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International Journal of Alzheimer's Disease
Volume 2012 (2012), Article ID 489428, 9 pages
Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade
1Department of Molecular Medicine, Suncoast Gerontology Center, Johnnie B. Byrd Sr. Alzheimer's Institute, University of South Florida, Tampa, FL 33620, USA
2Department of Neurology and Linda Crnic Institute for Downs Syndrome, School of Medicine, University of Colorado Aurora, CO 80045, USA
3Departments of Neurology, Pathology, and Psychiatry, New York University School of Medicine, New York, NY 10016, USA
Received 16 December 2011; Accepted 23 April 2012
Academic Editor: Laura Morelli
Copyright © 2012 Huntington Potter and Thomas Wisniewski. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or "pathological chaperone". Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.
1. Introduction
Alzheimer's disease (AD) is a neurodegenerative disorder that is clinically characterized by progressive mental decline and histopathologically defined by highly abundant amyloid deposits and neurofibrillary tangles in the brain parenchyma. The identification of mutations within the amyloid precursor protein (APP) and presenilin (PS) genes that cause autosomal dominantly inherited AD and that result in increased production of amyloid-prone forms of Aβ established beyond doubt that the processing of APP and the production of Aβ peptides are intimately involved in the disease process and led to the proposal and the reinforcement of the Alzheimer Amyloid Cascade Hypothesis [1, 2].
The role of amyloid in neuronal dysfunction has recently been extended by the discovery of small, soluble, oligomers of the Aβ peptide, some forms of which have been termed ADDLs (Aβ-derived diffusible ligands), protofibrils, or Aβ*56 [3–6]. These Aβ oligomers are not only potential intermediates in the formation of amyloid filaments, but they also have been shown to be neurotoxic themselves and to inhibit long-term potentiation (LTP), a cellular model of memory, in hippocampal slices [4, 7, 8]. Thus, the Amyloid Cascade Hypothesis now includes the essential role of Aβ oligomers in the neurodegeneration process.
Despite its strength, the Amyloid Cascade Hypothesis is incomplete without including the essential role of amyloid-associated inflammatory proteins. For example, biochemical and histological studies first showed that, in addition to Aβ, amyloid deposits also contained the inflammation/acute phase protein α1-antichymotrypsin (ACT) [9] and, later, apolipoprotein E (apoE) [10, 11], which were both hypothesized to serve as catalysts or "pathological chaperones" of amyloid formation [9, 11, 12]. These and other results also indicated that Alzheimer's disease and its manifestation in middle-aged Down syndrome may include an inflammatory process, for both ACT and apoE are inflammatory and/or acute phase proteins in other contexts, and both are overexpressed in affected regions of the AD brain (for reviews see [13–15]). Indeed, Alzheimer himself first identified the inflammatory component of Alzheimer's disease when he described reactive astrocytes and microglia in affected brain regions of his first patient [16]. However, until inflammatory proteins such as ACT, IL-1, HLA, and apoE were found to be overexpressed in AD and DS brains, the term "inflammation" was explicitly excluded from the clinical and pathological description of AD because of the lack of edema and lymphocyte infiltration [9–11, 17, 18].
The significance of these biochemical results instigated and was reinforced by parallel genetic discoveries implicating a role for inflammation in AD. In particular, inheritance of the apoE ε4 allele was found to be the strongest known risk factor for AD besides age, with one copy increasing AD risk 3–5-fold and two copies over 10-fold [19–21]. Furthermore, apoE ε4 promotes cognitive decline in middle-aged Down syndrome individuals [22].
Because of apoE's essential genetic, and therefore presumably biochemical, contribution to AD pathology and cognitive decline, it is critical that its role in the AD pathogenic pathway/amyloid cascade be elucidated in order for therapeutics based on apoE to be designed. While recent excellent and encyclopedic literature reviews describe the many potential roles that apoE plays in AD [23–26], this focused review will concentrate on the interaction between Aβ and apoE and other inflammatory proteins, on the effects of such interactions, and on their implications for designing apoE-based AD therapies. The central question we try to answer is whether increasing or decreasing apoE level and/or function will serve best to reduce AD/DS pathology and cognitive decline. Lack of a clear answer may lead to the development of drugs that, rather than serving as an AD therapy, instead potentially exacerbate the disease.
2. Background: ApoE as Amyloid Catalyst
To determine whether inflammation contributes to Alzheimer's disease rather than being merely a correlative pathological feature in the AD brain, we and others tested the hypothesis that ACT and/or apoE serve as amyloid catalysts or pathological chaperones. Numerous in vitro and in vivo studies showed that mature amyloid deposition and the associated cognitive decline is strongly stimulated by apoE and ACT in a dose-dependent and isoform-specific manner, with apoE4 being the strongest promoter of Aβ polymerization and apoE2 being an inhibitor, paralleling the effect of these two isoforms in humans [27–38]. Indeed, without one or the other of these amyloid catalysts expressed in the brain, amyloid deposition is profoundly delayed in APP transgenic mice and does not become filamentous. Such APP+/apoE KO animals also exhibit normal cognition despite levels of Aβ expression equal to the apoE-expressing APP animals. Elegant work by Manelli and colleagues also showed that native lipidated apoE4 from transgene replacement astrocytes increases Aβ neurotoxicity compared to apoE3 or E2, indicating that apoE4 provides a negative gain of function [39]. Finally, Jones and colleagues recently showed that apoE4 also promotes the conversion and enhanced synaptic localization of Aβ as oligomers, the most neurotoxic form of the Alzheimer amyloid peptide [40, 41]. These recent studies extended prior work showing that apoE copurifies with Aβ during biochemical isolation of amyloid from human brains, and that apoE preferentially interacts with Aβ peptides in a β-sheet structure [42–45].
Together these results show that inflammatory proteins, particularly apoE, are integral parts of the amyloid cascade, and that without them the cascade would be arrested at the level of the harmless Aβ monomer, and no AD would ensue.
3. Background: ApoE in Aβ/Amyloid Clearance
The view of apoE as an integral and pathological part of the amyloid cascade has been shaken by experiments that suggest that apoE, far from being an amyloid catalyst, serves to clear Aβ from the brain. Under this view, ApoE is protective, with human apoE4 being less protective than apoE3 or E2 (for the most recent discussion, see [46] and commentary at http://www.alzforum.com/).
The first experiments that suggested apoE's role as a neuroprotector examined the pathology and cognition of APP transgenic mice carrying a second transgene expressing one or another human apoE isoform. Contrary to expectations, amyloid deposition in these mice was inhibited by the human apoE transgene, as though human apoE was protective [47]. Ultimately, the mice did develop amyloid, with the apoE4-expressing strain accumulating earlier and more extensive pathology [33, 34, 48, 49]. It was proposed that human apoE might serve to inhibit Aβ clearance from the brain compared to mouse apoE, with apoE4 inhibiting clearance the most. Other experiments showed that indeed, clearance of Aβ species was inhibited by complexing with apoE, especially apoE4 [46, 50].
The possibility that interaction with apoE modulated an Aβ clearance mechanism appeared to be supported by the finding that introduction of anti-Aβ antibodies or other Aβ-binding proteins such as gelsolin, led to a reduced amyloid load in the brain and rapidly improved cognition, with little evidence of Aβ-binding agents invading the brain parenchyma [41–54]. We also introduced apoE itself into the circulation via parabiosis and found that it induced amyloid clearance without entering the brain in AD model mice [38]. Thus the "Peripheral Sink Hypothesis" became a viable alternative or addition to the Amyloid Cascade Hypothesis, with apoE potentially playing an additional role as an Aβ-binding peripheral protein.
Most recently, an approach to therapy has been investigated in AD mice that is based on activating the liver X receptor (LXR), which also exists on other cells including microglia [55–57]. Activation of LXR results in increased expression of many proteins including apoE and its lipidating enzyme, ATP-binding Cassette Transporter A1 (ABCA1). The results indicate that activating LXR with the ligand GW3965 or the FDA-approved antiskin cancer drug bexarotene reduces soluble and insoluble Aβ and improves cognition in APP Tg mice, while knocking out the ABCA1 gene in APP mice showed a tendency to reduced amyloid load. Because apoE expression and lipidation is stimulated by LXR activation, the results were interpreted as proof that increased apoE levels help microglia clear Aβ and amyloid, as indeed some earlier cell culture experiments had suggested. However, it has also been shown that genetic overexpression of ABCA1 reduces amyloid deposition in mice where the apoE levels are unchanged [58]. Hence, because LXR stimulation influences the levels of many proteins, it is problematic to definitively link its in vivo action to the altered level of one particular protein. Furthermore, the increased levels of ABCA1 induced by Bexarotene enhance apoE lipidation, a change that is known to alter apoE/Aβ interactions. Hence, it is important to consider the lipidation state of apoE, which affects its function, in addition to the absolute levels of apoE.
4. Synthesis
When trying to distinguish and weigh the value of two hypotheses, it is instructive to consider their testable predictions. If apoE is an amyloid catalyst, then reducing apoE levels or function in the brain should result in reduced amyloid deposition and reduced cognitive decline. If on the other hand, apoE is involved in Aβ clearance with human apoE4 being a greater inhibitor of clearance (or poorer clearer), then reducing apoE levels or apoE binding to Aβ should increase amyloid deposition and cognitive decline.
All experiments carried out so far in vitro or in transgenic mice indicate that the ability of Aβ to form neurotoxic filaments or oligomers and cause cognitive decline are increased in the presence of apoE, particularly mouse apoE and human apoE4, with apoE2 being protective. In contrast, in the complete absence of apoE, the mutant APP gene and its product Aβ are harmless, generating neither amyloid deposits, synaptic disfunction, or cognitive decline, with one copy of apoE having an intermediate effect, as discussed above. The in vitro experiments in particular indicate that apoE likely acts catalytically to promote Aβ polymerization, as the molar ratio of Aβ to apoE of about 200/1 was appropriate for the formation of neurotoxic products [27–30]. Most recently, earlier work showing that mice expressing only one apoE gene accumulated less amyloid than those with two apoE genes (32) was repeated in two different laboratories using human apoE knock-in mice, and the same result was found, that is, lower doses of apoE3 or apoE4 led to reduced amyloid deposition [59, 60].
The simplest interpretation of the in vitro, cell culture, and transgenic mouse data is that apoE is necessary for Aβ to polymerize into neurotoxic oliogomers/filaments, probably by binding to Aβ and thus altering its structure more toward the β-sheet and more easily allowing successive Aβ peptides to add on to the growing chain. The recent finding that apoE promotes Aβ oligomer formation in vivo reinforces this interpretation [40, 41]. Whether apoE is only needed to initiate the polymerization or also to prepare each peptide for addition to the growing filament is not yet known.
Even though the key predictions of the polymerization hypothesis, that is apoE serving as an Aβ filament catalyst, have been borne out, the compelling experiments demonstrating that human apoE inhibits filament formation in a mouse background require explanation. Furthermore, data from LaDu and colleagues and by others have shown that lipidated apoE, presumably the prevalent form in vivo, binds Aβ with an affinity of E2 > E3 > E4 [61–64]. Finally, the elegant and thorough experiments of Castellano and colleagues show very convincingly that expression of a human apoE4 transgene (in the absence of mouse apoE) leads to a longer half-life, (i.e., slower clearance) of Aβ in the brain interstitial fluid compared to E2 or E3 [46].
The apoE-Aβ binding studies might be interpreted as support for apoE functioning in Aβ clearance because apoE2, for example, would bind Aβ tightly and could thereby promote its removal from the interstitial fluid via LRP receptors [50, 61–64]. However, an important feature of any catalyst is that it must bind its substrate only tightly enough to convert it to the transition state structure and then release it as the reaction is completed [65, 66]. If a mutation leads to an overly tight substrate binding, then no further reaction can occur. Thus apoE2 could indeed bind Aβ most tightly, and thereby not only prevent apoE4 from binding and promoting Aβ oligo/polymerization, but also prevent the spontaneous polymerization of the peptide.
The ability of different apoE isoforms to bind Aβ with different strengths can also explain why human apoE isoforms slow amyloid deposition in the presence of the endogenous mouse apoE, for they may bind Aβ more tightly or differently than mouse apoE and slow the catalytic conversion of Aβ into oligomers/polymers in the mouse background.
The data showing that human apoE inhibits Aβ clearance can also be interpreted as reflecting apoE's role in catalyzing Aβ oligo/polymerization. Pathologic macromolecular structures are often resistant to various clearance mechanisms designed for monomeric species, whether by intracellular proteasome degradation or cross-membrane/BBB transfer, thus allowing their accumulation. Only when oligo/polymeric structures are anticipated and physiological clearance mechanisms are in place to handle them, as for antibody-antigen complexes, will clearance be facilitated by conversion to larger structures. Because apoE clearly has the ability to catalyze the conversion of Aβ into oligomeric and polymeric structures, it is reasonable to assume that those structures will be more difficult to clear, and that such difficulty will be detected as clearance inhibition in the brain, for instance, by apoE4, in pulse chase type experiments, while the higher apoE levels in blood may aid the clearance of Aβ from the circulations (Figure 1).
Finally, the ability of GW3965 and Bexarotene to reduce soluble and insoluble Aβ in the brain of Tg APP mice and improve cognition is most easily understood as resulting from a general activation of the phagocytic activity of microglia. Previous work showed that activation of microglia by acute intracerebral treatment of APP mice with LPS or with Granulocyte-macrophage stimulating factor can similarly reduce amyloid load and improve cognition [67–69] but that long-term peripheral treatment with LPS exacerbated amyloid deposition in an apoE-dependent manner [70]. Stimulation of microglial activity via induction of Toll-like receptor 9 (TLR9) has also been shown to greatly reduce amyloid load and improve cognition [71]. Clearly the interaction of neuroinflammation, microglia, and amyloid load is complex, and the fact that bexarotene "cures" AD in mice is more likely to be despite, rather than because it stimulates expression of apoE.
5. Aβ Binding Proteins and AD Therapy
A good test of any hypothesis about the pathogenesis of a disease is whether it successfully predicts how the pathogenesis can be inhibited or reversed. For example, small fragments of Aβ corresponding to the amino acid sequences to which ACT (Aβ1-12) and apoE (Aβ12-28) bind can serve as decoy peptides that prevent the binding of apoE to Aβ and its catalysis of Aβ into neurotoxic species [30]. This early in vitro work has recently been repeated and confirmed in other laboratories [72, 73]. The decoy principal was extended in vivo by preparing a version of Aβ12-28 that has a better plasma 1/2 life and is nonfibrillogenic/nontoxic. It was shown that this peptide could be peripherally introduced into a transgenic APP mouse, where it effectively entered the brain and prevented/reversed oligomer formation, amyloid deposition, and cognitive decline [74–76]. Similarly, amyloid plaques in APP mice contain mouse ACT and injecting Aβ1-11 into one side of the APP mouse brain to block ACT's binding site with endogenous Aβ rapidly reduced amyloid load compared to the other, vehicle-injected side of the brain. Furthermore the inflammatory cytokine IL-1 that is overexpressed in AD brain [18] induces astrocyte expression of ACT [77], and blocking IL-1 expression in APP transgenic mice by Ibuprofen treatment, thereby reducing mouse ACT expression, lowers amyloid formation and restores cognition [78]. Evidently, blocking ACT or apoE expression or function, both in vitro or in vivo, successfully prevents Aβ pathology and neurotoxicity.
Apolipoprotein J also binds Aβ and can be shown to aid its passage across the blood brain barrier [79–83]. Interestingly, knocking out either apoJ or apoE reduces amyloid deposition in APP transgenic animals, yet knocking out both leads to robust amyloid deposition at an even earlier age than arises in nonmanipulated APP animals [84]. This result may reflect the ability of mouse ACT to promote amyloid formation, but that in the presence of the stronger binding apoE and apoJ proteins mouse ACT is prevented from exhibiting its catalytic activity.
6. Potential Efficacy and Dangers of Aβ-Binding Antibodies as AD Therapy
The role of apoE and ACT in the Alzheimer pathogenic pathway has potentially general implications. One of the most studied classes of Aβ binding proteins are specific anti-Aβ antibodies, which form the basis of both passive and active immunization therapies for Alzheimer's disease (for review see [85]). The finding that apoE and ACT can catalyze Aβ oligo/polymerization begs the question of whether Aβ antibodies might also promote or inhibit Aβ polymerization. Indeed we found that two Aβ antibodies, 6E10 which is directed to the same the N-terminal sequence bound by ACT, and 13 M, which binds to the C-terminus, function very differently in the in vitro Aβ polymerization assay. 6E10 inhibits ACT-catalyzed polymerization of Aβ while 13 M inhibits ACT catalysis much less and even promotes some polymerization itself. Interestingly, the N-terminus of Aβ is also the target of many attempts at AD immunotherapy with the aim of inducing microglial phagocytosis of neurotoxic Aβ species. Yet removing the microglial-binding Fc portion of 3D6 antibodies to Aβ1-5 to generate Fab'2 fragments does not reduce the antibody's ability to remove diffuse amyloid in APP mice [86]. Evidently, only its Aβ-binding feature is required to allow the antibody to remove amyloid. A possible explanation for this result is that the antibody functions by blocking Aβ interaction with mouse ACT. The consequent suppression of ACT-catalyzed oligo/polymerization could thus tilt the dynamic process of plaque development toward depolymerization.
These results illustrate the fact that Aβ-binding proteins can have multiple effects on polymerization and that their full range of activities must be considered when using them as potential targets or tools for therapeutic intervention.
7. Potential Toxic Mechanism of ApoE-Induced Aβ Oligomers
Although Aβ oligomers have been shown to be highly neurotoxic in vitro and in vivo, and their formation is promoted by apoE4, the mechanism of their toxicity is still being elucidated. The data reviewed above coupled to other recent findings suggest a novel mechanism for Aβ toxicity that encompasses the essential role of apoE. Specifically, Aβ oligomers bind to and inhibit certain microtubule motors that are essential for the function and stability of the mitotic spindle—Eg5/kinesin5, Kif4A, and MCAK [87]. Similar motors, including kinesin 5, are also present in mature neurons [88, 89]. We have found recently that inhibition of MT motor function by Aβ or by the specific kinesin 5 inhibitor Monastrol prevents the efficient transport of receptors such as the LDLR, the NMDA neurotransmitter receptor, and the p75 neurotrophin receptor to the cell surface, resulting in reduced function ([90]; in preparation). Similarly, apoE, particularly apoE4, has been shown to reduce the cell surface levels and function of NMDA, AMPA, and apoEr2 receptors in neurons [91]. This latter finding can now be understood as potentially reflecting the ability of apoE4 to promote the conversion of endogenous neuronal Aβ into oligomers, which then inhibit MT-based transport of key cellular components such as receptors to their functional location.
8. Conclusion
In sum, it appears that the preponderance of the data can be most consistently interpreted as showing that the brain inflammatory protein apoE plays a catalytic role in the AD/DS amyloid cascade and consequent cognitive decline, with binding and clearance differences between the apoE isoforms reflecting their differing abilities to bind to Aβ and catalyze its conversion into neurotoxic macromolecular species (Figure 2). This conclusion, and the in vivo demonstration that blocking apoE-Aβ interaction prevents AD in a mouse model, suggests that this decoy approach should be translatable into human patients and serve as an effective new approach to AD therapy.
Other Aβ-binding proteins may be similarly manipulated by a decoy approach to reduce oligomerization and polymerization of Aβ into neurotoxic species. However, the finding that different antibodies to Aβ can both inhibit ACT-catalyzed Aβ polymerization and promote polymerization of Aβ itself, argues that immunotherapy must be approached with care to avoid the use or induction of antibodies that can catalyze further oligo/polymerization of Aβ, instead of inducing its phagocytosis and removal. Furthermore, human and mouse intracerebral environments may differ in important ways with respect to the pattern and activities of Aβ-binding proteins and may also respond differently to intervention or inflammation. Such differences may explain why so many treatments that were successful in reducing amyloid-dependent cognitive decline in transgenic mice have failed to translate into human AD patients.
Finally, the ability of Aβ oligomers to inhibit key microtubule motors and prevent the transport of neurotrophin, neurotransmitter, and other receptors to the cell surface may underlie their neuronal toxicity. It is apparently the ApoE, especially E4-dependent formation of such Aβ oligomers, that constitutes the key catalytic step in the AD pathogenic pathway.
Funding provided by the Byrd Alzheimer's Institute, the Eric Pfeiffer Chair for Research on Alzheimer's Disease, and the NIH (AG025711, AG037942, NS073502 and AG020245).
- J. Hardy, "Alzheimer's disease: the amyloid cascade hypothesis—an update and reappraisal," Journal of Alzheimer's Disease, vol. 9, no. 3, pp. 151–153, 2006. View at Scopus
- E. Karran, M. Mercken, and B. De Strooper, "The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics," Nature Reviews Drug Discovery, vol. 10, pp. 698–712, 2011.
- D. M. Walsh, A. Lomakin, G. B. Benedek, M. M. Condron, and D. B. Teplow, "Amyloid β-protein fibrillogenesis: detection of a protofibrillar intermediate," Journal of Biological Chemistry, vol. 272, no. 35, pp. 22364–22372, 1997. View at Publisher · View at Google Scholar · View at Scopus
- M. P. Lambert, A. K. Barlow, B. A. Chromy et al., "Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins," Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6448–6453, 1998. View at Scopus
- M. B. Podlisny, D. M. Walsh, P. Amarante et al., "Oligomerization of endogenous and synthetic amyloid β-protein at nanomolar levels in cell culture and stabilization of monomer by Congo red," Biochemistry, vol. 37, no. 11, pp. 3602–3611, 1998. View at Publisher · View at Google Scholar · View at Scopus
- S. Lesné, T. K. Ming, L. Kotilinek et al., "A specific amyloid-β protein assembly in the brain impairs memory," Nature, vol. 440, no. 7082, pp. 352–357, 2006. View at Publisher · View at Google Scholar · View at Scopus
- H. W. Wang, J. F. Pasternak, H. Kuo et al., "Soluble oligomers of β amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus," Brain Research, vol. 924, no. 2, pp. 133–140, 2002. View at Publisher · View at Google Scholar · View at Scopus
- D. M. Walsh, I. Klyubin, J. V. Fadeeva et al., "Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo," Nature, vol. 416, no. 6880, pp. 535–539, 2002. View at Publisher · View at Google Scholar · View at Scopus
- C. R. Abraham, D. J. Selkoe, and H. Potter, "Immunochemical identification of the serine protease inhibitor α1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease," Cell, vol. 52, no. 4, pp. 487–501, 1988. View at Scopus
- Y. Namba, M. Tomonaga, H. Kawasaki, E. Otomo, and K. Ikeda, "Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease," Brain Research, vol. 541, no. 1, pp. 163–166, 1991. View at Publisher · View at Google Scholar · View at Scopus
- T. Wisniewski and B. Frangione, "Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid," Neuroscience Letters, vol. 135, no. 2, pp. 235–238, 1992. View at Publisher · View at Google Scholar · View at Scopus
- T. Wisniewski, M. Lalowski, A. Golabek, T. Vogel, and B. Frangione, "Is Alzheimer's disease an apolipoprotein E amyloidosis?" The Lancet, vol. 345, no. 8955, pp. 956–958, 1995. View at Scopus
- L. Nilsson, J. Rogers, and H. Potter, "The essential role of inflammation and induced gene expression in the pathogenic pathway of Alzheimer's disease," Frontiers in Bioscience, vol. 3, pp. d436–d446, 1998. View at Scopus
- H. Potter, I. M. Wefes, and L. N. G. Nilsson, "The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation," Neurobiology of Aging, vol. 22, no. 6, pp. 923–930, 2001. View at Publisher · View at Google Scholar · View at Scopus
- A. J. M. Rozemuller, W. A. van Gool, and P. Eikelenboom, "The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications," Current Drug Targets, vol. 4, no. 3, pp. 223–233, 2005. View at Publisher · View at Google Scholar · View at Scopus
- A. Alzheimer, "Uber eine eigenartige Erkrankung der Hirnride," Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin, vol. 64, pp. 146–148, 1907.
- J. Rogers, J. Luber-Narod, S. D. Styren, and W. H. Civin, "Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease," Neurobiology of Aging, vol. 9, no. 4, pp. 339–349, 1988. View at Scopus
- W. S. T. Griffin, L. C. Stanley, C. Ling et al., "Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 19, pp. 7611–7615, 1989. View at Scopus
- W. J. Strittmatter, A. M. Saunders, D. Schmechel et al., "Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 5, pp. 1977–1981, 1993. View at Scopus
- E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families," Science, vol. 261, no. 5123, pp. 921–923, 1993. View at Scopus
- W. J. Strittmatter and A. D. Roses, "Apolipoprotein E and Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 92, pp. 4725–4727, 1995.
- D. C. Rubinsztein, J. Hon, F. Stevens et al., "Apo E genotypes and risk of dementia in Down syndrome," American Journal of Medical Genetics, vol. 88, pp. 344–347, 1999.
- R. W. Mahley, Y. Huang, and K. H. Weisgraber, "Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease," Current Alzheimer Research, vol. 4, no. 5, pp. 537–540, 2007. View at Publisher · View at Google Scholar · View at Scopus
- J. Kim, J. M. Basak, and D. M. Holtzman, "The role of apolipoprotein E in Alzheimer's disease," Neuron, vol. 63, no. 3, pp. 287–303, 2009. View at Publisher · View at Google Scholar · View at Scopus
- P. B. Verghese, J. M. Castellano, and D. M. Holtzman, "Apolipoprotein E in Alzheimer's disease and other neurological disorders," The Lancet Neurology, vol. 10, no. 3, pp. 241–252, 2011. View at Publisher · View at Google Scholar · View at Scopus
- P. S. Hauser, V. Narayanaswami, and R. O. Ryan, "Apolipoprotein E: from lipid transport to neurobiology," Progress in Lipid Research, vol. 50, no. 1, pp. 62–74, 2011. View at Publisher · View at Google Scholar · View at Scopus
- J. Ma, A. Yee, H. B. Brewer, S. Das, and H. Potter, "Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments," Nature, vol. 372, no. 6501, pp. 92–94, 1994. View at Publisher · View at Google Scholar · View at Scopus
- T. Wisniewski, E. M. Castano, A. Golabek, T. Vogel, and B. Frangione, "Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro," American Journal of Pathology, vol. 145, no. 5, pp. 1030–1035, 1994. View at Scopus
- D. A. Sanan, K. H. Weisgraber, S. J. Russell et al., "Apolipoprotein E associates with β amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform ApoE4 associates more efficiently than ApoE3," Journal of Clinical Investigation, vol. 94, no. 2, pp. 860–869, 1994. View at Scopus
- J. Ma, H. B. Brewer Jr., and H. Potter, "Alzheimer Aβ neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by Aβ-related peptides," Neurobiology of Aging, vol. 17, no. 5, pp. 773–780, 1996. View at Publisher · View at Google Scholar · View at Scopus
- K. R. Bales, T. Verina, R. C. Dodel et al., "Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition," Nature genetics, vol. 17, no. 3, pp. 263–264, 1997. View at Scopus
- K. R. Bales, T. Verina, D. J. Cummins et al., "Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 26, pp. 15233–15238, 1999. View at Publisher · View at Google Scholar · View at Scopus
- D. M. Holtzman, A. M. Fagan, B. Mackey et al., "Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model," Annals of Neurology, vol. 47, no. 6, pp. 739–747, 2000.
- D. M. Holtzman, K. R. Bales, T. Tenkova et al., "Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 6, pp. 2892–2897, 2000. View at Publisher · View at Google Scholar · View at Scopus
- L. Mucke, G. Q. Yu, L. McConlogue, E. M. Rockenstein, C. R. Abraham, and E. Masliah, "Astroglial expression of human α1-antichymotrypsin enhances Alzheimer-like pathology in amyloid protein precursor transgenic mice," American Journal of Pathology, vol. 157, no. 6, pp. 2003–2010, 2000. View at Scopus
- L. N. G. Nilsson, K. R. Bales, G. DiCarlo et al., "α-1-Antichymotrypsin promotes β-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease," Journal of Neuroscience, vol. 21, no. 5, pp. 1444–1451, 2001. View at Scopus
- H. Potter, "Beyond beta protein—the essential role of inflammation in Alzheimer Amyloid formation," in Inflammatory Events in Neurodegeneration, S. C. Bondy and A. Cambell, Eds., Prominent Press, 2001.
- L. N. G. Nilsson, S. Gografe, D. A. Costa, T. Hughes, D. Dressler, and H. Potter, "Use of fused circulations to investigate the role of apolipoprotein E as amyloid catalyst and peripheral sink in Alzheimer's disease," Technology and Innovation. In press.
- A. M. Manelli, L. C. Bulfinch, P. M. Sullivan, and M. J. LaDu, "Aβ42 neurotoxicity in primary co-cultures: effect of apoE isoform and Aβ conformation," Neurobiology of Aging, vol. 28, no. 8, pp. 1139–1147, 2007. View at Publisher · View at Google Scholar · View at Scopus
- P. B. Jones, K. W. Adams, A. Rozkalne et al., "Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain," PLoS ONE, vol. 6, no. 1, Article ID e14586, 2011. View at Publisher · View at Google Scholar · View at Scopus
- R. M. Koffie, T. Hashimoto, H.-C. Tai et al., "Apolipoprotein E4 effects in Alzheimer disease are mediated by synaptotoxic oligomeric amyloid-beta," Brain, vol. 135, pp. 2155–2168, 2012.
- T. Wisniewski, M. Lalowski, A. Golabek, T. Vogel, and B. Frangione, "Is Alzheimer's disease an apolipoprotein E amyloidosis?" The Lancet, vol. 345, no. 8955, pp. 956–958, 1995. View at Scopus
- J. Naslund, J. Thyberg, L. O. Tjernberg et al., "Characterization of stable complexes involving apolipoprotein E and the amyloid β peptide in Alzheimer's disease brain," Neuron, vol. 15, no. 1, pp. 219–228, 1995. View at Scopus
- A. A. Golabek, C. Soto, T. Vogel, and T. Wisniewski, "The Interaction between apolipoprotein E and Alzheimer's amyloid β-peptide is dependent on β-peptide conformation," Journal of Biological Chemistry, vol. 271, no. 18, pp. 10602–10606, 1996. View at Scopus
- S. E. Wahrle and D. M. Holtzman, "Apolipoprotein E, amyloid beta-peptide and Alzheimer's disease," in Neurobiology of Alzheimer's Disease, D. Dawbarn and S. J. Allen, Eds., pp. 161–172, Oxford University Press, 2007.
- J. M. Castellano, J. Kim, F. R. Stewart et al., "Human apoE isoforms differentially regulate brain amyloid-β peptide clearance," Science Translational Medicine, vol. 3, no. 89, Article ID 89ra57, 2011. View at Publisher · View at Google Scholar · View at Scopus
- D. M. Holtzman, K. R. Bales, S. Wu et al., "Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease," Journal of Clinical Investigation, vol. 103, no. 6, pp. R15–R21, 1999. View at Scopus
- A. M. Fagan, M. Watson, M. Parsadanian, K. R. Bales, S. M. Paul, and D. M. Holtzman, "Human and murine apoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's Disease," Neurobiology of Disease, vol. 9, no. 3, pp. 305–318, 2002. View at Publisher · View at Google Scholar · View at Scopus
- J. C. Dodart, R. A. Marr, M. Koistinaho et al., "Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 4, pp. 1211–1216, 2005. View at Publisher · View at Google Scholar · View at Scopus
- R. Deane, A. Sagare, K. Hamm et al., "apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain," Journal of Clinical Investigation, vol. 118, no. 12, pp. 4002–4013, 2008. View at Publisher · View at Google Scholar · View at Scopus
- R. B. DeMattos, K. R. Bales, D. J. Cummins, J. C. Dodart, S. M. Paul, and D. M. Holtzman, "Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 15, pp. 8850–8855, 2001. View at Publisher · View at Google Scholar · View at Scopus
- J. C. Dodart, K. R. Bales, K. S. Gannon et al., "Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model," Nature Neuroscience, vol. 5, no. 5, pp. 452–457, 2002. View at Publisher · View at Google Scholar · View at Scopus
- R. B. DeMattos, K. R. Bales, D. J. Cummins, S. M. Paul, and D. M. Holtzman, "Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease," Science, vol. 295, no. 5563, pp. 2264–2267, 2002. View at Publisher · View at Google Scholar · View at Scopus
- Y. Matsuoka, M. Saito, J. LaFrancois et al., "Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to β-amyloid," Journal of Neuroscience, vol. 23, no. 1, pp. 29–33, 2003. View at Scopus
- Q. Jiang, C. Y. D. Lee, S. Mandrekar et al., "ApoE promotes the proteolytic degradation of Aβ," Neuron, vol. 58, no. 5, pp. 681–693, 2008. View at Publisher · View at Google Scholar · View at Scopus
- J. J. Donkin, S. Stukas, V. Hirsch-Reinshagen et al., "ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice," Journal of Biological Chemistry, vol. 285, no. 44, pp. 34144–34154, 2010. View at Publisher · View at Google Scholar · View at Scopus
- P. E. Cramer, J. R. Cirrito, D. W. Wesson et al., "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models," Science, vol. 335, no. 6075, pp. 1503–1506, 2012.
- S. E. Wahrle, H. Jiang, M. Parsadanian et al., "Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease," Journal of Clinical Investigation, vol. 118, no. 2, pp. 671–682, 2008. View at Publisher · View at Google Scholar · View at Scopus
- J. Kim, H. Jiang, S. Park et al., "Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis," The Journal of Neuroscience, vol. 31, pp. 18007–18012, 2011.
- N. Bien-Ly, A. K. Gillespie, D. Walker, S. Y. Yuon, and Y. Huang, "Reducing human apolipoprotein E levels attenuates age dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice," The Journal of Neuroscience, vol. 32, no. 14, pp. 4803–4811, 2012.
- M. J. LaDu, M. T. Falduto, A. M. Manelli, C. A. Reardon, G. S. Getz, and D. E. Frail, "Isoform-specific binding of apolipoprotein E to β-amyloid," Journal of Biological Chemistry, vol. 269, no. 38, pp. 23403–23406, 1994. View at Scopus
- S. Aleshkov, C. R. Abraham, and V. I. Zannis, "Interaction of nascent apoe2, apoe3, and apoe4 isoforms expressed in mammalian cells with amyloid peptide β (1–40). Relevance to Alzheimer's disease," Biochemistry, vol. 36, no. 34, pp. 10571–10580, 1997. View at Publisher · View at Google Scholar · View at Scopus
- T. Tokuda, M. Calero, E. Matsubara et al., "Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides," Biochemical Journal, vol. 348, no. 2, pp. 359–365, 2000. View at Publisher · View at Google Scholar · View at Scopus
- R. Deane, Z. Wu, A. Sagare et al., "LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms," Neuron, vol. 43, no. 3, pp. 333–344, 2004. View at Publisher · View at Google Scholar · View at Scopus
- D. Dressler and H. Potter, Discovering Enzymes, Scientific American Library, W. H. Freeman, New York, NY, USA, 1991.
- A. Fersht, Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding, W. H. Freeman, New York, NY, USA, 1999.
- D. L. Herber, L. M. Roth, D. Wilson et al., "Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice," Experimental Neurology, vol. 190, no. 1, pp. 245–253, 2004. View at Publisher · View at Google Scholar · View at Scopus
- D. L. Herber, M. Mercer, L. M. Roth et al., "Microglial activation is required for Aβ clearance after intracranial injection of lipopolysaccharide in APP transgenic mice," Journal of Neuroimmune Pharmacology, vol. 2, no. 2, pp. 222–231, 2007. View at Publisher · View at Google Scholar · View at Scopus
- T. D. Boyd, S. P. Bennett, T. Mori et al., "GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice," Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 507–518, 2010. View at Publisher · View at Google Scholar · View at Scopus
- X. Qiao, D. J. Cummins, and S. M. Paul, "Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse," European Journal of Neuroscience, vol. 14, no. 3, pp. 474–482, 2001. View at Publisher · View at Google Scholar · View at Scopus
- H. Scholtzova, R. J. Kascsak, K. A. Bates et al., "Induction of toll-like receptor 9 signaling as a method for ameliorating alzheimer's disease-related pathology," Journal of Neuroscience, vol. 29, no. 6, pp. 1846–1854, 2009. View at Publisher · View at Google Scholar · View at Scopus
- J. Hao, W. Zhang, P. Zhang et al., "Aβ20-29 peptide blocking apoE/Aβ interaction reduces full-length Aβ42/40 fibril formation and cytotoxicity in vitro," Neuropeptides, vol. 44, no. 4, pp. 305–313, 2010. View at Publisher · View at Google Scholar · View at Scopus
- Q. Liu, W. H. Wu, C. L. Fang et al., "Mapping ApoE/Abeta binding regions to guide inhibitor discovery," Molecular BioSystems, vol. 7, pp. 1693–1700, 2011.
- M. Sadowski, J. Pankiewicz, H. Scholtzova et al., "A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice," American Journal of Pathology, vol. 165, no. 3, pp. 937–948, 2004. View at Scopus
- M. J. Sadowski, J. Pankiewicz, H. Scholtzova et al., "Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 49, pp. 18787–18792, 2006. View at Publisher · View at Google Scholar · View at Scopus
- J. Yang, Y. Ji, P. Mehta, K. A. Bates, Y. Sun, and T. Wisniewski, "Blocking the apolipoprotein E/Amyloid-β interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice," Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 269–285, 2011. View at Publisher · View at Google Scholar · View at Scopus
- S. Das and H. Potter, "Expression of the Alzheimer amyloid-promoting factor antichymotrypsin is induced in human astrocytes by IL-1," Neuron, vol. 14, no. 2, pp. 447–456, 1995. View at Scopus
- T. Morihara, B. Teter, F. Yang et al., "Ibuprofen suppresses interleukin-Iβ induction of pro-amyloidogenic α1-antichymotrypsin to ameliorate β-amyloid (aβ) pathology in Alzheimer's models," Neuropsychopharmacology, vol. 30, no. 6, pp. 1111–1120, 2005. View at Publisher · View at Google Scholar · View at Scopus
- J. Ghiso, E. Matsubara, A. Koudinov et al., "The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex," Biochemical Journal, vol. 293, no. 1, pp. 27–30, 1993. View at Scopus
- R. P. Koldamova, I. M. Lefterov, M. I. Lefterova, and J. S. Lazo, "Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Aβ aggregation and toxicity," Biochemistry, vol. 40, no. 12, pp. 3553–3560, 2001. View at Publisher · View at Google Scholar · View at Scopus
- A. C. Paula-Lima, M. A. Tricerri, J. Brito-Moreira et al., "Human apolipoprotein A-I binds amyloid-β and prevents Aβ-induced neurotoxicity," International Journal of Biochemistry and Cell Biology, vol. 41, no. 6, pp. 1361–1370, 2009. View at Publisher · View at Google Scholar · View at Scopus
- R. D. Bell, A. P. Sagare, A. E. Friedman et al., "Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system," Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 909–918, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. Ito, S. Ohtsuki, J. Kamiie, Y. Nezu, and T. Terasaki, "Cerebral clearance of human amyloid-β peptide (1-40) across the blood-brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes," Journal of Neurochemistry, vol. 103, no. 6, pp. 2482–2490, 2007. View at Publisher · View at Google Scholar · View at Scopus
- R. B. DeMattos, M. A. O'dell, M. Parsadanian et al., "Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 16, pp. 10843–10848, 2002. View at Publisher · View at Google Scholar · View at Scopus
- C. A. Lemere and E. Masliah, "Can Alzheimer disease be prevented by amyloid-β immunotherapy?" Nature Reviews Neurology, vol. 6, no. 2, pp. 108–119, 2010. View at Publisher · View at Google Scholar · View at Scopus
- B. J. Bacskai, S. T. Kajdasz, M. E. McLellan et al., "Non-Fc-mediated mechanisms are involved in clearance of amyloid-βin vivo by immunotherapy," Journal of Neuroscience, vol. 22, no. 18, pp. 7873–7878, 2002. View at Scopus
- S. I. Borysov, A. Granic, J. Padmanabhan, C. E. Walczak, and H. Potter, "Alzheimer Aβ disrupts the mitotic spindle and directly inhibits mitotic microtubule motors," Cell Cycle, vol. 10, no. 9, pp. 1397–1410, 2011. View at Publisher · View at Google Scholar · View at Scopus
- R. Takemura, T. Nakata, Y. Okada, H. Yamazaki, Z. Zhang, and N. Hirokawa, "mRNA expression of KIF1A, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, and cytoplasmic dynein during axonal regeneration," Journal of Neuroscience, vol. 16, no. 1, pp. 31–35, 1996. View at Scopus
- P. W. Baas, "The role of motor proteins in establishing the microtubule arrays of axons and dendrites," Journal of Chemical Neuroanatomy, vol. 14, no. 3-4, pp. 175–180, 1998. View at Publisher · View at Google Scholar · View at Scopus
- J. F. Abisambra, T. Fiorelli, J. Padmanabhan, P. Neame, I. Wefes, and H. Potter, "LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease," PLoS ONE, vol. 5, no. 1, Article ID e8556, 2010. View at Publisher · View at Google Scholar · View at Scopus
- Y. Chen, M. S. Durakoglugil, X. Xian, and J. Herz, "ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling," Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 26, pp. 12011–12016, 2010. View at Publisher · View at Google Scholar · View at Scopus


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Imagine when you have a car problem, a top rated mechanic comes to your home or office, fixes your car, and it costs you 30-50% less than shops and dealers. Sounds crazy, right?
We are making that happen. We are disrupting the car repair market by creating a marketplace for top mechanics (peer to peer disruption of a large antiquated market).
Customer Stories: https://www.yourmechanic.com/works#testimonials
CTO @YourMechanic. Ph.D. from @MIT. Started programming at 10. Started college at 14. Security Hacker since 16.
Large and small public company experience, joined Yelp as their 1st accounting person. My last three start-ups completed successful IPO's (YELP, SFLY, SHOP).
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Head of Vehicles, eBay Motors (2/14 - Present)
CarWoo! COO (11/11 - 1/14)
Partner in Silicon Valley Office of Pillsbury Winthrop Shaw Pittman LLP - Corporate, Securities & Venture Capital Lawyer

subset: commoncrawl


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Secret of 'Johar Dwar' - Pratap listens to Rani Jaivanta Bai and Rana Uday Singh's conversations. Pratap firmly decides to find out the meaning of the word 'Johar' and also orders Soham to help him out with the same.
Rani Jaivanta Bai meets Girja Tai. Pratap observes Rani Jaivanta Bai and Girija Tai heading towards 'Johar Dwar'. Will Soham and Pratap get caught?
You are now watching : Maharana Pratap
Please rate this show : 3.7 Ratings | 471 Reviews
Category: TV Serial Hindi TV Channel: Sony TV
Watch more episodes on : maharana pratap | tv serial | 6th june 2013 | sony tv | maharana pratap episode no 8 |
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James R. Andrews
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Book Cover Image (jpg): Any Given Monday
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2007 CLK 350 with COMMAND - CD Changer not working
I just bought a 2007 CLK 350 Cabriolet. Beautiful car, but I am having trouble getting
the CD Changer to work. This car has NAV, so the single CD slot is behind the center
display screen, and the CD Changer is in the glove box. I turned on the car and
selected the AUDIO display, but I encountered two problems / questions: 1) CD
Changer does not appear on AUDIO screen. The only soft buttons that appear are
RADIO and CD. 2) The Cd Changer EJECT button does not work - the magazine will
not eject.
The Owner's Manual doesn't address this - it simply refers to separate operating
instructions for the COMMAND System, but I don't know where to find them. Any
suggestions? Thanks!


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Celebrate your Oh No, The Big 50 with these fun purple, green, blue, and black 50th birthday 11 piece candle set.
More..." I have bought all my necessities from Zurchers for the past couple of years. I don't have a store close to me, but their internet staff has always... "


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Rethinking couture, The battle for Hermès, Obama debate continues, Jimmy Choo profits triple, Rankin's army
All about the Atelier (FT) "It's possible we're thinking about this all wrong – this being the now-shrunk-to-three-days-with-only-six-full-fledged-couture-brands couture shows. It's possible we're asking the wrong questions. It's possible that, instead of perennially rending our garments and plunging into the long tunnel of debate over whether couture is relevant in a not-entirely-post-recession 21st century, we should


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quote:To the poster who questions Wilbur Marshall's place on the list, I am curious if you saw him play college?
quote:Marshall was a force and I certainly have no problem with where he is ranked.
quote:Dorsey, Emmett Smith, Peterson, Reed, Hilliard, Faneca, Mawae, Ingram, Bradie James, George Teague, Jamal Lewis or a host of others
quote:come on. I am an LSU fan and can't even make the case for 7 other LSU players to make the list. Objectivity may be in order. While they were all excellent college players, I dont see them as top 16 since 1980.
quote:Tebow at 2 is dumb, no way he was better than Bo Pollack being 9 is retarded sCam Newton should be nowhere near the list, neither should McFadden
quote:and the real travesty... no Champ Bailey? wow
quote:Not knocking any of those guys but you could arguably replace any with the following; Dorsey, Emmett Smith, Peterson, Reed, Hilliard, Faneca, Mawae, Ingram, Bradie James, George Teague, Jamal Lewis or a host of others. Even one-hit-wonder Cam deserves a mention for one of the all-time great collegiate seasons.
quote:I love Kevin, but NFL=/=NCAA.
quote:the past 20 years
quote:and that Tennessee WR from about '98-'99 whose name I can't remember now)
quote:even though I knew it likely wasn't his fault.
quote:must have been really good to where you cant even remember his name
quote:tigerdup07 LA-Lafayette Fan


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Archive - Nov 2012North 3rd Street project coming to an endSubmitted by Katelyn Supa on Mon, 11/26/2012 - 12:55pm.READ MORE:
The North 3rd Street improvement project is finally coming to an end. Monday and Tuesday marks the final major road closures for the project.
Full story... » Man killed by security guard at NC restaurantSubmitted by Allyson Lorick on Mon, 11/26/2012 - 9:03am.READ MORE:
An off-duty Lenoir County sheriff's deputy working as a security guard at a restaurant in Kinston has shot and killed a man.
Full story... » Man shot to death in CharlotteSubmitted by Allyson Lorick on Mon, 11/26/2012 - 9:01am.READ MORE:
Police in Charlotte are investigating the weekend shooting death of a man.
Full story... » Caldwell wildfire under controlSubmitted by Allyson Lorick on Mon, 11/26/2012 - 8:55am.READ MORE:
Authorities say a wildfire that in northwest Caldwell County is now under control.
Full story... » Fire marshal investigates vehicle fireSubmitted by Allyson Lorick on Mon, 11/26/2012 - 8:03am.READ MORE:
New Hanover County firefighters are investigating a vehicle fire that started in the woods near Laney High School early Monday morning.
Full story... » Wilmington Police look for CVS robbery suspectSubmitted by Allyson Lorick on Mon, 11/26/2012 - 7:48am.READ MORE:
Police are looking for a suspect in connection to an overnight robbery at the CVS Pharmacy on Oleander Drive in Wilmington.
Full story... » WWAY's Sunday night sports - Nov. 25Submitted by John Rendleman on Sun, 11/25/2012 - 11:07pm.READ MORE:
On Sunday on WWAY we checked out college basketball action from Trask Coliseum. The UNCW Seahawks won their third home of the game of the season despite trailing most of the game against Hampton....The accolades for former Hoggard Viking Jonathan Cooper continue..... Wolfpack nation has a head coaching vacancy for football....
Full story... » Police search for missing teen in Pender CountySubmitted by WWAY on Sun, 11/25/2012 - 8:51pm.READ MORE: »Emergency crews respond to home off Market Street; one confirmed deadSubmitted by WWAY on Sun, 11/25/2012 - 8:20pm.READ MORE:
Market Street is reduced to three lanes at 20th Street while the Wilmington Police and Fire Department investigate a hazardous materials incident.
Full story... » Christmas tree charity hit by thievesSubmitted by Holden Kurwicki on Sun, 11/25/2012 - 5:15pm.READ MORE:
The Christmas tree is a huge part of many families' holiday celebrations but to what lengths would you go to get one?
Full story... » |


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Reproduction Thompson Mag Pouch, Khaki
Item # WX2-183019
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Reproduction Thompson Mag Pouch.
Dress up your "Tommy Gun" collection! The Thompson submachine gun tends to eat up ammo. So here's the Mag Pouch it needs! Made just like the one from WWII, it's cotton canvas. 3 slots have snap-flap tops. Belt clip in back.
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!!! Limited Quantities !!!
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Reproduction Thompson Mag Pouch, Khaki is rated out of 5 by 1.Rated 4 out of 5 by VINCE from Good value, would have liked it better if it was all made out of the same material. Flaps are different color and lighter weight.Date published: 2012-03-03
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- 800.878.7323
This item may be Check for Availability This title in other editionsThe Accidental City: Improvising New Orleans
Synopses & ReviewsPublisher Comments:This is the story of a city that shouldn't exist. In the seventeenth century, what is now America's most beguiling metropolis was nothing more than a swamp: prone to flooding, infested with snakes, battered by hurricanes. But through the intense imperial rivalries of Spain, France, and England, and the ambitious, entrepreneurial merchants and settlers from four continents who risked their lives to succeed in colonial America, this unpromising site became a crossroads for the whole Atlantic world.
Lawrence N. Powell, a decades-long resident and observer of New Orleans, gives us the full sweep of the city's history from its founding through Louisiana statehood in 1812. We see the Crescent City evolve from a French village, to an African market town, to a Spanish fortress, and finally to an Anglo-American center of trade and commerce. We hear and feel the mix of peoples, religions, and languages from four continents that make the place electric-and always on the verge of unraveling. The Accidental City is the story of land-jobbing schemes, stock market crashes, and nonstop squabbles over status, power, and position, with enough rogues, smugglers, and self-fashioners to fill a picaresque novel. Powell's tale underscores the fluidity and contingency of the past, revealing a place where people made their own history. This is a city, and a history, marked by challenges and perpetual shifts in shape and direction, like the sinuous river on which it is perched. Review:"This rich story of the emergence of the Crescent City from its unlikely floodplain site is the best history of early New Orleans ever written. Despite Powell's claim that the Big Easy was an accidental, improvised city, in this respect it was not unlike many other human habitations. But from its origins in the late 17th century, New Orleans was unlike all others on this continent in its mixed population; its distinctive overlay of French, Spanish, African, and American peoples, languages, and ways; and its unfavorable location. 'he place was cobbled together from the bricolage of cultural borrowings and solutions improvised on the fly.' Nothing in this book surpasses Powell's portrayal of the city's mixed American-born people and its free people of color. 'Early New Orleans was a place of reinvented identities, a crossroads of improvisation. People came there to make themselves anew.' In Katrina's aftermath and the shock of nature's claims on our lives, this timely work brings out the complexities of New Orleans's history as well as the rich tapestry of its gritty people. Scholarly but readable, this is a splendid telling presented in a clear, robust voice. 19 illus., 2 maps." Publishers Weekly (Starred Review) Copyright PWxyz, LLC. All rights reserved.
Synopsis:America's most beguiling metropolis started out as a snake-infested, hurricane-battered swamp. Through intense imperial rivalries and ambitious settlers who risked their lives to succeed in colonial America, the site became a crossroads for the Atlantic world. Powell gives us the full sweep of the city's history from its founding through statehood.
Synopsis:A Times Picayune Book of the Year, 2012
Synopsis:2012 Kemper and Leila Williams Prize, Historic New Orleans Collection and the Louisiana Historical Association
About the AuthorLawrence N. Powell holds the James H. Clark Endowed Chair in American Civilization and is Director of the New Orleans Center for the Gulf South at Tulane University.
Tulane University What Our Readers Are SayingBe the first to add a comment for a chance to win!Product Details
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Birds Choice BBC1024 Brome Squirrel Proof Plus Bird Feeder with Cardinal Ring
Bird Seed Not Included
Birds Choice BBC1024 Brome Squirrel Proof Plus Bird Feeder with Cardinal Ring
Product Description
Available while supplies last.
Brome Squirrel Proof Bird Feeder with Cardinal Ring
Openings in the wire shroud align with the seen ports providing birds access to the seed. When a squirrel climbs onto the feeder, its weight automatically forces the shroud down, closing the seed ports.
- Dismantles for easy cleaning
- Height with hanger: 28-in
- Squirrel-resistant
- Four ports
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Samsung Galaxy Tab 7.7 will make "a splash" in the next few months.
Samsung Galaxy Tab 7.7 video: Hands on
Samsung Galaxy Tab 7.7 video: Hands on
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Joining the original Samsung Galaxy Tab and the Galaxy Tab 10.1, is the Samsung Galaxy Tab 7.7. With the smaller screen, it's a throwback to the original Galaxy Tab that Samsung announced at IFA last year, and significantly smaller than the current Samsung tablet flagship, the Galaxy Tab 10.1.

It's also the first tablet with a Super AMOLED display, meaning consumers should expect all the rich contrast that wowed us on the Samsung Galaxy S2 smartphone.

Do all good things come in smaller packages? Watch our Samsung Galaxy Tab 7.7 video for more.

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Perry Open To Sending US Troops To Iraq
WASHINGTON (AP) - Texas Gov. Rick Perry signaled Thursday that he would be open to sending U.S. combat forces to Iraq to fight the deadly Islamic state after its attacks on a Christian minority and the beheading of an American journalist.
"We need to have all of our options open," Perry told a gathering at the conservative Heritage Foundation.
The potential 2016 presidential candidate also raised the prospect of members of the Islamic state crossing the U.S. -Mexico border, which he said is too porous because of inaction by President Barack Obama.
Perry arrived in Washington shrugging off a pair of indictments, saying he was "confident" in his defense.
Perry was indicted last week by a grand jury in Austin on charges stemming from his veto last summer of state funds for public corruption prosecutors. He pleaded not guilty on Tuesday shortly after he was fingerprinted and had his mug shot taken.
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Author: | Sorting Last Post on Top ↓ Message: |
SparkPoints: (171,163)
Fitness Minutes: (123,135) Posts: 8,494 9/30/13 1:31 P My SparkPage Send Private Message Reply |
Great reframing! Good going, Leslie!
Marsha's Keys to Success = Tracking! Super Foods! Step Up Cardio! And most important: Quit Quitting!!
SparkPoints: (66,133)
Fitness Minutes: (73,173) Posts: 680 9/29/13 8:05 A My SparkPage Send Private Message Reply |
I love reading this board because it reminds me of things I know but may be hiding in the back of my mind? I really enjoy feeling hungry. I feel it as "good health". Sick people often lose their appetite. This is something that I deliberately did using cognitive reframing. Boo Yah.
It's never over
SparkPoints: (171,163)
Fitness Minutes: (123,135) Posts: 8,494 9/29/13 3:29 A My SparkPage Send Private Message Reply |
Many parts of Beck Diet Solution I found very helpful. Identifying and addressing sabotaging thoughts was an approach I had never tried before. Realizing that every time I resist I am strengthening my resistance "muscle" and that every time I give in I'm strengthening my giving in "muscle" helps me stick to my eating plan. I'm still not a great planner, but
beck helped me get in the habit of thinking about what I'm going to eat the night before. I have proven to myself over and over I do better when I have a food plan. I also learned that hunger is not an emergency. I did a lot of preventive eating, just to make sure that I would not experience hunger. Once I learned I can tolerate some hunger it was very freeing. Marsha's Keys to Success = Tracking! Super Foods! Step Up Cardio! And most important: Quit Quitting!!
The book Feeling Good was meant to help people specifically with depression (but can also apply to issues of anxiety) deal with many of the irrational thoughts that affect their mood and feelings. It identified many of the categories of such thoughts and gave what I felt were very useful examples of how to change those thoughts. It didn't go into the biochemical foundations, but it wasn't meant to. It certainly can't solve all the problems, but just that strategy alone has improved or even reversed the condition of many people with milder forms of these problems and definitely boosted the results of medication. Many other things we ingest can definitely impact our thinking. I always tell members of the Living Binge Free team never to believe any of the critical, mean thoughts they have about themselves after a binge. (Actually, they are never to be believed, but especially then. Too many food chemicals AND simple pairing of previous experiences clouding the issues.)
It was kind of the granddaddy of such books for the public. I'm sure there are many "children" that have built on it. It seems rather obvious now, but what we think is pretty tied to what we feel. Of course, many things can affect what thoughts occur to us. *"The goal of weight loss is incompatible with recovering from disordered eating." Center for Clinical Interventions
*The No S Diet saved my emotional life! Five years and counting. nosdiet.com/ *Be happy with this moment. This moment is your life. *Get to the next meal hungry! www.sparkpeople.com/myspark/groups_i ndividual.asp
SparkPoints: (66,133)
Fitness Minutes: (73,173) Posts: 680 9/18/13 7:59 A My SparkPage Send Private Message Reply |
I have to say that book "feeling good" was kind of simplistic, but back then that was about all I was ready for. When I read it I weighed over 360 pounds, had a job I hated, a child of 17 who was home again and pregnant after a very short marriage ... Well. Since then I quit that career, became a nurse, began to look into obesity with a microscope, found out about my anxiety disorder.. yeah. There have been a bunch more books that have gone much deeper into the mind body connection, and as a nurse I have personally seen how belief affects general and specific health issues. I keep trying to tell my granddaughter that she gets to decide what to think? But for myself, the journey continues. I love my body today. That way back when book started me on that path and I have loved my body for years now. :)
It's never over
I read Feeling Good, too. It actually has helped at times, but a big career setback about 20 years ago threw me for a loop, and I started meds that I have been off and on since then. But, I have been thinking about applying the strategy for some situations recently.
And I made my food changes during some of the most stressful times of my life. So stress doesn't make me eat. It may make me want to eat, but it can't put the food in my mouth. Only I can do that. There are defintely ways to affect mood, or even learn to tolerate them more calmly. My spiritual teacher says we can have pain, but that does not mean we have to have suffering. I am much better at letting the moods come and go. *"The goal of weight loss is incompatible with recovering from disordered eating." Center for Clinical Interventions
*The No S Diet saved my emotional life! Five years and counting. nosdiet.com/ *Be happy with this moment. This moment is your life. *Get to the next meal hungry! www.sparkpeople.com/myspark/groups_i ndividual.asp
Leslie I like the way you put food journal along with brushing your teeth. As I have gotten older I am even more conscientious about keeping my teeth healthy to avoid very ugly problems. Food journals help the maintenance in the same way, keeps all the physical the numbers healthy.
Sunny in Southern California PST
Challenges are what make life full of stress and anxiety and overcoming them is what can wear you out. Stay stong. Don't stay down, every storm runs out of rain, runs out of rain. Just like every night runs out of dark and turns into day. Team leader for 50+ members with 10-24 pounds to lose Team
SparkPoints: (66,133)
Fitness Minutes: (73,173) Posts: 680 9/17/13 11:29 A My SparkPage Send Private Message Reply |
Re: cognitive reframing. Nell my first reaction to this was No Way that is happening for me I am too busy. Now see, I am retired now. I am so not too busy to do this. This is something I need to try out. Probably keep down the tossing out stuff I don't get around to eating because I forget it is there. So. I shall set an intention to make a planner for hmmm lets see. ... three days. Not too hard, not too easy.
It's never over
SparkPoints: (246,018)
Fitness Minutes: (173,410) Posts: 68,847 9/17/13 9:59 A My SparkPage Send Private Message Reply |
Leslie, I'm with you on the journal, though I call it a Planner. So much of life is unpredictable and uncontrollable. Just because I know what I will be eating for my 3 meals doesn't mean I'll know in advance everything that will happen in between. I can't expect that if my whole day goes as planned, I'll be able to eat to Plan. I can look at my Planner and know to take the ground beef out of the freezer today for tomorrow, or put 6 oz of beans on to soak when I make breakfast. I know that when I reach for the mustard, it will be there. At night I can turn the page and look at the next few days to see what needs to be done so my meals will be ready when I am ready to make them. I do it in black and white on paper because when my mind turns to whirling mush, the answer to at least one thing is there. I don't know about it keeping me in "reality", but it sure does keep me focused on the one thing over which I actually have control.
Reston, Virginia No one ever got up in the morning wishing she'd eaten more the night before. Original Goal: 114. Current old lady goal: 106.
SparkPoints: (66,133)
Fitness Minutes: (73,173) Posts: 680 9/17/13 8:26 A My SparkPage Send Private Message Reply |
One more little thing. The food journal keeps me in "reality". Being in reality is very helpful for maintenance. My head was telling me this past summer that I could stay at my preferred weight and not keep the journal. I had to change my head to "I journal. Just like I clean my teeth, brush my hair... bla bla." I don't MIND the journal, it is a tool to keep me healthy.
It's never over
SparkPoints: (66,133)
Fitness Minutes: (73,173) Posts: 680 9/17/13 8:23 A My SparkPage Send Private Message Reply |
I have been looking at this little thread and trying to organize my thoughts, because cognitive therapy was what caused me to turn in a new direction back in 1981 when I could hardly walk from my extreme morbid obesity. I read a little book by David Burns called "feeling good" about depression. I was in my early 30's, weighed over 350 pounds, was in a miserable life situation. I think the first reframing I did was to stop telling myself I was a lazy slob. I started with something like "my kitchen is always clean" Sounds funny, but when that began to work the whole idea blossomed. I joined Weight watchers who estimated my start weight at 365 when their scale began to register my actual weight a few weeks into that. Because this is a really long story I am going to "brief" it a bit, about 10 years ago a therapist diagnosed me with anxiety, and that has been invaluable for helping me to stay near my goal weight. I found that the anxiety was what would cause me to go into depression, then I would seek out help for that, but never learned to deal with what was causing it? Just recognizing "monkey mind" has allowed me to deal with a lot of that and I don't GET depressed so much any more. That said, Moods happen. Life does not stop being difficult at a normal weight. I no longer expect this to be an easy road, but thanks to careful monitoring of my Own mind, I know I can do it.
It's never over
I did not use Beck's recommendations about tracking food, planning all meals and food ahead, nor did I use the goal of weight loss and being thinner, but I definitely used the technique of coming up with specific thoughts to counter the thoughts that came that told me to eat and gave me all the bogus reasons to do it. I was more interested in reducing bingeing and overeating. I used a meal-based plan and restricted extras to weekends. Her thinking techniques were essential in my journey to establishing habits that are mostly second nature now. I used her list-of-reasons (still on my laptop) and response card techniques a lot. And a lot of sharing on Spark and the NO S Diet forum.
BTW, I have now lost about 40 lbs. over the course of 43 months and the fear of not being able to maintain does not haunt me. I have adjusted my eating downward as it became more natural, though I had to exert some effort during transitions. I'm not blase about it, though. Even thin cultures use external forces to moderate their eating. I knew of many good habits to adopt for years, but my thoughts got in the way. Beck very much helped me with that. *"The goal of weight loss is incompatible with recovering from disordered eating." Center for Clinical Interventions
*The No S Diet saved my emotional life! Five years and counting. nosdiet.com/ *Be happy with this moment. This moment is your life. *Get to the next meal hungry! www.sparkpeople.com/myspark/groups_i ndividual.asp
Several people claim to have invented varieties of Cognitive Behavior modification. I think it kind of arose as a reaction between Freudian and behaviorist models, and what distinguishes it, for me, is a focus on efficacy rather than purity of theory.
The Beck Diet Solution is a work that applies Cognitive Behavior Therapy techniques to weight management, but it is couched in the terms of weight loss. I have started reading it to see where it goes since ongoing maintenance is one of the benefits the book touts. My own experience with cognitive behavior involved dealing with anxiety disorder including PTSD and OCD. I was also working 12 step recovery for codependency, and it's a little hard to say what then was responsible for my depression going into remission. It could even have been a side effect of getting a lot of junk food out of my life. (I had no concept of calorie density or portion control so I remained overweight.) My troubles with OCD and PTSD arose around an incident of undereating I went through in 2003. I went to a therapist for a while and also did some reading on my own, mostly How to Control you Anxiety Before it Controls you by Albert Ellis. I learned that feelings are both valid in their own right and not to be taken at face value. I guess you could say I was learning to detach from my feelings, or stop being codependent toward myself. I was very tough on myself because I'd had a psychotic break when my son died in 1992 and I thought the solution was to shut down my emotions, but that doesn't really work long term, apparently. So that's a bit of my background as I start reading Beck Diet Solution and I'll comment on it here and I invite anyone else familiar with it to comment. I was impressed by their definition of ideal weight but dubious of how proprietary Beck seems about Cognitive Behavior. Edited by: VTRICIA at: 9/16/2013 (07:49)
Topics: | Last Post: |
Levels of Depression Prevention | 2/26/2014 1:45:57 PM |
Emotional Sabotage in the Overeating Cycle | 1/13/2014 1:22:52 PM |


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BusinessBroker.net now has several different ways that people can easily stay updated on new business for sale listings that hit the market. BBN now offers a free Listings-By-
Featured Listings for Brokers.
For its broker members, BBN now offers Featured Listings. Business brokers can now feature their businesses for sale to give them extra exposure and help promote them. Featured listings always appear at the top of all search results and are highlighted to standout. In addition, featured listings also appear on the homepage – in rotation with other featured listings. The featured status gives brokers a great opportunity to promote their preferred listings and attract more interested buyers.
BBN rolled out a new geo-targeted homepage – this feature customizes the homepage depending on the user's location. This new feature provides the users relevant content based on their State. Matt Maxwell, General Manager, stated – "this is a cool feature that allows us to better showcase our business brokers and featured listings to a very relevant audience of visitors – for example, if I live in Vermont, then I will see Vermont featured listings and Vermont based brokers on the homepage – making my experience much more meaningful."
Partnership with Franchise Gator.
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BusinessBroker.net looks forward to rolling out even more improvements for the back-half of 2011.
About BusinessBroker.net :
BusinessBroker.net, a unit of Landmark Interactive, a division of Dominion Enterprises, is a leading business for sale web site that features over 30,000 businesses and franchises for sale. Since 1999, BusinessBroker.net has been helping connect business buyers with business sellers. BusinessBroker.net is based in Atlanta, Georgia.


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Better yet, can I get these photos of Victoria Silvstedt made into 3-D fatheads? Basically I want to turn my place into some sort of boob obstacle course. At least that how it would look through those funny glasses.
Maybe I'm mistaken and they already have hot chick Fatheads. But if they don't I just gave a multimillion dollar idea to my readers. However the chances of any of you having the ambition to go out and execute this idea is roughly one in never.
[...] out but she has a nice body [F-Listed] It would be awesome to own a Victoria Silvstedt Fathead [Don Chavez] Salma Hayek graces everyone with her presence [Celebrity Odor] Tila Tequila is looking pretty good [...]
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"The harder you work, the luckier you get." by Gary Player
Below is the poem entitled Frog which was written by poet Caroline Lohrey. Please feel free to comment on this poem. However, please remember, PoetrySoup is a place of encouragement and growth.
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F riendly little fellow, always R eally happy and always O n the look out for a cricket, while G rinning form ear to ear.


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Latest Shale Stories
2015-02-02 08:22:37
Provides Revised 2015 Capital Budget and Production Guidance HOUSTON, Feb. 2, 2015 /PRNewswire/ -- Gastar Exploration Inc.
2015-01-15 20:20:45
Production from these Prolific Shale Plays Up 36% Compared to Year Ago Levels DENVER and HOUSTON, Jan.
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2005-05-25 17:58:42
Shale is a fine-grained sedimentary rock whose original constituents were clays or muds. It is characterized by thin laminae breaking with an irregular curving fracture, often splintery, and parallel to the often indistinguishable bedding planes. Non-fissile rocks of similar composition but made of particles smaller than 1/16 mm are mudstones. Rocks with similar particle sizes but with less clay and therefore grittier are siltstones. The fine particles that compose shale can remain...
Word of the Day
- A morbid dread of being buried alive. Also spelled 'taphiphobia'.
The word 'taphephobia' comes from Greek roots meaning 'burial' and 'fear'.


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Definition of Pastoral Epistles in English:
The books of the New Testament comprising the two letters of St Paul to St Timothy and the one to St Titus.
Definition of Pastoral Epistles in:
- US English dictionary
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We don't know what the title of Game of the Year 2031 is going to be, but we know the lead designer's name: Mary Schafer. How can we be so sure? Well, that's the name of Joystiq Favorite Living Human Tim Schafer's new daughter, born yesterday and sitting comfortably at 7lbs 10oz.
So, why are we suddenly in the baby business? It's not because our icy, black hearts have softened any (they haven't). But think about how big of a deal the announcement of a sequel to any Tim Schafer game would be. Huge, right? Well, we've done one better and announced the sequel to Tim Schafer. Hope Digg is well-stocked with shovels, because we're headed to China.
[Thanks, Danny]
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