BMS-191095 [121]. The effects of tetrodotoxin may be due to interactions between different types of perivascular nerves or between astroglia and perivascular nerves. Electrical activation of perivascular nerves, which might mimic superfusion with diazoxide and BMS-191095, elicits dilation of cerebral arteries, which is blocked by tetrodotoxin [122]. Additionally, BMS-191095 depolarizes mitochondria in cultured cortical neurons and enhances NO production by these cells. Thus, in addition to the endothelium, perivascular nerves, parenchymal neurons, and possibly astroglia as well [37,123] can provide mitochondrially initiated vasoactive signals to VSM [74,124,125] for the final determination of integrated changes in cerebrovascular diameter (fig. 6).
IR often precedes the development of type II diabetes by years or decades, and is considered a relatively silent phase of the metabolic syndrome despite developing vascular dysfunction and moderate arterial hypertension. We and others have characterized many of the general cardiovascular and brain effects of this disease [3,51,52,126,127,128] due to tissue and vascular inflammation and increased basal levels of ROS from both mitochondrial and non-mitochondrial sources [127,128].
We were among the first investigators to demonstrate that several pathological stressors are able to disrupt normal functioning of plasmalemmal KATP channels in cerebral arteries [126,127,128,129] and, therefore, it is not surprising that mitoKATP channels would be affected in a similar manner. For example, ischemia/reperfusion as well as nutritional and genetic models of IR reduced the function of several types of potassium channels in cerebral VSM, including KATP channels, through mechanisms involving enhanced baseline vascular levels of ROS [126,127,128]. However, effects of ischemia on KATP channels are transient, so that normal responses return by 4 h of reperfusion. Thus, ROS scavengers [127], PKC inhibition [126], or anti-inflammation therapies such as statin administration [128] are able to restore normal dilation to potassium channel activators despite continued IR. Even though enhanced ROS from mitochondria is associated with IR, reduced ROS production from NADPH oxidase results in restored KATP channel function in cerebral arteries. We speculate that ROS-induced ROS production, involving the mitochondrial electron transport chain and NADPH oxidase, might be necessary for the full dysfunction of KATP channels in IR. Similarly, a more severe, acute event, namely ischemia/reperfusion, is able to reduce KATP channel-dependent dilation in cerebral arteries [129]. Additionally, we have shown that immediate preconditioning which is dependent upon activation of mitoKATP channels is abolished in hearts of IR rats [51]. Thus, ischemic- as well as diazoxide-induced preconditioning fails to protect hearts from ischemia/reperfusion in IR rats whereas both of these approaches limited infarct size in hearts from non-IR rats. In these IR animals, prior to ischemia/reperfusion, a substantial number of the mitochondria in the heart were swollen or showed disruption of the normal pattern for cristae. Moreover, the isolated mitochondria from the hearts of IR animals had reduced responses to diazoxide. An additional finding from this study was that infarct size was enhanced in the hearts from Zucker obese compared with lean rats, which is similar to that which we [130] and others [53] have found in brains of IR, obese mice following middle cerebral artery occlusion. These results may indicate that normal protective mechanisms initiated at the level of the mitochondria are impaired in many common disease states, and thus the brain and other organs are more at risk during ischemic episodes.
Similar to preconditioning, mitochondrial-dependent responses in cerebral arteries are impaired in IR rats [52]. This attenuation of dilation appears to be due to reduced mitochondrial depolarization of VSM as well as reduced ROS generation in response to diazoxide. In addition, decreased NO production/bioavailability, despite increased endothelial NOS expression in IR arteries, appears to contribute to diminished relaxation of VSM. We have found similar impairment in cerebrovascular dilation to BMS-191095 in IR animals [32]. An unexpected result was that, in contrast to mitochondrial activation with diazoxide or BMS-191095, dilator responses to 3-NPA were modestly enhanced in arteries from IR rats [52]. Additionally, co-application of 3-NPA with diazoxide led to more than just an additive dilator effect, which was not attenuated in arteries from IR animals. The reason for this effect is unclear, but it seems to indicate that IR interferes with some, but not all vasoactive influences from mitochondria. The potential for the uncoupling of the tight relationship between metabolic need and blood flow in the brain due to cerebrovascular dysfunction associated with IR, as well as the elimination of normal, protective mechanisms involving mitochondria, such as preconditioning, may account for the increased risk and severity of neurological diseases and strokes in patients suffering from the metabolic syndrome. Similar to our findings with IR, anti-ROS treatment restores morphological structure in coronary endothelial cells in a mouse model of type 1 diabetes [131]. In addition, Kizhakekuttu et al. [125] provided evidence that mitochondrial derangements lead to reduced endothelium-induced dilation in human arteries. A possible therapeutic approach might involve the early detection and treatment of IR individuals with the aim toward reducing vascular inflammation and mitochondrial dysfunction prior to the further progression of this chronic disease. We have shown that even very short-term treatment with a statin, which reduced vascular ROS levels and restored normal KATP channel function without lowering blood cholesterol levels, was effective in IR rats [128].
Although mitochondrial failure is a major cause of cell death due to ischemia, our recent findings indicate that mitochondria in the endothelium may represent a useful target to prevent cell death and restore cerebral blood flow after stroke. Preconditioning before ischemia preserves endothelium-dependent dilation [132] and reduces permeability of the BBB in vivo [75], and postconditioning protects the endothelium in vitro against prior OGD (fig. 3). In recent preliminary studies, we examined the effects of experimental stroke on middle cerebral artery responses 2 days following reperfusion, and found that dilation was greater on the side ipsilateral to the middle cerebral artery occlusion compared with the contralateral, non-stroke side in both Wistar (fig. 7) and Sprague-Dawley rats [133]. At this time, dilator and constrictor responses to other, non-mitochondrial stimuli were reduced in middle cerebral arteries on the stroke side. Thus, not only are endothelial cells responsive to mitochondrial-induced postconditioning after anoxic stress, but vascular responsiveness to mitochondrial activators is also enhanced [133]. Therefore, because strokes occur unpredictably, therapeutic targeting of mitochondria after the onset of ischemic stroke may be a clinically useful approach. Cerebral ischemia, resultant cerebrovascular dysfunction, and parenchymal damage occur unexpectedly following occlusive and hemorrhagic strokes as well as from severe hypotension due to heart attacks and trauma. The only proven therapeutic approach for occlusive strokes is surgical or enzymatic removal of the clot from a cerebral artery, but even after clot removal, patients especially beyond the 3-hour 'window' often suffer from cerebral hypoperfusion, damage to the BBB, and continued parenchymal damage. We believe that activation of mitochondrial mechanisms after the insult may benefit the brain by protecting cerebrovascular cells by preventing further injury to the endothelium and VSM, correcting cerebral hypoperfusion, restoring normal cerebrovascular responsiveness and the BBB, and restricting further neuronal and glial cell death.
We can draw four major conclusions. First, mitochondrial influences are important initiators of pre- and postconditioning in the most vulnerable cell types within the neurovascular unit. Thus, targeting mitochondria may be a useful therapeutic approach to protect the cerebrovasculature and brain of patients prior to elective surgeries and also following the onset of strokes. Second, individual mitochondrial influences from the endothelium, perivascular nerves, and perhaps parenchymal neurons and astroglia are able to contribute to the direct mitochondrial-initiated dilator effects of VSM into a final, integrated change in cerebrovascular tone. Thus, production of vasoactive factors following activation of mitochondria in response to physiological stimuli in one or several of the cells comprising the neurovascular unit may represent the elusive signaling link between metabolic rate and blood flow. Third, important mitochondrial-derived mechanisms, such as those that induce preconditioning or cause changes in cerebrovascular tone, are disrupted by chronic disease processes such as IR and diabetes, even when signs and symptoms are relatively mild. Thus, direct or indirect targeting of mitochondria in the early stages of the metabolic syndrome might prove to be an effective treatment to reduce morbidity and mortality in these patients related to the increased risk of cardiovascular disease, stroke, and dementia, such as Alzheimer's disease. Fourth, preliminary evidence indicates that mitochondrial mechanisms promoting vasodilation are usually present to some extent following experimental strokes. Thus, targeting mitochondria following a patient's ischemic injury may help correct cerebral hypoperfusion and restore the BBB, and thereby restrict further neuronal and glia cell death.
The study of mitochondrial influences on the vasculature is a rapidly evolving field of investigation; however, there is much research to do in order to understand the intricacies of mitochondrial biology and the mitochondrial mechanisms involved in cerebral vascular control during health and disease. Nonetheless, it seems likely that the manipulation of mitochondrial numbers or function will represent an important therapeutic approach for the future treatment of many chronic and acute disease states.
The study was supported by NIH grants HL-077731, HL-030260, HL-065380, and HL-093554. We thank Nancy Busija, MA, CCC-SLP, for editorial assistance. We thank Ken Grant of the Cellular Imaging Shared Resource at Wake Forest University Health Sciences for assistance with electron microscopy.
Prof. David W. Busija
Department of Pharmacology, Tulane University School of Medicine
1430 Tulane Avenue, SL 83
New Orleans, LA 70112-2632 (USA)
E-Mail firstname.lastname@example.com
Received: October 14, 2013
Accepted: February 19, 2014
Published online: May 22, 2014
Issue release date: August 2014
Number of Print Pages: 15
Number of Figures: 7
Number of Tables: 0
ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)
For additional information: http://www.karger.com/JVR
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


text:
Top Definition
A word used black-outedly, either under the influence of alcohol, mary j. uana, mushrooms, or a combination of those, to describe a video game controller.
Drunk friend: "I wanna kill people. (referring to GTA IV) Gimmie my play handler."
Not as drunk friend: "You're drunk."
Not as drunk friend: "You're drunk."
by One Eyed Joe February 03, 2009
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subset: commoncrawl


text:
[1.11] Better Auto Jump Mod Download
Category: Minecraft Mods, Mods 1.11
Better Auto Jump Mod adds a settings option to the auto-jump: "Hold [Sprint]".
How to install Better Auto Jump Mod:
- Download and install Minecraft Forge.
- Download the mod.
- Click on the Start Menu in Windows.
- Type run into the search box, and select the Run program at the top of the results.
- Type %appdata% into the Run program, and press Enter.
- Go to .minecraft/mods folder.
- Drag and drop the downloaded jar (zip) file into that.
- Enjoy the mod.
More posts of Better Auto Jump Mod :


text:
More Videos...
RS4@540hp vs RS4@436hp vs RS4@420hp
left RS4@436hp and original K04 turbos. Middle has 540hp with K04 from RS6. Right RS4 is almost stock with a chip.
Our C63 AMG - hear the sound [EXHAUST SOUND]
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This was a RS4 I saw on my vacation, enjoy!
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FB: http://www.facebook.com/Jorrie2YT & http://www.facebook.com/jorrik.aben Jorrik records a good sounding Audi RS4 Avant B7. The owners came to Ziptuning to tune the RS4. I made some video's with the owner of the car! I hope you enjoy watching the video, please leave a comment and rate! Thanks! Jorrik Thanks to OmarKadirYT for editting!


text:
Hyla japonica
|Scope: Global
Language: English
|Scientific Name:
|Hyla japonica
|Species Authority:
|Günther, 1859
Common Name(s):
Hyla arborea Günther, 1859 ssp. japonica
Hyla stepheni Boulenger, 1887
Hyla ussuriensis Nikolsky, 1918
|Taxonomic Notes:
|Hyla japonica is a member of the Hyla arborea complex. A number of authors consider H. japonica to be a subspecies of H. arborea, but biochemical and morphological differences between these two forms confirm the specific rank of H. japonica. Fei (1999) considered H. ussuriensis from northern China, the Korean Peninsula, eastern Russia and Mongolia to be a separate species from H. japonica on Japan. Here we consider H. ussuriensis to be a synonym of H. japonica pending further taxonomic work on this complex.
|Red List Category & Criteria:
|Least Concern ver 3.1
|Year Published:
|Date Assessed:
Needs updating
|Sergius Kuzmin, Irina Maslova, Masafumi Matsui, Fei Liang, Yoshio Kaneko
|Global Amphibian Assessment Coordinating Team (Simon Stuart, Janice Chanson and Neil Cox)
Listed as Least Concern in view of its wide distribution, tolerance of a broad range of habitats, presumed large population, and because it is unlikely to be declining fast enough to qualify for listing in a more threatened category.
|Range Description:
|This species is widespread in Japan (Hokkaido, Honshu, Shikoku, Kyushu and other small islands), central, northern and northeastern China, it is found throughout both the Democratic People's Republic of Korea and the Republic of Korea, present in northern Mongolia and the southern Russian Far East.
|Countries occurrence:
Native:China; Japan; Korea, Democratic People's Republic of; Korea, Republic of; Mongolia; Russian Federation
|Additional data:
|Range Map:
|Click here to open the map viewer and explore range.
|This species is common throughout and is only rare and sporadically distributed in the area of Lake Baikal and Mongolia.
|Current Population Trend:
|Additional data:
|Habitat and Ecology:
|This species inhabits mixed and deciduous broadleaved forests, forest steppes, bush lands, meadows, swamps, paddy fields, ponds, and the surrounding vegetation. It is often found along the banks of rivers, streams, and lakes. Spawning and larval development takes place in stagnant ponds, puddles, oxbow lakes, flooded quarries, and lakes with dense herbaceous vegetation. The eggs are sometimes deposited in river and stream pools. The species tolerates some degree of habitat modification, and may even be found in large cities.
|Terrestrial; Freshwater
|Major Threat(s):
|The threats to this species are not well known, but are presumed to include general habitat loss, (often from changes in land use such as conversion of paddy fields to vegetable farming), pollution and prolonged drought in arid areas.
|Conservation Actions:
|The range of this species overlaps with many protected areas. It is listed in the Red Data Books of Buryatia and the Evreiskaya Autonomous Province of Russia.
|Sergius Kuzmin, Irina Maslova, Masafumi Matsui, Fei Liang, Yoshio Kaneko. 2004. Hyla japonica. The IUCN Red List of Threatened Species 2004: e.T55519A11323792. . Downloaded on 20 February 2017.
|To make use of this information, please check the <Terms of Use>.
|If you see any errors or have any questions or suggestions on what is shown on this page, please provide us with feedback so that we can correct or extend the information provided


text:
User-Agent: Mozilla/5.0 (Windows; U; Windows NT 6.1; WOW64; en-US; rv:1.9.3a5pre) Gecko/20100504 Minefield/3.7a5pre Firefox/3.6
Build Identifier: 20100504040059
Scrolling at the given URL is extremely slow. Memory appears to be leaking as you scroll.
Reproducible: Always
Steps to Reproduce:
1. Go to https://launchpad.net/ubuntu/+bugs
2. Scroll up/down
Actual Results:
scrolling is extremely slow and choppy with high memory usage.
Expected Results:
Smooth scrolling with minimal memory usage.
*** This bug has been marked as a duplicate of bug 551350 ***


text:
2013 Norco Diesel 18 BikeViews:
Compare to other Complete Bikes
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text:
With the loss of senior post players - forward Justin Greene and center Justin Manns - Kent State men's basketball coach Rob Senderoff's main goal this off season has been to land a much-needed big.
Consider it mission accomplished.
Thursday the Golden Flashes landed former Wake Forest forward Melvin Tabb, who turned down offers from perhaps more nationally-known hoops schools such as Seton Hall and James Madison.
No doubt a big reason the 6-foot-8, 245-pounder from Texas' Midland College choose Kent State was for the ability to walk right in to a starting position for next season.
However, the Tabb signing is a bit of a gamble for the Flashes. Tabb is not unlike some of the other "high-risk" players who've come before him to KSU looking for a second chance.
Tabb, a native of Raleigh, N.C., was dismissed from the Demon Deacons squad in February 2011 for "conduct detrimental to the team." He later plead guilty to stealing a classmate's IPod and attempting to pawn it.
As a freshman at Wake Forest, Tabb averaged 1.6 points and 2.0 rebounds in less than nine minutes per game. He saw action in just 14 games, missing four games at the end of the fall semester for academic reasons.


text:
Hi there. I'm learning how to write my own externals. I'm successfully writing my own functioning objects at this point, but I'm concerned that I'm not using the data types quite right. Here's a Warning message I get when I build.
warning C4047: 'function' : 't_atom *' differs in levels of indirection from 't_atom (*)[2]'
here's the function where this occurs
void minimum_list(t_minimum *x, t_symbol *s, short ac, t_atom *av)
short i;
t_atom listOut[2];
long numbers[2];
Not sure what it's warning me about..also I don't really understand why I have too go like this "listOut+i" instead of "listOut[i]". But it works.
The quick explaination is that pointers and arrays are almost the same thing in C – namely, an array can actually be seen as a pointer to its first element. So listOut is the same as &listOut[0], listOut+i is the same as &listOut[i] and the type for each of them is t_atom*. As a consequence, the type for &listOut is t_atom**, which is not what outlet_list wants.
In fact the matter is complex, and dealing successfully with the Max API requires quite a deep understanding of C pointers. So, my suggestion is to take a good C textbook (there's plenty of links in the forum) and study carefully everything about pointers and arrays.
Finally, questions about coding C externals should be posted on the Dev forum – you have more chances of getting a quick reply!
Thanks guys. I think I see what andrea means. t_atoms is already a pointer, and it becomes a pointer to a pointer the way it's used. Maybe I do need a refresher on pointers. I've read lots of C programming books…just a little rusty maybe.
I'll take a good read through the manual too.
Log in to reply
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text:
Effective Infographics with Interactivity
Download this episode
Infographics (short for Information Graphics) are part design, part data visualization. Come hear how we created the Descry set of data visualizations as well as tips for creating effective infographics in software.
Available formats for this video:
Actual format may change based on video formats available and browser capability.
More episodes in this series
Day Two Keynote
The Discussion
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chris isaak dark moon karaoke song download uoZr free file
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text: A sweet, earthy alternative singer/songwriter whose twangy, pop-oriented tunes compare favorably to the likes of Neko Case and Devon Sproule, Clare Burson began attracting notice in 2003 with the release of her home-made debut full-length. Burson's parents encouraged her to play music from an early age. " put a butter-box violin in my hands when I was two-and-a-half years old," Burson explained in an interview with New Beats Magazine. "I didn't have much say in the matter." A cl... Read more


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A new complex of villas with exclusive design used natural stones, wood, ceramics is situated in a pleasant area of the Bang Tao beach. Each villa made in an L-shape around the pool, consisting of a main hall with fully equipped western kitchen according with European standards of luxury interior. Kitchen connected with living room and dining room for 8 people
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All villas surrounded spacious yard with tropical plants, include BBQ zone and sunbath terrace.
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At Wednesday's groundbreaking ceremony, President Obama said the new National Museum of African American History and Culture in Washington, D.C., would be not just a record of tragedy, but a celebration of life.
"It is on this spot — alongside the monuments to those who gave birth to this nation, and those who worked so hard to perfect it — that generations will remember the sometimes difficult, often inspirational, but always central role that African-Americans have played in the life of our country," he said.
Any president of any party would have spoken at the museum's groundbreaking. But the appearance Wednesday of the nation's first African-American president, in the midst of his re-election campaign, highlighted a shift in Obama's approach to African-American voters.
While Obama tried not to focus on race in his 2008 campaign, he has decided to make his outreach to the black community more targeted and aggressive this year, says George Mason University professor Michael Fauntroy.
"What he's got to do is some of the things that he's begun to do — and that is to speak more directly to African-Americans," Fauntroy says. "As we look toward the campaign, we are certainly seeing more of that … being more sort of socially black, if you will."
Targeted Outreach
That statement may be controversial, but Fauntroy points to little things — like when the president sang a few bars of Al Green last month or "Sweet Home Chicago" with B.B. King at the White House on Tuesday night.
Some of this is just the president letting loose and having fun, but his campaign has a strategy. Earlier this month, Obama unveiled an initiative aimed at black voters.
"This month we're announcing the 2012 launch of African-Americans for Obama," he said in a video. "I don't think there's a better time than African-American History Month to consider the tremendous progress we've made through the sacrifices of so many."
African-Americans for Obama is part of the campaign's Operation Vote, which targets individual voting blocs, including Jews, Hispanics, gays and African-Americans.
"This campaign is powered by folks at every level, taking ownership where it matters most — around the kitchen table, in barber shops and beauty salons, in your faith community, at work or at school," Obama said.
Fauntroy says while this kind of targeted outreach may not have been necessary in 2008, it is today.
"History moves people, but it doesn't move people every time," he says. "You look at the economic downturn, the foreclosure crisis, and the just evisceration of black wealth around the country — you know there are a number of reasons why African-Americans would be less than excited to spend time concerning themselves with voting on Election Day, and he's got to overcome those things."
Concerns About Turnout
The president's approval rating among African-Americans hasn't budged — it's still in the 90s. But Fauntroy says what Obama has to worry about is turnout, particularly in states like North Carolina, Virginia and Florida, where a spike in African-American turnout put Obama over the top four years ago.
"It's not enough to get 95-96 percent of the black vote — he'll get that. The question is will the pie be the same size or larger?" Fauntroy says.
And so the president's message to African-American supporters is not too different from what he had to say Wednesday — as he compared the new National Museum of African American History and Culture to the other great institutions on the National Mall.
"Just like the Air and Space Museum challenges us to set our sights higher, or the Natural History Museum encourages us to look closer, or the Holocaust Museum calls us to fight persecution wherever we find it, this museum should inspire us as well," Obama said. "It should stand as proof that the most important things in life rarely come quickly or easily. It should remind us that although we have yet to reach the mountaintop, we cannot stop climbing."


text:
LeBron James Re-Signs With Cavaliers, Setting NBA Record; 17 NBA Teams Now Paying Historic Salaries
To no one's surprise, LeBron James has agreed to a new contract with the Cleveland Cavaliers– a three-year, $100-million deal that will make him the NBA's highest-paid player for a single season. For leading the Cavs to their historic title last June, he got himself a well-deserved raise exceeding $8 million.
James made $22.97 million read »Mitch Lawrence, Contributor


text:
There is a sense of despair when it comes to privacy in the digital age.
Many of us assume that so much of our electronic information is now compromised, whether by corporations or government agencies, that there is little that can be done about it. Sometimes we try to rationalize this by telling ourselves that privacy may no longer matter so much. After all, an upstanding citizen should have nothing to fear from surveillance.
In "Dragnet Nation: A Quest for Privacy, Security and Freedom in a World of Relentless Surveillance," author Julia Angwin seeks to challenge that defeatism.
In her book, published by Times Books, she argues that surveillance dragnets do matter and can damage lives. For example, she speaks to people who have had their driving licenses revoked after facial recognition software flagged them as looking too similar to another driver.
Other cases have involved sufferers of mental illness being horrified to discover that what they thought were private chat forums were being monitored and recorded by drug companies. And although the individual cases are still relatively isolated, Angwin points to an enormous potential for further harm.
She reminds us that the Stasi surveillance networks, which had such a chilling effect on East Germans, were nothing compared with the social mapping now available through services such as Facebook. Angwin is a Pulitzer Prize-winning journalist, formerly at the Wall Street Journal and now a senior reporter at the investigative website ProPublica.
In her book, she spends a year seeing if she can escape the dragnets. The project is exhausting and mostly futile.
She disconnects from 91 data brokers that have collected her information, a costly process that takes months. And at the end of it, another 120 companies, which do not offer an opt-out, still hold her data in their files.
She begins using a pre-paid "burner" phone for calls, and occasionally carries it in a metal-lined wallet to avoid it being tracked. But as a busy mother of two she finds being out of reach of the cellphone network impractical.
She tries software that encrypts her calls and emails but finds it difficult to use and struggles to find friends willing to use the software to decrypt her messages. "All the tools we have are awful," admits one of the developers of security software when Angwin turns to him for assistance.
She finds her countersurveillance measures — which include creating an alias with a fake address and false birth date details — stressful.
Mike Perry, a self-confessed "surveillance vegan" who keeps separate mobile phones for different facets of his life and has not even told his parents where he lives, offers an extreme example of where an obsession with privacy might lead.
"To be honest it's affected my ability to have close relationships," Perry tells the author with some poignancy.
It is hard to see all these efforts being worth it for anyone who is not:
a) a terrorist trying to avoid detection; or
b) the author of a book about surveillance.
But, apart from being an entertaining if somewhat disturbing read, this book does offer a few practical tips.
For example, creating stronger passwords is relatively easy and effective in increasing privacy. Angwin recommends a service called 1Password. Some other tools work reasonably well, too, such as Ghostery, which blocks Internet tracking, and DuckDuckGo, a Web browser that stores no search data. Even the less tech-savvy could try these.
Angwin tries to end on a positive note, arguing that, as with pollution, small steps and better laws might gradually improve Internet privacy.
"We didn't shut down the industrial economy to stop pollution. We simply asked the polluters to be more accountable for their actions.... Similarly we … just need to make the data handlers … more accountable for any harm," she writes.
But as freak snowstorms lash the U.S., it seems clear that the environmental analogy offers a fairly small hope to cling to.
The book is fast-paced and eye-opening, but don't count on it making you feel any better.
Palmer is a social media journalist at the Financial Times of London, in which this review first appeared.


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Hey everyone! This is just my monthly shout out for sponsors! Great things are happening with The Momma Diaries. There is no time better to display your button on my page!
So, you're interested in sponsoring The Momma Diaries in September?! Well, of course you are!! The Momma Diaries is a great way to boost your sales, gain more followers, and exposure for your site! Our readership is growing every day! I am looking for any relevant companies, brands, etsy shops, and blogs to take on sponsorship. I am offering four advertising options, all of which can be found and purchased here.
As of August 2012, here are The Momma Diaries stats:
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Average approximately 7,000 unique visitors per month


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Plantronics 85117-01 Plantronics BT300 BT USB ADAPTER,MOC (85117-01)
Plantronics BT300 BT USB ADAPTER,MOC (85117-01)Version optimized for Microsoft® Lync and Microsoft OCS 2007
Expand the connectivity options of your current Bluetooth headset with the BT300 Bluetooth USB adapter. Use with Plantronics Bluetooth headsets that feature multipoint connections and now you can manage both PC and mobile calls with a single headset.
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The Federal Reserve Bank of New York received a letter from 14 major dealers offering an outline of how they plan to improve the over-the-counter derivatives market. Plans include improvements in standardization and transparency. The letter follows a January meeting at the New York Fed to discuss issues in the sector.
Full Story:Risk.net (subscription required)


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Receive the latest in Footwear, Fashion, Music and Creativity in our newsletters.
High fashion designer Jeremy Scott returns with his signature collections, creatively designed for the spotlight this upcoming Fall/Winter season. His illustrious, glamorous, and fashionable approach to adidas Originals' classic sportswear is inspired this season by medieval times. Next to an updated version to his iconic Wings shoes, the JS Wings 2.0, you will also find the wings on apparel for the first time. The collection will be available in selected boutiques starting August 2010.


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Charley Snaps
Little Charley Bear, Series 1 Episode 20 of 39
Charley wants to take a photo using his camera, so he goes to the beach where there are plenty of amazing things to take a photo of. But Frozo sticks his head in every photo Charley takes, ruining them all. But then Charley realises that a photo with Frozo is it is just what he wants.
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I've been ordering Twinlab Mega Twin EPA Fish Oil from you for many, many, years. The arthritis doctor I see first recomended this product and I have been very please with it and with iHerb. Thanks, B. Failla
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The easiest way to get enough EPA and DHA in the wright proportion. Maybe the best omega 3 ever made, at least for the price.
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I have ordered the fish oil for quite a long time and the experience has always met my expectations.
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iPhone & iPod Skin
Thank You!by Chris Piascik
Skins are thin, easy-to-remove, vinyl decals for customizing your device. Skins are made from a patented material that eliminates air bubbles and wrinkles for easy application.
As many of you know, I currently have a Kickstarter project for the book I am making—1000 Days of Drawing. The book features my first 1000 daily drawings (if the title didn't give it away). While I am typing this there are 57 hours left of my campaign. I've been completely blown away by the incredible response it has received. If you are interested in pre-ordering a copy of the book head on over to my Kickstarter page! As part of the campaign I am drawing people's names, selling prints, posters and more. So go check it out before Wednesday!


text: Here's Video Of Newcastle's Danny Simpson Unconscious and Bleeding After A Late-Night Street FightBarry Petchesky2/04/13 6:10pm22EditPromoteGo to permalink Perhaps Danny Simpson is best known as a former Manchester United youth player, or as the boyfriend of a pop star and X Factor judge, rather than for his soccer skills. Now he can be the Newcastle defender who got knocked out outside a Manchester club late Saturday night! Surely that's an accomplishment.


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Flower Arranging Tips
From her New York City design studio, interior and floral designer Rebecca Cole is a pro at creating personal spaces in which her clients love to live. Through her Discovery Channel show, Surprise by Design, Cole has made it her life's work to inspire viewers to create individualized living environments. "The recent Harvard research is proof that if we live in places that lift our spirits, we can live happier, healthier lives," said Cole. "Fresh cut flowers are the perfect everyday accessory for any budget — they add color, fragrance and style — and now we know they even increase energy and compassion."
Where to Place Flowers
Participants in the Harvard study reported the greatest mood-boosting effects when fresh cut flowers were placed in common areas of the home such as the kitchen, dining room and family room. Cole's easy ideas for social and personal spaces include:
- Place bud vases in high traffic home areas — with even just a few flowers. Any decorative glass from the kitchen will do!
- The kitchen table might be the best place for flowers, because it's where people gather together. Stop by a florist or supermarket, where you'll find a wide selection of flowers from which to choose.
- In the foyer, create a space to hang your keys that also includes a weekly vase of flowers. It will be the last place you see on your way out the door and the first you see on your way back inside.
- Go big and bold for open spaces. An abundant arrangement of lilies, gladiolus, hydrangea or any large blooms create an inviting environment for an expansive entryway or dining room.
- A bouquet can also perk up personal spaces such as bathrooms and bedrooms.
- A bud vase with a simple cluster of flowers hidden in the center of a clear bubble bowl filled with potpourri is the perfect way to create a welcoming atmosphere in a guest room.
- Experiment to match a room's décor with one the hottest flower trends — monobotanic (arrangements of all one type of flower) and monochromatic (using all one color palette, such as a range of pinks).
- For a contemporary look, group several vases together holding just one or two stems. If you're using your own container, be creative! Use champagne glasses, china pieces or other items that fit the décor of the room.
- Old water pitchers, antique teapots, classic urns or even tattered clay pots make fascinating containers for a casually placed flower arrangement.
- For an easy, elegant table decoration, set a series of crystal vases on a fabric runner. Place fresh flowers in each of the vases and surround them with greenery.
- Float two or three blooms, such as open roses or gerbera daisies in a favorite crystal bowl.
- Choose soothing colors, like blues and greens, to create a tranquil feeling or bright reds and oranges for a more energetic arrangement. Yellows and peaches are nurturing and pinks and lavenders are romantic.
Thanks! You're on our list.
And your life's about to get more interesting.
Some people like to travel by train because it combines the slowness of a car with the cramped public exposure of an airplane.
Dennis Miller
I think my pilot was a little inexperienced. We were sitting on the runway, and he said, "OK, folks, we're gonna be taking off in a just few—whoa! Here we go."
Kevin Nealon
"I can't wait until your vacation is over." —Everyone following you on Instagram
A man knocked on my door and asked for a donation toward the local swimming pool. So I gave him a glass of water.
Comedian Greg Davies
Just found the worst page in the entire dictionary. What I saw was disgraceful, disgusting, dishonest, and disingenuous.
Client: We need you to log in to the YouTube and make all our company videos viral.
From clientsfromhell.net
My cat just walked up to the paper shredder and said, "Teach me everything you know."
"Just because you can't dance doesn't mean you shouldn't dance." —Alcohol
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My parents didn't want to move to Florida, but they turned 60 and that's the law.
—Jerry Seinfeld
Q: What do you call an Amish guy with his hand in a horse's mouth?
A: A mechanic.


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Lahmejun Baked & Raw
|Green bell peppers
|4 Medium
|Ripe tomatoes
|2 Pound (Pear-Shaped, Roma-Type)
|Lean ground lamb
|4 Pound
|Lightly packed minced parsley
|3 1⁄2 Cup (56 tbs)
|3 Clove (15 gm), minced or pressed
|Canned tomato paste
|12 Ounce (1 Can)
|Ground allspice
|4 Teaspoon
|4 Teaspoon
|4 Teaspoon
|To Taste
|8 inch flour tortillas
|Armenian cracker bread
Stem and seed bell peppers and finely chop.
Core tomatoes and finely chop.
Put vegetables in a 5- to 6-quart pan over medium heat; stir often until vegetables are juicy.
Increase heat to high and stir frequently until almost all liquid has evaporated; when you draw spoon across pan bottom, there should be no liquid.
Take care not to scorch.
Set aside until cool.
In a large bowl, thoroughly mix cooked vegetables, lamb, parsley, garlic, tomato paste, allspice, pepper, and paprika.
Season to taste with salt.
For raw lahmejun, set aside 1 1/2 cups of the lamb mixture; cover and refrigerate for up to 12 hours.
Fill 1 or 2 lightly greased 12- by 15-inch rimmed baking pans with a single layer of tortillas.
Spoon 1/2 cup of the meat mixture onto each tortilla; with your fingers or a fork, evenly pat or spread meat in thin coating over tortilla, leaving a 1/2-inch rim all around.
Bake in a 500° oven, 1 or 2 pans of lahmejun at a time, until tortilla rims are well browned and meat looks dry, 8 to 10 minutes; alternate pan positions halfway through baking.
Slide a spatula under hot lahmejun to make sure they are not stuck to pan, then let cool for several minutes for bottoms to firm.
Transfer with a wide spatula to a flat surface; reuse pans until all lahmejun are cooked.
While filled pans are in oven, pat lamb on more tortillas, making enough to refill pans.
Put in oven and start another batch.
You may need to wash, dry, and grease pans occasionally.
The cooking process goes much faster if you have more than 1 oven.
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 8827 Calories from Fat 4535
% Daily Value*
Total Fat 504 g774.7%
Saturated Fat 187.1 g935.3%
Trans Fat 0 g
Cholesterol 1324.5 mg441.5%
Sodium 9146 mg381.1%
Total Carbohydrates 646 g215.3%
Dietary Fiber 77.2 g308.9%
Sugars 84.3 g
Protein 408 g815.4%
Vitamin A 866.3% Vitamin C 1630.4%
Calcium 105% Iron 346.1%
*Based on a 2000 Calorie diet


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Free Speech Coalition (FSC) today issued this response to AIDS Healthcare Foundation's (AHF) earlier announcement (contained in the press release at this link). AHF reported that they have submitted 360,000 petition signatures in a continuing effort to mandate the use ...Read More
L.A. Condom Ordinance: Council Refers Implementation Plan Development to Arts, Parks, Health & Aging Committee
Free Speech Coalition (FSC) was notified today by the L.A. City Administrator's Office that the L.A. City Council has referred development of enforcement strategy for the city condom ordinance to the Arts, Parks, Health & Aging Committee. Until recently, the ...Read More
At the City Administrator's office this morning, the Working Group on the City of Los Angeles Safer Sex in the Adult Film Industry Ordinance met to review a report on enforcement strategy for condom ordinance on adult sets. The meeting ...Read More
Due to concerns raised over what type of HIV tests are acceptable and appropriate for monthly performer screenings, APHSS.org has announced that it will accept two different brands of HIV tests. For years, our industry utilized PCR-DNA as the off-label ...Read More


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Although organic foods entered mainstream supermarkets in 2000, with more than half of the $7.8 billion of organic food purchased in regular grocery stores, it is still unclear whether there is a significant health advantage to eating such foods, according to the U.S. Department of Agriculture. The lack of definitive research is partly due to the cost and complexity of logging the data, columnist Sally Squires writes.
Full Story:The Washington Post (tiered subscription model)


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1. Will the White Peoples Christian Church or the Ku Klux Klan,
(which claims to be a Christian denomination) be able to use taxes to teach
their religious belief that Jews and Blacks are subhuman? (they quote the Bible
in support of their views)
2. Will taxes now be used to teach children that Christians should be killed
because they are "infidels"?(reference the Koran) Or that Wiccans (witches)
should be killed? (reference the Bible)
3. Will taxes now be used to teach children that homosexuals are abominations
and should be killed? (reference the Bible , the Torah, the Koran)
4.. Will taxes now be used to teach children that women are subservient to
men and that wives must obey their husbands? (reference the Bible, the Torah,
the Koran)
5 Will taxes now be used to teach children that it is OK for them to be
beaten with rods? (reference the Bible)
6. Will taxes now be used to teach, as scientific fact, that
7.Will taxes now be used to teach that the Catholic Pope is the Anti-Christ?
(reference Bob Jones University ..where George Bush made a major campaign speech
for votes)
8. Will taxes now be used for the publication of religious tracts,
evangelical literature, etc.? This material will be handed out in school
rooms..how about door to door or in mass mailings? How will we know where the
funding came from?
9. Will taxes now be used to pay the salaries of ayatollahs, priests, rabbis,
ministers, nuns, etc? Who will decide that these people are really full time
teachers/educators and not full time clerics?
10.Will taxes now be used to employ a sufficient number of auditors to
investigate the religious teachings of voucher schools to guarantee that these
public funds are being spent in a way that reflects our nation�s public
If your answer is �yes� to any of the above, please explain how it reflects
our country�s public policy. If you support vouchers for the teaching of
religion, but do not think the above should be taught, how do propose we go
about deciding which religious teachings are acceptable and which are
----- Original Message -----
To: email@example.com
Sent: Thursday, July 04, 2002 8:11
Subject: Re: Happy 4th
I don't know why you are so upset. I kind of don't like the under
God addition because I came of age to vote when Eisenhower was running and it
was not part of the pledge then. Not all the years I went to Catholic
schools, where we indeed said the pledge, or public school after. Where
we also said the pledge.
The thing about separation of church and state in the constitution is
about having a national church like Britain does. Goodness knows Great
Britain has enough separatist congregations, and one of them came over here to
found America. But there is no established American church where it is the
law, more or less. So all this turmoil and complaint is sort of
And isn't this about hostas, anyhow? Mine are doing quite well,
though something has bitten them. And I have duly put out poison, which I hate
to do.
Ann James
A really old curmudgeon living in Conroe,


text: Hammonds has promoted Simon Miller to head the firm's Leeds office. Miller has been with the firm's commercial and dispute resolution practice since 1993 and became a partner in 2000. As a solicitor-advocate he has appeared in numerous interim applications, conducted trials and has also appeared in the Court of Appeal. Miller succeeds the previous office head Ian Greenfield, who served in the role for five years. Greenfield will now focus on fee-earning within the corporate team while continuing to play an ambassadorial role for the firm.


text: tuition Kansas Universities Seek Tuition Boosts; Requests Could Rise By Associated Press & Aileen LeBlanc • May 18, 2016 Jimmy Everson, DVM, flickr Creative Commons Kansas' state universities are calling for tuition increases of up to 5 percent, at least for now. The schools submitted their tuition proposals Wednesday to the governing Kansas Board of Regents. But those came before Gov. Sam Brownback signed a budget bill Wednesday afternoon that cuts higher education funding by 4 percent, 1 percent more than the universities had expected. Public University Leaders Encouraged To Work On Tuition Proposals Early By Associated Press • Jul 25, 2014 Public university leaders in Kansas are being encouraged to start working on next year's tuition proposals now, rather than wait until the spring semester. Kansas Board of Regents chairman Kenny Wilk says the revenue stream from tuition is too significant to wait until the last minute to get it figured out. The regents traditionally have received tuition and fee requests from the universities in May before approving them in June. KBOR Approves 5 Percent Tuition Hike For WSU By Carla Eckels • Jun 19, 2014 The Kansas Board of Regents is raising tuition and fees at state universities this fall, which includes Wichita State University. KMUW's Carla Eckels reports... The resident undergraduate rate for tuition and fees ranges from a 2.5 percent increase at Fort Hays State University to a 5.7 percent increase at Kansas State University-Salina. The increases will provide almost 29 million dollars in additional revenues for the universities in the system. Kansas Regents To Vote On Tuition Increases By Stephen Koranda • Jun 18, 2014 The Kansas Board of Regents will consider proposed tuition increases at a meeting this week. Breeze Richardson, with the board, says this will be the final step in the process. Universities have spent the last few months developing and submitting their proposals. "Those proposals were brought forth at last month's meeting," Richardson says. "And then the final proposals will be presented tomorrow and voted upon."


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Full profile →'">
The author is a Forbes contributor. The opinions expressed are those of the writer.
A handful of tech hubs in the world are working overtime to follow in the footsteps of northern California's Silicon Valley. Recently Tech & Science scoped out several world cities that are doing their best to earn their own "Silicon (something)" monikers. We took a look at why these cities were inspiring techonomies.
#4 London
The UK tech scene is ironing out a few kinks and gearing itself up to create a scene that will allow ideas to morph more quickly into ramped up companies. The government funded Tech City Investment Organization offers strategy, support and international connections to London and UK tech entrepreneurs, while the Technology Strategy Board hands out public money to worthy startups.
Some inspiring startups that have come out of London include TransferWise, a peer-to-peer platform that allows people to transfer money to others while abroad at a lower cost than banks can offer. There's also the bite-sized news aggregation app, Summly, from wiz kid Nick D'Aloisio. London's Canary Wharf is now home to Level39—an accelerator unveiled this past December by London Mayor Boris Johnson.
Want to see the lay of the London tech scene? Check out this map, it will freak you right out.
#3 Tel Aviv
Israel's Silicon Valley is known as "Silicon Wadi," (it means Silicon Valley) and Tel Aviv has had some tech successes to boast about. The mighty Google just set up shop in the city this past December, opening a one-floor shared work environment available for free to Israeli startups, developers and entrepreneurs. The word from those who ply their trade in Tel Aviv tell a story of a techonomy that is much closer knit than its northern Californian counterpart, which streamlines the process of getting things done and make projects tackled there quicker to come to fruition.
Some Tel Aviv startups on the move include the personal video stream creator, Vodio; and gaming company JamRT. You may have also heard of the open source freeware media player, Boxee.
#2 Washington D.C.
The center of political power in the United States draws more than just tourists, lobbyists and attention-hungry politicians; it's proven a magnet for tech entrepreneurs too. The population of engineers and idea-people with a mind to start a business has drawn venture money, according to a report.
Some D.C. startups you may have heard of include the deal aggregator LivingSocial, wedding organization assistant WeddingWire and social news platform Newsit.
For a massive list of startups budding in the nation's capitol, check out this site that tracks a ton of them.