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Oxidative stress is a key pathologic factor in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocytic NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of over-activated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, the suppression of PHOX activity correlates with less neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocytic NADPH oxidases in astroglia and neurons further reinforces the critical role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.
Neurodegenerative diseases are characterized by the decades-long gradual loss of subpopulations of neurons in discrete areas of the central nervous system (CNS). More than 36 million people worldwide suffer from Alzheimer's disease (AD) and Parkinson 's disease (PD), the two most common neurodegenerative diseases. Lack of effective treatment and failure of many clinical trials targeting various pathways or molecules reinforce the need to seek new targets for drug discovery for neurodegenerative diseases. High oxygen consumption, high production of ROS, abundant oxidation-sensitive lipids, low antioxidant defense, and a restricted renewal and regenerative capacity of neurons render the brain especially susceptible to oxidative insults. In fact, a great amount of evidence has implicated oxidative stress as a central mechanism of chronic neurodegeneration in various neurodegenerative diseases, such as AD, PD, and amyotrophic lateral sclerosis (ALS) [1, 2]. The failure of antioxidants (substances that inhibit oxidation by scavenging free radicals), such as ascorbic acid (vitamin C), tocopherol (vitamin E), and coenzyme Q10, in clinical trials demands the identification and the blockage of principal sources of oxidative stress in neurodegenerative diseases. It has been well documented that excessive activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is an important contributor to the pathogenesis of numerous peripheral inflammation-related diseases, such as atherosclerosis, diabetes, hypertension, ischemic stroke, and cardiovascular diseases [3, 4]. In this review, we summarize recent exciting progress regarding the crucial role of NADPH oxidases in neurodegenerative diseases, with an emphasis on phagocytic NADPH oxidase (PHOX) and its catalytic subunit NOX2 in neuroinflammation-mediated chronic neurodegeneration.
NADPH oxidases are membrane-bound, multi-subunit enzyme complexes that transfer electrons across the plasma membrane from NADPH to molecular oxygen and generate the free-radical superoxide and its downstream reactive oxygen species (ROS). Through producing ROS, activated NADPH oxidases participate in host defense, cellular signaling, regulations of gene expression, cell differentiation, and metabolism, posttranslational processing of proteins, stress response, and tissue homeostasis [5, 6]. According to the new terminology, the NOX family refers to the catalytic subunit of NADPH oxidases, which includes NOX2 (gp91phox) and its six homologs (NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2). All seven NOX isoforms are transmembrane proteins and are widely distributed in various tissues, with the particular isoforms concentrated in specific cell types or organs: NOX1 in the colon; NOX2 in phagocytes; NOX3 in the inner ear; NOX4 in the kidney and blood vessels; NOX5 in the testis and lymphoid tissue; and DUOX1 and DUOX2 in the thyroid . Many cells express several NOX isoforms; differences in subcellular distribution and activation mechanisms of different NOX isoforms might explain the nonredundancy in their functions [5, 6].
Most NADPH oxidases are activity-dependent enzyme complexes, and their activation usually requires the translocation of cytosolic subunits to the membrane-bound subunits p22phox and NOX isoforms. PHOX is the primary source of superoxide generation in various inflamed phagocytes including neutrophils, monocytes, macrophages, and microglia (the resident immune cells in the CNS). NOX2 (gp91phox), the catalytic subunit of PHOX, is the first identified and the best -characterized member of the NOX family [7]. Under normal circumstances, NOX2 is latent. Upon stimulation, the cytosolic subunits of PHOX (p47phox, p67phox, p40phox, and the small Rho GTPase, Rac1 or Rac2) translocate to the membrane-bound p22phox/ NOX2 heterodimer to assemble the active PHOX that catalyzes the reduction of oxygen to superoxide (Figure 1). Although p47phox was traditionally considered essential for PHOX activation, several recent studies have revealed a p47phox-independent mechanism of PHOX activation. In the absence of p47phox in cell-free assays or in p47phox-deficient macrophages, the PHOX activity is still preserved, but this requires the p resence of p67phox and Rac1 [8–10].
Like NOX2, NOX1 forms a heterodimer with p22phox. Rac proteins and cytosolic subunits of non-phagocytic NADPH oxidases, NOXO1 and NOXA1 (functional homologues of p47phox and p67phox, respectively) are required for NOX1 activation [5, 11, 12]. Both p22phox and NOXO1 are found to be essential for NOX3 activation, whereas the requirement of NOXA1 and Rac p roteins for NOX3 activation remains to be determined [13, 14]. NOX4, in contrast to other NOX isoforms, is constitutively active and produces large amounts of superoxide and its downstream product hydrogen peroxide [15, 16]. Although the involvement of Rac proteins is unclear, NOX4 activation appears not to require other cytosolic subunits. Collectively, for the activation of NADPH oxidases, NOX isoforms as the catalytic subunit are indispensable; p22phox is an essential component of both phagocytic and non-phagocytic NADPH oxidases; p47phox and NOXO1 serve as organizers or regulatory subunits; p67phox and NOXA1 are activators; and p40phox is nonessential, modulatory subunits [5, 17].
The investigation of potential CNS-specific activation mechanisms and biochemical function of the NOX family in neurons, microglia, and astroglia might provide fruitful information on redox-related development, aging, and disease formation in the CNS. Although little is known about the distribution and the function of NOX5, DUOX1, and DUOX2 in the CNS, NOX1 to NOX4 have been detected in whole brain samples, specific CNS regions, and various CNS cells [6, 18]. NOX2 is expressed in microglia at much higher level than in neurons and astroglia. The cellular distribution of NOX3 in the CNS is unclear. Both NOX1 and NOX4 have been detected in neurons, astroglia, and microglia [6]. These findings mainly came from in vitro studies on cultured cells. The in vivo expression of NOX isoforms in specific cell types in the CNS has not been thoroughly examined.
Recent evidence has begun to unravel the physiological function of NADPH oxidase enzymes in the CNS. It has long been recognized that mutations in genes that encode NOX2 (gp91phox), p47phox, p67phox, or p22phox lead to chronic granulomatous disease (CGD) in human and CGD-like phenotypes in mice [6, 19]. CGD, a diverse group of hereditary immunodeficiency diseases with recurrent, persistent infections and granuloma formation in many organs, results from an inability of PHOX-deficient phagocytes to kill ingested bacteria and fungi. Interestingly, an increased prevalence rate of cognitive deficits among CGD patients and impaired memory in gp91phox- and p47phox-deficient mice [20, 21] suggest the involvement of NADPH oxidases in the development and/ or the physiological function of the CNS.
NADPH oxidase has been identified as the primary source of neuronal superoxide production induced by the activation of NMDA receptor (a specific type of ionotropic glutamate receptor whose activation is important for synaptic plasticity, neural communication, memory formation, and learning) [22, 23]. Deficiency in p47phox or blockage of the assembly of p47phox with p22phox/ NOX2 heterodimer by a NADPH oxidase inhibitor apocynin blocks NMDA-elicited superoxide production and neurotoxicity in cultured neurons and mouse hippocampus [22]. Interestingly, the NMDA receptor antagonist ketamine also increases NADPH oxidase activity; an indirect effect involving neuronal production of interleukin -6 is likely responsible for such an effect [24, 25]. Nevertheless, NOX-derived ROS appear important for neuronal death induced by excessive excitation of NMDA receptor. Moreover, neurons in cerebral areas controlling blood -pressure express NOX isoforms, and NOX activity might regulate effects of angiotensin II (an endogenous peptide regulating cardiovascular homeostasis and blood pressure) on cerebral vasculature [26, 27]. NOX-derived ROS also participate in nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells and neurite outgrowth [28, 29], microglia proliferation [30], microglial induction of neuronal apoptosis during development [31], glutamate neurotransmitter release from activated microglia [32, 33], and astrocyte signaling [34]. Taken together, NOX function in microglia, astroglia, and neurons is important for the integrity and the normal function of the CNS.
Diseased CNS regions of patients with various neurodegenerative diseases reveal oxidative stress markers, such as lipid peroxidation and reduction of glutathione levels [1, 2]. Mitochondria are generally believed to be the major source of ROS. However, recent postmortem observations show increased activation of NOX enzymes in the CNS of patients with neurodegenerative diseases. For example, brain tissues of patients with AD (a neurodegenerative disorder characterized by an irreversible loss of neurons and progressive dementia) reveal an elevation in NADPH oxidase enzyme activity, upregulation and membrane translocation of cytosolic subunits of PHOX (p67phox, p47phox, and p40phox), and an increase in mRNA transcripts of NOX1 and NOX3 [35–37], which implies the involvement of NOX-associated oxidative damage in the pathogenesis of AD.
Emerging experimental evidence has indicated that multiple NOX isoforms, especially microglial NOX2, contribute to CNS oxidative stress and neuronal damage. The prime role of microglial NOX2 in neuroinflammation-mediated chronic neurodegeneration is detailed in the next section. Recently, microglia have been found to express NOX1, NOXO1, NOXA1, and Rac1/ 2. During microglial phagocytosis of zymosan (an insoluble cell wall preparation from the yeast Saccharomyces cerevisiae), NOX1/ p22phox heterodimer is recruited to phagosome membrane where activated NOX1 produces superoxide in zymosan-loaded phagosomes [38]. In microglia treated with a common inflammagen lipopolysaccharide (LPS, the major component of the outer membrane of Gram-negative bacteria), the activation of inducible nitric oxide synthase and the release of inflammatory/ neurotoxic factors nitrite species and interleukin-1β are promoted by NOX1-mediated superoxide production. After intra-striatum LPS injection, NOX1-derived superoxide exaggerates loss of presynaptic proteins in striatal neurons [38]. These findings suggest that microglial NOX1 promotes production of neurotoxic factors during neuroinflammation (CNS inflammation) and might contribute to chronic neurodegeneration.
Recent discoveries of NOX isoforms (e.g. NOX1, NOX2, and NOX4) in neurons further support a critical role of NOX enzymes in oxidative neuronal insults in neurodegenerative diseases. Paraquat increased NOX1 expression and activated Rac1 in dopaminergic neuronal N27 cells that express NOX1, NOX2, p67phox, and Rac1 [39, 40]. Paraquat is a pesticide; it shows a positive association with increased risk of PD, a neurodegenerative movement disorder that attacks nigral dopaminergic neurons. Apocynin, diphenyleneiodonium (DPI; a nonspecific NOX2 inhibitor that reacts with flavin-containing enzymes), or siRNA-mediated NOX1 knockdown markedly attenuated ROS production and death of N27 cells induced by paraquat and PD-producing neurotoxin 1-methyl-4-phenylpyridinium (MPP+) [39, 40]. Moreover, in a mouse model of PD, the pre-administration of apocynin significantly reduces paraquat - elicited upregulation of NOX1 and death of nigral dopaminergic neurons [40]. These findings suggest the participation of NOX1, NOX2, or both in PD pathogenesis. Remarkably, NOX1 deletion slows disease progression and significantly increases lifespan of an ALS mouse model that carries mutant superoxide dismutase 1 (SOD1), indicating NOX1 plays a role in the development of ALS (a fatal paralytic neurodegenerative disorder) [41]. NOX1, NOX2, and NOX4 as well as p22phox, p40phox, p47phox, and p67phox have been detected in cultured cerebellar granule neurons. NOX2 deletion or DPI mitigates NOX activity, ROS production, and apoptotic death triggered by staurosporine in these cells, which suggests an important role of NOX2 in apoptotic death of neurons [42, 43]. Knockdown of NOX2 and NOX4 expression in cultured HT22 neuronal cells reduces glutamate-induced hydrogen peroxide accumulation and cell death, indicating NOX family contributes to oxidative glutamate toxicity [44]. NOX4 is upregulated in human and mouse brain after ischemia; post -stroke inhibition of NOX4 induction in mice prevents oxidative stress and neurodegeneration [45]. Collectively, these preclinical findings indicate an important role of activated NOX family in CNS oxidative stress and consequent neurodegeneration.
Recently, growing experimental findings have documented a pivotal role of NOX2- derived ROS from activated microglia in neuroinflammation -mediated oxidative stress and chronic neurodegeneration. Neuroinflammation, a prominent feature shared by all neurodegenerative diseases, has been increasingly accepted as a crucial contributor to chronic neurodegeneration in various neurodegenerative diseases [46–48]. While astroglia participate in neuroinflammatory response, microglial activation is the principal component of neuroinflammation. A wide range of stimuli that disrupt CNS homeostasis, such as infection, toxic insults, trauma, ischemia, or autoimmune injury, can trigger microglial activation [46–48].
Activated microglia release a myriad of inflammatory and cytotoxic factors, such as cytokines, chemokines, eicosanoids, excitatory amino acids, proteases, and ROS. Among these factors, NOX2-derived ROS are recognized as a crucial player in chronic neurodegeneration [46–48]. H2O2 (non-radical oxidants) and peroxynitrite (a reactive product of superoxide and nitric oxide) derived from activated microglial NOX2 can enter neurons, in which they impair mitochondria integrity, reduce ATP production, and increase mitochondria-derived ROS. They also cause oxidation, nitration, aggregation, and accumulation of enzymes and other proteins (e.g. α-synuclein). ROS-induced dysfunction of the ubiquitin-proteasome system (UPS) will reduce protein degradation, which in turn exaggerates the accumulation of abnormal proteins. Impaired redox-sensitive signal transduction, oxidation of DNA, RNA, and lipids, and ROS-induced autophagy arising from over-activated NOX2 also contribute to oxidative neuronal damages during neuroinflammation [1, 2, 49] (Figure 2).
Aggregated β-amyloid (the prime pathogenic mediator of AD) stimulates microglia to release NOX2-derived ROS, and the resultant oxidative stress contributes to the pathogenesis of AD [50, 51]. ATP, released from β-amyloid-stimulated microglia, induces NOX2-dependent ROS production via activating the purinergic receptor P2X7 [52, 53]. Deletion of the NOX2 gene or inhibition of NOX2 activity by DPI prevented microglia-mediated neurotoxicity triggered by β-amyloid in neuron-glia mixed cultures [54] or in a co-culture system containing microglia/ macrophages and human neuroblastoma cells that transgenically overexpress wildtype or mutated amyloid protein precursor (APP) [55]. Inhibition of NADPH oxidase by apocynin or p47phox deletion switched microglial activation from a classical to an alternative state in response to an intracerebroventricular injection of LPS or β-amyloid [56]. DPI and apocynin block β-amyloid-induced ROS generation, glutathione depletion, and mitochondrial depolarization in both neurons and astrocytes, and they also prevent β-amyloid-induced neuronal death [57]. Such findings imply NOX2 in astrocyte and neurons plays a role in β-amyloid-induced neurodegeneration. Furthermore, in an AD mouse model overexpressing mutant APP, a membrane-permeable NOX2 peptide inhibitor NOX2 ds-tat (gp91ds-tat) or genetic deletion of NOX2 attenuates neuronal oxidative stress, cerebrovascular dysfunction, and behavioral deficits [58]. These findings together indicate NOX2-mediated oxidative stress is an important contributor to AD neurodegeneration.
Pathological examinations reveal upregulated microglial NOX2 in the substantia nigra of patients with PD and a mouse model of PD [59]. Moreover, ample preclinical research has demonstrated a critical role of NOX2 activation in microglia -mediated dopaminergic neurodegeneration [46, 60]. For example, aggregated α-synuclein (the key pathogenic mediator of PD) stimulates cultured microglia to release NOX2-derived ROS leading to the death of co-cultured dopaminergic neurons [61]. The presence of microglia enhances dopaminergic neurodegeneration induced by PD-producing neurotoxins 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), MPP+, and 6-hydroxydopamine; PD-associated pesticides rotenone and paraquat; inflammagens LPS and fMLP (formylmethionyl- leucyl-phenylalanine); nanometer size diesel particles; and angiotensin II in primary mesencephalic cultures; such microglia-mediated aggravation of dopaminergic neurodegeneration is mitigated by DPI, apocynin, or NOX2 deletion [62–71]. In addition, endogenous cellular components released or leaked from stressed/ damaged neurons into the extracellular milieu , such as aggregated α-synuclein, the active form of matrix metalloproteinase-3, and high-mobility group box 1 (HMGB1), trigger reactive microgliosis (secondary microglia reactions to neuronal lesions) and NOX2-dependent ROS production, which in turn contributes to dopaminergic neurodegeneration [61, 72, 73]. In a mouse model of PD, minocycline-induced inhibition of microglial activation and membrane translocation of p67phox in mouse brains are associated with reduced dopaminergic neurodegeneration evoked by MPTP [74]. Degeneration of nigral dopaminergic neurons induced by systemic administration of MPTP or an intra -nigral injection of LPS is significantly attenuated in NOX2-deficient mice compared with wild - type mice [66, 75].
ALS is characterized by a progressive loss of motor neurons in the spinal cord, the brainstem, and the motor cortex. Enhanced NOX2-mediated ROS production by microglia has been implicated in ALS pathogenesis. Microglia in the spinal cord of animal models and patients with ALS show elevated expression of NOX2, increased ROS production, and oxidative damage [60]. In BV2 microglial cell lines, overexpression of mutant SOD1 enhances p47phox-dependent ROS production and secretion of cytokine tumor necrosis factor α (TNFα ) induced by an activator of toll-like receptor 2 (TLR2), Pam3Cys-SKKKK [76]. In addition, apocynin prevents the loss of human-embryonic-stem- cell-derived motor neurons caused by co-cultured human-primary-astroglia overexpressing mutant SOD1 [77]. Recent in vitro studies using glial cells suggest that SOD1 regulates NOX2 activity by interacting with Rac1 and that mutant SOD1 enhances Rac1-dependent NOX2 activation [78, 79]. Importantly, NOX2-mediated redox imbalance exaggerates ALS-like motor neuron disease, whereas NOX2 deficiency delays motor neurodegeneration, slows disease progression, improves neurological symptoms (e.g. muscle weakness and atrophy), and extends survival in mice carrying mutant SOD1 [41, 60]. High doses of apocynin (30–300mg/ kg) also improve survival and slow ALS progression in SOD1-mutant mice [78, 79]. Altogether, increased microglia NOX2 activity is an important disease mechanism underlying the non-cell-autonomous nature of ALS neurodegeneration.
Multiple sclerosis (MS) is a neurodegenerative disease with widespread inflammatory axonal demyelination and neuronal injury in the brain and the spinal cord. The investigation on the role of NOX2 activation in the development of MS has generated conflicting and puzzling results. PHOX-dependent production of peroxynitrite is found to be important for microglia-mediated toxicity to cultured oligodendrocytes (a type of glial cells, which form myelin sheaths surrounding axons in the CNS) [80]. Phagocytosis of myelin by microglia leads to p47phox-mediated ROS generation and a marked suppression of microglial inflammatory responses, which are reversed by PHOX inhibition or by specific knockdown of p47phox [81]. p47phox-knockout mice develop decreased experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS, whereas p47phox-mutant mice that express a truncated and nonfunctional p47phox protein reveal enhanced EAE [82, 83]. Additionally, a low ROS-generating variant of p47phox promotes EAE development in rats [84]. NOX2-deficient mice are resistant to EAE [85]. The reasons for these seemingly discrepant findings are unclear; the interaction and the balance among superoxide, nitric oxide, and peroxynitrite might critically determine the outcome of the combined action of these reactive nitrogen and oxygen species.
In the CNS, pattern recognition receptors (PRRs) expressed on the microglial surface including toll-like receptors (TLRs) are necessary for detection and rapid elimination of invading microorganisms, and they also respond to host-derived ligands to activate inflammatory signaling cascades [86, 87]. PRRs appear to be important for transducing diverse stress stimuli into NOX2 activation and ROS production in microglia [61, 73, 76, 88, 89]. It has been reported that overexpression of mutant SOD1 enhances TLR2 stimulation-induced activation of microglial NOX2 and subsequent secretion of TNFα in a p47phox-dependent manner [76]. Regulation mechanisms of NADPH oxidases by TLR2, TLR4, and other TLRs identified in non-immune cells and peripheral immune cells have not been thoroughly investigated in microglia. The microglial surface receptor, integrin Mac1 (macrophage antigen complex 1; also known as complement receptor 3 or CD11/ CD18) can also function as a PRR to recognize LPS and some endogenous ligands (e.g. α-synuclein, β-amyloid, or HMGB1) to induce NOX2 activation [61, 73, 88, 89]. Membrane translocation of p47phox and/ or NOX2-dependent ROS production elicited by these ligands are blunted in Mac1-null microglia; such reduced NOX2 activation is associated with less neuronal impairment [61, 73, 88, 89]. Thus, the coupling between Mac1 and PHOX might be an important mechanism underlying microglia -mediated NOX2-dependent oxidative insults to neurons in neurodegenerative diseases. Interestingly, the deletion of the prostaglandin E2 receptor EP2 (an important regulator of inflammatory oxidative injury in innate immunity) diminishes the increased neuronal oxidative stress and the elevated expression of multiple proinflammatory enzymes including subunits of PHOX (p47phox, p67phox, p40phox, and p22phox) in the spinal cord of SOD-mutant mice; EP2 deletion also improves motor strength and extends survival [90]. Thus, prostaglandin-mediated regulation of PHOX activation could be important for inflammatory oxidative injury in ALS and perhaps other neurodegenerative diseases.
As described above, over-activated NOX2 has been implicated as a major contributor to chronic neurodegeneration in neurodegenerative diseases. Several in vitro studies using neuron-glia co-cultures reveal a correlation of NOX2 inhibition with neuroprotection by multiple anti-inflammatory drugs including sinomenine (a natural dextrorotatory morphinan analog), squamosamide derivative FLZ, pituitary adenylate cyclaseactivating polypeptides, TGF-β 1 (transforming growth factor -β 1; a known endogenous immune modulator), verapamil, and resveratrol (a nonflavonoid polyphenol with antioxidant and anti-inflammatory properties). All these drugs inhibit superoxide release from wild-type microglia; more importantly, they fail to exhibit neuroprotection in cultures from NOX2-deficient mice [91–96].
Several structurally and functionally different compounds that shared common properties of suppressing inflammation and inhibiting NOX2 activity provide significant neuroprotection in animal models of PD. For instance, dextromethorphan (a widely used anti-tussive agent) significantly attenuates MPTP-induced ROS production in mesencephalic neuron-glia cultures and loss of nigral dopaminergic neurons in wild-type mice; such neuroprotection is abolished in NOX2-deficient mice, which indicates NOX2 is a critical mediator of the neuroprotective property of dextromethorphan [75]. The longstanding clinical safety record makes dextromethorphan an attractive candidate for further investigation for its clinical use in PD treatment. Moreover, inhibition of microglial activation and PHOX activity by minocycline protects nigral dopaminergic neurons from thrombin- or MPTP-induced neurotoxicity [74, 97]. Through suppressing the activation of nuclear factor kappa B (NF-κB) and the membrane translocation of p47phox of microglial PHOX, compound A (a potent and selective inhibitor of IKK-β ) prevents microglia-mediated loss of nigral dopaminergic neurons induced by a stereotaxic injection of LPS [98]. Hydrogen sulfide (a biological gas) specifically inhibited NADPH oxidase activation and oxygen consumption evoked by 6-hydroxydopamine; systemic administration of NaHS (a hydrogen sulfide donor) prevent dopaminergic neurodegeneration induced by 6-hydroxydopamine and rotenone via suppression of NADPH oxidase activity and microglial activation [99].
Although the neuroprotective effect of inhibition of microglial activation and suppression of NOX2 activity has mostly been demonstrated in PD models, the potential benefit of NOX2 inhibition will not be limited to PD. For instance, an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation and superoxide production after 17-beta-estradiol administration are responsible for estrogen-induced attenuation of ischemic oxidative damage in stroke [100]. Galantamine, an alkaloid d rug currently used to treat AD, offers neuroprotection through the suppression of inducible nitric oxide synthase, NADPH oxidase, and ROS production in hippocampal slices subjected to anoxia/ reoxygenation (an in vitro brain ischemia-reperfusion model) [101]. Treatment of microglia or monocytes with ibuprofen (a nonsteroidal anti-inflammatory drug) inhibits β-amyloid-elicited Vav tyrosine phosphorylation, PHOX assembly, and superoxide production; more importantly, a 9-month treatment of aged R1.40 mice (a model of AD) with ibuprofen leads to a marked reduction in lipid peroxidation, tyrosine nitration, protein oxidation, microglial activation, and plaque burden. Thus, ibuprofen reduces oxidative damage and enhances plaque clearance through the inhibition of microglial NOX2 in AD [102]. Additionally, an intraperitoneal injection of a low dose of dextromethorphan (0.1 mg/ kg) attenuates moderate EAE (an animal model of MS) through the inhibition of NOX2 expression and the suppression of the infiltration of monocytes and lymphocytes into the spinal cord [103]. Taken together, the correlation of pharmacological inhibition of NOX2 activity with attenuated neurodegeneration in models of various neurodegenerative diseases strongly implicates NOX2 as a promising therapeutic target for neurodegenerative diseases.
Given the indispensable role of NOX2 in host defense and the important physiological function of NOX-derived ROS, the long-term administration of d rugs targeting NADPH oxidases in an attempt to retard chronic neurodegeneration and disease progression in neurodegenerative diseases might compromise the immune system or other ROS-regulated function. It is well-established that mutations in genes encoding NOX2, p47phox, p67phox, or p22phox predispose individuals to a markedly increased susceptibility to severe bacterial and fungal infections, leading to CGD in human [6]. Of more than 400 causative mutations identified so far , approximately 95% result in complete or partial loss of protein expression, whereas only 5% are loss-of-function mutations that lead to normal protein expression and impaired PHOX function. More than two-thirds of CGD cases are X-linked recessive, which result from mutations in X-linked CYBB gene that encodes NOX2, the remaining CGD cases are autosomal recessive. Importantly, female subjects with only one copy of causative genes exhibit reduced NOX2 activity but no CGD pathology or other ROS-associated illness. This gene-dosing effect, combined with the finding that only CGD patients whose phagocytic ROS generation is more than two orders of magnitude lower than that in healthy controls develop severe illness and poor long-term survival [104], suggests it is feasible to treat neurodegenerative diseases through modulating NADPH oxidase activity and to avoid compromising the immune system and other physiological function. In addition, the clinical safety record of several "old" drugs (e.g. dextromethorphan and galantamine) that show novel functions in NOX2 inhibition and neuroprotection in experimental settings [75, 101, 103] further hints at the feasibility of pharmacological modulation of over -activated NOX2 for the treatment of neurodegenerative diseases. Furthermore, the newly-discovered p47phox- independent mechanism of PHOX activation in in vitro studies [8–10] implies that it might be clinically safer to modulate NOX2 activity through targeting p47phox. Nonetheless, great caution must be exercised when developing therapeutic compounds to decrease — but not to abolish — the excessive activity of the NADPH oxidase enzyme for neurodegenerative d iseases.
Of several known NADPH oxidase inhibitors, apocynin and DPI are most widely used and are invaluable pharmacological tools in NADPH oxidase research . Apocynin (a methoxy-substituted catechol) blocks the assembly of p47phox with membrane-bound p22phox/ NOX2 heterodimer. It has also been reported to affect redox status in nonphagocytic cells acting as a radical scavenger [105] or a pro-oxidant under certain conditions [106]. DPI as an irreversible noncompetitive flavoprotein inhibitor abstracts electrons from the reduced flavin and prevents electron flow through the flavoprotein conduit. DPI has been widely used as a nonspecific NOX2 inhibitor because it shows more potent inhibition of NOX2 than of other flavin-containing enzymes, such as nitric oxide synthases, NADH dehydrogenase, xanthine oxidase, cytochrome p450 oxidoreductase, and NADH-ubiquinone oxidoreductase [3]. The lack of selectivity of DPI for NADPH oxidases and the pro-oxidant potential of apocynin might limit their clinical translation. The newly-developed NADPH oxidase inhibitors, 4-(2- aminoethyl)benzenesulfonyl fluoride (AEBSF) and the synthetic peptide NOX2ds-tat, inhibit the association of p47phox with p22phox/ NOX2 heterodimer. However, the irreversible off-target effect on serine proteases and the very low efficacy (IC50 >1 mM) of AEBSF and the unfavorable administration routes (non-oral routes) of NOX2ds-tat peptide might exclude them from clinical translation. The action mechanism and the selectivity of other putative NADPH oxidase inhibitors remain to be investigated thoroughly. More detailed information on NOX inhibitors has been discussed in recent comprehensive review articles [3, 107]. In view of limitations of known NOX2 inhibitors in clinical translation, novel blood-brain-barrier permeable NADPH oxidase inhibitors with improved efficacy, specificity and pharmacokinetic profiles might have potential for development into clinical therapeutics for various neurodegenerative d iseases.
Oxidative stress and neuroinflammation are the two most common features shared by various neurodegenerative diseases. Over-activated NADPH oxidases, especially PHOX and its catalytic subunit NOX2 have been recognized as a major mediator of inflammatory oxidative neurodegeneration in these diseases. Pharmacological inhibition of NOX2 activity with several structurally and functionally different compounds attenuates the neurodegeneration in models of neurodegenerative diseases. Such preclinical evidence provides a strong rationale for pharmacological modulation of NADPH oxidase activity in combating oxidative stress-mediated neurodegeneration in these diseases. Given the limitation of existing NOX2 inhibitors in clinical translation and the potential drawbacks to targeting NOX2, the next step is to develop novel blood-brainbarrier permeable NADPH oxidase inhibitors with improved specificity, efficacy, and pharmacokinetic profiles. Further examination of anti-inflammatory and NOX-inhibitory action as well as neuroprotective effects of a new generation of NADPH oxidase inhibitors in multiple animal models of neurodegenerative diseases will identify promising drug candidates for future clinical trials. Thus, with increasing awareness of the prime role of NADPH oxidases, especially NOX2, in oxidative stress-mediated chronic neurodegeneration, proper modulation of NOX activity might present a promising therapeutic strategy to retard the progression of many neurodegenerative diseases.
This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. We apologize for limiting citation of many excellent original contributions due to space l imitations. The authors declare they have no actual or potential competing financial interests.
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text:
Toying Around is a Super Pokemon Adventures episode.
- When Ash, Mitchie, Skeeter, Kimiko, Zak, Timon and Pumbaa go to Toys R Us, Ash discovers a custom Thomas VHS called Edward's Exploit and Other Thomas Stories which was released on May 30, 2000. So he takes it, but soon the Thomas toys come alive and luckily The Steamettes arrive to save the day. Note: Kimiko is wearing her The Shard of Lightning outfit.
- Ash Ketchum
- Mitchie Ohara
- Skeeter Valentine
- Kimiko Tohomiko
- Zak Saturday
- Timon
- Pumbaa
- Aya
- Satsuki
- Charmaine
Part 1
- (We See Ash and the gang at Toys R Us)
- Ash: Wow, lots of stuff going on.
- Mitchie: Look, a store full of Thomas stuff.
- Ash: Hey look, a 2000 VHS of Edward's Exploit and Other Stories.
- Zak: May it contains 8 episodes from this episode to Busy Going Backwards.
- Ash: Can i take it?
- Kimiko: Sure.
- (Ash takes the Edward's Exploit 2000 VHS)
- Timon: Wooden railway stuff. I'll take the Troublesome Brakevan and the Tar and Fuel tankers and then the cargo car.
- Pumbaa: To make Henry's Flying Kipper set.
- Mitchie: Books. Hey, Angie. A Thomas and The Rumours book.
- Mitchie: Can you read it?
- Mitchie: Sure, Angie.
- Ash: This is released by Video Treasures, eh?
- Kimiko: Lisa i'll take another Thomas book called the Thomas The Tank Engine Storybook. It contains 10 Season 3 episodes.
- Lisa: Okay.
- Mitchie: Thomas The Tank Engine loves his branch line.
- Angie: Hee hee hee!
- Kimiko: The lines runned around the coast by sandy beaches,

subset: commoncrawl


text: Welcome to the 2016/2017 school year! I am excited to make it a fun and successful one. Below, you will see my schedule. To be taken to a class' Powerschool Learning page, simply click on the class! To arrange time to meet, please do not hesitate to reach out via email.


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Fort Pierce Health Care
Talk to a Family Advisor:
Reviews of Fort Pierce Health Care
anni2006 October 27, 2014
I am a friend or relative of resident
I am working on getting my aunt out of there right now! This place is nasty: gnats flying, CNA's throwing clean linens over dirty ones on the patients, soiled briefs sitting outside the rooms. No dignity for the patient. Does not contact family of any changes in condition, incidents as in bruises, refusal of therapy. Not a pleasant or happy environment. Cannot get the nurses to explain health situations in person.
wsmitt August 25, 2013
I am a friend or relative of resident
This place must be one of the worst places in Ft Pierce. I had a friend stay here for wound care and his wound ended up getting infected
lynnlynn November 15, 2011
I am a friend or relative of resident
do not let your loved one go here, it is a dirty place,and there is a nurse named courtney who delights in being cruel to patients, if u value your lovd one don,t send them there there is a reason for one star out of five
Write a Review
About Fort Pierce Health Care
Fort Pierce Health Care is a nursing home in Fort Pierce, FL that provides patients with skilled nursing care as well as private or shared accommodations. Contact Fort Pierce Health Care for more details on housing, services, and rates.
Features of Fort Pierce Health Care
Medicare (ratings last updated: 06/16/17)
- Health:
- Overall:
- Quality:
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- Medicare Provider Number: 105257
- Ownership Type: For Profit Corporation
- Date Certified: 05/01/2017
- Resident Capacity: 171
Location of Fort Pierce Health Care
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Chief Minister K Chandrasekhar Rao today sanctioned Rs 10 crore for construction of a Kalyana Mandapam with all facilities at Timmapur Gutta Temple of Sri Venkateshwara at Birkur mandal of Nizamabad district here.
Appreciating the people for developing the temple, the Chief Minister vowed to develop it on the lines of Lord Venkateshwara temple of Tirumala Tirupathi Devasthamans in Chittoor district. KCR said he will soon pay a visit to TTD's Venkateshwara Swamy to donate ornaments worth Rs 5 crore to keep his promise during statehood movement. KCR also said Timmapur Gutta will be developed as Telangana Tirumala, he declared. "There was no dearth of donors and philanthropists in the country and I will try my best to collect funds for the temple development", KCR stated.
"We are focusing on developing the temples and encourage such meditation centers to rebuild the society to spread our precious cultural ambience and tradition, the chief minister averred. After participating in Sudharshana Yagam on the temple premises along with family members, KCR offered Rs 10,00,116 for the temple. He also announced to handover 387 acres to the temple to be turned into a tourist destination soon.
Earlier, the temple priests and officials accorded rousing reception to the CM team with Purnakumbham and then they proceeded to attend the ritual on the premises. (NSS)


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As an avid music fan, I was intrigued by the Muusa treatment, which promises a customised soundtrack in time with the therapist's strokes. The therapy was pioneered in Italy and is limited to a few spas; Hong Kong day spa Sense of Touch debuts this treatment in Asia.
The Muusa creators point out that soundtracks can never be replicated, even if you have another Muusa massage with the same therapist, as every massage is different. Once the treatment is over, you take home the music created during the session on a CD - the idea being to relive the tranquil spa vibe back at home.
Arriving at Sense of Touch's spa in Repulse Bay, I'm given four options. There is the 90-minute 'Awaken Your Senses' with a coffee scrub blended with peppermint, followed by a sandalwood and lemon grass-scented massage paired with celestial choirs. The three 60-minute treatments are 'Infinite Harmony', which uses warm basalt stones, geranium and lavender, and natural rhythms to reduce stress; a camomile and sandalwood massage, 'Everything Flows', that embraces ethnic sounds; and 'Seventh Heaven', long massage strokes with delicate piano. I'm booked in for the latter and already feel less tense after lounging on the white leather sofa in reception with a glass of chrysanthemum tea.
I enter the candlelit treatment room, where a bed with white cotton drapes beckons. After I inhale the scent of lavender oil, the therapist strokes along my back, while soft, tinkling piano plays against rustling winds and flowing rivers. At first, I think the sound of birds is part of the tune but am pleasantly surprised when I later realise it's coming from outside the spa.
The music - tracked by sensors attached to the therapist - falls almost silent as she places pressure on my spine then sparks back into life as she sweeps down my back. But as her movements become more repetitive so does the tune. My personalised soundtrack begins to sound like relaxing CDs you hear in most spas, and isn't quite the dramatic backdrop I was expecting.
Some days later, I put on my CD at home and attempt to recreate that blissed-out spa feeling. Listening to the meditative sounds of the gentle keys once more and imagining the therapist's hands reviving my stressed-out muscles is certainly enjoyable, but I can't help wishing that I could actually feel my shoulders being pummelled.
The Muusa treatment is available at Sense of Touch, Repulse Bay, The Repulse Bay Arcade, 109 Repulse Bay Road. Tel: 2592 9668, senseoftouch.com.hk
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Make-A-Wish Wisconsin will grant its 6,000th wish to 4-year-old Lincoln Durik of Wales who has a life-threatening neurological condition and has been diagnosed with autism.
Lincoln's wish was for a sensory room, and he'll get just that, complete with a custom mural painted by local artists Carrie Chimenti and Colleen Drew. The room will include a sensory panel filled with hands-on activities, including a heat-sensitive panel, a bead maze panel and panels filled with different colors and textures, lights and sounds. A ball pit, bean bag chair, bubble tube, LED light strands and a projector that projects different colorful images on the wall are also part of the room, according to a news release.
Lincoln's family and friends will be at the Duriks' home in Wales at 10 a.m. Friday, April 21, for the unveiling of the sensory room. Members of the Make-A-Wish staff will also be on hand, as will members of the town of Genesee Fire Department who have helped the Durik family in responding to medical calls for Lincoln's seizures.
"Lincoln's wish is just a really special wish," said Make-A-Wish Wisconsin Director of Marketing and Communications Forest Doolen. "His wish and story is unique for the same reason that all of our kids are unique in who they are as individuals and who they are as a family, and just the very unique situation that they have to go through."
Sarah Durik, Lincoln's mother, is grateful for Make-A-Wish Wisconsin and what they are doing, and was surprised to get a call from the organization.
"They called me up one day and they said they would love to grant Lincoln his wish," Durik said of the phone call. "In fact, every time they call me, they're like 'We are so excited about this.' They are so awesome. These people are amazing."
Durik said that Lincoln has inspired a lot of people, and said he wakes up with a smile on his face every day.
"He is super; he is inspiring," Durik said. "In fact, It blows my mind because he has touched more people's lives than most human beings do in their lifetime. I even had a lady tell me she has a heart condition, and when she's having her issues, she says she thinks about Lincoln, and if Lincoln can do it, she can do it. That's pretty powerful."
Lincoln's wish is the 6,000th wish granted by Make-A-Wish Wisconsin since it started in 1984. The first wish the organization ever granted was to 11-year-old Catina, who wanted to meet Michael Jackson. In 2016, the chapter granted a record 378 wishes, with a plan to grant more than 380 this year.
The organization is granting Lincoln's wish in honor of World Wish Day, which takes place annually April 29 to honor the day that inspired Make-A-Wish's founding.


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Sunday, September 24 at 2:00 pm at The Barn
Back by popular demand, and looking for more requests! Westben roasts up
a colourful afternoon of musical "chestnuts" in a special fall fundraising concert featuring Donna Bennett, Kimberly Dafoe, Gabrielle Prata, Robert Longo,
Frank Moore and Brian Finley. Complete with chestnuts roasting on an open fire, expect a heart-warming concert based on patron requests performed by favourite Westben performers. Visit the wine tent and food auction tables for delicious treats all in support of Westben.


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Description of Special Collection
University Library
Collection Level Description: Roper, H.L.
- Collection name: Roper, H.L.
- Collection code: GB 0033 SAD
- Date range: ca.1923-1955
- Extent: 0.5 box
- Language: English
- Held by: Durham University Library, Archives and Special Collections
- Part of : Sudan Archive
Personal correspondence, 131 photographs of N. Sudan; 2 cinefilms recording life in Red Sea Province, with VHS copy; 4 throwing knives; printed material
About the creator:
Sudan Customs Department, 1922-1949 ; Director of Customs, 1944-1949
Throwing knives presented by Roper, 1966. Other material donated, Mrs A. Ramsay, 1992
Online catalogue
Index termsRoper, H. L., fl.1922-1966.
Sudan -- Description and travel.
Nuba Mountains.
Kassala (Sudan : Province)
Date last modified: 25 November 2008
This is part of the Sudan ArchiveThe collections that are part of Sudan Archive are:


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Firms' Contribution to the Reconciliation between Work and Family
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If you experience problems downloading a file, check if you have the proper application to view it first. In case of further problems read the IDEAS help page. Note that these files are not on the IDEAS site. Please be patient as the files may be large.
Volume (Year): 1 (2003)
Issue (Month): 4 (October)
Pages: 08-12
|Contact details of provider:
| Postal: Poschingerstr. 5, 81679 München
Phone: +49-89-9224-0
Fax: +49-89-985369
Web page: http://www.cesifo-group.de
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References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- Gilbert Cette & Nicolas Dromel & Dominique Méda, 2004.
"Les déterminants du jugement des salariés sur la RTT,"
Économie et Statistique,
Programme National Persée, vol. 376(1), pages 117-151.
- Gilbert Cette & Nicolas Dromel & Dominique Méda, 2005. "Les Déterminants du Jugement des Salariés sur la RTT," Post-Print halshs-00641127, HAL.
- John M. Evans, 2001. "Firms' Contribution to the Reconciliation between Work and Family Life," OECD Labour Market and Social Policy Occasional Papers 48, OECD Publishing. Full references (including those not matched with items on IDEAS)
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Let us know when your receive great advice so we can thank our lawyers and point others with similar questions in the right direction.Got it!
the accident happened on July 16, 2010. So i am very close to the end of my statute on limitations.
Wow. You need to call someone fast. Hopefully you have all the medicals organized. If not, contact an attorney soon so they can get everything organized. I would be glad to help if need be. Just take a look around on here or online to find someone in your local area. There are plenty of good attorneys in Decatur who can help.Ask a similar question
Unfortunately, If your dates are correct, I believe you are out of time to file. OCGA 9-3-33 gives the injured party 2 years to file a case in Georgia. That means your time lapsed on July 16, 2012. Let me know if I misunderstood something.
For more information, contact us at email@example.com or (770) 984-5380. The initial consultation is always free. This post is intended to provide general guidance, and should not be construed as legal advice. While I am an attorney, unless we sign a retainer agreement, I am not your attorney, and any information shared on Avvo does not create an attorney-client relationship. Please mark this answer as "Helpful" or "Best Answer" if you like it.Ask a similar question
Yeah I was assuming he/she meant 11. Hopefully since they mentioned the SOL, they meant 11. They must have done some looking about.
I think you may have missed the SOL already, unless I am reading your facts incorrectly, did the accident happen some place OTHER than Georgia?
This is general advice and does not establish an attorney-client relationship.Ask a similar question
It sounds like you may possibly have waited too long. The statute is two years in Georgia. Since you say it is another state, you need to call a lawyer in that state and see what the statute is (which may be different). Rush. Dont wait past today.
If you find this answer helpful, please mark it here on AVVO as helpful. In answering you, I am attempting to communicate general legal information and am not representing you (and am not your lawyer). Do feel free to call me at 404-768-3509 if you wish to discuss actual representation (the phone call also does not retain counsel; that requires an office visit and appropriate paperwork). In that a forum such as this provides me with limited details and doesn't allow me to review details and documents, it is possible that answers here, while meant to be helpful, may in some cases not be complete or accurate, and I highly recommend that you retain legal counsel rather than rely on the answers here. (You can also email my office at firstname.lastname@example.com . An email also does not retain my office, but can help you get an appointment set if you prefer not to call). I am happy to discuss possible representation with you. Any information in this communication is for discussion purposes only, and is not offered as legal advice. There is no right to rely on the information contained in this communication and no attorney-client relationship is formed. Nothing in my answer should be considered as tax-advice. To ensure compliance with IRS Circular 230, any U.S. federal tax advice provided in this communication is not intended or written to be used, and it cannot be used by the recipient or any other taxpayer (i) for the purpose of avoiding tax penalties that may be imposed on the recipient or any other taxpayer, or (ii) in promoting, marketing or recommending to another party a partnership or other entity, investment plan, arrangement or other transaction addressed herein. I am also required to advise you, if your question concerns bankruptcy, that the U.S. Congress has designated Ashman Law Office as a debt relief agency that can help people file bankruptcy.Ask a similar question
I'm happy to answer any question you may have. My email is firstname.lastname@example.com a similar question
There are a lot of personal injury attorneys from GA on this site or you can check with the local bar association.Ask a similar question
Where this accident happened is pivotal. If it were in South Carolina for example, you would have a three year statute of limitations which means you still have time to bring your claim. Where did the accident happen?Ask a similar question
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- You are here:
- goodtoknow
- Recipes
- Food pictures
19. Apple and raspberry cake
Flavours: A soft crumbly topping with a tangy apple filling.
Time it takes to make: 30 mins
Why we love it: Apple and raspberry in a cake? Yes, please! This fruity cake is a pure slice of summer - the sweet flavours and crumbly topping will not fail to put a smile on your face.
Top tip: To make the topping even quicker, blitz all the ingredients in a food processor.
Get the recipe: Apple and raspberry cake
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John Sebastian - Younger Generation @ Woodstock 1969 MP3
John Sebastian with "Younger Generation" from a film about Woodstock 1969 :-)
The Lovin Spoonful- Younger Generation MP3
Why must every generation, Think their folks are square? And no matter where their heads are, They know mom's ain't there, Cause I swore when I was small, ...
THE YOUNGER GENERATION - We Rap More Mellow (12" - 1979) MP3
Early release from Grandmaster Flash & The Furious Five.
Younger Generation MP3
John Sebastian singing a song he wrote called "Younger Generation".
Gentleman - Younger Generation (Featuring Luciano & Mikey General) - Journey To Jah Album MP3
Playlists Journey To Jah Album - http://www.youtube.com/view_play_list?p=8BCFCA31BC8990AC Gentleman ...
John Sebastian - Younger generation HQ woodstock MP3
ISIS using apps to reach younger generation MP3
Most parents think their biggest concerns when it comes to video games is the violence, but those games could actually be breeding hubs for ISIS recruitment.
John Sebastian - Younger Generation - 7/21/1970 - Tanglewood (Official) MP3
John Sebastian - Younger Generation Recorded Live: 7/21/1970 - Tanglewood - Lenox, MA More John Sebastian at Music Vault: http://www.musicvault.com ...
The Lovin' Spoonful - Younger Generation (HQ) MP3
Released 1967. Uploaded by Nicholas Kriisa in accordance with Fair Use laws.
Jose Feliciano - Younger Generation MP3
Song: Jose Feliciano - Younger Generation Artist: Jose Feliciano Album: Souled Year: 1968.
Gentleman - Younger Generation MP3
Gentleman mit dem Lied Younger Generation aus dem Album Journey to Jah. Track 10.
We Rap More Mellow -Marvelous Three & The Younger Generation MP3
Released: 1979 Label: Brass Records.
The Adicts- Younger Generation MP3
The Adicts "Younger Generation" LYRICS: Start to moan when there's nothing to do Scream and bawl when there's nothing to do at all (at all!) Wanna go out but ...
Prince Far I- Younger Generation MP3
The Younger Generation - We Rap More Mellow (Joey Negro Remix) MP3
Z Records (release date: 2015-03-02) Available@ http://www.zrecords.ltd.uk/ ...
the adicts younger generation subtitulado MP3
Rappin' All Over- Marvelous Three & The Younger Generation MP3
Released: 1980 Label: Brass Records.
Younger Generation, by Aaron Copland MP3
ENMU Chamber Singers singing "Younger Generation" by Aaron Copland.
Why younger generation fails to show patience towards people with disabilities MP3
In this social experiment, our actor is Jaquiline, a very talented former Indian hockey player who now for some years has suffered from a disability. Like we know ...
Adults who are Friends w/ The Younger Generation -- Multi-Fandom Collab (10 vidders!) MP3
Voiceovers are transcribed below! ~~ I was originally going to say the theme for this collab was "Parents who are Friends w/ Their Kids' Friends". That was too ...
Younger Generation MP3
Provided to YouTube by The Orchard Enterprises Younger Generation · José Feliciano Grandes Éxitos De José Feliciano ℗ 2004 OK Records Released on: ...
The Younger Generation - We Rap More Mellow MP3
[Mini Version] - 1979 https://www.facebook.com/Phase2rap?ref=hl.
J2 - the younger generation watching SPN MP3
Jensen and Jared discuss what it is like knowing that kids are growing up with their show. Salute to Supernatural San Francisco 2015.
My advice to younger generation military! MP3
Please like, comment, and share this so that the younger generation of our military don't make the same mistakes I did coming up.
"Younger Generation Blues" - Janis Ian (1967) MP3
From her 1967 debut album. This album also featured her big hit "Society's Child." For entertainment only-No copyright implied.
The Stupidity Of The Younger Generation Must Stop MP3
FREE Registration to our ONLINE CLASSES, go to http://www.israelunite.org. For more videos visit us at http://www.israelunite.org/videos and for israelite ...
GOTH?! ((A Video for the Younger Generation.)) MP3
Below are links to my social networking sites: Instagram: the_goblin_queen Tumblr: http://allisoneckfeldtblog.tumblr.com/ Ask Me Anything: ...
GOTHIC ROCK?! ((A Video for the Younger Generation.)) MP3
Below are links to my social networking sites: Instagram: the_goblin_queen Tumblr: http://allisoneckfeldtblog.tumblr.com/ Ask Me Anything: ...
Django Reinhardt - Younger Generation - Paris, 30.06.1939 MP3
Django Reinhardt et le Quintette du Hot Club de France, avec Stéphane Grappelli Stéphane Grappelli (vln); Django Reinhardt (g solo); Eugène Vées, Pierre ...


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This is an example of a WordPress page, you could edit this to put information about yourself or your site so readers know where you are coming from. You can create as many pages like this one or sub-pages as you like and manage all of your content inside of WordPress.
The URI to TrackBack this entry is: https://hablandoensirio.wordpress.com/about/trackback/


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Celebrity Pink Body Sculpt by Juniors' Lifter Skinny Jeans
Every girl needs a pair of classic skinny jeans, and Celebrity Pink's pair fits the bill with traditional five-pocket styling and a light wash with whiskering and fading. Mid rise: waistband sits below natural waist Slim fit through hips and thighs Skinny leg Stretch fabric shapes and lifts Front button closure with zipper fly; belt loops Five-pocket styling; two shaped back patch pockets Sculpted back panels Available in multiple washes Approximate inseam: 29 inches Cotton/polyester/rayon/spandex Machine washable Imported Web ID: 2636328
Celebrity Pink Body Sculpt by Trendy Plus Size The Lifter Skinny Jeans
Featuring a lifting design, Body Sculpt by Celebrity Pink plus size skinny jeans are must-haves for your casual look. Mid rise Skinny fit through hips and thighs Skinny leg Innovative stretch fabric holds everything in place like shapewear, while design of the jean shapes and lifts your best asset Front zipper and button closure; belt loops Classic 5-pocket styling Deep red wash with no whiskering or fading Approximate inseam: 30" Cotton/polyester/spandex Machine washable Imported Web ID: 2822430


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Bernard Mizeki (sometimes spelt Bernard Mzeki; c. 1861 – 18 June 1896) was an African Christian missionary and martyr. He was born Mamiyeri Mitseka Gwambe in Inhambane, Portuguese East Africa (Mozambique), but moved to Cape Town, Cape Colony (South Africa), when he was about twelve years old.
Through the work of the Cowley Fathers' mission, and particularly the German missionary Baroness Paula Dorothea von Blomberg he became a Christian and was one of the first to be baptized in St Philip's Mission, Sir Lowry Road, on 7 March 1886. Shortly after his baptism, Bernard started work at St Columba's Hostel, which was run by the missionaries for African men. Within a few months he was sent to Zonnebloem College to train as a catechist.
In January 1891, Bernard accompanied the new missionary bishop of Mashonaland, George William Knight-Bruce, as a lay catechist among the Shona people in Southern Rhodesia (Zimbabwe). He was sent to work in the Marandellas (Marondero) district among the Nhowe people, and settled in the kraal of Mangwende Mungati. Bernard built his home there, and took people who wanted to learn into his home to teach them the gospel. In March 1896, Bernard married Mutwa (later 'Lily'), a granddaughter of the Mangwende and a Christian convert.
During the Matabeleland Rebellion, Bernard Mizeki was murdered outside of his home. While missionary workers were being ordered to safety, Bernard felt that his absent bishop's orders to stay could not be overruled. On the night of 18 June 1896, he was dragged from his home and stabbed. Mutwa found him still alive and went for help. Before she could return, she and others reported seeing a great white light all over that place, and a loud noise "like many wings of great birds". Bernard's body was then found to have disappeared. Mchemwa, a son of the Mangwende and an ally of the witch doctors, was later found to be responsible for Bernard's murder and the removal of his body, as well as the destruction of the mission settlement there.
Bernard Mizeki's work among the Shona bore fruit. After long years of earlier mission work in Mashonaland by white missionaries, the first Shona convert to be baptised was one of the young men whom Bernard had taught: John Kapuya. John was baptised only a month after Bernard's death, on 18 July 1896. Bernard Mizeki is revered as a hero of the faith in Africa. Today, Bernard Mizeki College stands close to where he lived, and the Mangwende's kraal, above the village, is crowned with a large cross to commemorate Bernard.[1]
1Farrant, Jean, 1966, Mashonaland Martyr: Bernard Mizeki and the Pioneer Church, Oxford University Press, London.
- ↑ Farrant, Jean, 1966, Mashonaland Martyr: Bernard Mizeki and the Pioneer Church, Oxford University Press, London.


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how do I change my email address?Asked by Joni Long on April 18, 2013 at 11:45 AM
@Joni Long
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text: OTTAWA, June 25, 2013 (GLOBE NEWSWIRE) -- Validian Corp. (OTCQB:VLDI), first-to-market with next generation cyber security technology that provides secure access, transfer and storage of digital information on wired, wireless and mobile networks over the Internet, is pleased to report on the recently attended NIBA Conference in New York City. Presenting at the National Investment Banking Association (NIBA) Conference was the first time that the Validian story has been shared in such an important format mainly because until this point in time, Validian and its core Cyber Security Technology have been waiting for the Juggernaut shift to mobile to stabilize. That time has arrived now that all four major mobile operating system platforms have become available as of March 2013. For this NIBA event, the conference setting comprised rooms where each company maintained a booth for standard conference interaction with attendees and a presentation room where on Tuesday June 18th each of the companies presenting ran through their key points in a maximum time period of 10 minutes to a large room filled with attendees. In summary, the opportunity to present the Validian story to both the investment community and those interested in potential collaboration using the technology looks to be an overwhelming success. There were a large number of investment bankers and brokerage professionals in the audience at this event, which immediately translated into many follow up meetings that required CEO Bruce Benn and Validian support personnel to extend their stay for the remainder of the week in NYC. In order to accommodate an overload of interested parties, a second presentation was held for an additional 35 interested parties on Friday, June 21 st in midtown Manhattan at an off site location. Furthermore, Validian already is scheduling follow up conference calls and additional meetings and presentations through the rest of June and July. There already has been tremendous interest to provide substantial investment into Validian at attractive valuations for the continued development, implementation and roll out of its technology as well as interest from third parties for the potential co-development and implementation of solutions that will utilize Validian's core technology for their particular cyber security and/or privacy needs.


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Used 2002 Chevrolet Corvette
30+ days ago
St. Marys, OH 45885, USA
28,105 Miles
St. Marys, OH
St. Marys, OH
Ask for Tom or Dave in the HUGE Corvette showroom at BUDS Chevrolet in St. Marys, Ohio. Call toll free at 800-688- (BUDS) 2837.Here's a great car that belonged to a great friend and customer of BUDS Chevrolet. It is peter metallic with black sport leather interior and top. it's an automatic with head ...
28,105 Miles
28,105 Miles


text: Butterick 6209; ca. 1952; Girls' School or Party Dress. Make it for parties, play or school. (A) Pretty bodice with a cuffed bateau neckline tops a floor length skirt with contrast insertion; tied-in back sash. (B) Day-length, rick rack trim. (C) Fill in neckline with yoke and collar in contrast.


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Abet Synonym, Antonyms
Synonyms and Antonyms of Abet
Synonym for abet at synonym.co.in with antonyms, and definitions from English Dictionary with examples. More- than 13 Synonyms and 16 Antonyms of abet are added to this page.
Synonyms: Aid, support, promote, countenance, uphold, assist, instigate, encourage, incite, advocate, sanction, subsidize, embolden.
Antonyms : Thwart, contradict, obstruct, oppose, baffle, confound, discourage, disapprove, disconcert, counteract,deter, dissuade, frustrate, impede, denounce, expose.
Meaning of "abet" in the English Dictionary
- encourage or help someone to do something


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Simple and serene RV park in a great location, just west of the Wright Brothers Memorial. Clean and well kept, surrounded by wetlands and the Sound. Gravel pads and roads. Playset for the kids. Full hookups with 20/30/50 amp connections, cable and WiFi included.
Property: OBX CampgroundAddress: 126 Marshy Ridge Rd, Kill Devil Hills, NC 27948-8092
Location: United States > North Carolina > North Carolina Coast > Outer Banks > Kill Devil Hills
Free High Speed Internet ( WiFi ) Free Parking Pets Allowed ( Dog / Pet Friendly ) Wheelchair access
Ranked #1 of 2 Specialty Lodging in Kill Devil Hills
Price Range (Based on Average Rates): $
Number of rooms: 56
- Official Description (provided by the hotel):
- Modern RV park. NO TENTS! ... more less
- Also Known As:
- OBX Campground Outer Banks, NC - Kill Devil Hills


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Brewing your own beer can make you the most popular guy in your neighborhood, especially if every bottle also comes with a stack of homemade money. Get crafty with this Groupon.
Choose Between Two Options
- $35 for a basic beer-making class for two (a $70 value)
- $70 for a basic beer-making class for four (a $140 value)
Learn To Brew
Learn To Brew was created by a professional brewer in an effort to provide patrons with a one-stop-shop for supplies, hands-on classes, and how-to videos for crafting beer and wine. In addition to taps and kegerators for homes or businesses, staff members stock ingredients such as hops, malts, and yeasts. In their classes, they cover everything from balancing acids for wine to fermenting honey for mead.


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Customers can select options when they see a configurable product, e.g. colour or size. This is useful when you want them to click on a generic product name and then tailor the product to suit their needs.
The first thing you have to do is create any new attributes you require. After specifying the values for these, you then create a new attribute set. Drag the new attributes into a new group called Selectable Options.
Next, you create the configurable product. Select the new attribute set and then select only the options you wish to include for this product. You can see by doing this that you could have one attribute set per configurable product type, or you could have one configurable product for all products in the shop.
After doing this you can assign simple products to the configurable product by clicking on Associated Products and selecting them. If the simple products don't appear in the list as expected, then it's most probable you either haven't set the attribute scope to Global (required for all configurable product attributes) or you have assigned a different attribute set to the product.
Rule #1: Attributes used in configurable products need to have a global scope.
Rule #2: Simple products assigned to configurable products need to be assigned the same attribute set.


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AR-DE used to be project/yacht name Argyll; N'paradise. This 31 metre (101 foot) luxury yacht was manufactured by Burger Boats in 1996. Motor Yacht AR-DE is a well sized superyacht. The firm of naval architecture responsible for this yacht's plans and general arangement in respect of this ship was Don O'keeffe. Her initial interior design and styling was the work of the talented Barbara Wagner/Benson Design. Luxury yacht AR-DE is a interesting yacht that can accommodate up to 6 people on board and has approximately 4 crew.
Don O'keeffe was the naval architecture company involved in the technical nautical plans for AR-DE. Also the company Don O'keeffe successfully collaborated on this project. Interior designer Barbara Wagner/Benson Design was employed for the creative interior ambience. Created at Burger Boats the yacht was completed in the recognised yachting country the United States. She was officially launched in Manitowoc Wi in 1996 before being transferred to the owner. Her core hull was crafted from aluminium. The motor yacht main superstructure is fabricated for the most part with aluminium. With a beam of 6.71 m or 22 feet AR-DE has moderate size. She has a shallow draught of 1.85m (6ft).
The 3412 DITA engine powering the yacht is built by CATERPILLAR. Coupled to the AR-DE engines are twin screw propellers. The engine of the ship produces 1250 horse power (or 932 kilowatts). She is fitted with 2 engines. The combined output for the boat is 2500 HP or 1864 KW. With respect to stabalisers she was supplied with Van Der Velden. The bow thrusters are Van Der Velden.
Having bedding for a limit of 6 welcome guests sleeping aboard, the AR-DE accommodates everyone comfortably. Normally the vessel utilises approximately 4 expert crew members to manage.
The propulsion comes from two 1250 HP or 932 kW Caterpillar. Model: 3412 DITA diesel. - Overall output: 2500 HP /1864 KW. - Cruising at a speed of 18 nautical miles per hour. - Her top Speed is around 21 knots. - Approximate range: 3000 at a speed of 12 knots. - Fuel Capacity: 37850 L. - Potable water capacity: 4731.00. - Power generation: Northern Lights 2 times 40 kilowatts. - Stabaliser Stabality devices: Van Der Velden. - Thrusters: Van Der Velden. - Yacht Beam: 6.71m/22ft. - Waterline Length (LWL): 26.91m/88.3ft. - Draught Maximum: 1.85m/6ft.
Her deck material is predominantly a teak deck.
The luxury yacht AR-DE displayed on this page is merely informational and she is not necessarily available for yacht charter or for sale, nor is she represented or marketed in anyway by CharterWorld. This web page and the superyacht information contained herein is not contractual. All yacht specifications and informations are displayed in good faith but CharterWorld does not warrant or assume any legal liability or responsibility for the current accuracy, completeness, validity, or usefulness of any superyacht information and/or images displayed. All boat information is subject to change without prior notice and may not be current.
30.7m (100.7'), 1996, The United States, Burger Boat Company, Don O'keeffe
BOWIE, M/Y PALADIN, Sailing Yacht GOF, EXPLORER 1, 57m Feadship Motor Yacht


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The new face of banking is the Omni banking branchless banking which UBL has recently introduced in Pakistan. Its ever growing popularity is the proof of its convenience to the users. By now UBL Omni branchless banking has reached to more than six hundred cities of Pakistan.
For a layman understanding Omni offers you all what you expect from a bank but truly speaking it is more convenient than a bank. Most important thing is its timings which is not restricted like a bank that usually is 9 am to 5 pm. You can make utility bill payment, send or receive money till as late as your nearby Omni Dukaan is not closed.
UBL Omni Charges and Fees & Money Receiving and Sending Procedure Step by Step
- 1. Visit any UBL Omni Dukaan with your original CNIC and its copy to initiate the money transfer.
- 2. Provide the following details to the UBL Omni Dukaandar which is required for sending money:- Your CNIC number
– Your mobile number
– City where you are sending money
– Receiver CNIC number
– Amount
– Receiver mobile number (Optional)
- You also have the choice of keeping a disbursal code on your own, or you can let Omni keep a code for you. The disbursal code will be used by the receiver to collect money from the UBL Omni Dukaan. If you choose to keep the disbursal code on your own, you will be required to enter that disbursal code on agent's mobile or PC.
- UBL Omni Dukaandar will enter the details on his mobile or PC and ask you for a copy of your CNIC which he will keep for submission to UBL. On successful transaction you will receive an SMS from 8257 on the mobile number you provided which will contain the 5 digit disbursal code for this transaction, and a transaction ID. It is VERY important that you provide your own mobile number as:
– The disbursal code will only be sent on the mobile number
– The disbursal code will be required by the receiver to collect the funds
- UBL Omni Dukaandar will also hand over a printed transaction receipt containing all the transaction details. Please keep this slip safe until the receiver has successfully collected the funds. Communicate the 5 digit disbursal code you received on your mobile to the receiver.
Receiving Process
- Receiver can visit any UBL Omni Dukaan to collect funds by presenting the following:
– Own (Receiver) CNIC
– Copy of own (Receiver) CNIC
– 5 digit disbursal code (necessary)
- UBL Omni Dukaandar will verify the receiver's CNIC copy with the original and initiate the transaction. On successful execution of the transaction, a confirmation SM
Omni account user can deposit and withdraw cash, make utility bill payments, send or receive money, purchase mobile card vouchers, make postpaid mobile bill payment from any branch of Omni which is near you. Keep in touch with us for more details of prices.
|Do you want to sell This ?
|Do you want to Buy ?


text:
Robert Mugabe is the President of Zimbabwe, in much the same way as Saddam Hussein was the Prime Minister of Iraq. One difference between the two is that we all know Iraq exists (good grief, how we know!). Whereas there is strong gutvidence that Zimbabwe, being a country in the mythical continent of Africa, doesn't exist.
One thing's for sure: if this Mugabe guy does exist he is nobody's black friend. Especially not the governments of America or Britain. He also apparently really loves to inflate things.


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Domaine Les Eminades
- Organic certified
- Biodynamic uncertified
Created in 2002 when Luc, an oenologist, stumbled across isolated, very old vines in the hills behind Béziers. His intuitive wine making is already making marvels and the French press is raving about these wines. Driven organically, the vineyard is a mosaic of soils, expositions and altitudes.


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What is JotForm?
JotForm is a free online form builder which helps you create online forms without writing a single line of code. No sign-up required.
At JotForm, we want to make sure that you're getting the online form builder help that you need. Our friendly customer support team is available 24/7.
We believe that if one user has a question, there could be more users who may have the same question. This is why many of our support forum threads are public and available to be searched and viewed. If you'd like help immediately, feel free to search for a similar question, or submit your question or concern.
Why did I just upgrade, but don't see it reflected on my account?Asked by handstand on September 02, 2014 at 11:01 AM
I upgraded and even received a receipt upon doing so. After looking online - my account has not been upgraded?!
Whats going on here? you just take money that is attached to an email address on one of your accounts but don't attach it to the actual account?
I'm very confused as to how this could happen?
I have corrected this order#INT140902-7450-37815 on our end. Your account is now set to premium.
Please contact us again if you still need further help.


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For most people, having a leg amputated below the knee as a teenager could be a catastrophic and possibly life-limiting event. But Justin Godfrey is not like most people.
Just a few years ago, with no prior experience, Justin took on the world of triathlons and has since achieved an impressive number of top ten rankings in International and World ParaTriathlon Championships. Justin has become a member of Triathlon Australia's High Performance Paratriathlon Squad while also working full-time as a valued member of the Coates Hire Albury branch and raising a young family.
In November last year Justin underwent major surgery to graft tissue and skin from his good leg to his stump to build it up – and then went on to win Gold in the ITU Oceania Paratriathlon Championships in Penrith just nine weeks later. This amazing performance was all despite his leg still healing and being able to use only one of the three prosthetic legs he usually uses in events.
In February 2015 he also entered the challenging new world of Cross Paratriathlons, which involve swimming, mountain bike riding and tough trail runs, coming first in his PT3 Category in his first-ever Cross Paratriathlon event.
This was then quickly followed by Gold in the PT3 Category in the ITU World Paratriathlon Championships at Twin Waters on the Gold Coast in March 2015 before Justin received Bronze in Yokohama in May.
The degree of dedication and determination is 'above and beyond' – qualities hugely admired by John Herring, Coates Hire Area Manger – North VIC, who works with Justin.
"Justin's a very good team player, probably due to his discipline in his sport; some days he's up at 4am to train, to be at work by 7am – that's the commitment he has," John Herring explained. "We're very proud of Justin's achievements.
"To not only have overcome losing a leg, but to have the kind of motivation to reach this peak in his sporting endeavours says so much about Justin; he inspires us all to know we can achieve anything we set our minds to."
Despite having his hopes for participating in the 2016 Rio Paralympics dashed by changes to category entries which have left him ineligible to attend, and the medical challenges he continues to face after his November surgery, Justin remains upbeat about all future possibilities.
"With every event I've been improving my personal bests, so I'm pretty happy despite being disappointed about Rio," Justin said. "Right now I'm focusing on healing and training to get for the World Championships in Chicago in September - as an amputee there's a fine line in getting the amount of training I need riding and running, but still managing my leg so it doesn't break down.
"It helps enormously to have the great support I've got, firstly from my wife and two beautiful daughters - my 'Number One Support Crew' – and also from Coates Hire and my work colleagues, particularly my Branch Manager Dave Simic and my fellow Sales-Coordinator Vincent Nix.
"This support network is what helps me achieve my dreams."
Following major surgery on both his good and his amputated leg, Coates Hire employee, Justin Godfrey showed incredible determination to bring home Bronze in his PT3 Category at the recent ITU World ParaTriathlon Championships in Yokohama.
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Kohar Tickets
Find the Kohar tickets you're looking for on viagogo, the world's largest ticket marketplace. Select an event to view the range of tickets available or view the Kohar tour dates to find an upcoming event near you. You can also sell your spare Kohar Concert Tickets on viagogo, and listing tickets is free. All Kohar tickets are covered by the viagogo Ticket guarantee!
Sign Up for Kohar Ticket Alerts
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The four civic responsibilities will provide you with the skills and knowledge you need to be an active and engaged citizen in a complex, diverse, and global society.
Race and ethnicity
Issues of race and ethnicity reside at the heart of America's national identity and underlie some of the nation's most persistent problems. The goal of this civic responsibility is to help students understand the nature of race and ethnicity and the impact both have on our lives in modern communities.
The ideas and practices about gender and sexuality mold identities, institutions, nations, and global interactions. The goal of this civic responsibility is to explore how the construct of gender affects our society.
Global Awareness
The world is becoming increasingly interconnected, and students must develop the intercultural skills that will allow them to participate effectively in the global community.
Community Engagement
TCNJ seeks to prepare its students to sustain and advance the communities in which they live. All incoming students at TCNJ participate in a project or experience that is not only educational for the students but also helps improve the quality of life for others in our region.


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McCall's 5747; ©1960; Misses' Coat in Two Lengths. Single breasted coat, in two lengths, with unmounted long or three-quarter sleeves. Three-quarter sleeves with or without bias cuffs. Patch pockets, optional collar. When collar is omitted, neck, front, pockets and sleeves are trimmed with stitching and stitch trimmed back belt is used, tacked in place under button at either end. Long collarless coat may be closed with nylon tape fastener in place of buttons. Coats are lined and may be interlined.
Links to reviews/blog posts Edit
Sources/Vendors Edit
- Heychica (Bust 34)
- SewUniqueClassique Bust 36
Gallery Edit
[insert your photos of this pattern made up]
Wishlist Edit
[insert your username, and make sure your preferences allow for people to contact you via e-mail. Do not list your email address here!]


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McDonald's: Archenemies.
McDonald's. Choose Lovin'. Featuring: Movie Mavens: King Kong and the Plane & Dorothy and the Wicked Witch of the West & Freddy and Jason. Cartoon Favorites: Coyote and Roadrunner & Smurfs and Gargamel & SpongeBob and Plankton. Animal Hounds: Dog and Postman & Shark and a Swimmer & Grumpy Cat and his Owner. Gamer Geeks: Pacman and Ghost & Rock'em Sock'em & (da) Bears vs. Packers. Hero and Villains: SuperMario and Bowser & Batman and The Joker & a Knight and dragon. Everyday adventurers: Lumberjack and the tree & the Donkey and the Elephant. http://www.McDonalds.com
Having a hard time remembering what happened this year? Here are the highlights in one minute of gifs! 2014 we miss u already. Subscribe now for more Animation Domination High-Def clips: http://bit.ly/RXLBii You can make your own GIF of any moment in this video at http://www.foxadhd.com Like Animation Domination High-Def on Facebook: http://bit.ly/ADHD_FB Follow Animation Domination High-Def on Twitter: http://bit.ly/ADHD_Twitter Follow Animation Domination High-Def on Instagram: http://instagram.com/foxadhd Follow Animation Domination High-Def on Tumblr: http://bit.ly/ADHD_Tumblr Animation Domination High-Def is a block of cartoons that air every Saturday on FOX at 11PM/10c and all over the Internet all the time. GIFs by: Jeremy Sengly: http://jeremysengly.tumblr.com Henry Bonsu: http://henrytheworst.tumblr.com Parker Jackson: http://the-ocular-occult.tumblr.com Josh Freydkis: http://joshfreydkis.tumblr.com Faye Orlove: http://fayeorlove.tumblr.com/ Polly Guo: http://pollyguo.tumblr.com/ Violet Bruce: http://violetbrucedrawings.tumblr.com/ Sean Solomon: http://foreversean.tumblr.com/ Produced by Hillary Buckholtz Edited by Kyle Goodrich kyle-goodrich.tumblr.com STORIES: Obama: Pot no 'more dangerous' than alcohol Vladimir Putin Is The World's Most Powerful Person Pharrell's hat becomes Internet meme, gets a Twitter account NBC readies for Jay Leno's departure and Jimmy Fallon's 'Tonight' takeover Harold Ramis, 'Ghostbusters' Star and Writer, Dead at 69 You Won't Believe How Many School Shootings There Were in 2014 Michael Sam of Missouri Tigers says he's gay Sochi Is Seriously Not Ready To Host The Winter Olympics Ellen DeGeneres takes a selfie at the Oscars A Madrid demonstrator holds a poster depicting Russian President Vladimir Putin with make-up in protests against homophobia Missing Malaysia Airlines plane 'a mystery' Current California Drought Is Driest In State's History Pizza chain Sbarro files for bankruptcy Obama formally proposes end to NSA's bulk collection of data LA Clippers Owner Donald Sterling's Racist Rant Caught On Tape The Ultimate Warrior, pro wrestling legend, dead at 54 Still no trace of 200 kidnapped girls in Nigeria Legendary author Maya Angelou dies at age 86 Solange Knowles Attacks Jay Z in an Elevator H.R. Giger, Surrealist Artist and 'Alien' Designer, Dead at 74 2014 Was the Beginning of the End for the Gay-Marriage Fight Isis insurgents seize control of Iraqi city of Mosul World Cup 2014 World's first legal recreational marijuana sales begin in Colorado Ebola virus epidemic in West Africa Wisconsin 12-year-old accused in 'Slender Man' stabbing Medical marijuana is now officially legal in New York Punk rock icon Tommy Ramone dies The 2014 Israel-Hamas War Sales of Recreational Marijuana Begin in Washington State Legendary comedian Joan Rivers dead at 81 Nicki Minaj Drops Butt-Baring Album Cover Robin Williams: Autopsy Confirms Death by Suicide David Lynch and Seth Meyers nominate Putin for Ice Bucket Challenge Hands-up gesture animates Ferguson protests Police Militarization In Ferguson J-Law, Kate Upton Nudes Leak: Web Explodes U.S. airline stocks grounded by Ebola fears Could Putin be in Obama's 'broad coalition' against ISIS? Oscar Pistorius guilty of negligent killing, not murder Scottish independence referendum, 2014 Unprecedented number of medical staff infected with Ebola Ferguson Erupts After Grand Jury Clears Officer in Michael Brown Killing Postal Service uses "spying" programs similar to NSA Obama Asks FCC to Adopt Tough Net Neutrality Rules Japan recession worse than first reported Mexicans rage against student massacre Rape allegations won't go away for Bill Cosby Bob Geldof predicts climate change could wipe out humans in the next two decades Data Shows That Cops Kill Black People at a Higher Rate Than White People "I Can't Breathe": Asthmatic Father Dies After NYPD Chokehold There Are Only 5 Northern White Rhinos Left in the World The CIA Didn't Just Torture, It Experimented on Human Beings Official: North Korea behind Sony hack 2014 IN ONE MINUTE | ANIMATION DOMINATION HIGH-DEF http://www.youtube.com/user/foxadhd
Virgin Atlantic: 25 Years, Still Red Hot
British TV advert celebrating the 25th anniversary of Virgin Atlantic, featuring the air hostesses.


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Dear Bill Gates:
I'm concerned about your summer reading list, heavy on nonfiction titles, lacking in fiction, classics, poetry, which reflect the common core of what I believe every educated American should read (of course, I will readily admit that this is totally subjective, and I want to stress that I am happy that you are reading at all, something I stress to my own children).
So, I have some alternative titles to your summer reading list for you to consider:
-The Complete Works of Emily Dickinson, short poems, easy to read at the beach, or choose any other poetry collection.
-1984 by George Orwell. I am amazed at how often George Orwell's 1984 is quoted, especially in relations to politics and to technology. I plan to re-read this summer, and I think you should too. "He who controls the past controls the future. He who controls the presents controls the past."
-The "Battle Royal" section of Invisible Man by Ralph Ellison to understand the history of racism and pain in America. The entire the book is moving too, but it's that chapter you have to read.
-Hilary Mantel's Assassination of Margaret Thatcher: Stories, or Lydia Davis' Collected Stories, or George Pellecanos' Martini Shot, if you'd like some terrific genre short fiction— one nice thing about short story collections is you can feel free to skip a story or two and still say you read the book. I've been reading a lot of short fiction lately—short fiction focuses the mind, and these stories all present character, image, conflict in the most concise way.
-The Absolutely True Diary of a Part-time Indian by Sherman Alexie, my son just read this in 9 grade – talks about being the 'outsider' and 'other' here in America better than any young adult novel. One other thought: Jacqueline Woodson's Brown Girl Dreaming, winner of this year's National Book Award for Young People's Literature, written in verse. I have it on my TBR list and so should you.
-Fun Home by Alison Bechdel, the Broadway show is a big hit, but the graphic novel is a deep and moving tale of a father and daughter— and coming out. And it's always cool to say you read graphic novels.
I'm sure others would have suggestions for you that go beyond your limited nonfiction and science/tech-focused summer book reading choices— any others out there?
I'd just urge you to go farther and wider and be more open and curious in your reading, and if you do, to share it with us all.
Read on, Bill! Have a great Memorial Day Weekend!
Caroline Bock
*Full disclosure: I am the author of two critically acclaimed young adult novels: Before My Eyes (St. Martin's Press, 2014) and LIE (St. Martin's Press, 2011). You can also always read these book:)! More at www.carolinebock.com