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Sample records for a-i apo a-i

  1. High serum apolipoprotein E determines hypertriglyceridemic dyslipidemias, coronary disease and apoA-I dysfunctionality.

    PubMed

    Onat, Altan; Can, Günay; Ornek, Ender; Ayhan, Erkan; Erginel-Ünaltuna, Nihan; Murat, Sani N

    2013-01-01

    The relevance of serum apolipoprotein E (apoE) levels to two hypertriglyceridemic dyslipidemias has not been clarified. We explored, in a cross-sectional (and short-term prospective) evaluation, the independent relationship of serum apoE to the atherogenic dyslipidemia, hypertriglyceridemia with elevated apoB (HtgB) and to apoA-I dysfunctionality, previously shown in Turkish adults to be independent of apoE genotype. Serum apoE concentrations were measured by immunonephelometry in 1,127 middle-aged adults. In multivariable regression analysis, apoE concentrations showed log-linear associations with apoB and apoA-I levels, waist circumference, independent of C-reactive protein (CRP), homeostatic model assessment (HOMA) index and other confounders. The likelihood of atherogenic dyslipidemia and of HtgB roughly tripled per 1-SD increment in apoE concentrations, additively to apoE genotype, HOMA, apoA-I, CRP concentrations and waist circumference; yet apoA-I, protective against atherogenic dyslipidemia, appeared to promote HtgB, a finding consistent with apoA-I dysfunctionality in this setting. Each 1-SD increment in the apoE level was moreover, associated in both genders with MetS (at OR 1.5), after adjustment for sex, age, apoB, apoA-I and CRP, or for apoE genotypes. Circulating apoE predicted in both genders age-adjusted prevalent and incident coronary heart disease (CHD), independent of apoE genotype and CRP (OR 1.32 [95 % CI 1.11; 1.58]). To conclude, in a general population prone to MetS, elevated apoE concentrations are strongly linked to HtgB and atherogenic dyslipidemia, irrespective of apoE genotype, are associated with MetS and CHD. Excess apoE reflects pro-inflammatory state and likely autoimmune activation.

  2. Apo A-I inhibits foam cell formation in apo E–deficient mice after monocyte adherence to endothelium

    PubMed Central

    Dansky, Hayes M.; Charlton, Sherri A.; Barlow, Courtenay B.; Tamminen, Minna; Smith, Jonathan D.; Frank, Joy S.; Breslow, Jan L.

    1999-01-01

    We have previously shown that expression of the human apo A-I transgene on the apo E–deficient background increases HDL cholesterol and greatly diminishes fatty streak lesion formation. To examine the mechanism, prelesional events in atherosclerotic plaque development were examined in 6- to 8-week-old apo E–deficient and apo E–deficient/human apo A-I transgenic mice. A quantitative assessment of subendothelial lipid deposition by freeze-fracture and deep-etch electron microscopy indicated that elevated apo A-I did not affect the distribution or amount of aortic arch subendothelial lipid deposits. Immunohistochemical staining for VCAM-1 demonstrated similar expression on endothelial cells at prelesional aortic branch sites from both apo E–deficient and apo E–deficient/human apo A-I transgenic mice. Transmission electron microscopy revealed monocytes bound to the aortic arch in mice of both genotypes, and immunohistochemical staining demonstrated that the area occupied by bound mononuclear cells was unchanged. Serum paraoxonase and aryl esterase activity did not differ between apo E–deficient and apo E–deficient/human apo A-I transgenic mice. These data suggest that increases in apo A-I and HDL cholesterol inhibit foam cell formation in apo E–deficient/human apo A-I transgenic mice at a stage following lipid deposition, endothelial activation, and monocyte adherence, without increases in HDL-associated paraoxonase. PMID:10393696

  3. HDL-apoA-I Exchange: Rapid Detection and Association with Atherosclerosis

    PubMed Central

    Borja, Mark S.; Zhao, Lei; Hammerson, Bradley; Tang, Chongren; Yang, Richard; Carson, Nancy; Fernando, Gayani; Liu, Xiaoqin; Budamagunta, Madhu S.; Genest, Jacques; Shearer, Gregory C.; Duclos, Franck; Oda, Michael N.

    2013-01-01

    High density lipoprotein (HDL) cholesterol levels are associated with decreased risk of cardiovascular disease, but not all HDL are functionally equivalent. A primary determinant of HDL functional status is the conformational adaptability of its main protein component, apoA-I, an exchangeable apolipoprotein. Chemical modification of apoA-I, as may occur under conditions of inflammation or diabetes, can severely impair HDL function and is associated with the presence of cardiovascular disease. Chemical modification of apoA-I also impairs its ability to exchange on and off HDL, a critical process in reverse cholesterol transport. In this study, we developed a method using electron paramagnetic resonance spectroscopy (EPR) to quantify HDL-apoA-I exchange. Using this approach, we measured the degree of HDL-apoA-I exchange for HDL isolated from rabbits fed a high fat, high cholesterol diet, as well as human subjects with acute coronary syndrome and metabolic syndrome. We observed that HDL-apoA-I exchange was markedly reduced when atherosclerosis was present, or when the subject carries at least one risk factor of cardiovascular disease. These results show that HDL-apoA-I exchange is a clinically relevant measure of HDL function pertinent to cardiovascular disease. PMID:24015188

  4. PPARγ Represses Apolipoprotein A-I Gene but Impedes TNFα-Mediated ApoA-I Downregulation in HepG2 Cells.

    PubMed

    Shavva, Vladimir S; Mogilenko, Denis A; Bogomolova, Alexandra M; Nikitin, Artemy A; Dizhe, Ella B; Efremov, Alexander M; Oleinikova, Galina N; Perevozchikov, Andrej P; Orlov, Sergey V

    2016-09-01

    Apolipoprotein A-I (ApoA-I) is the main anti-atherogenic component of human high-density lipoproteins (HDL). ApoA-I gene expression is regulated by several nuclear receptors, which are the sensors for metabolic changes during development of cardiovascular diseases. Activation of nuclear receptor PPARγ has been shown to impact lipid metabolism as well as inflammation. Here, we have shown that synthetic PPARγ agonist GW1929 decreases both ApoA-I mRNA and protein levels in HepG2 cells and the effect of GW1929 on apoA-I gene transcription depends on PPARγ. PPARγ binds to the sites A and C within the hepatic enhancer of apoA-I gene and the negative regulation of apoA-I gene transcription by PPARγ appears to be realized via the site C (-134 to -119). Ligand activation of PPARγ leads to an increase of LXRβ and a decrease of PPARα binding to the apoA-I gene hepatic enhancer in HepG2 cells. GW1929 abolishes the TNFα-mediated decrease of ApoA-I mRNA expression in both HepG2 and Caco-2 cells but does not block TNFα-mediated inhibition of ApoA-I protein secretion by HepG2 cells. These data demonstrate that complex of PPARγ with GW1929 is a negative regulator involved in the control of ApoA-I expression and secretion in human hepatocyte- and enterocyte-like cells. J. Cell. Biochem. 117: 2010-2022, 2016. © 2016 Wiley Periodicals, Inc.

  5. Increased methionine sulfoxide content of apoA-I in type 1 diabetes.

    PubMed

    Brock, Jonathan W C; Jenkins, Alicia J; Lyons, Timothy J; Klein, Richard L; Yim, Eunsil; Lopes-Virella, Maria; Carter, Rickey E; Thorpe, Suzanne R; Baynes, John W

    2008-04-01

    Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q(84)-M(86)-K(88), W(108)-M(112)-R(116), and L(144)-M(148)-R(149). These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met(86), Met(112), and Met(148)) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N(epsilon)-malondialdehyde-lysine or N(epsilon)-(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.

  6. RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist

    PubMed Central

    McLure, Kevin G.; Gesner, Emily M.; Tsujikawa, Laura; Kharenko, Olesya A.; Attwell, Sarah; Campeau, Eric; Wasiak, Sylwia; Stein, Adam; White, Andre; Fontano, Eric; Suto, Robert K.; Wong, Norman C. W.; Wagner, Gregory S.; Hansen, Henrik C.; Young, Peter R.

    2013-01-01

    Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis. PMID:24391744

  7. The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

    PubMed Central

    Zhao, Guo-Jun; Yin, Kai; Fu, Yu-chang; Tang, Chao-Ke

    2012-01-01

    Reverse cholesterol transport (RCT) has been characterized as a crucial step for antiatherosclerosis, which is initiated by ATP-binding cassette A1 (ABCA1) to mediate the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I (apoA-I). However, the mechanisms underlying apoA-I/ABCA1 interaction to lead to the lipidation of apoA-I are poorly understood. There are several models proposed for the interaction of apoA-I with ABCA1 as well as the lipidation of apoA-I mediated by ABCA1. ApoA-I increases the levels of ABCA1 protein markedly. In turn, ABCA1 can stabilize apoA-I. The interaction of apoA-I with ABCA1 could activate signaling molecules that modulate posttranslational ABCA1 activity or lipid transport activity. The key signaling molecules in these processes include protein kinase A (PKA), protein kinase C (PKC), Janus kinase 2 (JAK2), Rho GTPases and Ca2+, and many factors also could influence the interaction of apoA-I with ABCA1. This review will summarize these mechanisms for the apoA-I interaction with ABCA1 as well as the signal transduction pathways involved in these processes. PMID:22064972

  8. Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes.

    PubMed

    Kameyama, Hirokazu; Nakajima, Hiroyuki; Nishitsuji, Kazuchika; Mikawa, Shiho; Uchimura, Kenji; Kobayashi, Norihiro; Okuhira, Keiichiro; Saito, Hiroyuki; Sakashita, Naomi

    2016-01-01

    The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1-83) of apoA-I containing this mutation deposit as amyloid fibrils in patients' tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.

  9. Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes

    PubMed Central

    Kameyama, Hirokazu; Nakajima, Hiroyuki; Nishitsuji, Kazuchika; Mikawa, Shiho; Uchimura, Kenji; Kobayashi, Norihiro; Okuhira, Keiichiro; Saito, Hiroyuki; Sakashita, Naomi

    2016-01-01

    The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis. PMID:27464946

  10. Conformation and Lipid Binding of a C-Terminal (198-243) Peptide of Human Apolipoprotein A-I (apoA-I)†

    PubMed Central

    Zhu, Hongli L.; Atkinson, David

    2008-01-01

    Human apolipoprotein A-I (apoA-I) is the principle apolipoprotein of high-density lipoproteins that are critically involved in reverse cholesterol transport. The intrinsically flexibility of apoA-I has hindered studies of the structural and functional details of the protein. Our strategy is to study peptide models representing different regions of apoA-I. Our previous report on [1-44]apoA-I demonstrated that this N-terminal region is unstructured and folds into ~ 60% α-helix with a moderate lipid binding affinity. We now present details of the conformation and lipid interaction of a C-terminal 46 residue peptide, [198-243]apoA-I, encompassing putative helix repeats 10, 9 and the second half of repeat 8 from the C-terminus of apoA-I. Far ultraviolet circular dichroism spectra show that [198-243] apoA-I is also unfolded in aqueous solution. However, self-association induces ~ 50% α-helix in the peptide. The self-associated peptide exists mainly as a tetramer, as determined by native electrophoresis, cross-linking with glutaraldehyde and unfolding data from circular dichroism (CD) and differential scanning calorimetry (DSC). In the presence of a number of lipid mimicking detergents, above their CMC, ~ 60% α-helix was induced in the peptide. In contrast, SDS, an anionic lipid mimicking detergent, induced helical folding in the peptide at a concentration of ~ 0.003% (~ 100 μM), ~ 70 fold below its typical CMC (0.17–0.23% or 6–8 mM). Both monomeric and tetrameric peptide can solublize dimyristoyl phosphatidyl choline (DMPC) liposomes and fold into ~ 60% α-helix. Fractionation by density gradient ultracentrifugation and visualization by negative staining electromicroscopy, demonstrated that the peptide binds to DMPC with high affinity to form at least two sizes of relatively homogenous discoidal HDL-like particles depending on the initial lipid:peptide ratio. The characteristics (lipid:peptide w/w, diameter and density) of both complexes are similar to those of

  11. Can novel Apo A-I polymorphisms be responsible for low HDL in South Asian immigrants?

    PubMed Central

    Dodani, Sunita; Dong, Yanbin; Zhu, Haidong; George, Varghese

    2008-01-01

    Coronary artery disease (CAD) is the leading cause of death in the world. Even though its rates have decreased worldwide over the past 30 years, event rates are still high in South Asians. South Asians are known to have low high-density lipoprotein (HDL) levels. The objective of this study was to identify Apolipoprotein A-I (Apo A-I) polymorphisms, the main protein component of HDL and explore its association with low HDL levels in South Asians. A pilot study on 30 South Asians was conducted and 12-h fasting samples for C-reactive protein, total cholesterol, HDL, low-density lipoprotein (LDL), triglycerides, Lipoprotein (a), Insulin, glucose levels, DNA extraction, and sequencing of Apo A-I gene were done. DNA sequencing revealed six novel Apo A-I single nucleotide polymorphisms (SNPs) in South Asians, one of which (rs 35293760, C938T) was significantly associated with low (<40 mg/dl) HDL levels (P = 0.004). The association was also seen with total cholesterol (P = 0.026) and LDL levels (P = 0.032). This pilot work has highlighted some of the gene-environment associations that could be responsible for low HDL and may be excess CAD in South Asians. Further larger studies are required to explore and uncover these associations that could be responsible for excess CAD risk in South Asians. PMID:20300285

  12. Significance of the hydrophobic residues 225-230 of apoA-I for the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Tiniakou, Ioanna; Kateifides, Andreas K; Gkolfinopoulou, Christina; Chroni, Angeliki; Stratikos, Efstratios; Zannis, Vassilis I; Kardassis, Dimitris

    2013-12-01

    We studied the significance of four hydrophobic residues within the 225-230 region of apoA-I on its structure and functions and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of an apoA-I[F225A/V227A/F229A/L230A] mutant in apoA-I⁻/⁻ mice decreased plasma cholesterol, HDL cholesterol, and apoA-I levels. When expressed in apoA-I⁻/⁻ × apoE⁻/⁻ mice, approximately 40% of the mutant apoA-I as well as mouse apoA-IV and apoB-48 appeared in the VLDL/IDL/LDL. In both mouse models, the apoA-I mutant generated small spherical particles of pre-β- and α4-HDL mobility. Coexpression of the apoA-I mutant and LCAT increased and shifted the-HDL cholesterol peak toward lower densities, created normal αHDL subpopulations, and generated spherical-HDL particles. Biophysical analyses suggested that the apoA-I[225-230] mutations led to a more compact folding that may limit the conformational flexibility of the protein. The mutations also reduced the ability of apoA-I to promote ABCA1-mediated cholesterol efflux and to activate LCAT to 31% and 66%, respectively, of the WT control. Overall, the apoA-I[225-230] mutations inhibited the biogenesis of-HDL and led to the accumulation of immature pre-β- and α4-HDL particles, a phenotype that could be corrected by administration of LCAT. PMID:24123812

  13. Recombinant amyloidogenic domain of ApoA-I: Analysis of its fibrillogenic potential

    SciTech Connect

    Di Gaetano, Sonia; Guglielmi, Fulvio; Arciello, Angela; Mangione, Palma; Monti, Maria; Pagnozzi, Daniela; Raimondi, Sara; Giorgetti, Sofia; Orru, Stefania; Canale, Claudio; Pucci, Piero; Dobson, Christopher M.; Bellotti, Vittorio; Piccoli, Renata . E-mail: piccoli@unina.it

    2006-12-08

    A variety of amyloid diseases are associated with fibrillar aggregates from N-terminal fragments of ApoA-I generated through a largely unexplored multi-step process. The understanding of the molecular mechanism is impaired by the lack of suitable amounts of the fibrillogenic polypeptides that could not be produced by recombinant methods so far. We report the production and the conformational analysis of recombinant ApoA-I 1-93 fragment. Similarly to the polypeptide isolated ex vivo, a pH switch from 7 to 4 induces a fast and reversible conformational transition to a helical state and leads to the identification of a key intermediate in the fibrillogenesis process. Limited proteolysis experiments suggested that the C-terminal region is involved in helix formation. The recombinant polypeptide generates fibrils at pH 4 on a time scale comparable with that of the native fragment. These findings open the way to studies on structural, thermodynamic, and kinetic aspects of ApoA-I fibrillogenesis.

  14. Dysfunctional HDL containing L159R apoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, the effect of the mutation L159R apoA-I or apoA-IL159R (FIN) was assessed. apoA-IL159R (FIN) is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Transgenic mice lines were created through strategic mati...

  15. Dysfunctional HDL Containing L159R ApoA-I Leads to Exacerbation of Atherosclerosis in Hyperlipidemic Mice

    PubMed Central

    Sorci-Thomas, Mary G.; Zabalawi, Manal; Bharadwaj, Manish S.; Wilhelm, Ashley J.; Owen, John S.; Asztalos, Bela F.; Bhat, Shaila; Thomas, Michael J.

    2013-01-01

    The mutation L159R apoA-I or apoA-IL159R (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL−/−, apoA-I−/−) (double knockout or DKO) were crossed > 9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr−/−, ApoA-I−/− (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12 weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α3-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-IL159R contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. PMID:21944998

  16. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

    PubMed

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen A; Zhou, Zhou; Sun, Lijie; Mathison, Angela J; Garcia-Barrio, Minerva T; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J; Rader, Daniel J; Urrutia, Raul; Chen, Y Eugene

    2015-10-01

    Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis.

  17. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

    PubMed

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen A; Zhou, Zhou; Sun, Lijie; Mathison, Angela J; Garcia-Barrio, Minerva T; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J; Rader, Daniel J; Urrutia, Raul; Chen, Y Eugene

    2015-10-01

    Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis. PMID:26368306

  18. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

    PubMed Central

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen A.; Zhou, Zhou; Sun, Lijie; Mathison, Angela J.; Garcia-Barrio, Minerva T.; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J.; Rader, Daniel J.; Urrutia, Raul; Chen, Y. Eugene

    2015-01-01

    Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E–deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis. PMID:26368306

  19. Influence of Apolipoprotein (Apo) A-I Structure on Nascent High Density Lipoprotein (HDL) Particle Size Distribution*

    PubMed Central

    Vedhachalam, Charulatha; Chetty, Palaniappan Sevugan; Nickel, Margaret; Dhanasekaran, Padmaja; Lund-Katz, Sissel; Rothblat, George H.; Phillips, Michael C.

    2010-01-01

    The principal protein of high density lipoprotein (HDL), apolipoprotein (apo) A-I, in the lipid-free state contains two tertiary structure domains comprising an N-terminal helix bundle and a less organized C-terminal domain. It is not known how the properties of these domains modulate the formation and size distribution of apoA-I-containing nascent HDL particles created by ATP-binding cassette transporter A1 (ABCA1)-mediated efflux of cellular phospholipid and cholesterol. To address this issue, proteins corresponding to the two domains of human apoA-I (residues 1–189 and 190–243) and mouse apoA-I (residues 1–186 and 187–240) together with some human/mouse domain hybrids were examined for their abilities to form HDL particles when incubated with either ABCA1-expressing cells or phospholipid multilamellar vesicles. Incubation of human apoA-I with cells gave rise to two sizes of HDL particles (hydrodynamic diameter, 8 and 10 nm), and removal or disruption of the C-terminal domain eliminated the formation of the smaller particle. Variations in apoA-I domain structure and physical properties exerted similar effects on the rates of formation and sizes of HDL particles created by either spontaneous solubilization of phospholipid multilamellar vesicles or the ABCA1-mediated efflux of cellular lipids. It follows that the sizes of nascent HDL particles are determined at the point at which cellular phospholipid and cholesterol are solubilized by apoA-I; apparently, this is the rate-determining step in the overall ABCA1-mediated cellular lipid efflux process. The stability of the apoA-I N-terminal helix bundle domain and the hydrophobicity of the C-terminal domain are important determinants of both nascent HDL particle size and their rate of formation. PMID:20679346

  20. Modified apolipoprotein (apo) A-I by artificial sweetener causes severe premature cellular senescence and atherosclerosis with impairment of functional and structural properties of apoA-I in lipid-free and lipid-bound state.

    PubMed

    Jang, Wookju; Jeoung, Nam Ho; Cho, Kyung-Hyun

    2011-05-01

    Long-term consumption of artificial sweeteners (AS) has been the recent focus of safety concerns. However, the potential risk of the AS in cardiovascular disease and lipoprotein metabolism has not been investigated sufficiently. We compared the influence of AS (aspartame, acesulfame K, and saccharin) and fructose in terms of functional and structural correlations of apolipoprotein (apo) A-I and high-density lipoproteins (HDL), which have atheroprotective effects. Long-term treatment of apoA-I with the sweetener at physiological concentration (3 mM for 168 h) resulted in loss of antioxidant and phospholipid binding activities with modification of secondary structure. The AS treated apoA-I exhibited proteolytic cleavage to produce 26 kDa-fragment. They showed pro-atherogenic properties in acetylated LDL phagocytosis of macrophages. Each sweetener alone or sweetener-treated apoA-I caused accelerated senescence in human dermal fibroblasts. These results suggest that long-term consumption of AS might accelerate atherosclerosis and senescence via impairment of function and structure of apoA-I and HDL.

  1. Different Functional and Structural Characteristics between ApoA-I and ApoA-4 in Lipid-Free and Reconstituted HDL State: ApoA-4 Showed Less Anti-Atherogenic Activity

    PubMed Central

    Yoo, Jeong-Ah; Lee, Eun-Young; Park, Ji Yoon; Lee, Seung-Taek; Ham, Sihyun; Cho, Kyung-Hyun

    2015-01-01

    Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties. PMID:25997739

  2. Different Functional and Structural Characteristics between ApoA-I and ApoA-4 in Lipid-Free and Reconstituted HDL State: ApoA-4 Showed Less Anti-Atherogenic Activity.

    PubMed

    Yoo, Jeong-Ah; Lee, Eun-Young; Park, Ji Yoon; Lee, Seung-Taek; Ham, Sihyun; Cho, Kyung-Hyun

    2015-06-01

    Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties. PMID:25997739

  3. Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux.

    PubMed

    Anthanont, Pimjai; Asztalos, Bela F; Polisecki, Eliana; Zachariah, Benoy; Schaefer, Ernst J

    2015-01-01

    We report a novel heterozygous apolipoprotein A-I (apoA-I) missense mutation (c.517C>A, p.Arg149Ser, designated as apoA-IBoston) in a 67-year-old woman and her 2 sons, who had mean serum high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-I in very large α-1 HDL that were 10%, 35%, and 16% of normal, respectively (all P < .05). The percentage of HDL cholesterol in the esterified form was also significantly (P < .05) reduced to 52% of control values. Cholesteryl ester tranfer protein (CETP) activity was normal. The mean global, adenosine triphosphate (ATP)-binding cassette transporter A1 and scavenger receptor B type I-mediated cellular cholesterol efflux capacity in apoB-depleted serum from affected family members were 41%, 37%, 47%, 54%, and 48% of control values, respectively (all P < .05). lecithin-cholesterol acyltransferase (LCAT) activity in plasma was 71% of controls, whereas in the cell-based assay, it was 73% of control values (P < .05). The data indicate that this novel apoA-I missense is associated with markedly decreased levels of HDL cholesterol and very large α-1 HDL, as well as decreased serum cellular cholesterol efflux and LCAT activity, but not with premature coronary heart disease, similar to other apoA-I mutations that have been associated with decreased LCAT activity.

  4. Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux.

    PubMed

    Anthanont, Pimjai; Asztalos, Bela F; Polisecki, Eliana; Zachariah, Benoy; Schaefer, Ernst J

    2015-01-01

    We report a novel heterozygous apolipoprotein A-I (apoA-I) missense mutation (c.517C>A, p.Arg149Ser, designated as apoA-IBoston) in a 67-year-old woman and her 2 sons, who had mean serum high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-I in very large α-1 HDL that were 10%, 35%, and 16% of normal, respectively (all P < .05). The percentage of HDL cholesterol in the esterified form was also significantly (P < .05) reduced to 52% of control values. Cholesteryl ester tranfer protein (CETP) activity was normal. The mean global, adenosine triphosphate (ATP)-binding cassette transporter A1 and scavenger receptor B type I-mediated cellular cholesterol efflux capacity in apoB-depleted serum from affected family members were 41%, 37%, 47%, 54%, and 48% of control values, respectively (all P < .05). lecithin-cholesterol acyltransferase (LCAT) activity in plasma was 71% of controls, whereas in the cell-based assay, it was 73% of control values (P < .05). The data indicate that this novel apoA-I missense is associated with markedly decreased levels of HDL cholesterol and very large α-1 HDL, as well as decreased serum cellular cholesterol efflux and LCAT activity, but not with premature coronary heart disease, similar to other apoA-I mutations that have been associated with decreased LCAT activity. PMID:26073399

  5. Role of urea on recombinant Apo A-I stability and its utilization in anion exchange chromatography.

    PubMed

    Angarita, Monica; Arosio, Paolo; Müller-Späth, Thomas; Baur, Daniel; Falkenstein, Roberto; Kuhne, Wolfgang; Morbidelli, Massimo

    2014-08-01

    Apolipoprotein A-I (Apo A-I) is an important lipid-binding protein involved in the transport and metabolism of cholesterol. High protein purity, in particular with respect to endotoxins is required for therapeutic applications. The use of urea during the purification process of recombinant Apo A-I produced in Escherichia coli has been suggested so as to provide high endotoxin clearance. In this work, we show that urea can be used as a sole modifier during the ion exchange chromatographic purification of Apo A-I and we investigate the molecular mechanism of elution by correlating the effect of urea on self-association, conformation and adsorption equilibrium properties of a modified model Apo A-I. In the absence of urea the protein was found to be present as a population of oligomers represented mainly by trimers, hexamers and nonamers. The addition of urea induced oligomer dissociation and protein structure unfolding. We correlated the changes in protein association and conformation with variations of the adsorption equilibrium of the protein on a strong anion exchanger. It was confirmed that the adsorption isotherms, described by a Langmuir model, were dependent on both protein and urea concentrations. Monomers, observed at low urea concentration (0.5M), were characterized by larger binding affinity and adsorption capacity compared to both protein oligomers (0M) and unfolded monomers (2-8M). The reduction of both the binding strength and maximum adsorption capacity at urea concentrations larger than 0.5M explains the ability of urea of inducing elution of the protein from the ion exchange resin. The dissociation of the protein complexes occurring during the elution could likely be the origin of the effective clearance of endotoxins originally trapped inside the oligomers.

  6. Role of the hydrophobic and charged residues in the 218-226 region of apoA-I in the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Kateifides, Andreas K; Gkolfinopoulou, Christina; Georgiadou, Dimitra; Beck, Melissa; Gründler, Katharina; Chroni, Angeliki; Stratikos, Efstratios; Kardassis, Dimitris; Zannis, Vassilis I

    2013-12-01

    We investigated the significance of hydrophobic and charged residues 218-226 on the structure and functions of apoA-I and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of apoA-I[L218A/L219A/V221A/L222A] in apoA-I⁻/⁻ mice decreased plasma cholesterol and apoA-I levels to 15% of wild-type (WT) control mice and generated pre-β- and α4-HDL particles. In apoA-I⁻/⁻ × apoE⁻/⁻ mice, the same mutant formed few discoidal and pre-β-HDL particles that could not be converted to mature α-HDL particles by excess LCAT. Expression of the apoA-I[E223A/K226A] mutant in apoA-I⁻/⁻ mice caused lesser but discrete alterations in the HDL phenotype. The apoA-I[218-222] and apoA-I[E223A/K226A] mutants had 20% and normal capacity, respectively, to promote ABCA1-mediated cholesterol efflux. Both mutants had ∼65% of normal capacity to activate LCAT in vitro. Biophysical analyses suggested that both mutants affected in a distinct manner the structural integrity and plasticity of apoA-I that is necessary for normal functions. We conclude that the alteration of the hydrophobic 218-222 residues of apoA-I disrupts apoA-I/ABCA1 interactions and promotes the generation of defective pre-β particles that fail to mature into α-HDL subpopulations, thus resulting in low plasma apoA-I and HDL. Alterations of the charged 223, 226 residues caused milder but discrete changes in HDL phenotype. PMID:23990662

  7. Direct detection of ABCA1-dependent HDL formation based on lipidation-induced hydrophobicity change in apoA-I[S

    PubMed Central

    Omura, Risa; Nagao, Kohjiro; Kobayashi, Norihiro; Ueda, Kazumitsu; Saito, Hiroyuki

    2014-01-01

    ABCA1 mediates the efflux of cholesterol and phospholipids into apoA-I to form HDL, which is important in the prevention of atherosclerosis. To develop a novel method for the evaluation of HDL formation, we prepared an apoA-I-POLARIC by labeling the specific residue of an apoA-I variant with a hydrophobicity-sensitive fluorescence probe that detects the environmental change around apoA-I during HDL formation. apoA-I-POLARIC possesses the intact ABCA1-dependent HDL formation activity and shows 4.0-fold higher fluorescence intensity in HDL particles than in the lipid-free state. Incubation of apoA-I-POLARIC with ABCA1-expressing cells, but not ABCA1-non-expressing cells, caused a 1.7-fold increase in fluorescence intensity. Gel filtration analysis demonstrated that the increase in fluorescence intensity of apoA-I-POLARIC represents the amount of apoA-I incorporated into the discoidal HDL particles rather than the amount of secreted cholesterol. THP-1 macrophage-mediated HDL formation and inhibition of HDL formation by cyclosporine A could also be measured using apoA-I-POLARIC. Furthermore, HDL formation-independent lipid release induced by microparticle formation or cell death was not detected by apoA-I-POLARIC. These results demonstrate that HDL formation by ABCA1-expressing cells can be specifically detected by sensing hydrophobicity change in apoA-I, thus providing a novel method for assessing HDL formation and screening of the HDL formation modulator. PMID:25214539

  8. Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels

    PubMed Central

    Francone, Omar L.; Ishida, Brian Y.; de la Llera-Moya, Margarita; Royer, Lori; Happe, Christiane; Zhu, Jian; Chalkey, Robert J.; Schaefer, Peter; Cox, Cheryl; Burlingame, Al; Kane, John P.; Rothblat, George H.

    2011-01-01

    Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered. PMID:21771977

  9. Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo A-I Milano Gene Therapy on Regression of Atherosclerosis.

    PubMed

    Wang, Lai; Tian, Fang; Arias, Ana; Yang, Mingjie; Sharifi, Behrooz G; Shah, Prediman K

    2016-05-01

    Apolipoprotein A-1 (Apo A-I) Milano, a naturally occurring Arg173to Cys mutant of Apo A-1, has been shown to reduce atherosclerosis in animal models and in a small phase 2 human trial. We have shown the superior atheroprotective effects of Apo A-I Milano (Apo A-IM) gene compared to wild-type Apo A-I gene using transplantation of retrovirally transduced bone marrow in Apo A-I/Apo E null mice. In this study, we compared the effect of dietary lipid lowering versus lipid lowering plus Apo A-IM gene transfer using recombinant adeno-associated virus (rAAV) 8 as vectors on atherosclerosis regression in Apo A-I/Apo E null mice. All mice were fed a high-cholesterol diet from age of 6 weeks until week 20, and at 20 weeks, 10 mice were euthanized to determine the extent of atherosclerosis. After 20 weeks, an additional 20 mice were placed on either a low-cholesterol diet plus empty rAAV (n = 10) to serve as controls or low-cholesterol diet plus 1 single intravenous injection of 1.2 × 10(12)vector genomes of adeno-associated virus (AAV) 8 vectors expressing Apo A-IM (n = 10). At the 40 week time point, intravenous AAV8 Apo A-IM recipients showed a significant regression of atherosclerosis in the whole aorta (P< .01), aortic sinuses (P< .05), and brachiocephalic arteries (P< .05) compared to 20-week-old mice, whereas low-cholesterol diet plus empty vector control group showed no significant regression in lesion size. Immunostaining showed that compared to the 20-week-old mice, there was a significantly reduced macrophage content in the brachiocephalic (P< .05) and aortic sinus plaques (P< .05) of AAV8 Apo A-IM recipients. These data show that although dietary-mediated cholesterol lowering halts progression of atherosclerosis, it does not induce regression, whereas combination of low-cholesterol diet and AAV8 mediated Apo A-I Milano gene therapy induces rapid and significant regression of atherosclerosis in mice. These data provide support for the potential feasibility of this

  10. Increased HDL Size and Enhanced Apo A-I Catabolic Rates Are Associated With Doxorubicin-Induced Proteinuria in New Zealand White Rabbits.

    PubMed

    López-Olmos, Victoria; Carreón-Torres, Elizabeth; Luna-Luna, María; Flores-Castillo, Cristobal; Martínez-Ramírez, Miriam; Bautista-Pérez, Rocío; Franco, Martha; Sandoval-Zárate, Julio; Roldán, Francisco-Javier; Aranda-Fraustro, Alberto; Soria-Castro, Elizabeth; Muñoz-Vega, Mónica; Fragoso, José-Manuel; Vargas-Alarcón, Gilberto; Pérez-Méndez, Oscar

    2016-03-01

    The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

  11. The Carboxy-Terminal Region of apoA-I is Required for the ABCA1-Dependent Formation of α-HDL but not preβ-HDL Particles In Vivo

    PubMed Central

    Chroni, Angeliki; Koukos, Georgios; Duka, Adelina; Zannis, Vassilis I.

    2008-01-01

    ABCA1-mediated lipid efflux to lipid poor apoA-I results in the gradual lipidation of apoA-I. This leads to the formation of discoidal HDL which are subsequently converted to spherical HDL by the action of LCAT. We have investigated the effect of point mutations and deletions in the carboxy-terminal region of apoA-I on the biogenesis of HDL using adenovirus-mediated gene transfer in apoA-I deficient mice. It was found that the plasma HDL levels were greatly reduced in mice expressing the carboxy-terminal deletion mutants apoA-I[Δ(185-243)] and apoA-I[Δ(220-243)], shown previously to diminish the ABCA1-mediated lipid efflux. The HDL levels were normal in mice expressing the WT apoA-I, the apoA-I[Δ(232-243)] deletion mutant or the apoA-I[E191A/H193A/K195A] point mutant, which promote normal ABCA1-mediated lipid efflux. Electron microscopy and two-dimensional gel electrophoresis showed that the apoA-I[Δ(185-243)] and apoA-I[Δ(220-243)] mutants formed mainly preβ-HDL particles and few spherical particles enriched in apoE, while WT apoA-I, apoA-I[Δ(232-243)] and apoA-I[E191A/H193A/K195A] formed spherical α-HDL particles. The findings establish that a) deletions that eliminate the 220-231 region of apoA-I prevent the synthesis of α-HDL, but allow the synthesis of preβ-HDL particles in vivo, b) the amino-terminal segment 1-184 of apoA-I can promote synthesis of preβ-HDL type particles in an ABCA1-independent process and c) the charged residues in the 191-195 region of apoA-I do not influence the biogenesis of HDL. PMID:17447731

  12. Cellular interaction and cytotoxicity of the iowa mutation of apolipoprotein A-I (ApoA-IIowa) amyloid mediated by sulfate moieties of heparan sulfate.

    PubMed

    Kuwabara, Kaori; Nishitsuji, Kazuchika; Uchimura, Kenji; Hung, Shang-Cheng; Mizuguchi, Makoto; Nakajima, Hiroyuki; Mikawa, Shiho; Kobayashi, Norihiro; Saito, Hiroyuki; Sakashita, Naomi

    2015-10-01

    The single amino acid mutation G26R in human apolipoprotein A-I (apoA-I) is associated with familial amyloid polyneuropathy III. ApoA-I carrying this mutation (apoA-IIowa) forms amyloid fibrils in vitro. Heparan sulfate (HS) is a glycosaminoglycan that is abundant at the cell surface and in the extracellular matrix. Although HS and its highly sulfated domains are involved in aggregation of amyloid-β and accumulate in cerebral amyloid plaques of patients with Alzheimer disease and mouse models of this disease, the role of HS in familial amyloid polyneuropathy III has never been addressed. Here, we used cell models to investigate the possible role of HS in the cytotoxicity of apoA-IIowa amyloid. Wild-type CHO cells, but not pgsD-677 cells, an HS-deficient CHO mutant, demonstrated uptake of apoA-IIowa amyloid after incubation with the amyloid. Addition of sulfated glycosaminoglycans to culture media prevented interaction with and cytotoxicity of apoA-IIowa amyloid to CHO cells. Elimination of cell surface HS or inhibition of HS sulfation with chemical reagents interfered with interaction of apoA-IIowa amyloid with CHO cells. We also found that cellular interaction and cytotoxicity of apoA-IIowa amyloid were significantly attenuated in CHO cells that stably expressed the human extracellular endoglucosamine 6-sulfatases HSulf-1 and HSulf-2. Our results thus suggest that cell surface HS mediates cytotoxicity of apoA-IIowa amyloid and that enzymatic remodeling of HS mitigates the cytotoxicity.

  13. APOA1-75 G to A Substitution Associated with Severe Forms of CAD, Lower Levels of HDL and apoA-I among Northern Indians

    PubMed Central

    Chhabra, S.; Narang, R.; Lakshmy, R.; Das, N.

    2005-01-01

    Apolipoprotein A-I (APOA1 gene, apoA-I protein) is the major protein for plasma high density lipoprotein (HDL). The relationship of APOA1-75G/A polymorphism with lipid profile and coronary artery disease (CAD) is unclear. Out of 370 individuals initially recruited, 164 angiographically proven CAD patients (≥ 70% stenosis) and 36 individuals with normal coronaries or insignificant CAD (NCAD, ≤ 50% stenosis) from Delhi and adjoining areas were selected for analysis based on the set criteria. Polymorphism was determined by PCR followed by MspI restriction digestion. Lipid profile was estimated by enzymatic kit and apoA-I levels by immunoturbidimetry. A highly significant increasing trend in ‘A’ allele frequency was observed with the rise in severity of CAD: NCAD (0.097) < SVD (single vessel disease) (0.117) < DVD (double vessel disease) (0.223) < TVD (triple vessel disease) (0.291). In comparison to GG individuals, the OR of ‘A’ allele carriers to develop SVD, DVD, TVD was 1.3, 2.8 and 4.2 respectively (ptrend = 0.007). Analysis of intergenotypic variations in the lipid profile revealed significantly lower levels of HDL and apoA-I among ‘A’ allele carriers as compared to GG (patients). Our study, first of its kind from India, suggests that ‘A’ allele may contribute to severity of CAD and low levels of HDL & apoA-I. However, an in depth study with a larger set of sample is necessary. PMID:16403951

  14. Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I.

    PubMed Central

    von Eckardstein, A; Funke, H; Henke, A; Altland, K; Benninghoven, A; Assmann, G

    1989-01-01

    Six unrelated families with genetically determined structural variants of apo A-I were found in the course of an electrophoretic screening program for apo A-I variants in dried blood samples of newborns. The following structural variations were identified by the combined use of HPLC, time-of-flight secondary ion mass spectrometry (TOF-SIMS), and automated gas phase sequencing: Pro3----Arg (1x), Pro4----Arg (1x), and Pro165----Arg (4x). All variant carriers were heterozygous for their mutant of apo A-I. Subjects heterozygous for apo A-I(Pro165----Arg) (n = 12) were found to exhibit lower mean values for apo A-I (109 +/- 16 mg/dl) and HDL cholesterol (37 +/- 9 mg/dl) than unaffected family members (n = 9): 176 +/- 41 and 64 +/- 18 mg/dl, respectively (P less than 0.001). In 9 of 12 apo A-I(Pro165----Arg) variant carriers the concentrations of apo A-I were below the fifth percentile of sex-matched controls. By two-dimensional immunoelectrophoresis as well as by densitometry the relative concentration of the variant apo A-I in heterozygous carriers of apo A-I(Pro165----Arg) was determined to account for only 30% of the total plasma apo A-I mass instead of the expected 50%. Thus, the observed apo A-I deficiency may be largely a consequence of the decreased concentration of the variant apo A-I. In the case of the apo A-I(Pro3----Arg) mutant, densitometry of HDL apolipoproteins demonstrated a distinctly increased concentration of the variant proapo A-I relative to normal proapo A-I. This phenomenon was not observed in the apo A-I(Pro4----Arg) mutant or in other mutants. This suggests that the interspecies conserved proline residue in position 3 of mature apo A-I is functionally important for the regular enzymatic conversion of proapo A-I to mature apo A-I. Images PMID:2512329

  15. Effects of Iron Supplementation With and Without Docosahexaenoic Acid on the Cardiovascular Disease Risk Based on Paraoxonase-1, hs-CRP, and ApoB/ApoA-I Ratio in Women with Iron Deficiency Anemia.

    PubMed

    Shidfar, Farzad; Amani, Samira; Vafa, Mohammadreza; Shekarriz, Ramin; Hosseini, Sharieh; Shidfar, Shahrzad; Eshraghian, Mohammadreza; Mousavi, Seyedeh Neda

    2016-01-01

    Numerous studies have demonstrated that tissue deposition of iron following prolonged high dose of oral supplementation for treatment of iron deficiency anemia (IDA) leads to body iron overload and oxidative stress, which starts the process of atherosclerosis. This study aimed to determine the effect of iron supplementation in combination with docosahexaenoic acid (DHA) on the cardiovascular disease risk based on paraoxonase-1 (PON-1), high-sensitivity C-reactive protein (hs-CRP), and ApoB/ApoA-I ratio in women with IDA. In this randomized controlled trial, 76 women with IDA, aged 15-45 years, were included. The patients were randomly assigned to receive 500 mg of DHA supplement or placebo with an iron tablet, once daily for 12 weeks. The participants were assessed by measurement of the serum iron, ferritin, PON-1, hs-CRP levels, and the ApoB/ApoA-I ratio at the beginning and end of study. Serum hs-CRP decreased in the DHA-supplemented group (p = 0.036), and ApoA-I decreased in the placebo group (p = 0.013). No significant difference was detected for the serum PON-1 concentration and the ApoB/ApoA-I ratio in two groups. Iron supplementation combined with DHA may have favorable effects on serum hs-CRP in women with IDA.

  16. Effects of Iron Supplementation With and Without Docosahexaenoic Acid on the Cardiovascular Disease Risk Based on Paraoxonase-1, hs-CRP, and ApoB/ApoA-I Ratio in Women with Iron Deficiency Anemia.

    PubMed

    Shidfar, Farzad; Amani, Samira; Vafa, Mohammadreza; Shekarriz, Ramin; Hosseini, Sharieh; Shidfar, Shahrzad; Eshraghian, Mohammadreza; Mousavi, Seyedeh Neda

    2016-01-01

    Numerous studies have demonstrated that tissue deposition of iron following prolonged high dose of oral supplementation for treatment of iron deficiency anemia (IDA) leads to body iron overload and oxidative stress, which starts the process of atherosclerosis. This study aimed to determine the effect of iron supplementation in combination with docosahexaenoic acid (DHA) on the cardiovascular disease risk based on paraoxonase-1 (PON-1), high-sensitivity C-reactive protein (hs-CRP), and ApoB/ApoA-I ratio in women with IDA. In this randomized controlled trial, 76 women with IDA, aged 15-45 years, were included. The patients were randomly assigned to receive 500 mg of DHA supplement or placebo with an iron tablet, once daily for 12 weeks. The participants were assessed by measurement of the serum iron, ferritin, PON-1, hs-CRP levels, and the ApoB/ApoA-I ratio at the beginning and end of study. Serum hs-CRP decreased in the DHA-supplemented group (p = 0.036), and ApoA-I decreased in the placebo group (p = 0.013). No significant difference was detected for the serum PON-1 concentration and the ApoB/ApoA-I ratio in two groups. Iron supplementation combined with DHA may have favorable effects on serum hs-CRP in women with IDA. PMID:26077874

  17. Effects of blackberry (Morus nigra L.) consumption on serum concentration of lipoproteins, apo A-I, apo B, and high-sensitivity-C-reactive protein and blood pressure in dyslipidemic patients

    PubMed Central

    Aghababaee, Sahar Keshtkar; Vafa, Mohammadreza; Shidfar, Farzad; Tahavorgar, Atefeh; Gohari, Mahmoodreza; Katebi, Davod; Mohammadi, Vida

    2015-01-01

    Background: This study investigated blackberry (Persian mulberry) effects on apo A-I, apo B, high-sensitivity-C-reactive protein (hs-CRP), and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in dyslipidemic patients. Materials and Methods: In this 8-week randomized clinical trial, 72 dyslipidemic patients were randomly divided into two groups: Intervention (300 mL/day blackberry juice with pulp) and control group (usual diets). Before and after the intervention, fasting blood samples were taken from both groups and serum concentration of lipoprotein, apo A-I and apo B, serum lipids (total cholesterol, low-density lipoprotein, high-density lipoprotein [HDL], and triglyceride), hs-CRP were measured. Blood pressure before and after the study was measured with a mercury manometer. Results: At week 8 in the intervention group, apo A-I and HDL increased significantly (P = 0.015, P = 0.001, respectively), apo B and hs-CRP decreased significantly (P = 0.044, P = 0.04, respectively). Mean changes in apo A-I and HDL and apo B/apo A-I ratio were significant between the groups (P = 0.005, P = 0.014, and P = 0.009, respectively). After 8 weeks, there was a significant difference between hs-CRP mean values (P = 0.01) of the groups. At week 8, SBP decreased significantly (P = 0.005) in the intervention group with no significant differences for SBP mean values between the groups. No significant changes were observed in other lipid parameters and DBP in the intervention group and between the groups. Conclusion: Blackberry consumption may exert beneficial effects on apolipoproteins, blood pressure, and inflammatory markers in individuals with lipid disorders. PMID:26622259

  18. An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide.

    PubMed

    Wool, Geoffrey D; Vaisar, Tomas; Reardon, Catherine A; Getz, Godfrey S

    2009-09-01

    Modifying apolipoprotein (apo) A-I mimetic peptides to include a proline-punctuated alpha-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL (moHDL) and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL level. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin (Hb). In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance. Administration of acetylated Pro to apoE(-/-) mice significantly decreases plasma serum amyloid A levels, while acetylated 4F does not have this ability. In contrast to previous reports that inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with Hb-containing plasma fractions. bPro, however, specifically binds to moHDL in vivo. In addition, the number of amphipathic alpha-helices and their linker influences the anti-inflammatory effects of apoA-I mimetic peptides in vivo. PMID:19433476

  19. Optimized bacterial expression of human apolipoprotein A-I.

    PubMed

    Ryan, Robert O; Forte, Trudy M; Oda, Michael N

    2003-01-01

    Apolipoprotein A-I (apoA-I) serves critical functions in plasma lipoprotein metabolism as a structural component of high density lipoprotein, activator of lecithin:cholesterol acyltransferase, and acceptor of cellular cholesterol as part of the reverse cholesterol transport pathway. In an effort to facilitate structure:function studies of human apoA-I, we have optimized a plasmid vector for production of recombinant wild type (WT) and mutant apoA-I in bacteria. To facilitate mutagenesis studies, subcloning, and DNA manipulation, numerous silent mutations have been introduced into the apoA-I cDNA, generating 13 unique restriction endonuclease sites. The coding sequence for human apoA-I has been modified by the introduction of additional silent mutations that eliminate 18 separate codons that employ tRNAs that are of low or moderate abundance in Escherichia coli. Yields of recombinant apoA-I achieved using the optimized cDNA were 100+/-20 mg/L bacterial culture, more than fivefold greater than yields routinely obtained with the original cDNA. Site-directed mutagenesis of the apoA-I cDNA was performed to generate a Glu2Asp mutation in the N-terminal sequence of apoA-I. This modification, which creates an acid labile Asp-Pro peptide bond between amino acids 2 and 3, permits specific chemical cleavage of an N-terminal His-Tag fusion peptide used for rapid protein purification. The product protein's primary structure is identical to WT apoA-I in all other respects. Together, these changes in apoA-I cDNA and bacterial expression protocol significantly improve the yield of apoA-I protein without compromising the relative ease of purification.

  20. An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide

    PubMed Central

    Wool, Geoffrey D.; Vaisar, Tomas; Reardon, Catherine A.; Getz, Godfrey S.

    2009-01-01

    Modifying apolipoprotein (apo) A-I mimetic peptides to include a proline-punctuated α-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL (moHDL) and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL level. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin (Hb). In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance. Administration of acetylated Pro to apoE−/− mice significantly decreases plasma serum amyloid A levels, while acetylated 4F does not have this ability. In contrast to previous reports that inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with Hb-containing plasma fractions. bPro, however, specifically binds to moHDL in vivo. In addition, the number of amphipathic α-helices and their linker influences the anti-inflammatory effects of apoA-I mimetic peptides in vivo. PMID:19433476

  1. Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene

    SciTech Connect

    Matsunaga, Tomoyuki; Yanagi, Hisako; Hattori, Naoko; Yamakawa, Kimiko; Yamanouchi, Yasuko; Hamaguchi, Hideo ); Hiasa, Yoshikazu; Maeda, Toshihiro ); Tanaka, Isao; Obara, Takashi )

    1991-04-01

    The molecular genetic defect of a female patient with apolipoprotein A-I (apoA-I) deficiency and premature atherosclerosis was examined. Her parents were first cousins. Her plasma density fraction from 1.063 to 1.21 g/ml contained no apoA-I on SDS/PAGE and no measurable high density lipoprotein cholesterol. Southern blot hybridization showed no gross abnormality to be present in the patient's apoA-I gene and homozygosity for a haplotype of restriction fragment length polymorphisms in the apoA-I gene region. Sequencing after amplification by PCR revealed a codon 84 nonsense mutation (CAG {r arrow} TAG, Gln {r arrow} stop) of exon 4 and a codon 37 missense mutation (GCC{r arrow} ACC, Ala {r arrow} Thr) of exon 3 in the patient's apoA-I gene. The data from dot-blot hybridization with allele-specific oligonucleotide probes indicated that she was homozygous for the apoA-I gene with regard to the two mutations. The codon 37 missense mutation was also detected in the apoA-I gene of 6 out of 60 controls, who all had normal levels of apoA-I and high density lipoprotein cholesterol, suggesting that the missense mutation is polymorphic and not associated with apoA-I deficiency. These finding indicate that homozygosity for the apoA-I gene with codon 84 nonsense mutation causes the deficiency of apoA-I and of high density lipoprotein cholesterol in the patient.

  2. Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia.

    PubMed Central

    Ng, D S; Leiter, L A; Vezina, C; Connelly, P W; Hegele, R A

    1994-01-01

    We report a Canadian kindred with a novel mutation in the apolipoprotein (apo) A-I gene causing analphalipoproteinemia. The 34-yr-old proband, product of a consanguineous marriage, had bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata. High density lipoprotein cholesterol (HDL-C) was < 0.1 mM and apoA-I was undetectable. Genomic DNA sequencing of the proband's apoA-I gene identified a nonsense mutation at codon [-2], which we designate as Q[-2]X. This mutation causes a loss of endonuclease digestion sites for both BbvI and Fnu4HI. Genotyping identified four additional homozygotes, four heterozygotes, and two unaffected subjects among the first-degree relatives. Q[-2]X homozygosity causes a selective failure to produce any portion of mature apoA-I, resulting in very low plasma level of HDL. Heterozygosity results in approximately half-normal apoA-I and HDL. Gradient gel electrophoresis and differential electroimmunodiffusion assay revealed that the HDL particles of the homozygotes had peak Stokes diameter of 7.9 nm and contained apoA-II without apoA-I (Lp-AII). Heterozygotes had an additional fraction of HDL3-like particles. Two of the proband's affected sisters had documented premature coronary heart disease. This kindred, the third reported apoA-I gene mutation causing isolated complete apoA-I deficiency, appears to be at significantly increased risk for atherosclerosis. Images PMID:8282791

  3. The Effect of Regular Aerobic Exercise on Reverse Cholesterol Transport A1 and Apo Lipoprotein A-I Gene Expression in Inactive Women

    PubMed Central

    Tofighi, Asghar; Rahmani, Fatemeh; Jamali Qarakhanlou, Bahram; Babaei, Solmaz

    2015-01-01

    Background: Atherosclerotic cardiovascular disease is currently a cause of mortality in some parts of the world. The ATP-Binding Cassette Transporter (ABCA1) gene prepares instructions to produce the ATP-binding cassette transporter protein whose operation is for export of phospholipids and cholesterol, outside cells where they are limited to Apolipoprotein A1 (apoA1). Increased ABCA1 activity could inhibit atherosclerosis. Objectives: In the present study, the effect of aerobic exercise was investigated on gene expression and biochemical parameters. Patients and Methods: The participants included 36 inactive women, which were randomly assigned to control (CON) and experimental (EX) groups. The EX group performed 12 weeks of aerobic exercise and the CON group remained inactive. Fasting blood samples were collected 24 hours before the first session and 48 hours after completion of the course. The ABCA1 and APOA1 gene expressions were measured using semi-quantitative-RT-PCR. Data were analyzed by the SPSS software (version 18). Results: A significant increase in blood ABCA1 (EX group P < 0.002, t = - 9.876) and Apo A-I (EX group P < 0.05, t = 2.76) gene expression was shown following the 12 weeks of training. Plasma high-density lipoprotein-cholesterol (HDL-C) concentration increased (P < 0.001, t = 4.90 respectively) while plasma low-density lipoprotein-cholesterol (LDL-C) concentration decreased (P < 0.001, t = 4.27) in the EX group compared with the CON group. Conclusions: Aerobic exercises can increase ABCA1 and APO-A1 gene expression. Induction of these genes can effectively prevent cardiovascular disease. PMID:26023346

  4. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

    PubMed

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  5. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma

    PubMed Central

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  6. Deletion of the propeptide of apolipoprotein A-I impairs exit of nascent apolipoprotein A-I from the endoplasmic reticulum.

    PubMed Central

    McLeod, R S; Robbins, C; Burns, A; Yao, Z; Pritchard, P H

    1994-01-01

    Human apolipoprotein (apo) A-I is secreted as a proprotein of 249 amino acids and is processed extracellularly to the mature form (243 amino acids) by removal of a six-residue propeptide segment. We have examined the role of the apoA-I propeptide in intracellular transport and secretion using transfected baby hamster kidney cells that secreted either proapoA-I (from the wild-type cDNA, A-Iwt) or mature-form apoA-I (from A-I delta pro, a cDNA in which the propeptide sequence was deleted). Deletion of the propeptide from the apoA-I sequence did not affect the rate of apoA-I synthesis, nor did it affect the fidelity of proteolytic removal of the prepeptide. However, the propeptide deletion caused mature-form apoA-I to accumulate within the cells as determined by pulse-chase experiments; the intracellular retention times for the mature-form apoA-I in which the propeptide was prematurely removed was three times longer than that of proapoA-I (t1/2 > 3 h compared with approximately 50 min). There was no detectable degradation of either form of newly synthesized apoA-I. Immunofluorescence microscopy revealed that, whereas the proapoA-I was located predominantly in the Golgi apparatus, large quantities of the mature-form apoA-I were detected in the endoplasmic reticulum and very little was in the Golgi apparatus of A-I delta pro-transfected cells. These findings suggest that the propeptide sequence may be involved in the intracellular transport of apoA-I from the endoplasmic reticulum to the Golgi apparatus. We propose that the function of the propeptide sequence is to facilitate efficient transport of apoA-I through the secretory pathway. Images Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 PMID:7945187

  7. Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I.

    PubMed

    Chan, Gary K L; Witkowski, Andrzej; Gantz, Donald L; Zhang, Tianqi O; Zanni, Martin T; Jayaraman, Shobini; Cavigiolio, Giorgio

    2015-04-24

    High plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, whereas dysfunctional apoA-I is a cause of atherosclerosis. In the atherosclerotic plaques, amyloid deposition increases with aging. Notably, apoA-I is the main component of these amyloids. Recent studies identified high levels of oxidized lipid-free apoA-I in atherosclerotic plaques. Likely, myeloperoxidase (MPO) secreted by activated macrophages in atherosclerotic lesions is the promoter of such apoA-I oxidation. We hypothesized that apoA-I oxidation by MPO levels similar to those present in the artery walls in atherosclerosis can promote apoA-I structural changes and amyloid fibril formation. ApoA-I was exposed to exhaustive chemical (H2O2) oxidation or physiological levels of enzymatic (MPO) oxidation and incubated at 37 °C and pH 6.0 to induce fibril formation. Both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after a few hours of incubation. The amyloid fibrils were composed of full-length apoA-I with differential oxidation of the three methionines. Met to Leu apoA-I variants were used to establish the predominant role of oxidation of Met-86 and Met-148 in the fibril formation process. Importantly, a small amount of preformed apoA-I fibrils was able to seed amyloid formation in oxidized apoA-I at pH 7.0. In contrast to hereditary amyloidosis, wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus, MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid deposition in the atherosclerotic plaques in vivo.

  8. Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I*

    PubMed Central

    Chan, Gary K. L.; Witkowski, Andrzej; Gantz, Donald L.; Zhang, Tianqi O.; Zanni, Martin T.; Jayaraman, Shobini; Cavigiolio, Giorgio

    2015-01-01

    High plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, whereas dysfunctional apoA-I is a cause of atherosclerosis. In the atherosclerotic plaques, amyloid deposition increases with aging. Notably, apoA-I is the main component of these amyloids. Recent studies identified high levels of oxidized lipid-free apoA-I in atherosclerotic plaques. Likely, myeloperoxidase (MPO) secreted by activated macrophages in atherosclerotic lesions is the promoter of such apoA-I oxidation. We hypothesized that apoA-I oxidation by MPO levels similar to those present in the artery walls in atherosclerosis can promote apoA-I structural changes and amyloid fibril formation. ApoA-I was exposed to exhaustive chemical (H2O2) oxidation or physiological levels of enzymatic (MPO) oxidation and incubated at 37 °C and pH 6.0 to induce fibril formation. Both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after a few hours of incubation. The amyloid fibrils were composed of full-length apoA-I with differential oxidation of the three methionines. Met to Leu apoA-I variants were used to establish the predominant role of oxidation of Met-86 and Met-148 in the fibril formation process. Importantly, a small amount of preformed apoA-I fibrils was able to seed amyloid formation in oxidized apoA-I at pH 7.0. In contrast to hereditary amyloidosis, wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus, MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid deposition in the atherosclerotic plaques in vivo. PMID:25759391

  9. Classification Accuracy of Serum Apo A-I and S100B for the Diagnosis of Mild Traumatic Brain Injury and Prediction of Abnormal Initial Head Computed Tomography Scan

    PubMed Central

    Blyth, Brian J.; He, Hua; Mookerjee, Sohug; Jones, Courtney; Kiechle, Karin; Moynihan, Ryan; Wojcik, Susan M.; Grant, William D.; Secreti, LaLainia M.; Triner, Wayne; Moscati, Ronald; Leinhart, August; Ellis, George L.; Khan, Jawwad

    2013-01-01

    Abstract The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78–0.92]) was similar to that using apoA-I (0.902 [0.87–0.93]), and the sensitivity using S100B (0.252 [0.22–0.28]) was similar to that using apoA-I (0.249 [0.22–0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p=0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p<0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of <0.060 μg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI. PMID:23758329

  10. Production and Analysis of Biological Properties of Recombinant Human Apolipoprotein A-I.

    PubMed

    Ryabchenko, A V; Kotova, M V; Tverdohleb, N V; Knyazev, R A; Polyakov, L M

    2015-11-01

    Production of recombinant human apolipoprotein A-I (apoA-I) in E. coli cells is described and its biological properties are compared with those of natural protein. Recombinant apoA-I was isolated as a chimeric polypeptide and then processed to a mature form apoA-I (rapo-I). We studied the ability of the resulting protein to penetrate into hepatocyte nuclei and regulate the rate of DNA biosynthesis in complex with estriol. Penetration of rapoA-I conjugated with FITC into hepatocyte nuclei was demonstrated. rapoA-I-estriol and apoA-I-estriol complexes induced similar increase in DNA biosynthesis rate in isolated hepatocytes, which confi rms functional similarity of the obtained recombinant mature protein (rapoA-I) and native human apoA-I.

  11. Surface behavior of apolipoprotein A-I and its deletion mutants at model lipoprotein interfaces.

    PubMed

    Wang, Libo; Mei, Xiaohu; Atkinson, David; Small, Donald M

    2014-03-01

    Apolipoprotein A-I (apoA-I) has a great conformational flexibility to exist in lipid-free, lipid-poor, and lipid-bound states during lipid metabolism. To address the lipid binding and the dynamic desorption behavior of apoA-I at lipoprotein surfaces, apoA-I, Δ(185-243)apoA-I, and Δ(1-59)(185-243)apoA-I were studied at triolein/water and phosphatidylcholine/triolein/water interfaces with special attention to surface pressure. All three proteins are surface active to both interfaces lowering the interfacial tension and thus increasing the surface pressure to modify the interfaces. Δ(185-243)apoA-I adsorbs much more slowly and lowers the interfacial tension less than full-length apoA-I, confirming that the C-terminal domain (residues 185-243) initiates the lipid binding. Δ(1-59)(185-243)apoA-I binds more rapidly and lowers the interfacial tension more than Δ(185-243)apoA-I, suggesting that destabilizing the N-terminal α-helical bundle (residues 1-185) restores lipid binding. The three proteins desorb from both interfaces at different surface pressures revealing that different domains of apoA-I possess different lipid affinity. Δ(1-59)(185-243)apoA-I desorbs at lower pressures compared with apoA-I and Δ(185-243)apoA-I indicating that it is missing a strong lipid association motif. We propose that during lipoprotein remodeling, surface pressure mediates the adsorption and partial or full desorption of apoA-I allowing it to exchange among different lipoproteins and adopt various conformations to facilitate its multiple functions.

  12. The Effects of Berberis vulgaris Fruit Extract on Serum Lipoproteins, apoB, apoA-I, Homocysteine, Glycemic Control and Total Antioxidant Capacity in Type 2 Diabetic Patients

    PubMed Central

    Shidfar, Farzad; Ebrahimi, Shima Seyyed; Hosseini, Sharieh; Heydari, Iraj; Shidfar, Shahrzad; Hajhassani, Giti

    2012-01-01

    Type 2 diabetes is a well-known endocrine and metabolic disorder which has reached epidemic proportions worldwide and represents a serious public health concern. Hyperglycemia and dyslipidemia are two major abnormalities which are major cardiovascular risk factors. Berberine is a major alkaloid in Berberis vulgaris fruit extract (BVFE) which have important role in regulation of serum glucose and fat metabolism in-vivo and in-vitro but its role in type 2 diabetes have not been extensively examined. The aim of this study was the effect of BVFE on serum lipoproteins, apoB, apoA-I, homocysteine, glycemic control and total antioxidant capacity in type 2 diabetic patients. In a double-blind randomised clinical trial, 31 diabetic patients were randomly assigned to 3 g/d BVFE or placebo for 3 months. Serum glucose, lipoproteins, apoB, apoA-I, insulin, homocysteine and HbA1c were measured at the baseline and also at the end of the 3rd month. At the beginning and end of 1st, 2nd and 3rd months, a 24-h dietary recall questionnaire about each patients was completed. Data were analyzed by SPSS version 16. There were significant decreases in serum TG, TC, LDL-c, apo B, glucose, and insulin and also a significant increase in TAC at the end of the study in BVFE group compared to the control group (p = 0.001, p = 0.001, p = 0.001, p = 0.001, p = 0.002, p = 0.01 and p = 0.0001 respectively). There were significant differences in serum TG (p = 0.0001), TC (p = 0.001), LDL-c (p = 0.001), apoB (p = 0.001), glucose (p = 0.002), insulin (p = 0.01), TAC (p = 0.005), and insulin resistance (p = 0.01) between the two groups at the end of the study; but homocysteine, HbA1c and HDL-c showed no significant changes between the two groups at the end of study. The intake of 3 g/d BVFE for 3 months may have benefical effects on lipoproteins, apoproteins, glycemic control and TAC in type 2 diabetic patients. PMID:24250489

  13. Apolipoprotein A-I metabolism in cynomolgus monkey. Identification and characterization of beta-migrating pools

    SciTech Connect

    Melchior, G.W.; Castle, C.K.

    1989-07-01

    Fresh plasma from control (C) and hypercholesterolemic (HC) cynomolgus monkeys was analyzed by agarose electrophoresis-immunoblotting with antibody to cynomolgus monkey apolipoprotein (apo) A-I. Two bands were evident on the autoradiogram: an alpha-migrating band (high density lipoprotein) and a beta-migrating band that comigrated exactly with cynomolgus monkey low density lipoprotein (LDL). The presence of beta-migrating apo A-I in the plasma of these monkeys was confirmed by Geon-Pevikon preparative electrophoresis, crossed immunoelectrophoresis, and isotope dilution studies in which radiolabeled apo A-I was found to equilibrate also with alpha- and beta-migrating pools of apo A-I in the plasma. Subfractionation of C and HC plasma by agarose column chromatography (Bio-Gel A-0.5M and A-15M) followed by agarose electrophoresis-immunoblotting indicated that the beta-migrating apo A-I in C was relatively homogeneous and eluted with proteins of Mr approximately 50 kD (apo A-I(50 kD)), whereas two beta-migrating fractions were identified in HC, one that eluted with the 50-kD proteins, and the other that eluted in the LDL Mr range (apo A-I(LDL)). The apo A-I(LDL) was precipitated by antibody to cynomolgus monkey apo B. The apo A-I(50 kD) accounted for 5 +/- 1% (mean +/- SD) of the plasma apo A-I in C plasma, and 15 +/- 7% in HC plasma. No apo A-I(LDL) was detected in C plasma, but that fraction accounted for 9 +/- 7% of the apo A-I in HC plasma. These data establish the presence of multiple pools of apo A-I in the cynomolgus monkey, which must be taken into consideration in any comprehensive model of apo A-I metabolism in this species.

  14. Structural and Functional Analysis of the ApolipoproteinA-I A164S Variant

    PubMed Central

    Dalla-Riva, Jonathan; Lagerstedt, Jens O.; Petrlova, Jitka

    2015-01-01

    Apolipoprotein A-I (apoA-I) is the main protein involved in the formation of high-density lipoprotein (HDL), it is the principal mediator of the reverse cholesterol transfer (RCT) pathway and provides cardio-protection. In addition to functional wild-type apoA-I, several variants have been shown to associate with hereditary amyloidosis. In this study we have performed biophysical and biochemical analyses of the structure and functional properties of the A164S variant of apoA-I (1:500 in the Danish general population), which is the first known mutation of apoA-I that leads to an increased risk of ischaemic heart disease (IHD), myocardial infarction and mortality without associated low HDL cholesterol levels. Despite the fact that epidemiologically IHD is associated with low plasma levels of HDL, the A164S mutation is linked to normal plasma levels of lipids, HDL and apoA-I, suggesting impaired functionality of this variant. Using biophysical techniques (e.g., circular dichroism spectroscopy and electron microscopy) to determine secondary structure, stability and pro-amyloidogenic property of the lipid free A164S apoA-I variant, our observations suggest similarity in structural properties between apoA-I WT and apoA-I A164S. However, the A164S apoA-I variant exhibits lower binding affinity to lipids but forms similar sized HDL particles to those produced by WT. PMID:26605794

  15. A role for Apolipoprotein A-I in the pathogenesis of multiple sclerosis.

    PubMed

    Meyers, Lindsay; Groover, Chassidy J; Douglas, Joshua; Lee, Sangmin; Brand, David; Levin, Michael C; Gardner, Lidia A

    2014-12-15

    Apolipoprotein A1 (Apo A-I), the most abundant component of high-density lipoprotein (HDL), is an anti-inflammatory molecule, yet its potential role in the pathogenesis of multiple sclerosis (MS) has not been fully investigated. In this study, Western blot analyses of human plasma showed differential Apo A-I expression in healthy controls compared to MS patients. Further, primary progressive MS patients had less plasma Apo A-I than other forms of MS. Using experimental allergic encephalomyelitis (EAE) as a model for MS, Apo A-I deficient mice exhibited worse clinical disease and more neurodegeneration concurrent with increased levels of pro-inflammatory cytokines compared to wild-type animals. These data suggest that Apo A-I plays a role in the pathogenesis of EAE, a model for MS, creating the possibility for agents that increase Apo A-I levels as potential therapies for MS.

  16. Human Apolipoprotein A-I Natural Variants: Molecular Mechanisms Underlying Amyloidogenic Propensity

    PubMed Central

    Ramella, Nahuel A.; Schinella, Guillermo R.; Ferreira, Sergio T.; Prieto, Eduardo D.; Vela, María E.; Ríos, José Luis

    2012-01-01

    Human apolipoprotein A-I (apoA-I)-derived amyloidosis can present with either wild-type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA-I variants deposit causing multiple organ failure. More than 15 single amino acid replacement amyloidogenic apoA-I variants have been described, but the molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here, we have investigated by fluorescence and biochemical approaches the stabilities and propensities to aggregate of two disease-associated apoA-I variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that both variants share common structural properties including decreased stability compared to Wt apoA-I and a more flexible structure that gives rise to formation of partially folded states. Interestingly, however, distinct features appear to determine their pathogenic mechanisms. ApoA-ILys107-0 has an increased propensity to aggregate at physiological pH and in a pro-inflammatory microenvironment than Wt apoA-I, whereas apoA-IGly26Arg elicited macrophage activation, thus stimulating local chronic inflammation. Our results strongly suggest that some natural mutations in apoA-I variants elicit protein tendency to aggregate, but in addition the specific interaction of different variants with macrophages may contribute to cellular stress and toxicity in hereditary amyloidosis. PMID:22952757

  17. Apolipoprotein A-I: A Molecule of Diverse Function.

    PubMed

    Mangaraj, Manaswini; Nanda, Rachita; Panda, Suchismita

    2016-07-01

    Apolipoprotein A-I (apo A-I) an indispensable component and a major structural protein of high-density lipoprotein (HDL), plays a vital role in reverse cholesterol transport and cellular cholesterol homeostasis since its identification. Its multifunctional role in immunity, inflammation, apoptosis, viral, bacterial infection etc. has crossed its boundary of its potential of protecting cardiovascular system and lowering cardiovascular disease risk, attributing HDL to be known as a protective fat removal particle. Its structural homology with prostacyclin stabilization factor has contributed to its anti-clotting and anti-aggregatory effect on platelet which has potentiated its cardio-protective role as well as its therapeutic efficacy against Alzheimer's disease. The binding affinity and neutralising action against endotoxin lipopolysaccharide, reduces the toxic manifestations of septic shock. As a negative acute phase protein, it blocks T-cell signalling of macrophages. However the recently identified anti-tumor activity of apo A-I has been highlighted in various models of melanoma, lung cancer, ovarian cancer, lymphoblastic leukaemia, gastric as well as pancreatic cancers. These cancer fighting effects are directed towards regression of tumor size and distant metastasis by its immuno modulatory activity as well as its clearing effect on serum lysophospholipids. This lowering effect on lysophospholipid concentration is utilized by apo A-I mimetic peptides to be used in retarding tumor cell proliferation and as a potential cancer therapeutic agent. Not only that, it inhibits the tumor associated neo-angiogenesis as well as brings down the matrix degrading enzymes associated with tumor metastasis. However this efficient therapeutic potential of apo A-I as an anti tumor agent awaits further future experimental studies in humans. PMID:27382195

  18. Apolipoprotein A-I: A Molecule of Diverse Function.

    PubMed

    Mangaraj, Manaswini; Nanda, Rachita; Panda, Suchismita

    2016-07-01

    Apolipoprotein A-I (apo A-I) an indispensable component and a major structural protein of high-density lipoprotein (HDL), plays a vital role in reverse cholesterol transport and cellular cholesterol homeostasis since its identification. Its multifunctional role in immunity, inflammation, apoptosis, viral, bacterial infection etc. has crossed its boundary of its potential of protecting cardiovascular system and lowering cardiovascular disease risk, attributing HDL to be known as a protective fat removal particle. Its structural homology with prostacyclin stabilization factor has contributed to its anti-clotting and anti-aggregatory effect on platelet which has potentiated its cardio-protective role as well as its therapeutic efficacy against Alzheimer's disease. The binding affinity and neutralising action against endotoxin lipopolysaccharide, reduces the toxic manifestations of septic shock. As a negative acute phase protein, it blocks T-cell signalling of macrophages. However the recently identified anti-tumor activity of apo A-I has been highlighted in various models of melanoma, lung cancer, ovarian cancer, lymphoblastic leukaemia, gastric as well as pancreatic cancers. These cancer fighting effects are directed towards regression of tumor size and distant metastasis by its immuno modulatory activity as well as its clearing effect on serum lysophospholipids. This lowering effect on lysophospholipid concentration is utilized by apo A-I mimetic peptides to be used in retarding tumor cell proliferation and as a potential cancer therapeutic agent. Not only that, it inhibits the tumor associated neo-angiogenesis as well as brings down the matrix degrading enzymes associated with tumor metastasis. However this efficient therapeutic potential of apo A-I as an anti tumor agent awaits further future experimental studies in humans.

  19. Isolation and function analysis of apolipoprotein A-I gene response to virus infection in grouper.

    PubMed

    Wei, Jingguang; Gao, Pin; Zhang, Ping; Guo, Minglan; Xu, Meng; Wei, Shina; Yan, Yang; Qin, Qiwei

    2015-04-01

    Apolipoproteins, synthesized mainly in liver and intestine and bounded to lipids, play important roles in lipid transport and uptake through the circulation system. In this study, an apolipoprotein A-I gene homologue was cloned from orange-spotted grouper Epinephelus coioides (designed as Ec-ApoA-I) by rapid amplification of cDNA ends (RACE) PCR. The full-length cDNA of Ec-ApoA-I was comprised of 1278 bp with a 792 bp open reading frame (ORF) that encodes a putative protein of 264 amino acids. Quantitative real-time PCR (qPCR) analysis revealed that Ec-ApoA-I was abundant in liver and intestine, and the expression in liver was significantly (P < 0.01) up-regulated after the stimulation of LPS, Poly(I:C), Vibrio alginolyticus, and Singapore grouper iridovirus (SGIV). Recombinant Ec-ApoA-I (rEc-ApoA-I) was produced in Escherichia coli BL21 (DE3) expression system exhibited bacteriolyticactivity against Microcococcus lysodeikticus and Aeromonas hydrophila. Intracellular localization revealed that Ec-ApoA-I distributed in both cytoplasm and nucleus, and predominantly in the cytoplasm. Overexpression of Ec-ApoA-I in grouper Brain (GB) cells could inhibit the replication of SGIV. These results together indicated that Ec-ApoA-I perhaps is involved in the responses to bacterial and viral challenge.

  20. Role of thyroid hormones in apolipoprotein A-I gene expression in rat liver.

    PubMed Central

    Strobl, W; Gorder, N L; Lin-Lee, Y C; Gotto, A M; Patsch, W

    1990-01-01

    To study the regulation of hepatic apo A-I gene expression, we measured synthesis and abundance of cellular apo A-I mRNA and its nuclear precursors in livers of hypothyroid and hyperthyroid rats. In hypothyroid animals, both synthesis and abundance of apo A-I mRNA was reduced to half of control values. After injection of a receptor-saturating dose of triiodothyronine into euthyroid rats, apo A-I gene transcription increased at 20 min, reached a maximum of 179% of control (P less than 0.01) at 3.5 h, and remained elevated for up to 48 h. The abundance of nuclear and total cellular apo A-I mRNA increased at 1 and 2 h, respectively, and exceeded the levels expected from enhanced transcription more than two fold at 24 h after hormone injection. Upon chronic administration of thyroid hormones, levels of nuclear and cytoplasmic apo A-I mRNA remained elevated but transcription of the apo A-I gene fell to 42% of control (P less than 0.01). Thus, thyroid hormones rapidly stimulate apo A-I gene transcription. Posttranscriptional events leading to increased stability of nuclear apo A-I RNA precursors become the principal mechanism for enhanced gene expression in chronic hyperthyroidism and may cause feedback inhibition of apo A-I gene transcription. Our results furthermore imply that the majority of hepatic nuclear apo A-I RNA precursors are degraded in euthyroid animals. Images PMID:2107206

  1. Matrix metalloproteinase 8 degrades apolipoprotein A-I and reduces its cholesterol efflux capacity.

    PubMed

    Salminen, Aino; Åström, Pirjo; Metso, Jari; Soliymani, Rabah; Salo, Tuula; Jauhiainen, Matti; Pussinen, Pirkko J; Sorsa, Timo

    2015-04-01

    Various cell types in atherosclerotic lesions express matrix metalloproteinase (MMP)-8. We investigated whether MMP-8 affects the structure and antiatherogenic function of apolipoprotein (apo) A-I, the main protein component of HDL particles. Furthermore, we studied serum lipid profiles and cholesterol efflux capacity in MMP-8-deficient mouse model. Incubation of apoA-I (28 kDa) with activated MMP-8 yielded 22 kDa and 25 kDa apoA-I fragments. Mass spectrometric analyses revealed that apoA-I was cleaved at its carboxyl-terminal part. Treatment of apoA-I and HDL with MMP-8 resulted in significant reduction (up to 84%, P < 0.001) in their ability to facilitate cholesterol efflux from cholesterol-loaded THP-1 macrophages. The cleavage of apoA-I by MMP-8 and the reduction in its cholesterol efflux capacity was inhibited by doxycycline. MMP-8-deficient mice had significantly lower serum triglyceride (TG) levels (P = 0.003) and larger HDL particles compared with wild-type (WT) mice. However, no differences were observed in the apoA-I levels or serum cholesterol efflux capacities between the mouse groups. Proteolytic modification of apoA-I by MMP-8 may impair the first steps of reverse cholesterol transport, leading to increased accumulation of cholesterol in the vessel walls. Eventually, inhibition of MMPs by doxycycline may reduce the risk for atherosclerotic vascular diseases.

  2. Apolipoprotein A-I mutant proteins having cysteine substitutions and polynucleotides encoding same

    DOEpatents

    Oda, Michael N.; Forte, Trudy M.

    2007-05-29

    Functional Apolipoprotein A-I mutant proteins, having one or more cysteine substitutions and polynucleotides encoding same, can be used to modulate paraoxonase's arylesterase activity. These ApoA-I mutant proteins can be used as therapeutic agents to combat cardiovascular disease, atherosclerosis, acute phase response and other inflammatory related diseases. The invention also includes modifications and optimizations of the ApoA-I nucleotide sequence for purposes of increasing protein expression and optimization.

  3. Effect of TNF{alpha} on activities of different promoters of human apolipoprotein A-I gene

    SciTech Connect

    Orlov, Sergey V.; Mogilenko, Denis A.; Shavva, Vladimir S.; Dizhe, Ella B.; Ignatovich, Irina A.; Perevozchikov, Andrej P.

    2010-07-23

    Research highlights: {yields} TNF{alpha} stimulates the distal alternative promoter of human apoA-I gene. {yields} TNF{alpha} acts by weakening of promoter competition within apoA-I gene (promoter switching). {yields} MEK1/2 and nuclear receptors PPAR{alpha} and LXRs take part in apoA-I promoter switching. -- Abstract: Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoproteins. The expression of the apolipoprotein A-I gene (apoA-I) in hepatocytes is repressed by pro-inflammatory cytokines such as IL-1{beta} and TNF{alpha}. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNF{alpha}-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNF{alpha} on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNF{alpha} leads to activation of the distal alternative apoA-I promoter and downregulation of the proximal alternative and the canonical apoA-I promoters. This effect is mediated by weakening of the promoter competition within human apoA-I 5'-regulatory region (apoA-I promoter switching) in the cells treated by TNF{alpha}. The MEK1/2-ERK1/2 cascade and nuclear receptors PPAR{alpha} and LXRs are important for TNF{alpha}-mediated apoA-I promoter switching.

  4. Francisella tularensis subsp. tularensis Group A.I, United States

    PubMed Central

    Birdsell, Dawn N.; Johansson, Anders; Öhrman, Caroline; Kaufman, Emily; Molins, Claudia; Pearson, Talima; Gyuranecz, Miklós; Naumann, Amber; Vogler, Amy J.; Myrtennäs, Kerstin; Larsson, Pär; Forsman, Mats; Sjödin, Andreas; Gillece, John D.; Schupp, James; Petersen, Jeannine M.; Keim, Paul

    2014-01-01

    We used whole-genome analysis and subsequent characterization of geographically diverse strains using new genetic signatures to identify distinct subgroups within Francisella tularensis subsp. tularensis group A.I: A.I.3, A.I.8, and A.I.12. These subgroups exhibit complex phylogeographic patterns within North America. The widest distribution was observed for A.I.12, which suggests an adaptive advantage. PMID:24755401

  5. BREFELDIN A INHIBITS CHOLESTEROL EFFLUX WITHOUT AFFECTING THE RATE OF CELLULAR UPTAKE AND RESECRETION OF APOLIPOPROTEIN A-I IN ADIPOCYTES

    PubMed Central

    Verghese, Philip B; Arrese, Estela L; Howard, Alisha D; Soulages, Jose L

    2008-01-01

    A possible role of cellular uptake and re-secretion of apoA-I in the mechanism of cholesterol efflux induced by apoA-I was investigated using a novel experimental approach. Incubation of adipocytes with a recombinant human apoA-I containing a consensus PKA phosphorylation site, pka-ApoA-I, leads to the appearance of phosphorylated protein in the cell culture medium unambiguously proving cellular uptake and re-secretion of pka-ApoA-I. Phosphorylation of apoA-I is abolished by PKA inhibitors and enhanced by PKA activators demonstrating the specific involvement of PKA. Studies on the concentration dependence of pka-apoA-I phosphorylation and competition experiments with human apoA-I suggest that apolipoprotein uptake is a receptor mediated process. A possible role of apoA-I recycling in the mechanism of cholesterol efflux was investigated by determining the rates of apoA-I induced cholesterol efflux and apoA-I recycling in the presence and in the absence of Brefeldin A (BFA). The studies showed that BFA strongly inhibits cholesterol efflux without affecting the rate of apoA-I recycling. Since BFA affects vesicular trafficking of ABCA1, this study suggests that the interaction of apoA-I with ABCA1 does not mediate apolipoprotein uptake and re-secretion. This result suggests that lipidation of apoA-I and apolipoprotein uptake/re-secretion are independent processes. PMID:18708026

  6. The Conformation of Lipid-Free Human Apolipoprotein A-I in Solution

    PubMed Central

    Pollard, Ricquita D.; Fulp, Brian; Samuel, Michael P.; Sorci-Thomas, Mary G.; Thomas, Michael J.

    2014-01-01

    Apolipoprotein AI (apoA-I) is the principal acceptor of lipids from ATP-binding cassette transporter A1, a process that yields nascent high density lipoproteins. Analysis of lipidated apoA-I conformation yields a belt or twisted belt in which two strands of apoA-I lie antiparallel to one another. In contrast, biophysical studies have suggested that a part of lipid-free apoA-I was arranged in a 4-helix bundle. To understand how lipid-free apoA-I opens from a bundle to a belt while accepting lipid it was necessary to have a more refined model for the conformation of lipid-free apoA-I. This study reports the conformation of lipid-free human apoA-I using lysine-to-lysine chemical cross-linking in conjunction with disulfide cross-linking achieved using selective cysteine mutations. After proteolysis cross-linked peptides were verified by sequencing using tandem mass spectrometry. The resulting structure is compact with roughly 4 helical regions, amino acids 44 through 186, bundled together. C- and N-terminal ends, amino acids 1-43 and 187-243, respectively, are folded such that they lie close to one another. An unusual feature of the molecule is the high degree of connectivity of lysine40 with 6 other lysines, lysines that are close, e.g., lysine59, to distant lysines, e.g., lysine239, that are at the opposite end of the primary sequence. These results are compared and contrasted with other reported conformations for lipid-free human apoA-I and an NMR study of mouse apoA-I. PMID:24308268

  7. Role of apolipoprotein A-I in HDL binding to a rat hepatoma cell in culture

    SciTech Connect

    Gottlieb, B.A.

    1985-01-01

    The binding of HDL to rat Fu5AH hepatoma cells at 4/sup 0/, and uptake and degradation at 37/sup 0/, was investigated in monolayer cultures. HDL, free of apo E and apo A-IV, was obtained from the plasma of nephrotic rats (HDLne). /sup 125/I-labeled HDLne bound to the cells in a specific, saturable manner. By Scatchard analysis, two classes of binding sites were obtained: a high affinity binding site (Kd = 1.25 +/- 0.023 ..mu..g/ml, or 5 x 10/sup -9/ M), and a lower affinity site (Kd = 45 +/- 15 ..mu..g/ml, or 1.8 x 10/sup -7/ M). In competitive binding experiments, normal rat HDL was nearly as effective as HDLne, but rat VLDL and human lipoproteins were ineffective. Rat apo A-I/phospholipid complexes also did not complete effectively for HDLne binding, although they were capable of binding to the cells. However, LDL (1.02 < d < 1.063) from nephrotic rat plasma, containing 20% of apo A-I, was as effective as rat HDL in competing for HDLne binding when the competition was expressed as a function of apo A-I content. Control experiments indicated that labeled apo A-I from HDLne did not exchange appreciably with unlabeled apo A-I on the LDLne. When the hepatoma cells were allowed to internalize and degrade HDLne at 37/sup 0/, the acid-soluble products (iodotyrosine and iodide) were derived almost entirely from the breakdown of apo A-I. We conclude that the rat hepatoma cell (Fu5AH) has high affinity HDL binding sites which recognize apo A-I-lipid complexes in which apo A-I an appropriate conformation.

  8. A model of lipid-free Apolipoprotein A-I revealed by iterative molecular dynamics simulation

    SciTech Connect

    Zhang, Xing; Lei, Dongsheng; Zhang, Lei; Rames, Matthew; Zhang, Shengli

    2015-03-20

    Apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, has been proven inversely correlated to cardiovascular risk in past decades. The lipid-free state of apo A-I is the initial stage which binds to lipids forming high-density lipoprotein. Molecular models of lipid-free apo A-I have been reported by methods like X-ray crystallography and chemical cross-linking/mass spectrometry (CCL/MS). Through structural analysis we found that those current models had limited consistency with other experimental results, such as those from hydrogen exchange with mass spectrometry. Through molecular dynamics simulations, we also found those models could not reach a stable equilibrium state. Therefore, by integrating various experimental results, we proposed a new structural model for lipidfree apo A-I, which contains a bundled four-helix N-terminal domain (1–192) that forms a variable hydrophobic groove and a mobile short hairpin C-terminal domain (193–243). This model exhibits an equilibrium state through molecular dynamics simulation and is consistent with most of the experimental results known from CCL/MS on lysine pairs, fluorescence resonance energy transfer and hydrogen exchange. This solution-state lipid-free apo A-I model may elucidate the possible conformational transitions of apo A-I binding with lipids in high-density lipoprotein formation.

  9. Apolipoprotein A-I expression suppresses COX-2 expression by reducing reactive oxygen species in hepatocytes.

    PubMed

    Mao, Jing; Liu, Wei; Wang, Yutong

    2014-11-21

    Abnormal lipid metabolism may contribute to the increase of reactive oxygen species (ROS) and inflammation in the pathogenesis of non-alcoholic steatohepatitis (NASH). Apolipoprotein A-I (apoA-I) accepts cellular cholesterol and phospholipids transported by ATP-binding cassette transporter A1 to generate nascent high density lipoprotein particles. Previous studies revealed that the overexpression of ABCA1 or apoA-I alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of apoA-I overexpression on ROS and genes involved in inflammation in both BEL-7402 hepatocytes and mice. Human apoA-I was overexpressed by transfection in BEL-7402 hepatocytes and by an adenoviral vector in C57BL/6J mice fed a methionine choline-deficient diet. The overexpression of apoA-I in both models resulted in decreased ROS and lipid peroxidation levels, as well as a reduced MAPK phosphorylation and decreased expression levels of c-Fos and COX-2. These results suggest that apoA-I overexpression can reduce steatosis by decreasing ROS levels and suppressing COX-2-induced inflammation in hepatocytes. MAPK and c-Fos are involved in this regulatory process.

  10. A model of lipid-free Apolipoprotein A-I revealed by iterative molecular dynamics simulation

    DOE PAGES

    Zhang, Xing; Lei, Dongsheng; Zhang, Lei; Rames, Matthew; Zhang, Shengli

    2015-03-20

    Apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, has been proven inversely correlated to cardiovascular risk in past decades. The lipid-free state of apo A-I is the initial stage which binds to lipids forming high-density lipoprotein. Molecular models of lipid-free apo A-I have been reported by methods like X-ray crystallography and chemical cross-linking/mass spectrometry (CCL/MS). Through structural analysis we found that those current models had limited consistency with other experimental results, such as those from hydrogen exchange with mass spectrometry. Through molecular dynamics simulations, we also found those models could not reach a stable equilibrium state. Therefore,more » by integrating various experimental results, we proposed a new structural model for lipidfree apo A-I, which contains a bundled four-helix N-terminal domain (1–192) that forms a variable hydrophobic groove and a mobile short hairpin C-terminal domain (193–243). This model exhibits an equilibrium state through molecular dynamics simulation and is consistent with most of the experimental results known from CCL/MS on lysine pairs, fluorescence resonance energy transfer and hydrogen exchange. This solution-state lipid-free apo A-I model may elucidate the possible conformational transitions of apo A-I binding with lipids in high-density lipoprotein formation.« less

  11. A Model of Lipid-Free Apolipoprotein A-I Revealed by Iterative Molecular Dynamics Simulation

    PubMed Central

    Zhang, Xing; Lei, Dongsheng; Zhang, Lei; Rames, Matthew; Zhang, Shengli

    2015-01-01

    Apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, has been proven inversely correlated to cardiovascular risk in past decades. The lipid-free state of apo A-I is the initial stage which binds to lipids forming high-density lipoprotein. Molecular models of lipid-free apo A-I have been reported by methods like X-ray crystallography and chemical cross-linking/mass spectrometry (CCL/MS). Through structural analysis we found that those current models had limited consistency with other experimental results, such as those from hydrogen exchange with mass spectrometry. Through molecular dynamics simulations, we also found those models could not reach a stable equilibrium state. Therefore, by integrating various experimental results, we proposed a new structural model for lipid-free apo A-I, which contains a bundled four-helix N-terminal domain (1–192) that forms a variable hydrophobic groove and a mobile short hairpin C-terminal domain (193–243). This model exhibits an equilibrium state through molecular dynamics simulation and is consistent with most of the experimental results known from CCL/MS on lysine pairs, fluorescence resonance energy transfer and hydrogen exchange. This solution-state lipid-free apo A-I model may elucidate the possible conformational transitions of apo A-I binding with lipids in high-density lipoprotein formation. PMID:25793886

  12. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, Q[22]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in...

  13. Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease.

    PubMed

    Yao, Xianglan; Gordon, Elizabeth M; Figueroa, Debbie M; Barochia, Amisha V; Levine, Stewart J

    2016-08-01

    Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic α-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies.

  14. Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice.

    PubMed

    Black, Leland L; Srivastava, Roshni; Schoeb, Trenton R; Moore, Ray D; Barnes, Stephen; Kabarowski, Janusz H

    2015-11-15

    Apolipoprotein (Apo)A-I, the major lipid-binding protein of high-density lipoprotein, can prevent autoimmunity and suppress inflammation in hypercholesterolemic mice by attenuating lymphocyte cholesterol accumulation and removing tissue-oxidized lipids. However, whether ApoA-I mediates immune-suppressive or anti-inflammatory effects under normocholesterolemic conditions and the mechanisms involved remain unresolved. We transferred bone marrow from systemic lupus erythematosus (SLE)-prone Sle123 mice into normal, ApoA-I-knockout (ApoA-I(-/-)) and ApoA-I-transgenic (ApoA-I(tg)) mice. Increased ApoA-I in ApoA-I(tg) mice suppressed CD4(+) T and B cell activation without changing lymphocyte cholesterol levels or reducing major ApoA-I-binding oxidized fatty acids. Unexpectedly, oxidized fatty acid peroxisome proliferator-activated receptor γ ligands 13- and 9-hydroxyoctadecadienoic acid were increased in lymphocytes of autoimmune ApoA-I(tg) mice. ApoA-I reduced Th1 cells independently of changes in CD4(+)Foxp3(+) regulatory T cells or CD11c(+) dendritic cell activation and migration. Follicular helper T cells, germinal center B cells, and autoantibodies were also lower in ApoA-I(tg) mice. Transgenic ApoA-I also improved SLE-mediated glomerulonephritis. However, ApoA-I deficiency did not have the opposite effects on autoimmunity or glomerulonephritis, possibly as the result of compensatory increases in ApoE on high-density lipoprotein. We conclude that, although compensatory mechanisms prevent the proinflammatory effects of ApoA-I deficiency in normocholesterolemic mice, increasing ApoA-I can attenuate lymphocyte activation and autoimmunity in SLE independently of cholesterol transport, possibly through oxidized fatty acid peroxisome proliferator-activated receptor γ ligands, and it can reduce renal inflammation in glomerulonephritis.

  15. Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.

    PubMed

    Mei, Xiaohu; Atkinson, David

    2015-07-01

    Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1-184] forms a helix bundle while the C-terminal domain [185-243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.

  16. Definition of human apolipoprotein A-I epitopes recognized by autoantibodies present in patients with cardiovascular diseases.

    PubMed

    Teixeira, Priscila Camillo; Ducret, Axel; Ferber, Philippe; Gaertner, Hubert; Hartley, Oliver; Pagano, Sabrina; Butterfield, Michelle; Langen, Hanno; Vuilleumier, Nicolas; Cutler, Paul

    2014-10-10

    Autoantibodies to apolipoprotein A-I (anti-apoA-I IgG) have been shown to be both markers and mediators of cardiovascular disease, promoting atherogenesis and unstable atherosclerotic plaque. Previous studies have shown that high levels of anti-apoA-I IgGs are independently associated with major adverse cardiovascular events in patients with myocardial infarction. Autoantibody responses to apoA-I can be polyclonal and it is likely that more than one epitope may exist. To identify the specific immunoreactive peptides in apoA-I, we have developed a set of methodologies and procedures to isolate, purify, and identify novel apoA-I endogenous epitopes. First, we generated high purity apoA-I from human plasma, using thiophilic interaction chromatography followed by enzymatic digestion specifically at lysine or arginine residues. Immunoreactivity to the different peptides generated was tested by ELISA using serum obtained from patients with acute myocardial infarction and high titers of autoantibodies to native apoA-I. The immunoreactive peptides were further sequenced by mass spectrometry. Our approach successfully identified two novel immunoreactive peptides, recognized by autoantibodies from patients suffering from myocardial infarction, who contain a high titer of anti-apoA-I IgG. The discovery of these epitopes may open innovative prognostic and therapeutic opportunities potentially suitable to improve current cardiovascular risk stratification.

  17. Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

    PubMed Central

    Ramella, Nahuel A.; Rimoldi, Omar J.; Prieto, Eduardo D.; Schinella, Guillermo R.; Sanchez, Susana A.; Jaureguiberry, María S.; Vela, María E.

    2011-01-01

    Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis. PMID:21811627

  18. Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.

    PubMed

    Persey, M R; Booth, D R; Booth, S E; van Zyl-Smit, R; Adams, B K; Fattaar, A B; Tennent, G A; Hawkins, P N; Pepys, M B

    1998-02-01

    We report a family with autosomal-dominant hereditary systemic amyloidosis in three generations, presenting with renal involvement. Two members of the current generation received renal transplants for end-stage renal failure 16 and 18 years ago, and remain very well clinically despite massive visceral amyloidosis. Two other members of this generation, aged 32 and 47 years, have massive systemic amyloid but no clinical disability. Individuals known to be affected in previous generations died of renal failure in early adult life. Amyloid deposits in the proband, one of the transplanted individuals, were composed of apolipoprotein A-I (apoA-I), and among living family members there was complete concordance between amyloidosis and the presence of a novel 9 base pair in-frame deletion mutation in exon 4 of the apoA-I gene, causing a loss of residues Glu70Phe71Trp72. This predicts the acquisition of a single extra positive charge by mature apoA-I, and this variant was detected in the plasma of all carriers. All the previously reported amyloidogenic variants of apoA-I also carry an extra positive charge, indicating that this electrostatic change is likely to be relevant to the amyloidogenicity of apoA-I. PMID:9461086

  19. Formation of stable nanodiscs by bihelical apolipoprotein A-I mimetic peptide.

    PubMed

    Kariyazono, Hirokazu; Nadai, Ryo; Miyajima, Rin; Takechi-Haraya, Yuki; Baba, Teruhiko; Shigenaga, Akira; Okuhira, Keiichiro; Otaka, Akira; Saito, Hiroyuki

    2016-02-01

    Nanodiscs are composed of scaffold protein or peptide such as apolipoprotein A-I (apoA-I) and phospholipids. Although peptide-based nanodiscs have an advantage to modulate the size of nanodiscs by changing phospholipid/peptide ratios, they are usually less stable than apoA-I-based nanodiscs. In this study, we designed a novel nanodisc scaffold peptide (NSP) that has proline-punctuated bihelical amphipathic structure based on apoA-I mimetic peptides. NSP formed α-helical structure on 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) nanodiscs prepared by cholate dialysis method. Dynamic light scattering measurements demonstrated that diameters of NSP nanodiscs vary depending upon POPC/NSP ratios. Comparison of thermal unfolding of nanodiscs monitored by circular dichroism measurements demonstrated that NSP forms much more stable nanodiscs with POPC than monohelical peptide, 4F, exhibiting comparable stability to apoA-I-POPC nanodiscs. Intrinsic Trp fluorescence measurements showed that Trp residues of NSP exhibit more hydrophobic environment than that of 4 F on nanodiscs, suggesting the stronger interaction of NSP with phospholipids. Thus, the bihelical structure of NSP appears to increase the stability of nanodiscs because of the enhanced interaction of peptides with phospholipids. In addition, NSP as well as 4F spontaneously solubilized POPC vesicles into nanodiscs without using detergent. These results indicate that bihelical NSP forms nanodiscs with comparable stability to apoA-I and has an ability to control the size of nanodiscs simply by changing phospholipid/peptide ratios.

  20. Concentration and pattern changes of porcine serum apolipoprotein A-I in four different infectious diseases.

    PubMed

    Marco-Ramell, Anna; Hummel, Karin; Razzazi-Fazeli, Ebrahim; Bassols, Anna; Miller, Ingrid

    2015-02-01

    Apolipoprotein A-I (Apo A-I) is a major protein in lipid/lipoprotein metabolism and decreased serum levels have been observed in many species in response to inflammatory and infectious challenges. Little is known about the porcine homologue, therefore in this work we have characterized it through biochemical and proteomic techniques. In 2DE, porcine serum Apo A-I is found as three spots, the two more acidic ones corresponding to the mature protein, the more basic spot to the protein precursor. Despite high sequence coverage in LC-MS/MS, we did not find a sequence or PTM difference between the two mature protein species. Besides this biochemical characterization, we measured overall levels and relative species abundance of serum Apo A-I in four different viral and bacterial porcine infectious diseases. Lower overall amounts of Apo A-I were observed in Salmonella typhimurium and Escherichia coli infections. In the 2DE protein pattern, an increase of the protein precursor together with a lower level of mature protein species were detected in the porcine circovirus type 2-systemic disease and S. typhimurium infection. These results reveal that both the porcine serum Apo A-I concentration and the species pattern are influenced by the nature of the infectious disease.

  1. Kinetic and thermodynamic analyses of spontaneous exchange between high-density lipoprotein-bound and lipid-free apolipoprotein A-I.

    PubMed

    Handa, Daisuke; Kimura, Hitoshi; Oka, Tatsuya; Takechi, Yuki; Okuhira, Keiichiro; Phillips, Michael C; Saito, Hiroyuki

    2015-02-01

    It is thought that apolipoprotein A-I (apoA-I) spontaneously exchanges between high-density lipoprotein (HDL)-bound and lipid-free states, which is relevant to the occurrence of preβ-HDL particles in plasma. To improve our understanding of the mechanistic basis for this phenomenon, we performed kinetic and thermodynamic analyses for apoA-I exchange between discoidal HDL-bound and lipid-free forms using fluorescence-labeled apoA-I variants. Gel filtration experiments demonstrated that addition of excess lipid-free apoA-I to discoidal HDL particles promotes exchange of apoA-I between HDL-associated and lipid-free pools without alteration of the steady-state HDL particle size. Kinetic analysis of time-dependent changes in NBD fluorescence upon the transition of NBD-labeled apoA-I from HDL-bound to lipid-free state indicates that the exchange kinetics are independent of the collision frequency between HDL-bound and lipid-free apoA-I, in which the lipid binding ability of apoA-I affects the rate of association of lipid-free apoA-I with the HDL particles and not the rate of dissociation of HDL-bound apoA-I. Thus, C-terminal truncations or mutations that reduce the lipid binding affinity of apoA-I strongly impair the transition of lipid-free apoA-I to the HDL-bound state. Thermodynamic analysis of the exchange kinetics demonstrated that the apoA-I exchange process is enthalpically unfavorable but entropically favorable. These results explain the thermodynamic basis of the spontaneous exchange reaction of apoA-I associated with HDL particles. The altered exchangeability of dysfunctional apoA-I would affect HDL particle rearrangement, leading to perturbed HDL metabolism.

  2. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

    PubMed Central

    Claudel, Thierry; Sturm, Ekkehard; Duez, Hélène; Torra, Inés Pineda; Sirvent, Audrey; Kosykh, Vladimir; Fruchart, Jean-Charles; Dallongeville, Jean; Hum, Dean W.; Kuipers, Folkert; Staels, Bart

    2002-01-01

    Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid–activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells. PMID:11927623

  3. Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis.

    PubMed

    Gkouskou, K K; Ioannou, M; Pavlopoulos, G A; Georgila, K; Siganou, A; Nikolaidis, G; Kanellis, D C; Moore, S; Papadakis, K A; Kardassis, D; Iliopoulos, I; McDyer, F A; Drakos, E; Eliopoulos, A G

    2016-05-12

    In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

  4. HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity

    PubMed Central

    Borja, Mark S.; Ng, Kit F.; Irwin, Angela; Hong, Jaekyoung; Wu, Xing; Isquith, Daniel; Zhao, Xue-Qiao; Prazen, Bryan; Gildengorin, Virginia; Oda, Michael N.; Vaisar, Tomáš

    2015-01-01

    HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT. PMID:26254308

  5. HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity.

    PubMed

    Borja, Mark S; Ng, Kit F; Irwin, Angela; Hong, Jaekyoung; Wu, Xing; Isquith, Daniel; Zhao, Xue-Qiao; Prazen, Bryan; Gildengorin, Virginia; Oda, Michael N; Vaisar, Tomáš

    2015-10-01

    HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT.

  6. The Social Stratification of /aI/ in Tuscaloosa, Alabama.

    ERIC Educational Resources Information Center

    Crane, L. Ben

    This study is a sociolinguistic analysis of the variant pronunciation of /aI/, a selected phonological variable, by white informants in Tuscaloosa, Alabama. Through a purposive sampling procedure, 56 informants were interviewed to determine their pronunciation of /aI/. Informants were ranked according to education, income, and occupation to…

  7. High-Density Lipoprotein Biogenesis: Defining the Domains Involved in Human Apolipoprotein A-I Lipidation.

    PubMed

    Pollard, Ricquita D; Fulp, Brian; Sorci-Thomas, Mary G; Thomas, Michael J

    2016-09-01

    The first step in removing cholesterol from a cell is the ATP-binding cassette transporter 1 (ABCA1)-driven transfer of cholesterol to lipid-free or lipid-poor apolipoprotein A-I (apoA-I), which yields cholesterol-rich nascent high-density lipoprotein (nHDL) that then matures in plasma to spherical, cholesteryl ester-rich HDL. However, lipid-free apoA-I has a three-dimensional (3D) conformation that is significantly different from that of lipidated apoA-I on nHDL. By comparing the lipid-free apoA-I 3D conformation of apoA-I to that of 9-14 nm diameter nHDL, we formulated the hypothetical helical domain transitions that might drive particle formation. To test the hypothesis, ten apoA-I mutants were prepared that contained two strategically placed cysteines several of which could form intramolecular disulfide bonds and others that could not form these bonds. Mass spectrometry was used to identify amino acid sequence and intramolecular disulfide bond formation. Recombinant HDL (rHDL) formation was assessed with this group of apoA-I mutants. ABCA1-driven nHDL formation was measured in four mutants and wild-type apoA-I. The mutants contained cysteine substitutions in one of three regions: the N-terminus, amino acids 34 and 55 (E34C to S55C), central domain amino acids 104 and 162 (F104C to H162C), and the C-terminus, amino acids 200 and 233 (L200C to L233C). Mutants were studied in the locked form, with an intramolecular disulfide bond present, or unlocked form, with the cysteine thiol blocked by alkylation. Only small amounts of rHDL or nHDL were formed upon locking the central domain. We conclude that both the N- and C-terminal ends assist in the initial steps in lipid acquisition, but that opening of the central domain was essential for particle formation.

  8. Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties

    PubMed Central

    Wool, Geoffrey D.; Reardon, Catherine A.; Getz, Godfrey S.

    2008-01-01

    We hypothesize that apolipoprotein A-I (apoA-I) mimetic peptides better mimicking the punctuated α-helical repeats of full-length apoA-I are more anti-inflammatory and anti-atherogenic. This study compares a monomeric apoA-I mimetic helix to three different tandem helix peptides in vitro: 4F (18 mer), 4F-proline-4F (37 mer, Pro), 4F-alanine-4F (37 mer, Ala), and 4F-KVEPLRA-4F [the human apoA-I 4/5 interhelical sequence (IHS), 43 mer]. All peptides cleared turbid lipid suspensions, with 4F being most effective. In contrast to lipid clearance, tandem peptides were more effective at remodeling mouse HDL. All four peptides displaced apoA-I and apoE from the HDL, leaving a larger particle containing apoA-II and peptide. Peptide-remodeled HDL particles show no deficit in ABCG1 cholesterol efflux despite the loss of the majority of apoA-I. Tandem peptides show greater ability to efflux cholesterol from lipid-loaded murine macrophages, compared with 4F. Although 4F inhibited oxidation of purified mouse LDL, the Ala tandem peptide increased oxidation. We compared several tandem 4F-based peptides with monomeric 4F in assays that correlated with suggested anti-inflammatory/anti-atherogenic pathways. Tandem 4F-based peptides, which better mimic full-length apoA-I, exceed monomeric 4F in HDL remodeling and cholesterol efflux but not LDL oxidation protection. In addition, apoA-I mimetic peptides may increase reverse cholesterol transport through both ABCA1 as well as ABCG1 pathways. PMID:18323574

  9. A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients1[S

    PubMed Central

    Cubedo, Judit; Padró, Teresa; García-Arguinzonis, Maisa; Vilahur, Gemma; Miñambres, Inka; Pou, Jose María; Ybarra, Juan; Badimon, Lina

    2015-01-01

    Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients. PMID:26168996

  10. A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients.

    PubMed

    Cubedo, Judit; Padró, Teresa; García-Arguinzonis, Maisa; Vilahur, Gemma; Miñambres, Inka; Pou, Jose María; Ybarra, Juan; Badimon, Lina

    2015-09-01

    Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients.

  11. The A's Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma.

    PubMed

    Yao, Xianglan; Gordon, Elizabeth M; Barochia, Amisha V; Remaley, Alan T; Levine, Stewart J

    2016-08-01

    New treatments are needed for patients with asthma who are refractory to standard therapies, such as individuals with a phenotype of "type 2-low" inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. ApoA-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. The ability of the apoA-I/ABCA1 pathway to promote cholesterol efflux from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have shown that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation, primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in patients with asthma. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma, and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for patients with severe asthma who are unresponsive to other therapies.

  12. Interaction of apolipoprotein A-I with lecithin-cholesterol vesicles in the presence of phospholipase C.

    PubMed

    Gudheti, Manasa V; Gonzalez, Yamaira I; Lee, Sum P; Wrenn, Steven P

    2003-12-30

    Here we study the anti-nucleating mechanism of apolipoprotein A-I (apo A-I) on model biliary vesicles in the presence of phospholipase C (PLC) utilizing dynamic light scattering (DLS), steady-state fluorescence spectroscopy, cryogenic transmission electron microscopy (cryo-TEM), and UV/Vis spectroscopy. PLC induces aggregation of cholesterol-free lecithin vesicles from an initial, average size of 100 nm to a maximal size of 600 nm. The presence of apo A-I likely inhibits vesicle aggregation by shielding the PLC-generated hydrophobic moieties, which results in vesicles of an average size of 200 nm. A similar phenomenon is observed in cholesterol-enriched lecithin vesicles. Whereas PLC alone produces aggregates of 300 nm, no aggregation is observed when apo A-I is present along with PLC. However, the ability of apo A-I to inhibit aggregation is temporary, and after 8 h, a broad particle size distribution with sizes as high as 800 nm is observed. Apo A-I possibly induces the formation of small apo A-I/lecithin/cholesterol complexes of about 5-20 nm similar to the discoidal pre-HDL complexes found in blood when it can no longer effectively shield all the DAG molecules. Concomitant with formation of complexes, DAG molecules coalesce into large oil droplets, which account for the large particles observed by light scattering. Thus, apo A-I acts as an anti-nucleating agent by two mechanisms, anti-aggregation and microstructural transition. The mode of protection is dependent on the cholesterol content and the relative amounts of DAG and apo A-I present. This study supports the possibility of apo A-I solubilizing lipids in bile in a similar fashion as it does in blood and also delineates the mechanism of formation of the complexes.

  13. Combined N- and C-terminal truncation of human apolipoprotein A-I yields a folded, functional central domain.

    PubMed

    Beckstead, Jennifer A; Block, Brian L; Bielicki, John K; Kay, Cyril M; Oda, Michael N; Ryan, Robert O

    2005-03-22

    A combined N- and C-terminal truncation variant of human apolipoprotein A-I (apoA-I) was designed, expressed in Escherichia coli, isolated, and characterized. Hydrodynamic experiments yielded a weight average molecular weight of 34000, indicating apoA-I-(44-186) exists in solution predominantly as a dimer. An axial ratio of 4.2 was calculated for the dimer based on sedimentation velocity experiments. Far-UV circular dichroism spectroscopy of apoA-I-(44-186) in buffer indicated the presence of 65% alpha-helix secondary structure. Guanidine hydrochloride denaturation experiments yielded a transition midpoint of 0.5 M for apoA-I-(44-186). ApoA-I-(44-186) induced solubilization of dimyristoylphosphatidylcholine vesicles at a rate comparable to that of full-length apoA-I, displayed lipoprotein binding ability, and was an acceptor of ABCA1-mediated cholesterol efflux from cultured macrophages. Fluorescence quenching studies with KI indicate that the three Trp residues in apoA-I-(44-186) are shielded from the aqueous environment. Taken together, the data indicate that lipid-free apoA-I-(44-186) adopts a folded conformation in solution that possesses lipid binding capability. The central region of apoA-I appears to adopt a globular amphipathic alpha-helix bundle organization that is stabilized by intramolecular and/or intermolecular helix-helix interactions. Lipid association likely results in a conformational adaptation wherein helix-helix contacts are substituted for helix-lipid interactions.

  14. The Effect of Preoperative Apolipoprotein A-I on the Prognosis of Surgical Renal Cell Carcinoma

    PubMed Central

    Guo, Shengjie; He, Xiaobo; Chen, Qian; Yang, Guangwei; Yao, Kai; Dong, Pei; Ye, Yunlin; Chen, Dong; Zhang, Zhiling; Qin, Zike; Liu, Zhuowei; Li, Zaishang; Xue, Yunfei; Zhang, Meng; Liu, Ruiwu; Zhou, Fangjian; Han, Hui

    2016-01-01

    Abstract The prognostic value of serum lipid-profile in renal cell cancer (RCC) remains unknown. The purpose of the study is to explore the association between the serum lipid-profile and RCC patients. The levels of preoperative serum lipid-profile (including cholesterol, triglycerides, high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], apolipoprotein A-I [ApoA-I], and apolipoprotein B [ApoB]) were retrospectively performed in 786 patients with RCC. The cutoff values of the lipids were determined by the receiver-operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic value of serum lipids in RCC. Combined ROC analysis and univariate and multivariate Cox regression analyses, for overall survival (OS), revealed patients with low ApoA-I (<1.04) had significantly lower OS than the high ApoA-I (≥1.04) group (multivariate Cox regression analyses, hazard ratio [HR], 0.57; P = 0.003). Not only in the whole RCC cohort but also in the subgroups stratified according to the pT1-2 (P = 0.002), pN0 (P < 0.001), and pM0 (P = 0.001) status, respectively. Moreover, in the 755 patients with nonmetastasis, the low ApoA-I group was also associated with shortened disease-free survival (DFS) time compared to the high ApoA-I group (multivariate Cox regression analyses, HR, 0.65; P = 0.033). However, the other lipids were not independent prognostic factors for surgical RCC. An elevated level of preoperative ApoA-I was demonstrated to be related with better survival in patients with surgical RCC. Measuring the preoperative ApoA-I might be a simple way for finding the poor prognostic patients who should enrolled in further clinical trials and management. PMID:27015197

  15. Molecular crowding impacts the structure of apolipoprotein A-I with potential implications on in vivo metabolism and function.

    PubMed

    Petrlova, Jitka; Hilt, Silvia; Budamagunta, Madhu; Domingo-Espín, Joan; Voss, John C; Lagerstedt, Jens O

    2016-10-01

    The effect molecular crowding, defined as the volume exclusion exerted by one soluble inert molecule upon another soluble molecule, has on the structure and self-interaction of lipid-free apoA-I were explored. The influence of molecular crowding on lipid-free apoA-I oligomerization and internal dynamics has been analyzed using electron paramagnetic resonance (EPR) spectroscopy measurements of nitroxide spin label at selected positions throughout the protein sequence and at varying concentrations of the crowding agent Ficoll-70. The targeted positions include sites previously shown to be sensitive for detecting intermolecular interaction via spin-spin coupling. Circular dichroism was used to study secondary structural changes in lipid-free apoA-I imposed by increasing concentrations of the crowding agent. Crosslinking and SDS-PAGE gel analysis was employed to further characterize the role molecular crowding plays in inducing apoA-I oligomerization. It was concluded that the dynamic apoA-I structure and oligomeric state was altered in the presence of the crowding agent. It was also found that the C-terminal was slightly more sensitive to molecular crowding. Finally, the data described the region around residue 217 in the C-terminal domain of apoA-I as the most sensitive reporter of the crowding-induced self-association of apoA-I. The implications of this behavior to in vivo functionality are discussed. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 683-692, 2016.

  16. Regulation of apolipoprotein A-I gene expression in Hep G2 cells depleted of Cu by cupruretic tetramine.

    PubMed

    Wu, J Y; Zhang, J J; Wang, Y; Reaves, S K; Wang, Y R; Lei, P P; Lei, K Y

    1997-10-01

    Studies were designed to examine the regulation of apolipoprotein (apo) A-I gene expression in Cu-depleted Hep G2 cells. The cupruretic chelator N,N'-bis(2-aminoethyl)-1,3-propanediamine 4 HCl (2,3,2-tetramine or TETA) was used to maintain a 77% reduction in cellular Cu in Hep G2 cells. After two passages of TETA treatment, the relative abundance of apoA-I mRNA was elevated 52%. In TETA-treated cells, the rate of apoA-I mRNA decay measured by an actinomycin D chase study was accelerated 108%, and the synthesis of apoA-I mRNA determined by a nuclear runoff assay was enhanced 2.5-fold in TETA-treated cells. All of those changes could be reverted toward the control values with Cu supplementation for only 2 days. In transient transfection assays, a 26.7% increase in chloramphenicol O-acetyltransferase (CAT) activity for the reporter construct -256AI-CAT was observed in the treated cells. However, the ability of apoA-I regulatory protein 1 (ARP-1) to repress the CAT activity was not affected by the depressed Cu status. In addition, gel retardation experiments demonstrated that Cu depletion enhanced the binding of hepatocyte nuclear factor 4 (HNF-4) and other undefined nuclear factors to oligonucleotides containing site A, one of three regulatory sites of the apoA-I gene promoter. Moreover, the relative abundance of HNF-4 mRNA was increased 58% in the Cu-depleted cells. Thus the observed increase in apoA-I gene transcription may be mediated mostly by an elevated level of the regulatory factor, HNF-4. In summary, the present findings established the mechanism by which a depressed cellular Cu status can enhance apoA-I mRNA production and subsequently increase apoA-I synthesis. PMID:9357782

  17. Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes*

    PubMed Central

    Mizuguchi, Chiharu; Ogata, Fuka; Mikawa, Shiho; Tsuji, Kohei; Baba, Teruhiko; Shigenaga, Akira; Shimanouchi, Toshinori; Okuhira, Keiichiro; Otaka, Akira; Saito, Hiroyuki

    2015-01-01

    The N-terminal amino acid 1–83 fragment of apolipoprotein A-I (apoA-I) has a strong propensity to form amyloid fibrils at physiological neutral pH. Because apoA-I has an ability to bind to lipid membranes, we examined the effects of the lipid environment on fibril-forming properties of the N-terminal fragment of apoA-I variants. Thioflavin T fluorescence assay as well as fluorescence and transmission microscopies revealed that upon lipid binding, fibril formation by apoA-I 1–83 is strongly inhibited, whereas the G26R mutant still retains the ability to form fibrils. Such distinct effects of lipid binding on fibril formation were also observed for the amyloidogenic prone region-containing peptides, apoA-I 8–33 and 8–33/G26R. This amyloidogenic region shifts from random coil to α-helical structure upon lipid binding. The G26R mutation appears to prevent this helix transition because lower helical propensity and more solvent-exposed conformation of the G26R variant upon lipid binding were observed in the apoA-I 1–83 fragment and 8–33 peptide. With a partially α-helical conformation induced by the presence of 2,2,2-trifluoroethanol, fibril formation by apoA-I 1–83 was strongly inhibited, whereas the G26R variant can form amyloid fibrils. These findings suggest a new possible pathway for amyloid fibril formation by the N-terminal fragment of apoA-I variants: the amyloidogenic mutations partially destabilize the α-helical structure formed upon association with lipid membranes, resulting in physiologically relevant conformations that allow fibril formation. PMID:26175149

  18. Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes.

    PubMed

    Mizuguchi, Chiharu; Ogata, Fuka; Mikawa, Shiho; Tsuji, Kohei; Baba, Teruhiko; Shigenaga, Akira; Shimanouchi, Toshinori; Okuhira, Keiichiro; Otaka, Akira; Saito, Hiroyuki

    2015-08-21

    The N-terminal amino acid 1-83 fragment of apolipoprotein A-I (apoA-I) has a strong propensity to form amyloid fibrils at physiological neutral pH. Because apoA-I has an ability to bind to lipid membranes, we examined the effects of the lipid environment on fibril-forming properties of the N-terminal fragment of apoA-I variants. Thioflavin T fluorescence assay as well as fluorescence and transmission microscopies revealed that upon lipid binding, fibril formation by apoA-I 1-83 is strongly inhibited, whereas the G26R mutant still retains the ability to form fibrils. Such distinct effects of lipid binding on fibril formation were also observed for the amyloidogenic prone region-containing peptides, apoA-I 8-33 and 8-33/G26R. This amyloidogenic region shifts from random coil to α-helical structure upon lipid binding. The G26R mutation appears to prevent this helix transition because lower helical propensity and more solvent-exposed conformation of the G26R variant upon lipid binding were observed in the apoA-I 1-83 fragment and 8-33 peptide. With a partially α-helical conformation induced by the presence of 2,2,2-trifluoroethanol, fibril formation by apoA-I 1-83 was strongly inhibited, whereas the G26R variant can form amyloid fibrils. These findings suggest a new possible pathway for amyloid fibril formation by the N-terminal fragment of apoA-I variants: the amyloidogenic mutations partially destabilize the α-helical structure formed upon association with lipid membranes, resulting in physiologically relevant conformations that allow fibril formation.

  19. Membrane effects of N-terminal fragment of apolipoprotein A-I: a fluorescent probe study.

    PubMed

    Trusova, Valeriya; Gorbenko, Galyna; Girych, Mykhailo; Adachi, Emi; Mizuguchi, Chiharu; Sood, Rohit; Kinnunen, Paavo; Saito, Hiroyuki

    2015-03-01

    The binding of monomeric and aggregated variants of 1-83 N-terminal fragment of apolipoprotein A-I with substitution mutations G26R, G26R/W@8, G26R/W@50 and G26R/W@72 to the model lipid membranes composed of phosphatidylcholine and its mixture with cholesterol has been investigated using fluorescent probes pyrene and Laurdan. Examination of pyrene spectral behavior did not reveal any marked influence of apoA-I mutants on the hydrocarbon region of lipid bilayer. In contrast, probing the membrane effects by Laurdan revealed decrease in the probe generalized polarization in the presence of aggregated proteins. suggesting that oligomeric and fibrillar apoA-I species induce increase in hydration degree and reduction of lipid packing density in the membrane interfacial region. These findings may shed light on molecular details of amyloid cytotoxicity.

  20. Expression of human hepatic lipase negatively impacts apolipoprotein A-I production in primary hepatocytes from Lipc-null mice.

    PubMed

    Bamji-Mirza, Michelle; Zhang, Wandong; Yao, Zemin

    2014-05-01

    This study aimed to examine whether expression of human hepatic lipase (hHL) exerted an intracellular effect on hepatic production of apolipoprotein (apo) A-I. The levels of secreted and cell-associated apoA-I were contrasted between primary hepatocytes isolated from Lipc-null and C57BL/6 mice, and between Lipc-null hepatocytes transfected with either hHL-encoding or control adenovirus. An HSPG-binding deficient hHL protein (hHLmt) was used to determine the impact of cell surface binding on HL action. Accumulation of apoA-I in conditioned media of primary hepatocytes isolated from Lipc-null mice was increased as compared to that from C57BL/6 mice. Metabolic labeling experiments showed that secretion of (35)S-apoA-I from Lipc-null cells was significantly higher than that from C57BL/6 cells. Expression of hHL in Lipc-null hepatocytes, through adenovirus-mediated gene transfer, resulted in decreased synthesis and secretion of (35)S-apoA-I, but not (35)S-apoE, as compared with cells transfected with control adenovirus. Expression of HSPG-binding deficient hHLmt in Lipc-null cells also exerted an inhibitory effect on apoA-I production, even though hHLmt displayed impaired exit from the endoplasmic reticulum as compared with hHL. Subcellular fractionation revealed that expression of hHL or hHLmt led to increased microsome-association of apoA-I relative to non-transfected control. Expression of hHL negatively impacts hepatic production of apoA-I.

  1. Characterization of High Density Lipoprotein Particles in Familial Apolipoprotein A-I Deficiency With Premature Coronary Atherosclerosis, Corneal Arcus and Opacification, and Tubo-Eruptive and Planar Xanthomas

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We describe two male siblings with homozygous familial apolipoprotein (apo) A-I deficiency, markedly decreased high density lipoprotein (HDL) cholesterol levels, undetectable plasma apoA-1, tubo-eruptive and planar xanthomas, and mild corneal arcus and opacification. Sequencing of the apoA-I gene re...

  2. [Structure of the interaction sites of eukaryotic DNA with steroid hormone-apolipoprotein A-I complexes].

    PubMed

    Panin, L E; Gimautdinova, O I; Kuznetsov, P A; Velichko, E Iu; Bazaluk, V V

    2007-01-01

    A high affinity of apolipoprotein A-I for DNA and synthetic oligonucleotides was found using the affinity chromatography, affinity modification, and enzyme analysis. The competitive inhibition and Southern hybridization allowed disclosing the specificity of the interaction of the tetrahydrocortisol-apolipoprotein A-I complex (THC-ApoA-I) with high molecular weight DNA in regions contained GCC/CGG-sequences. The S1 nuclease sensitivity of the duplex CC(GCC)3 x GG(CGG)3 was found to occur under the action of THC-ApoA-I complex. The role of the interaction sites of eukaryotic DNA with steroid (THC, androsterone)-ApoA-I complexes in the initiation of the copy reaction in vitro was revealed. PMID:17936984

  3. Site-specific Nitration of Apolipoprotein A-I at Tyrosine 166 Is Both Abundant within Human Atherosclerotic Plaque and Dysfunctional*

    PubMed Central

    DiDonato, Joseph A.; Aulak, Kulwant; Huang, Ying; Wagner, Matthew; Gerstenecker, Gary; Topbas, Celalettin; Gogonea, Valentin; DiDonato, Anthony J.; Tang, W. H. Wilson; Mehl, Ryan A.; Fox, Paul L.; Plow, Edward F.; Smith, Jonathan D.; Fisher, Edward A.; Hazen, Stanley L.

    2014-01-01

    We reported previously that apolipoprotein A-I (apoA-I) is oxidatively modified in the artery wall at tyrosine 166 (Tyr166), serving as a preferred site for post-translational modification through nitration. Recent studies, however, question the extent and functional importance of apoA-I Tyr166 nitration based upon studies of HDL-like particles recovered from atherosclerotic lesions. We developed a monoclonal antibody (mAb 4G11.2) that recognizes, in both free and HDL-bound forms, apoA-I harboring a 3-nitrotyrosine at position 166 apoA-I (NO2-Tyr166-apoA-I) to investigate the presence, distribution, and function of this modified apoA-I form in atherosclerotic and normal artery wall. We also developed recombinant apoA-I with site-specific 3-nitrotyrosine incorporation only at position 166 using an evolved orthogonal nitro-Tyr-aminoacyl-tRNA synthetase/tRNACUA pair for functional studies. Studies with mAb 4G11.2 showed that NO2-Tyr166-apoA-I was easily detected in atherosclerotic human coronary arteries and accounted for ∼8% of total apoA-I within the artery wall but was nearly undetectable (>100-fold less) in normal coronary arteries. Buoyant density ultracentrifugation analyses showed that NO2-Tyr166-apoA-I existed as a lipid-poor lipoprotein with <3% recovered within the HDL-like fraction (d = 1.063–1.21). NO2-Tyr166-apoA-I in plasma showed a similar distribution. Recovery of NO2-Tyr166-apoA-I using immobilized mAb 4G11.2 showed an apoA-I form with 88.1 ± 8.5% reduction in lecithin-cholesterol acyltransferase activity, a finding corroborated using a recombinant apoA-I specifically designed to include the unnatural amino acid exclusively at position 166. Thus, site-specific nitration of apoA-I at Tyr166 is an abundant modification within the artery wall that results in selective functional impairments. Plasma levels of this modified apoA-I form may provide insights into a pathophysiological process within the diseased artery wall. PMID:24558038

  4. Inhibition of inflammatory signaling pathways in 3T3-L1 adipocytes by apolipoprotein A-I.

    PubMed

    Sultana, Afroza; Cochran, Blake J; Tabet, Fatiha; Patel, Mili; Torres, Luisa Cuesta; Barter, Philip J; Rye, Kerry-Anne

    2016-06-01

    Activation of inflammatory signaling pathways links obesity with metabolic disorders. TLR4-mediated activation of MAPKs and NF-κB are 2 such pathways implicated in obesity-induced inflammation. Apolipoprotein A-I (apoA-I) exerts anti-inflammatory effects on adipocytes by effluxing cholesterol from the cells via the ATP binding cassette transporter A1 (ABCA1). It is not known if these effects involve inhibition of inflammatory signaling pathways by apoA-I. This study asks if apoA-I inhibits activation of MAPKs and NF-κB in mouse 3T3-L1 adipocytes and whether this inhibition is ABCA1 dependent. Incubation of differentiated 3T3-L1 adipocytes with apoA-I decreased cell surface expression of TLR4 by 16 ± 2% and synthesis of the TLR4 adaptor protein, myeloid differentiation primary response 88, by 24 ± 4% in an ABCA1-dependent manner. ApoA-I also inhibited downstream activation of MAPKs, such as ERK, p38MAPK, and JNK, as well as expression of proinflammatory adipokines in bacterial LPS-stimulated 3T3-L1 adipocytes in an ABCA1-dependent manner. ApoA-I, by contrast, suppressed nuclear localization of the p65 subunit of NF-κB by 30 ± 3% in LPS-stimulated 3T3-L1 adipocytes in an ABCA1-independent manner. In conclusion, apoA-I inhibits TLR4-mediated inflammatory signaling pathways in adipocytes by preventing MAPK and NF-κB activation.-Sultana, A., Cochran, B. J., Tabet, F., Patel, M., Cuesta Torres, L., Barter, P. J., Rye, K.-A. Inhibition of inflammatory signaling pathways in 3T3-L1 adipocytes by apolipoprotein A-I.

  5. Localization of the structural gene for human apolipoprotein A-I on the long arm of human chromosome 11.

    PubMed Central

    Cheung, P; Kao, F T; Law, M L; Jones, C; Puck, T T; Chan, L

    1984-01-01

    Apolipoprotein A-I (apo A-I), the major apolipoprotein in human high density lipoproteins, is involved in the disease atherosclerosis. Cloned apo A-I cDNA (pA1-3) was used as a probe in chromosome mapping studies to detect the human apo A-I structural gene sequence in human-Chinese hamster cell hybrids. Southern blot analysis of 13 hybrids localized the gene to human chromosome 11. Confirmation of the chromosomal assignment was obtained by analysis of a hybrid (J1) containing a single human chromosome, no. 11. Regional mapping was achieved by using deletion subclones of J1 that localized the human apo A-I structural gene to the region 11q13 leads to qter. Since the human apolipoprotein C-III (apo C-III) structural gene is closely linked to apo A-I, it can be assigned to the same region on the long arm of chromosome 11. By extension of methods previously described, it now appears possible to carry out fine-structure analysis of this and related gene regions on chromosome 11 and to study the biochemical concomitants of these genes and of genes on other chromosomes for analysis of their role in atherosclerosis. Images PMID:6420790

  6. Try P.R.A.I.S.E.

    ERIC Educational Resources Information Center

    Wollam, Scott A.

    1979-01-01

    P.R.A.I.S.E. (Positive Reinforcement and Individualized Systematic Economics) is a multifaceted money system which utilizes positive and negative reinforcement and, at the same time, incorporates peer pressure and reinforcement for behavior modification. The system motivates, relates closely to life situations, and can be applied to all areas of…

  7. Molecular characterization and developmental expression patterns of apolipoprotein A-I in Senegalese sole (Solea senegalensis Kaup).

    PubMed

    Román-Padilla, J; Rodríguez-Rúa, A; Manchado, M; Hachero-Cruzado, I

    2016-05-01

    The apolipoprotein A-I (ApoA-I) is an essential component of the high density lipoproteins (HDL). In this study, the cDNA and genomic sequences of this apolipoprotein were characterized for first time in Solea senegalensis. The predicted polypeptide revealed conserved structural features including ten repeats in the lipid-binding domain and some residues involved in cholesterol interaction and binding. The gene structure analysis identified four exons and three introns. Moreover, the synteny analysis revealed that apoA-I did not localize with other apolipoproteins indicating a divergent evolution with respect to the apoA-IV and apoE cluster. The phylogenetic analyses identified two distinct apoA-I paralogs in Ostariophysi (referred to as Ia and Ib) and only one (Ib) in Acanthopterygii. Whole-mount in situ hybridization located the apoA-I signal mainly in the yolk syncytial layer in lecitotrophic larval stages. Later at mouth opening, the mRNA signals were detected mainly in liver and intestine compatible with its role in the HDL formation. Moreover, a clear signal was detected in some regions of the brain, retina and neural cord suggesting a role in local regulation of cholesterol homeostasis. After metamorphosis, apoA-I was also detected in other tissues such as gills, head kidney and spleen suggesting a putative role in immunity. Expression analyses in larvae fed two diets with different triacylglycerol levels indicated that apoA-I mRNA levels were more associated to larval size and development than dietary lipid levels. Finally, qPCR analyses of immature and mature transcripts revealed distinct expression profiles suggesting a posttranscriptional regulatory mechanism.

  8. Conservation of apolipoprotein A-I's central domain structural elements upon lipid association on different high-density lipoprotein subclasses.

    PubMed

    Oda, Michael N; Budamagunta, Madhu S; Geier, Ethan G; Chandradas, Sajiv H; Shao, Baohai; Heinecke, Jay W; Voss, John C; Cavigiolio, Giorgio

    2013-10-01

    The antiatherogenic properties of apolipoprotein A-I (apoA-I) are derived, in part, from lipidation-state-dependent structural elements that manifest at different stages of apoA-I's progression from lipid-free protein to spherical high-density lipoprotein (HDL). Previously, we reported the structure of apoA-I's N-terminus on reconstituted HDLs (rHDLs) of different sizes. We have now investigated at the single-residue level the conformational adaptations of three regions in the central domain of apoA-I (residues 119-124, 139-144, and 164-170) upon apoA-I lipid binding and HDL formation. An important function associated with these residues of apoA-I is the activation of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for catalyzing HDL maturation. Structural examination was performed by site-directed tryptophan fluorescence and spin-label electron paramagnetic resonance spectroscopies for both the lipid-free protein and rHDL particles 7.8, 8.4, and 9.6 nm in diameter. The two methods provide complementary information about residue side chain mobility and molecular accessibility, as well as the polarity of the local environment at the targeted positions. The modulation of these biophysical parameters yielded new insight into the importance of structural elements in the central domain of apoA-I. In particular, we determined that the loosely lipid-associated structure of residues 134-145 is conserved in all rHDL particles. Truncation of this region completely abolished LCAT activation but did not significantly affect rHDL size, reaffirming the important role of this structural element in HDL function. PMID:23984834

  9. Apolipoprotein A-I configuration and cell cholesterol efflux activity of discoidal lipoproteins depend on the reconstitution process.

    PubMed

    Cuellar, Luz Ángela; Prieto, Eduardo Daniel; Cabaleiro, Laura Virginia; Garda, Horacio Alberto

    2014-01-01

    Discoidal high-density lipoproteins (D-HDL) are critical intermediates in reverse cholesterol transport. Most of the present knowledge of D-HDL is based on studies with reconstituted lipoprotein complexes of apolipoprotein A-I (apoA-I) obtained by cholate dialysis (CD). D-HDL can also be generated by the direct microsolubilization (DM) of phospholipid vesicles at the gel/fluid phase transition temperature, a process mechanistically similar to the "in vivo" apoAI lipidation via ABCA1. We compared the apoA-I configuration in D-HDL reconstituted with dimyristoylphosphatidylcholine by both procedures using fluorescence resonance energy transfer measurements with apoA-I tryptophan mutants and fluorescently labeled cysteine mutants. Results indicate that apoA-I configuration in D-HDL depends on the reconstitution process and are consistent with a "double belt" molecular arrangement with different helix registry. As reported by others, a configuration with juxtaposition of helices 5 of each apoAI monomer (5/5 registry) predominates in D-HDL obtained by CD. However, a configuration with helix 5 of one monomer juxtaposed with helix 2 of the other (5/2 registry) would predominate in D-HDL generated by DM. Moreover, we also show that the kinetics of cholesterol efflux from macrophage cultures depends on the reconstitution process, suggesting that apoAI configuration is important for this HDL function. PMID:24201377

  10. Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl).

    PubMed

    Hadfield, Katrina A; Pattison, David I; Brown, Bronwyn E; Hou, Liming; Rye, Kerry-Anne; Davies, Michael J; Hawkins, Clare L

    2013-01-15

    Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate). PMID:23088652

  11. High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease

    PubMed Central

    Gordon, Elizabeth M.; Figueroa, Debbie M.; Barochia, Amisha V.; Yao, Xianglan; Levine, Stewart J.

    2016-01-01

    Apolipoprotein A-I (apoA-I) and high-density lipoproteins (HDL) mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury (ALI), asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of ALI, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach. PMID:27708582

  12. Surface-induced assembly of apolipoprotein A-I: Implications for symmetry-driven non-cooperative clustering

    NASA Astrophysics Data System (ADS)

    Winford, Sidney; Tobin, Moriah; Gross, Eitan

    2012-03-01

    In condensed matter physics the geometry of a crystal is determined by the mechanism of condensation. In biology, the link between clustering mechanisms and the shape of a protein crystal is not well defined. To gain more insight into the problem, we studied clustering of apolipoprotein A-I (apo A-I) on a solid surface using AFM. The amyloidogenic protein apo A-I is the main protein component of high density lipoprotein and thus reduces the risk of atherosclerosis. We found that apo A-I clustered to form nano-scale, symmetrical clusters on mica. Statistical analysis of size distribution for several thousand clusters suggested that the clustering reaction followed a non-cooperative kinetic scheme characterized by a single equilibrium constant of 0.92·106 M-1 and a change in free energy (ΔG) of -0.03 kJ mole-1/residue. This is close to ΔG of-0.04 kJ mole-1/residue for apo A-I binding to phospholipid membrane; and 30-fold smaller than ΔG for β-amyloid formation by apo A-I. The high symmetry of the clusters is consistent with an isotropic diffusion coefficient of protein monomers on the surface of the substrate. This previously unrecognized link between protein clustering mechanism and the symmetry of the growth pattern may have important implications in medicine, pharmaceutics and polymer science.

  13. On the mechanism of cholesterol interaction with apolipoproteins A-I and E.

    PubMed

    Klimov, A N; Kozhevnikova, K A; Klueva, N N; Belova, E V

    1992-10-01

    It is shown that cholesterol may interact with some substances containing the guanidine group (guanidine itself, arginine, metformin and dodecylguanidine bromide) and with arginine-rich proteins--apoproteins A-I and E. In the latter case the interaction produces the formation of cholesterol-apoprotein complexes. Analysis of such complexes has shown that one apo A-I molecule binds 17-22 and one apo E molecule binds 30-35 sterol molecules, which approximately corresponds to the amount of arginine residues in these proteins. Formation of cholesterol-apoprotein complexes has been suggested to occur due to: (1) formation of hydrogen bond and/or ion-dipole interaction between cholesterol hydroxyl and guanidine groups of the apoprotein arginine residues and (2) hydrophobic interaction of the cholesterol aliphatic chain with nonpolar side chains of the amino acids occupying the third position from arginine in the protein molecule. PMID:1468123

  14. Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages.

    PubMed

    Brown, Bronwyn E; Nobecourt, Estelle; Zeng, Jingmin; Jenkins, Alicia J; Rye, Kerry-Anne; Davies, Michael J

    2013-01-01

    Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross-linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in kslow) and 3 mM glycolaldehyde (50% decrease in kfast, 60% decrease in kslow) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA-I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages.

  15. The Effect of Aerobic Exercise on Total Cholesterol, High-Density Lipoprotein, Apolipoprotein B, Apolipoprotein A-I, and Percent Body Fat in Adolescent Females.

    ERIC Educational Resources Information Center

    Lungo, Diane; And Others

    The effect of aerobic exercise on total cholesterol (TC), high-density lipoprotein (HDL), apolipoprotein B (Apo B), apolioprotein A-I (Apo A-I), and percent body fat in adolescent females was studied. The control subjects (n=86) were volunteers who had completed a physical education class at least six months prior to the commencement of the study,…

  16. Apolipoprotein A-I from striped bass (Morone saxatilis) demonstrates antibacterial activity in vitro.

    PubMed

    Johnston, L Danielle; Brown, Gwynne; Gauthier, David; Reece, Kimberly; Kator, Howard; Van Veld, Peter

    2008-10-01

    HDL and apolipoprotein A-I from teleostean fishes demonstrate in vitro activity against gram-positive and gram-negative bacteria. In this study, we purified ApoA-1 from striped bass (Morone saxatilis) plasma and examined its in vitro antibacterial activity against Streptococcus sp., Escherichia coli, and Mycobacterium marinum. In addition, we obtained sequence for a putative striped bass ApoA-1 gene, which when translated contained the identical sequence generated from N-terminal sequencing of the purified ApoA-1. The predicted secondary and tertiary structures contained the characteristic proline residues and high alpha-helical content conserved between mammals and fishes. Purified ApoA-1 exhibited antibacterial activity against the bacteria assayed. Concentrations of 125 microg/mL for E. coli, 250 microg/mL for Streptococcus sp., and 250 microg/mL for M. marinum, inhibited bacterial growth by 50% compared to control. ApoA-1 plasma concentrations in experimental and wild fish ranged from undetectable levels to greater than 5 mg/mL, indicating that striped bass ApoA-1 is an effective antibacterial agent at concentrations below the range of physiological concentrations in striped bass plasma. We therefore conclude that ApoA-1 could play a role in innate defense against bacterial pathogens in striped bass.

  17. Mycoplasma gallisepticum (HS strain) surface lipoprotein pMGA interacts with host apolipoprotein A-I during infection in chicken.

    PubMed

    Hu, Fuli; Zhao, Chengcheng; Bi, Dingren; Tian, Wei; Chen, Jiao; Sun, Jianjun; Peng, Xiuli

    2016-02-01

    The adhesin protein from Mycoplasma gallisepticum (HS strain), namely pMGA1.2, is required for M. gallisepticum (MG) infection in chicken. However, the host factor(s) that interact with pMGA1.2 is not known. In this study, we prepared the membrane fraction of trachea epithelial cells from chicken embryos. Using an improved virus overlay protein blot assay (VOPBA) and glutathione S-transferase (GST) pull-down assay, we found that pMGA1.2 specifically bound to a ∼30 kDa host protein. This host protein was further identified by mass spectrometry as chicken apolipoprotein A-I (ApoA-I). We expressed and purified the recombinant ApoA-I protein in Escherichia coli and confirmed that it bound to the purified pMGA1.2 protein in vitro. Transiently expressed pMGA1.2 and ApoA-I were colocalized in HeLa cells. Finally, we designed small interfering RNA (siRNA) molecules to knock down the expression of either ApoA-I or pMGA1.2, which inhibited the MG-induced cell cycle disruption in cells of chicken embryo fibroblast cell line (DF-1). Similarly, knockdown of ApoA-I inhibited the cilia loss and damage in chicken trachea cells in MG infection. In summary, ApoA-I may be an essential host factor in MG infection through interacting with pMGA1.2.

  18. Predictive value of serum apolipoprotein B/apolipoprotein A-I ratio in metabolic syndrome risk: a Chinese cohort study.

    PubMed

    Chou, Yu-Ching; Kuan, Jen-Chun; Bai, Chyi-Huey; Yang, Tsan; Chou, Wan-Yun; Hsieh, Po-Chien; You, San-Lin; Hwang, Lee-Ching; Chen, Chien-Hua; Wei, Cheng-Yu; Sun, Chien-An

    2015-06-01

    The purpose of this study was to evaluate whether the apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio is a promising risk predictor of metabolic syndrome (MetS) and to determine the optimal cut-off value of this ratio in detecting subjects with MetS in a Chinese population. A prospective study was conducted using a representative sample of non-institutionized people in Taiwan. A total of 3,343 participants with mean age (±SD) of 39.86 (±15.61) years old were followed up from 2002 to 2007. The primary outcome was the incidence of MetS. The MetS was defined according to a unified criterion established by several major organizations. There were 462 cases of incident MetS during a mean follow-up period of 5.26 years. A significantly stepwise increase in the incidence of MetS across quartiles of the apoB/apoA-I ratio was noted in both sexes after adjustment for potential confounders (p for trend <0.001). Compared with the lowest quartile of apoB/apoA-I ratio, participants in the highest quartile had a significantly higher risk of MetS in both men [adjusted hazard ratio (HR) = 6.29, 95 % confidence interval (CI) = 2.79-9.13] and women (adjusted HR = 3.82, 95 % CI = 1.06-6.63). Comparisons of receiver operating characteristics curves indicated that the predictive ability of apoB/apoA-I ratio to detect MetS was better than conventional lipid ratio measurements. Furthermore, the optimal cut-off value of apoB/apoA-I ratio for MetS diagnosis was 0.71 in men and 0.56 in women. These results suggest that an elevated apoB/apoA-I ratio might constitute a potentially crucial measure linked to the risk of developing MetS.

  19. Adsorption of apolipoprotein A-I to biological membranes. A statistical mechanical model

    NASA Astrophysics Data System (ADS)

    Gross, Eitan

    2012-07-01

    Apolipoprotein A-I (apo A-I), the main protein component of high-density lipoprotein (HDL), reduces the risk for atherosclerosis by removing cholesterol from the membrane of foam cells. Experiments with model membrane systems have indicated, however, that membrane cholesterol reduces apo A-I binding to the membrane. Foam cells resolve this discrepancy electrostatically by co-inserting negatively charged phospholipids in their membrane. Here we present a statistical mechanical model to account for the effect of cholesterol. Our model is based on the Haugen and May model which takes into account the dipolar nature of the zwitterionic phospholipid head group in the membrane, in which the positive end of the zwitterionic dipole moment can move randomly on a hemispherical surface with a radius equal to the arm of the dipole moment and with the negative end fixed at the hydrocarbon layer. Adsorption of a positively charged apo A-I macroion to the surface of the membrane modifies the electric field within the head group region and induces lateral demixing of phospholipid molecules in the membrane. Results from numerical integration of model equations show that i) as a result of the strong charge-dipole electrostatic coupling, the positive end of the dipoles tilts away from the adsorbed macroion in a cooperative manner; and ii) cholesterol reduces macroion adsorption to the membrane by reducing the surface area of the membrane and restricting the dipoles range of rotation. Model predictions for the change in free energy of adsorption to zwitterionic membrane are in good agreement with previously reported experimental data with liposomes. The model can assist in designing new mimetic peptides.

  20. Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells.

    PubMed

    Medina-Echeverz, José; Vasquez, Marcos; Gomar, Celia; Ardaiz, Nuria; Berraondo, Pedro

    2015-06-01

    Transforming growth factor beta (TGF-β) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-β peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-β peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to generate hepatic metastases. While overexpression of ApoA-I had no effect on the parameters analyzed, ApoA-I fused to P144 markedly diminished the tumorigenic capacity and metastatic potential of MC38 in vitro and in vivo, thus generating a highly immunogenic cell line. MC38 cells transfected with ApoA-I fused to P144 triggered memory T cell responses able to eliminate the parental cell line upon re-challenge. In summary, expression of ApoA-I fused to P144 is a novel strategy to modulate TGF-β in tumor cells. These results highlight the potential of TGF-β as a target in the development of new antitumor treatments.

  1. Apolipoprotein A-I and its mimetics for the treatment of atherosclerosis

    PubMed Central

    Smith, Jonathan D

    2011-01-01

    Although statin treatment leads consistently to a reduction in major adverse coronary events and death in clinical trials, approximately 60 to 70% residual risk of these outcomes still remains. One frontier of investigational drug research is treatment to increase HDL, the ‘good cholesterol’ that is associated with a reduced risk of coronary artery disease. HDL and its major protein apolipoprotein A-I (apoAI) are protective against atherosclerosis through several mechanisms, including the ability to mediate reverse cholesterol transport. This review focuses on the preclinical and clinical findings for two types of therapies for the treatment of atherosclerosis: apoAI-containing compounds and apoAI mimetic peptides. Both of these therapies have excellent potential to be useful clinically to promote atherosclerosis regression and stabilize existing plaques, but significant hurdles must be overcome in order to develop these approaches into safe and effective therapies. PMID:20730693

  2. Association of carotid intima-media thickness with leptin and apoliprotein b/apoliprotein a-I ratio reveals imminent predictors of subclinical atherosclerosis in psoriasis patients.

    PubMed

    Asha, Kumari; Sharma, Suman B; Singal, Archana; Aggarwal, Amitesh

    2014-01-01

    Psoriasis patients are often susceptible to cardiovascular diseases (CVD), including atherosclerosis. Traditional markers (biochemical and inflammatory) and diagnostic tools could detect occlusive but not subclinical atherosclerosis. Carotid intima-media thickness (CIMT), has recently been recognised as a non invasive diagnostic tool for identification of premature atherosclerosis. Therefore we evaluated 80 psoriasis patients and 80 age sex matched healthy controls for serum leptin levels and apolipoprotein B/apolipoprotein A-I ratio (apoB/apoA-I ratio) in relation with CIMT of carotid artery. Carotid intima-media thickness and carotid plaques were simultaneously measured by carotid sonography. Serum concentration of leptin and apolipoprotein were measured using enzyme-linked immuno sorbent assay (ELISA) and nephelometry respectively. Raised CIMT correlated to age of onset of the disease, serum leptin and apoB/apoA-I ratio in psoriasis patients. Taking into account, values that were above the 75 percentile of the three markers (leptin, apoB/apoA-I ratio and CIMT) the odds ratio was 4.26 (2.06-8.80 CI). Leptin and apoB/apoA-I ratio showed significant cumulative association with CIMT. Results of predictive analysis supports measurement of CIMT along with estimation of serum leptin and apoB/apoA-I ratio for prediction of premature atherosclerosis in psoriasis patients.

  3. Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno-Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding.

    PubMed

    Kempen, Herman J; Bellus, Daniel; Fedorov, Oleg; Nicklisch, Silke; Filippakopoulos, Panagis; Picaud, Sarah; Knapp, Stefan

    2013-01-01

    Expression and secretion of apolipoprotein A-I (apoA-I) by cultured liver cells can be markedly stimulated by triazolodiazepines (TZDs). It has been shown previously that the thieno-TZD Ro 11-1464 increases plasma levels of apoA-I and in vivomacrophage reverse cholesterol transport in mice. However, these effects were only seen at high doses, at which the compound could act on central benzodiazepine (BZD) receptors or platelet activating factor (PAF) receptors, interfering with its potential utility. In this work, we describe 2 new thieno-TZDs MDCO-3770 and MDCO-3783, both derived from Ro 11-1464. These compounds display the same high efficacy on apoA-I production, metabolic stability, and lack of cytotoxicity in cultured hepatocytes as Ro 11-1464, but they do not bind to the central BZD receptor and PAF receptor. The quinazoline RVX-208 was less efficacious in stimulating apoA-I production and displayed signs of cytotoxicity. Certain TZDs stimulating apoA-I production are now known to be inhibitors of bromodomain (BRD) extra-terminal (BET) proteins BRDT, BRD2, BRD3, and BRD4, and this inhibition was inferred as a main molecular mechanism for their effect on apoA-I expression. We show here that the thieno-TZD (+)-JQ1, a potent BET inhibitor, strongly stimulated apoA-I production in Hep-G2 cells, but that its enantiomer (-)-JQ1, which has no BET inhibitor activity, also showed considerable effect on apoA-I production. MDCO-3770 and MDCO-3783 also inhibited BRD3 and BRD4 in vitro, with potency somewhat below that of (+)-JQ1. We conclude that the effect of thieno-TZDs on apoA-I expression is not due to inhibition of the BZD or PAF receptors and is not completely explained by transcriptional repression by BET proteins. PMID:25278768

  4. Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno-Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding

    PubMed Central

    Kempen, Herman J; Bellus, Daniel; Fedorov, Oleg; Nicklisch, Silke; Filippakopoulos, Panagis; Picaud, Sarah; Knapp, Stefan

    2013-01-01

    Expression and secretion of apolipoprotein A-I (apoA-I) by cultured liver cells can be markedly stimulated by triazolodiazepines (TZDs). It has been shown previously that the thieno-TZD Ro 11-1464 increases plasma levels of apoA-I and in vivomacrophage reverse cholesterol transport in mice. However, these effects were only seen at high doses, at which the compound could act on central benzodiazepine (BZD) receptors or platelet activating factor (PAF) receptors, interfering with its potential utility. In this work, we describe 2 new thieno-TZDs MDCO-3770 and MDCO-3783, both derived from Ro 11-1464. These compounds display the same high efficacy on apoA-I production, metabolic stability, and lack of cytotoxicity in cultured hepatocytes as Ro 11-1464, but they do not bind to the central BZD receptor and PAF receptor. The quinazoline RVX-208 was less efficacious in stimulating apoA-I production and displayed signs of cytotoxicity. Certain TZDs stimulating apoA-I production are now known to be inhibitors of bromodomain (BRD) extra-terminal (BET) proteins BRDT, BRD2, BRD3, and BRD4, and this inhibition was inferred as a main molecular mechanism for their effect on apoA-I expression. We show here that the thieno-TZD (+)-JQ1, a potent BET inhibitor, strongly stimulated apoA-I production in Hep-G2 cells, but that its enantiomer (−)-JQ1, which has no BET inhibitor activity, also showed considerable effect on apoA-I production. MDCO-3770 and MDCO-3783 also inhibited BRD3 and BRD4 in vitro, with potency somewhat below that of (+)-JQ1. We conclude that the effect of thieno-TZDs on apoA-I expression is not due to inhibition of the BZD or PAF receptors and is not completely explained by transcriptional repression by BET proteins. PMID:25278768

  5. Contribution of apolipoprotein A-I to the reduction in high-sensitivity C-reactive protein levels by different statins: comparative study of pitavastatin and atorvastatin.

    PubMed

    Tani, Shigemasa; Takahashi, Atsuhiko; Nagao, Ken; Hirayama, Atsushi

    2015-11-01

    Recently, investigation may have focused on modification of apolipoprotein A-I (apoA-I) associated with anti-inflammatory effect for the potential prevention of cardiovascular events. The purpose of this study was to evaluate the effects of atorvastatin and pitavastatin on serum apoA-I levels and to investigate the role of apoA-I in the anti-inflammatory effect of statin. We conducted a 6-month, prospective, randomized, open-label study in which we assigned hypercholesterolemic patients to a pitavastatin group (n = 52; 2 mg/day) or an atorvastatin group (n = 52; 10 mg/day) to investigate the effects of these two statins on the serum apoA-I levels and serum high-sensitivity C-reactive protein (hs-CRP) levels. There were no significant differences between the two groups in the changes in the low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), or hs-CRP levels, but the change in apoA-I in the pitavastatin group was significantly greater than in the atorvastatin group (5.3 vs. 1.4 %; p = 0.0001). A stepwise regression analysis revealed that the percent change in (Δ) serum apoA-I level was an independent predictor of the Δ serum hs-CRP (standard correlation coefficient = -0.198; p = 0.047). However, there was a significant negative correlation between the Δ apoA-I levels and Δ hs-CRP levels in the pitavastatin group (r = -0.283, p = 0.042), but not the atorvastatin group (r = -0.133, p = 0.356). The results suggest that the contribution of apoA-I to the reduction in serum hs-CRP levels by these two statins may be different. A decrease in hs-CRP level accompanied by an increase in apoA-I level may be involved in the pleiotropic effects of pitavastatin.

  6. The secondary structure of apolipoprotein A-I on 9.6-nm reconstituted high-density lipoprotein determined by EPR spectroscopy

    PubMed Central

    Oda, Michael N; Budamagunta, Madhu S; Borja, Mark S; Petrlova, Jitka; Voss, John C; Lagerstedt, Jens O

    2013-01-01

    Apolipoprotein A-I (ApoA-I) is the major protein component of high-density lipoprotein (HDL), and is critical for maintenance of cholesterol homeostasis. During reverse cholesterol transport, HDL transitions between an array of subclasses, differing in size and composition. This process requires ApoA-I to adapt to changes in the shape of the HDL particle, transiting from an apolipoprotein to a myriad of HDL subclass-specific conformations. Changes in ApoA-I structure cause alterations in HDL-specific enzyme and receptor-binding properties, and thereby direct the HDL particle through the reverse cholesterol transport pathway. In this study, we used site-directed spin label spectroscopy to examine the conformational details of the ApoA-I central domain on HDL. The motional dynamics and accessibility to hydrophobic/hydrophilic relaxation agents of ApoA-I residues 99–163 on 9.6-nm reconstituted HDL was analyzed by EPR. In previous analyses, we examined residues 6–98 and 164–238 (of ApoA-I's 243 residues), and combining these findings with the current results, we have generated a full-length map of the backbone structure of reconstituted HDL-associated ApoA-I. Remarkably, given that the majority of ApoA-I's length is composed of amphipathic helices, we have identified nonhelical residues, specifically the presence of a β-strand (residues 149–157). The significance of these nonhelical residues is discussed, along with the other features, in the context of ApoA-I function in contrast to recent models derived by other methods. PMID:23668303

  7. A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia.

    PubMed

    Pisciotta, Livia; Fasano, Tommaso; Calabresi, Laura; Bellocchio, Antonella; Fresa, Raffaele; Borrini, Claudia; Calandra, Sebastiano; Bertolini, Stefano

    2008-05-01

    We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49-50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77+/-0.15 mmol/l vs. 1.15+/-0.20 mmol/l, P<0.005; 71.4+/-9.1mg/dl vs. 134.0+/-14.7 mg/dl, P<0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C. PMID:17950741

  8. Amyloidogenic propensity of a natural variant of human apolipoprotein A-I: stability and interaction with ligands.

    PubMed

    Rosú, Silvana A; Rimoldi, Omar J; Prieto, Eduardo D; Curto, Lucrecia M; Delfino, José M; Ramella, Nahuel A; Tricerri, M Alejandra

    2015-01-01

    A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I) have been associated with hereditary amyloidoses. The molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here we examined the effects of the Arg173Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as well as on the ability to bind to putative ligands. Our results indicate that the mutation induces a drastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiological pH, which could determine the observed higher tendency to aggregate as pro-amyloidogenic complexes. Incubation under acidic conditions does not seem to induce significant desestabilization or aggregation tendency, neither does it contribute to the binding of the mutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutant as compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends on pH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggest that binding to ligands as heparin or other glycosaminoglycans could be key events tuning the fine details of the interaction of apoA-I variants with the micro-environment, and probably eliciting the toxicity of these variants in hereditary amyloidoses. PMID:25950566

  9. Amyloidogenic Propensity of a Natural Variant of Human Apolipoprotein A-I: Stability and Interaction with Ligands

    PubMed Central

    Rosú, Silvana A.; Rimoldi, Omar J.; Prieto, Eduardo D.; Curto, Lucrecia M.; Delfino, José M.

    2015-01-01

    A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I) have been associated with hereditary amyloidoses. The molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here we examined the effects of the Arg173Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as well as on the ability to bind to putative ligands. Our results indicate that the mutation induces a drastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiological pH, which could determine the observed higher tendency to aggregate as pro-amyloidogenic complexes. Incubation under acidic conditions does not seem to induce significant desestabilization or aggregation tendency, neither does it contribute to the binding of the mutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutant as compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends on pH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggest that binding to ligands as heparin or other glycosaminoglycans could be key events tuning the fine details of the interaction of apoA-I variants with the micro-environment, and probably eliciting the toxicity of these variants in hereditary amyloidoses. PMID:25950566

  10. 22 CFR 214.31 - A.I.D. Advisory Committee Representative.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false A.I.D. Advisory Committee Representative. 214... MANAGEMENT Operation of Advisory Committees § 214.31 A.I.D. Advisory Committee Representative. (a) For each advisory committee used by A.I.D., the Administrator designates an A.I.D., employee to serve as the...

  11. A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein.

    PubMed

    Gu, Xiaodong; Wu, Zhiping; Huang, Ying; Wagner, Matthew A; Baleanu-Gogonea, Camelia; Mehl, Ryan A; Buffa, Jennifer A; DiDonato, Anthony J; Hazen, Leah B; Fox, Paul L; Gogonea, Valentin; Parks, John S; DiDonato, Joseph A; Hazen, Stanley L

    2016-03-18

    The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu(159)-Leu(170)) in nascent HDL, the so-called "solar flare" (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861-868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro(165), Tyr(166), Ser(167), and Asp(168)) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr(166) was further supported using reconstituted HDL generated from apoA-I mutants (Tyr(166) → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr(166)-apoA-I, a specific post-translational modification on apoA-I that is abundant within human atherosclerotic plaque, was further investigated by using the recombinant protein generated from E. coli containing a mutated orthogonal tRNA synthetase/tRNACUA pair enabling site-specific insertion of the unnatural amino acid into apoA-I. NO2-Tyr(166)-apoA-I, after subcutaneous injection into hLCAT(Tg/Tg), apoA-I(-/-) mice, showed impaired LCAT activation in vivo, with significant reduction in HDL cholesteryl ester formation. The present results thus identify multiple structural features within the solvent-exposed SF region of apoA-I of nascent HDL essential for optimal LCAT binding and catalytic efficiency.

  12. Apolipoprotein A-I in Labeo rohita: Cloning and functional characterisation reveal its broad spectrum antimicrobial property, and indicate significant role during ectoparasitic infection.

    PubMed

    Mohapatra, Amruta; Karan, Sweta; Kar, Banya; Garg, L C; Dixit, A; Sahoo, P K

    2016-08-01

    Apolipoprotein A-I (ApoA-I) is the most abundant and multifunctional high-density lipoprotein (HDL) having a major role in lipid transport and potent antimicrobial activity against a wide range of microbes. In this study, a complete CDS of 771 bp of Labeo rohita (rohu) ApoA-I (LrApoA-I) encoding a protein of 256 amino acids was amplified, cloned and sequenced. Tissue specific transcription analysis of LrApoA-I revealed its expression in a wide range of tissues, with a very high level of expression in liver and spleen. Ontogenic study of LrApoA-I expression showed presence of transcripts in milt and 3 h post-fertilization onwards in the larvae. The expression kinetics of LrApoA-I was studied upon infection with three different types of pathogens to elucidate its functional significance. Its expression was found to be up-regulated in the anterior kidney of L. rohita post-infection with Aeromonas hydrophila. Similarly following poly I:C (poly inosinic:cytidylic) stimulation, the transcript levels increased in both the anterior kidney and liver tissues. Significant up-regulation of LrApoA-I expression was observed in skin, mucous, liver and anterior kidney of the fish challenged with the ectoparasite Argulus siamensis. Immunomodulatory effect of recombinant LrApoA-I (rApoA-I) produced in Escherichia coli was demonstrated against A. hydrophila challenge in vivo. L. rohita administered with rApoA-I at a dose of 100 μg exhibited significantly higher protection (∼55%) upon challenge with A. hydrophila 12 h post-administration of the protein, in comparison to that observed in control group, along with higher level of expression of immune-related genes. The heightened expression of ApoA-I observed post-infection reflected its involvement in immune responses against a wide range of infections including bacterial, viral as well as parasitic pathogens. Our results also suggest the possibility of using rApoA-I as an immunostimulant, particularly rendering protection

  13. A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein.

    PubMed

    Gu, Xiaodong; Wu, Zhiping; Huang, Ying; Wagner, Matthew A; Baleanu-Gogonea, Camelia; Mehl, Ryan A; Buffa, Jennifer A; DiDonato, Anthony J; Hazen, Leah B; Fox, Paul L; Gogonea, Valentin; Parks, John S; DiDonato, Joseph A; Hazen, Stanley L

    2016-03-18

    The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu(159)-Leu(170)) in nascent HDL, the so-called "solar flare" (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861-868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro(165), Tyr(166), Ser(167), and Asp(168)) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr(166) was further supported using reconstituted HDL generated from apoA-I mutants (Tyr(166) → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr(166)-apoA-I, a specific post-translational modification on apoA-I that is abundant within human atherosclerotic plaque, was further investigated by using the recombinant protein generated from E. coli containing a mutated orthogonal tRNA synthetase/tRNACUA pair enabling site-specific insertion of the unnatural amino acid into apoA-I. NO2-Tyr(166)-apoA-I, after subcutaneous injection into hLCAT(Tg/Tg), apoA-I(-/-) mice, showed impaired LCAT activation in vivo, with significant reduction in HDL cholesteryl ester formation. The present results thus identify multiple structural features within the solvent-exposed SF region of apoA-I of nascent HDL essential for optimal LCAT binding and catalytic efficiency. PMID:26797122

  14. Analysis of the haptoglobin binding region on the apolipoprotein A-I-derived P2a peptide.

    PubMed

    Spagnuolo, Maria Stefania; Di Stasi, Rossella; De Rosa, Lucia; Maresca, Bernadetta; Cigliano, Luisa; D'Andrea, Luca D

    2013-04-01

    Apolipoprotein A-I (ApoA-I) is the main protein component of the high density lipoproteins and it plays an important role in the reverse cholesterol transport. In particular, it stimulates cholesterol efflux from peripheral cells toward liver and activates the enzyme lecithin-cholesterol acyltransferase (LCAT). Haptoglobin (Hpt), a plasma α2-glycoprotein belonging to the family of acute-phase proteins, binds to ApoA-I inhibiting the stimulation of the enzyme LCAT. Previously, we reported that a synthetic peptide, P2a, binds to and displaces Hpt from ApoA-I restoring the LCAT cholesterol esterification activity in the presence of Hpt. Here, we investigate the molecular determinants underlining the interaction between Hpt and P2a peptide. Analysis of truncated P2a analogs showed that P2a sequence can only be slight reduced in length at the N-terminal to preserve the ability of binding to Hpt. Binding assays showed that charged residues are not involved in Hpt recognition; actually, E146A and D157A substitutions increase the binding affinity to Hpt. Biological characterization of the corresponding P2a peptide analogs, Apo146 and Apo157, showed that the two peptides interfere with Hpt binding to HDL and are more effective than P2a peptide in rescue LCAT activity from Hpt inhibition. This result suggests novel hints to design peptides with anti-atherogenic activity. PMID:23420675

  15. High yield of recombinant human Apolipoprotein A-I expressed in Pichia pastoris by using mixed-mode chromatography.

    PubMed

    Narasimhan Janakiraman, Vignesh; Noubhani, Abdelmajid; Venkataraman, Krishnan; Vijayalakshmi, Mookambeswaran; Santarelli, Xavier

    2016-01-01

    A vast majority of the cardioprotective properties exhibited by High-Density Lipoprotein (HDL) is mediated by its major protein component Apolipoprotein A-I (ApoA1). In order to develop a simplified bioprocess for producing recombinant human Apolipoprotein A-I (rhApoA1) in its near-native form, rhApoA1was expressed without the use of an affinity tag in view of its potential therapeutic applications. Expressed in Pichia pastoris at expression levels of 58.2 mg ApoA1 per litre of culture in a reproducible manner, the target protein was purified by mixed-mode chromatography using Capto™ MMC ligand with a purity and recovery of 84% and 68%, respectively. ApoA1 purification was scaled up to Mixed-mode Expanded Bed Adsorption chromatography to establish an 'on-line' process for the efficient capture of rhApoA1 directly from the P. pastoris expression broth. A polishing step using anion exchange chromatography enabled the recovery of ApoA1 up to 96% purity. Purified ApoA1 was identified and verified by RPLC-ESI-Q-TOF mass spectrometry. This two-step process would reduce processing times and therefore costs in comparison to the twelve-step procedure currently used for recovering rhApoA1 from P. pastoris.

  16. Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation.

    PubMed

    Nguyen, Su Duy; Javanainen, Matti; Rissanen, Sami; Zhao, Hongxia; Huusko, Jenni; Kivelä, Annukka M; Ylä-Herttuala, Seppo; Navab, Mohamad; Fogelman, Alan M; Vattulainen, Ilpo; Kovanen, Petri T; Öörni, Katariina

    2015-06-01

    Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20:1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20:1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modified LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention.

  17. Human apolipoprotein A-I is associated with dengue virus and enhances virus infection through SR-BI.

    PubMed

    Li, Yujia; Kakinami, Cherie; Li, Qi; Yang, Baojun; Li, Hongwei

    2013-01-01

    Diseases caused by dengue virus (DV) infection vary in severity, with symptoms ranging from mild fever to life threatening dengue hemorrhage fever (DHF) and dengue shock syndrome (DSS). Clinical studies have shown that significant decrease in the level of lipoproteins is correlated with severe illness in DHF/DSS patients. Available evidence also indicates that lipoproteins including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are able to facilitate cell entry of HCV or other flaviviruses via corresponding lipoprotein receptors. In this study, we found that pre-incubation of DV with human serum leads to an enhanced DV infectivity in various types of cells. Such enhancement could be due to interactions between serum components and DV particles. Through co-immunoprecipitation we revealed that apolipoprotein A-I (ApoA-I), the major protein component in HDL, is associated with DV particles and is able to promote DV infection. Based on that observation, we further found that siRNA knockdown of the scavenger receptor class B type I (SR-BI), the cell receptor of ApoA-I, abolished the activity of ApoA-I in enhancement of DV infection. This suggests that ApoA-I bridges DV particles and cell receptor SR-BI and facilitates entry of DV into cells. FACS analysis of cell surface dengue antigen after virus absorption further confirmed that ApoA-I enhances DV infection via promoting initial attachment of the virus to cells. These findings illustrate a novel entry route of DV into cells, which may provide insights into the functional importance of lipoproteins in dengue pathogenesis. PMID:23894648

  18. Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition.

    PubMed

    Karavia, Eleni A; Hatziri, Aikaterini; Kalogeropoulou, Christina; Papachristou, Nikolaos I; Xepapadaki, Eva; Constantinou, Caterina; Natsos, Anastasios; Petropoulou, Peristera-Ioanna; Sasson, Shlomo; Papachristou, Dionysios J; Kypreos, Kyriakos E

    2015-11-01

    Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1(-/-)) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1(-/-) mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [(3)H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1(-/-) mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.

  19. Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I.

    PubMed

    Shao, Baohai; Fu, Xiaoyun; McDonald, Thomas O; Green, Pattie S; Uchida, Koji; O'Brien, Kevin D; Oram, John F; Heinecke, Jay W

    2005-10-28

    Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, but the factors that control its reactions with nucleophilic groups on proteins remain poorly understood. Lipid peroxidation and threonine oxidation by myeloperoxidase are potential sources of acrolein during inflammation. Because both pathways are implicated in atherogenesis and high density lipoprotein (HDL) is anti-atherogenic, we investigated the possibility that acrolein might target the major protein of HDL, apolipoprotein A-I (apoA-I), for modification. Tandem mass spectrometric analysis demonstrated that lysine 226, located near the center of helix 10 in apoA-I, was the major site modified by acrolein. Importantly, this region plays a critical role in the cellular interactions and ability of apoA-I to transport lipid. Indeed, we found that conversion of Lys-226 to N(epsilon)-(3-methylpyridinium)lysine by acrolein associated quantitatively with decreased cholesterol efflux from cells via the ATP-binding cassette transporter A1 pathway. In the crystal structure of truncated apoA-I, Glu-234 lies adjacent to Lys-226, suggesting that negatively charged residues might direct the modification of specific lysine residues in proteins. Finally, immunohistochemical studies with a monoclonal antibody revealed co-localization of apoA-I with acrolein adducts in human atherosclerotic lesions. Our observations suggest that acrolein might interfere with normal reverse cholesterol transport by HDL by modifying specific sites in apoA-I. Thus, acrolein might contribute to atherogenesis by impairing cholesterol removal from the artery wall. PMID:16126721

  20. A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities.

    PubMed Central

    Funke, H; von Eckardstein, A; Pritchard, P H; Karas, M; Albers, J J; Assmann, G

    1991-01-01

    Epidemiologic data of recent years have identified an important role of HDL deficiency in the etiology of atherosclerosis. Biochemical data suggest that some of these deficiencies may be a consequence of defects in the structural genes of HDL apolipoproteins or of plasma enzymes that modify HDL. We analyzed the genetic defect in a 42-yr-old patient suffering from corneal opacities and complete absence of HDL cholesterol but not of coronary artery disease, thus clinically resembling fish eye disease. The observation of an abnormal immunoblot banding pattern of apolipoprotein A-I (apo A-I) and of reduced lecithin: cholesterol acyltransferase (LCAT) activity in plasma led to sequence analysis of the genes for apo A-I and LCAT in this patient and his family. Direct sequencing of polymerase chain reaction amplified DNA segments containing the exons of the candidate genes, resulted in the identification of a frameshift mutation in apo A-I while the LCAT sequence was identical to the wild type. The apo A-I mutation was predictive for an extensive alteration of the COOH-terminal sequence of the encoded protein. Evidence for the release of this mutant protein into the plasma compartment and for the absence of normal apo A-I was derived from ultraviolet laser desorption/ionization mass spectrometry analysis. Our results suggest that a defective apo A-I is the causative defect in this case of HDL deficiency with corneal opacities. Images PMID:1898657

  1. Composition, structure and substrate properties of reconstituted discoidal HDL with apolipoprotein A-I and cholesteryl ester

    NASA Astrophysics Data System (ADS)

    Dergunov, Alexander D.; Shabrova, Elena V.; Dobretsov, Gennady E.

    2010-03-01

    To investigate the influence of lipid unsaturation and neutral lipid on the maturation of high density lipoproteins, the discoidal complexes of apoA-I, phosphatidylcholine and cholesteryl ester (CE) were prepared. Saturated dipalmitoylphosphatidylcholine (DPPC) and unsaturated palmitoyllinoleoylphosphatidylcholine (PLPC), palmitoyloleoylphosphatidylcholine (POPC), and fluorescent probe cholesteryl 1-pyrenedecanoate (CPD) that forms in a diffusion- and concentration-dependent manner short-lived dimer of unexcited and excited molecules (excimer) were used. The apoA-I/DPPC/CPD complexes were heterogeneous by size, composition and probe location. CPD molecules incorporated more efficiently into larger complexes and accumulated in a central part of the discs. The apoA-I/POPC(PLPC)/CPD were also heterogeneous, however, probe molecules distributed preferentially into smaller complexes and accumulated at disc periphery. The kinetics of CPD transfer by recombinant cholesteryl ester transfer protein (CETP) to human plasma LDL is well described by two-exponential decay, the fast component with a shorter transfer time being more populated in PLPC compared to DPPC complexes. The presence of CE molecules in discoidal HDL results in particle heterogeneity. ApoA-I influences the CETP activity modulating the properties of apolipoprotein-phospholipid interface. This may include CE molecules accumulation in the boundary lipid in unsaturated phosphatidylcholine and cluster formation in the bulk bilayer in saturated phosphatidylcholine.

  2. Effect of an isoenergetic traditional Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The impact of the Mediterranean diet (MedDiet) on high-density lipoprotein (HDL) kinetics has not been studied to date. The objective of this study was therefore to investigate the effect of the MedDiet in the absence of changes in body weight on apolipoprotein (apo) A-I kinetic in men with metaboli...

  3. Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal.

    PubMed

    Domingo-Espín, Joan; Lindahl, Maria; Nilsson-Wolanin, Oktawia; Cushman, Samuel W; Stenkula, Karin G; Lagerstedt, Jens O

    2016-07-01

    Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I-stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes. PMID:27207515

  4. Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal.

    PubMed

    Domingo-Espín, Joan; Lindahl, Maria; Nilsson-Wolanin, Oktawia; Cushman, Samuel W; Stenkula, Karin G; Lagerstedt, Jens O

    2016-07-01

    Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I-stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

  5. Apolipoprotein A-I, an antimicrobial protein in Oncorhynchus mykiss: evaluation of its expression in primary defence barriers and plasma levels in sick and healthy fish.

    PubMed

    Villarroel, Franz; Bastías, Adriana; Casado, Alin; Amthauer, Rodolfo; Concha, Margarita I

    2007-07-01

    Antimicrobial proteins and peptides play an important role in the primary defence barriers in vertebrates and invertebrates. In a previous study it was shown that high-density lipoprotein (HDL) and its major apolipoproteins, ApoA-I and ApoA-II display antimicrobial activity in the carp (Cyprinus carpio L.). The aim of this study was to evaluate if ApoA-I conserves this defensive function in a salmonid fish like the rainbow trout, in spite of the low level of primary sequence conservation between fish ApoA-I. Here it is shown that trout ApoA-I displays an antimicrobial activity in the micromolar range against Gram positive and Gram negative bacteria, including some fish pathogens. In addition, its expression was also demonstrated by immunohistochemistry and RT-PCR in epidermis, gills and intestinal mucosa, which constitute the main primary defence barriers in fish. Finally, no significant difference in the hepatic expression and plasma levels of this abundant apolipoprotein was found in groups of healthy and diseased fish, in clear contrast with mammals where ApoA-I have been considered a negative acute phase reactant. These findings suggest that ApoA-I could constitute an important innate immunity effector in trout and perhaps other teleost fish. PMID:17391986

  6. Endotoxin contamination of apolipoprotein A-I: effect on macrophage proliferation--a cautionary tale.

    PubMed

    Jin, Xueting; Xu, Qing; Champion, Keith; Kruth, Howard S

    2015-05-01

    This technical report addresses the problem of endotoxin contamination of apolipoprotein reagents. Using a bromodeoxyuridine incorporation cell proliferation assay, we observed that human plasma ApoA-I as low as 1 μg/ml resulted in a >90% inhibition in macrophage proliferation. However, not all ApoA-I from different sources showed this effect. We considered the possibility that endotoxin contamination of the apolipoproteins contributed to the differential inhibition of macrophage cell proliferation. Endotoxin alone very potently inhibited macrophage proliferation (0.1 ng/ml inhibited macrophage proliferation>90%). Measurement of endotoxin levels in the apolipoprotein products, including an analysis of free versus total endotoxin, the latter which included endotoxin that was masked due to binding to protein, suggested that free endotoxin mediated inhibition of macrophage proliferation. Despite the use of an advanced endotoxin removal procedure and agents commonly used to inhibit endotoxin action, the potency of endotoxin precluded successful elimination of endotoxin effect. Our findings show that endotoxin contamination can significantly influence apparent apolipoprotein-mediated cell effects (or effects of any other biological products), especially when these products are tested on highly endotoxin-sensitive cells, such as macrophages.

  7. Sequence-specific apolipoprotein A-I effects on lecithin:cholesterol acyltransferase activity.

    PubMed

    Dergunov, Alexander D

    2013-06-01

    Existing kinetic data of cholesteryl ester formation by lecithin:cholesterol acyltransferase in discoidal high-density lipoproteins with 34 mutations of apoA-I that involved all putative helices were grouped by cluster analysis into four noncoincident regions with mutations both without any functional impairment and with profound isolated (V- and K-mutations) or common (VK-mutations) effect on V(max)(app) and K(m)(app). Data were analyzed with a new kinetic model of LCAT activity at interface that exploits the efficiency of LCAT binding to the particle, particle dimensions, and surface concentrations of phosphatidylcholine and cholesterol. V-mutations with major location in the central part and C-domain affected the second-order rate constant of cholesteryl ester formation at the solvolysis of acyl-enzyme intermediate by cholesterol as nucleophile. The central region in apoA-I sequence is suggested to influence the proper positioning of cholesterol molecule toward LCAT active center with major contribution of arginine residue(s). K-mutations with major location in N-domain may affect binding and stability of enzyme-phosphatidylcholine complex. VK-mutations may possess mixed effects; the independent binding measurement may segregate individual steps. PMID:23516040

  8. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve.

    PubMed Central

    Boyles, J K; Zoellner, C D; Anderson, L J; Kosik, L M; Pitas, R E; Weisgraber, K H; Hui, D Y; Mahley, R W; Gebicke-Haerter, P J; Ignatius, M J

    1989-01-01

    Recent work has demonstrated that apo E secretion and accumulation increase in the regenerating peripheral nerve. The fact that apoE, in conjunction with apoA-I and LDL receptors, participates in a well-established lipid transfer system raised the possibility that apoE is also involved in lipid transport in the injured nerve. In the present study of the crushed rat sciatic nerve, a combination of techniques was used to trace the cellular associations of apoE, apoA-I, and the LDL receptor during nerve repair and to determine the distribution of lipid at each stage. After a crush injury, as axons died and Schwann cells reabsorbed myelin, resident and monocyte-derived macrophages produced large quantities of apoE distal to the injury site. As axons regenerated in the first week, their tips contained a high concentration of LDL receptors. After axon regeneration, apoE and apoA-I began to accumulate distal to the injury site and macrophages became increasingly cholesterol-loaded. As remyelination began in the second and third weeks after injury, Schwann cells exhausted their cholesterol stores, then displayed increased LDL receptors. Depletion of macrophage cholesterol stores followed over the next several weeks. During this stage of regeneration, apoE and apoA-I were present in the extracellular matrix as components of cholesterol-rich lipoproteins. Our results demonstrate that the regenerating peripheral nerve possesses the components of a cholesterol transfer mechanism, and the sequence of events suggests that this mechanism supplies the cholesterol required for rapid membrane biogenesis during axon regeneration and remyelination. Images PMID:2493483

  9. Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice*

    PubMed Central

    Lefterov, Iliya; Fitz, Nicholas F.; Cronican, Andrea A.; Fogg, Allison; Lefterov, Preslav; Kodali, Ravindra; Wetzel, Ronald; Koldamova, Radosveta

    2010-01-01

    A hallmark of Alzheimer disease (AD) is the deposition of amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ40 aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of Aβ42 and decreases Aβ42 toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1ΔE9 to apoA-IKO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1ΔE9 mice. Further characterization of APP/PS1ΔE9/apoA-IKO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Aβ oligomer levels, Aβ plaque load, or levels of insoluble Aβ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Aβ isolated from cerebral blood vessels. Our data show that in APP/PS1ΔE9/apoA-IKO mice, insoluble Aβ40 is increased more than 10-fold, and Aβ42 is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1ΔE9/apoA-IKO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Aβ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1ΔE9 mice in parallel to significantly increased cerebral amyloid angiopathy. PMID:20739292

  10. Anti-CD20 single chain variable antibody fragment-apolipoprotein A-I chimera containing nanodisks promote targeted bioactive agent delivery to CD20-positive lymphomas.

    PubMed

    Crosby, Natasha M; Ghosh, Mistuni; Su, Betty; Beckstead, Jennifer A; Kamei, Ayako; Simonsen, Jens B; Luo, Bing; Gordon, Leo I; Forte, Trudy M; Ryan, Robert O

    2015-08-01

    A fusion protein comprising an α-CD20 single chain variable fragment (scFv) antibody, a spacer peptide, and human apolipoprotein (apo) A-I was constructed and expressed in Escherichia coli. The lipid interaction properties intrinsic to apoA-I as well as the antigen recognition properties of the scFv were retained by the chimera. scFv•apoA-I was formulated into nanoscale reconstituted high-density lipoprotein particles (termed nanodisks; ND) and incubated with cultured cells. α-CD20 scFv•apoA-I ND bound to CD20-positive non-Hodgkins lymphoma (NHL) cells (Ramos and Granta) but not to CD20-negative T lymphocytes (i.e., Jurkat). Binding to NHL cells was partially inhibited by pre-incubation with rituximab, a monoclonal antibody directed against CD20. Confocal fluorescence microscopy analysis of Granta cells following incubation with α-CD20 scFv•apoA-I ND formulated with the intrinsically fluorescent hydrophobic polyphenol, curcumin, revealed α-CD20 scFv•apoA-I localizes to the cell surface, while curcumin off-loads and gains entry to the cell. Compared to control incubations, viability of cultured NHL cells was decreased upon incubation with α-CD20 scFv•apoA-I ND harboring curcumin. Thus, formulation of curcumin ND with α-CD20 scFv•apoA-I as the scaffold component confers cell targeting and enhanced bioactive agent delivery, providing a strategy to minimize toxicity associated with chemotherapeutic agents.

  11. Anti-CD20 single chain variable antibody fragment-apolipoprotein A-I chimera containing nanodisks promote targeted bioactive agent delivery to CD20-positive lymphomas.

    PubMed

    Crosby, Natasha M; Ghosh, Mistuni; Su, Betty; Beckstead, Jennifer A; Kamei, Ayako; Simonsen, Jens B; Luo, Bing; Gordon, Leo I; Forte, Trudy M; Ryan, Robert O

    2015-08-01

    A fusion protein comprising an α-CD20 single chain variable fragment (scFv) antibody, a spacer peptide, and human apolipoprotein (apo) A-I was constructed and expressed in Escherichia coli. The lipid interaction properties intrinsic to apoA-I as well as the antigen recognition properties of the scFv were retained by the chimera. scFv•apoA-I was formulated into nanoscale reconstituted high-density lipoprotein particles (termed nanodisks; ND) and incubated with cultured cells. α-CD20 scFv•apoA-I ND bound to CD20-positive non-Hodgkins lymphoma (NHL) cells (Ramos and Granta) but not to CD20-negative T lymphocytes (i.e., Jurkat). Binding to NHL cells was partially inhibited by pre-incubation with rituximab, a monoclonal antibody directed against CD20. Confocal fluorescence microscopy analysis of Granta cells following incubation with α-CD20 scFv•apoA-I ND formulated with the intrinsically fluorescent hydrophobic polyphenol, curcumin, revealed α-CD20 scFv•apoA-I localizes to the cell surface, while curcumin off-loads and gains entry to the cell. Compared to control incubations, viability of cultured NHL cells was decreased upon incubation with α-CD20 scFv•apoA-I ND harboring curcumin. Thus, formulation of curcumin ND with α-CD20 scFv•apoA-I as the scaffold component confers cell targeting and enhanced bioactive agent delivery, providing a strategy to minimize toxicity associated with chemotherapeutic agents. PMID:25994015

  12. Anti-CD20 single chain variable antibody fragment–apolipoprotein A-I chimera containing nanodisks promote targeted bioactive agent delivery to CD20-positive lymphomas

    PubMed Central

    Crosby, Natasha M.; Ghosh, Mistuni; Su, Betty; Beckstead, Jennifer A.; Kamei, Ayako; Simonsen, Jens B.; Luo, Bing; Gordon, Leo I.; Forte, Trudy M.; Ryan, Robert O.

    2015-01-01

    A fusion protein comprising an α-CD20 single chain variable fragment (scFv) antibody, a spacer peptide, and human apolipoprotein (apo) A-I was constructed and expressed in Escherichia coli. The lipid interaction properties intrinsic to apoA-I as well as the antigen recognition properties of the scFv were retained by the chimera. scFv•apoA-I was formulated into nanoscale reconstituted high-density lipoprotein particles (termed nanodisks; ND) and incubated with cultured cells. α-CD20 scFv•apoA-I ND bound to CD20-positive non-Hodgkins lymphoma (NHL) cells (Ramos and Granta) but not to CD20-negative T lymphocytes (i.e., Jurkat). Binding to NHL cells was partially inhibited by pre-incubation with rituximab, a monoclonal antibody directed against CD20. Confocal fluorescence microscopy analysis of Granta cells following incubation with α-CD20 scFv•apoA-I ND formulated with the intrinsically fluorescent hydrophobic polyphenol, curcumin, revealed α-CD20 scFv•apoA-I localizes to the cell surface, while curcumin off-loads and gains entry to the cell. Compared to control incubations, viability of cultured NHL cells was decreased upon incubation with α-CD20 scFv•apoA-I ND harboring curcumin. Thus, formulation of curcumin ND with α-CD20 scFv•apoA-I as the scaffold component confers cell targeting and enhanced bioactive agent delivery, providing a strategy to minimize toxicity associated with chemotherapeutic agents. PMID:25994015

  13. 22 CFR 221.24 - Subrogation of A.I.D.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Subrogation of A.I.D. 221.24 Section 221.24 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ISRAEL LOAN GUARANTEE STANDARD TERMS AND CONDITIONS Procedure for Obtaining Compensation § 221.24 Subrogation of A.I.D. In the event of payment by A.I.D. to...

  14. 22 CFR 224.39 - Appeal to A.I.D. Administrator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Appeal to A.I.D. Administrator. 224.39 Section... CIVIL REMEDIES ACT § 224.39 Appeal to A.I.D. Administrator. (a) Any defendant who has filed a timely... appeal such decision to the A.I.D. Administrator by filing a notice of appeal with the...

  15. 22 CFR 214.22 - Responsibilities within A.I.D.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Responsibilities within A.I.D. 214.22 Section... Termination and Renewal of Advisory Committees § 214.22 Responsibilities within A.I.D. Responsibilities within A.I.D. for the renewal of advisory committees are as follows: (a) The Office or Bureau through...

  16. A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype.

    PubMed

    Tougaard, Birgitte G; Pedersen, Katja Venborg; Krag, Søren Rasmus; Gilbertson, Janet A; Rowczenio, Dorota; Gillmore, Julian D; Birn, Henrik

    2016-09-01

    Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations. PMID:27240838

  17. A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype.

    PubMed

    Tougaard, Birgitte G; Pedersen, Katja Venborg; Krag, Søren Rasmus; Gilbertson, Janet A; Rowczenio, Dorota; Gillmore, Julian D; Birn, Henrik

    2016-09-01

    Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.

  18. Expression of apolipoprotein A-I and A-II in rainbow trout reproductive tract and their possible role in antibacterial defence.

    PubMed

    Dietrich, Mariola A; Nynca, Joanna; Adamek, Mikołaj; Steinhagen, Dieter; Karol, Halina; Ciereszko, Andrzej

    2015-08-01

    Antimicrobial proteins such as apolipoproteins A (ApoA-I and ApoA-II) play an important role in the primary defence barrier in vertebrates including fish. The aims of the present study were to isolate and characterise rainbow trout seminal plasma ApoA-I and ApoA-II, to examine the mRNA expression of each apolipoprotein in testis and spermatic ducts, and to test the antibacterial properties of the apolipoproteins. Using a three-step isolation procedure consisting of ion-exchange chromatography, gel filtration and preparative SDS-PAGE, apolipoproteins were purified and identified as ApoA-I and ApoA-II. Both apolipoproteins were represented by several proteoforms. The expression of ApoA-I and ApoA-II mRNA in the reproductive tract and their antibacterial properties against Escherichia coli suggest that seminal apolipoproteins play an important role in innate immunity in the rainbow trout reproductive tract. The functions of seminal ApoA can be related to protection of sperm and reproductive tissue from microbial attack and to the maintenance of sperm membrane integrity.

  19. Comparison of deuterated leucine, valine, and lysine in the measurement of human apolipoprotein A-I and B-100 kinetics

    SciTech Connect

    Lichtenstein, A.H.; Cohn, J.S.; Hachey, D.L.; Millar, J.S.; Ordovas, J.M.; Schaefer, E.J. )

    1990-09-01

    The production rates of apolipoprotein (apo)B-100 in very low density lipoprotein and in low density lipoprotein and apolipoprotein A-I in high density lipoprotein were determined using a primed-constant infusion of (5,5,5,-2H3)leucine, (4,4,4,-2H3)valine, and (6,6-2H2,1,2-13C2)lysine. The three stable isotope-labeled amino acids were administered simultaneously to determine whether absolute production rates calculated using a stochastic model were independent of the tracer species utilized. Three normolipidemic adult males were studied in the constantly fed state over a 15-h period. The absolute production rates of very low density lipoprotein apoB-100 were 11.4 +/- 5.8 (leucine), 11.2 +/- 6.8 (valine), and 11.1 +/- 5.4 (lysine) mg per kg per day (mean +/- SDM). The absolute production rates for low density lipoprotein apoB-100 were 8.0 +/- 4.7 (leucine), 7.5 +/- 3.8 (valine), and 7.5 +/- 4.2 (lysine) mg per kg per day. The absolute production rates for high density lipoprotein apoA-I were 9.7 +/- 0.2 (leucine), 9.4 +/- 1.7 (valine), and 9.1 +/- 1.3 (lysine) mg per kg per day. There were no statistically significant differences in absolute synthetic rates of the three apolipoproteins when the plateau isotopic enrichment values of very low density lipoprotein apoB-100 were used to define the isotopic enrichment of the intracellular precursor pool. Our data indicate that deuterated leucine, valine, or lysine provided similar results when used for the determination of apoA-I and apoB-100 absolute production rates within plasma lipoproteins as part of a primed-constant infusion protocol.

  20. Fructated apolipoprotein A-I exacerbates cellular senescence in human umbilical vein endothelial cells accompanied by impaired insulin secretion activity and embryo toxicity.

    PubMed

    Park, Ki-Hoon; Kim, Jae-Yong; Choi, Inho; Kim, Jae-Ryong; Won, Kyu Chang; Cho, Kyung-Hyun

    2016-08-01

    Glycation of apolipoproteins is a major feature of the production of dysfunctional high-density lipoprotein (HDL), which is associated with the incidence of several metabolic diseases such as coronary artery disease and diabetes. In this report, fructated apoA-I (fA-I) induced by fructose treatment showed a covalently multimerized band without cross-linking, and lysine residues were irreversibly modified to prevent crosslinking. Using pancreatic β-cells, insulin secretion was impaired by fA-I in the lipid-free and reconstituted HDL (rHDL) states, by up to 35%, and 40%, respectively, under hyperglycemic conditions (25 mmol/L glucose). Treatment of human umbilical vein endothelial cells (HUVECs) with fA-I and HDL from elderly patients caused a 1.8-fold and 1.5-fold increased cellular senescence, respectively, along with increased lysosomal enlargement. In the lipid-free and rHDL states, fA-I increased embryo death by 1.5-fold and 2.5-fold, respectively, along with the production of oxidized species. Furthermore, rHDL containing fA-I (fA-I-rHDL) showed a higher isoelectric point (pI, approximately 8.5), whereas rHDL containing nA-I (nA-I-rHDL) showed a narrow band range with lower pI (around 8.0) as well as a much smaller particle size than that of nA-I-rHDL. In conclusion, fructose-mediated apoA-I fructation resulted in the severe loss of several beneficial functions of apoA-I and HDL, including anti-senescence and insulin secretion activities, accompanied with increased susceptibility to protein degradation and structural modification.

  1. Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F.

    PubMed

    Datta, Geeta; Kramer, Philip A; Johnson, Michelle S; Sawada, Hirotaka; Smythies, Lesley E; Crossman, David K; Chacko, Balu; Ballinger, Scott W; Westbrook, David G; Mayakonda, Palgunachari; Anantharamaiah, G M; Darley-Usmar, Victor M; White, C Roger

    2015-05-01

    The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPARγ (peroxisome-proliferator-activated receptor γ) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen-consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in ΔΨm (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPARγ antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism.

  2. Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.

    PubMed

    Gregorini, Gina; Izzi, Claudia; Ravani, Pietro; Obici, Laura; Dallera, Nadia; Del Barba, Andrea; Negrinelli, Alessandro; Tardanico, Regina; Nardi, Matilde; Biasi, Luciano; Scalvini, Tiziano; Merlini, Giampaolo; Scolari, Francesco

    2015-06-01

    Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.

  3. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.

    PubMed

    Rubin, E M; Ishida, B Y; Clift, S M; Krauss, R M

    1991-01-15

    In Western societies high density lipoprotein (HDL) levels correlate inversely with the risk for coronary heart disease. The primary protein component of both human and mouse HDL is apolipoprotein A-I (apoAI), which comprises greater than 70% of HDL protein and 30% of HDL mass. Human HDLs include particles of several distinct size subpopulations, whereas HDLs from inbred C57BL/6 mice contain a single population of particles. To study the regulation of apoAI expression and its role in HDL assembly, we created transgenic C57BL/6 mice containing the human apoAI gene. Two independent lines of transgenic mice with approximately twice the normal plasma levels of total apoAI were studied. The level of mouse apoAI is reduced greater than 4-fold in both transgenic lines, comprising only 4% of total plasma apoAI levels in one transgenic line and 13% in the other. We demonstrate that the mechanism responsible for the decrease in mouse apoAI is posttranscriptional. Parallel to the replacement of mouse with human apoAI, the single HDL species normally present in the plasma of C57BL/6 is replaced by two HDL subclasses similar in size to human HDL2b and HDL3a. The changes in murine apolipoprotein levels and HDL subclass size are inherited by all transgenic offspring of the two founder animals. These results suggest a dominant role of apoAI in determining the HDL particle size distribution and a mechanism involving expression of human apoAI transgenes that alters the plasma levels of mouse apoAI.

  4. 22 CFR 204.22 - Right of A.I.D. to cure default.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Right of A.I.D. to cure default. 204.22 Section... CONDITIONS Procedure for Obtaining Compensation § 204.22 Right of A.I.D. to cure default. Within sixty (60) days after the Date of Application for Compensation, A.I.D. may at any time make payments to the...

  5. Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters

    SciTech Connect

    Chajekshaul, T.; Hayek, T.; Walsh, A.; Breslow, J.L. )

    1991-08-01

    Transgenic mice carrying the human apolipoprotein (apo) A-I gene (HuAITg mice) were used to examine the effects of overexpression of the human gene on high density lipoprotein (HDL) particle size distribution and metabolism. On a chow diet, control mice had HDL cholesterol and apo A-I levels of 49 {plus minus} 2 and 137 {plus minus} 12 mg/dl of plasma, respectively. HuAITg mice had HDL cholesterol, human apo A-I, and mouse apo A-I levels of 88 {plus minus} 2, 255 {plus minus} 19, and 16 {plus minus} 2 mg/dl, respectively. Nondenaturing gradient gel electrophoresis revealed control mouse plasma HDL to be primarily monodisperse with a particle diameter of 10.2 nm, whereas HuAITg mouse plasma HDL was polydisperse with particles of diameter 11.4, 10.2, and 8.7 nm, which correspond in size to human HDL1, HDL2, and HDL3, respectively. In vivo turnover studies of HDL labeled with (3H)cholesteryl linoleyl ether and 125I-apo A-I were performed. In control animals, the fractional catabolic rate (FCR) for HDL cholesteryl ester was significantly more than the apo A-I FCR. In the HuAITg mice, the HDL cholesteryl ester FCR was the same as the apo A-I FCR. There were no significant differences between control and HuAITg animals in the sites of tissue removal of HDL cholesteryl ester, with the liver extracting most of the injected radioactivity. Control and HuAITg animals had comparable liver and intestinal cholesterol synthesis and LDL FCR. In conclusion, HuAITg mice have principally human and not mouse apo A-I in their plasma. This apparently causes a change in HDL particle size distribution in the transgenic mice to one resembling the human pattern. The replacement of mouse by human apo A-I also apparently causes the loss of the selective uptake pathway of HDL cholesteryl esters present in control mice.

  6. An experimentally robust model of monomeric apolipoprotein A-I created from a chimera of two X-ray structures and molecular dynamics simulations.

    PubMed

    Segrest, Jere P; Jones, Martin K; Shao, Baohai; Heinecke, Jay W

    2014-12-01

    High-density lipoprotein (HDL) retards atherosclerosis by accepting cholesterol from the artery wall. However, the structure of the proposed acceptor, monomeric apolipoprotein A-I (apoA-I), the major protein of HDL, is poorly understood. Two published models for monomeric apoA-I used cross-linking distance constraints to derive best fit conformations. This approach has limitations. (i) Cross-linked peptides provide no information about secondary structure. (ii) A protein chain can be folded in multiple ways to create a best fit. (iii) Ad hoc folding of a secondary structure is unlikely to produce a stable orientation of hydrophobic and hydrophilic residues. To address these limitations, we used a different approach. We first noted that the dimeric apoA-I crystal structure, (Δ185-243)apoA-I, is topologically identical to a monomer in which helix 5 forms a helical hairpin, a monomer with a hydrophobic cleft running the length of the molecule. We then realized that a second crystal structure, (Δ1-43)apoA-I, contains a C-terminal structure that fits snuggly via aromatic and hydrophobic interactions into the hydrophobic cleft. Consequently, we combined these crystal structures into an initial model that was subjected to molecular dynamics simulations. We tested the initial and simulated models and the two previously published models in three ways: against two published data sets (domains predicted to be helical by H/D exchange and six spin-coupled residues) and against our own experimentally determined cross-linking distance constraints. We note that the best fit simulation model, superior by all tests to previously published models, has dynamic features of a molten globule with interesting implications for the functions of apoA-I. PMID:25423138

  7. Apolipoprotein A-I Attenuates Palmitate-Mediated NF-κB Activation by Reducing Toll-Like Receptor-4 Recruitment into Lipid Rafts

    PubMed Central

    Tateya, Sanshiro; Schwartz, Jay; Tang, Chongren; Mitra, Poulami; Oram, John F.; Chait, Alan; Kim, Francis

    2012-01-01

    While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A–I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation. PMID:22479476

  8. Identification of Apolipoprotein A-I as a Retinoic Acid-binding Protein in the Eye.

    PubMed

    Summers, Jody A; Harper, Angelica R; Feasley, Christa L; Van-Der-Wel, Hanke; Byrum, Jennifer N; Hermann, Marcela; West, Christopher M

    2016-09-01

    All-trans-retinoic acid may be an important molecular signal in the postnatal control of eye size. The goal of this study was to identify retinoic acid-binding proteins secreted by the choroid and sclera during visually guided ocular growth. Following photoaffinity labeling with all-trans-[11,12-(3)H]retinoic acid, the most abundant labeled protein detected in the conditioned medium of choroid or sclera had an apparent Mr of 27,000 Da. Following purification and mass spectrometry, the Mr 27,000 band was identified as apolipoprotein A-I. Affinity capture of the radioactive Mr 27,000 band by anti-chick apolipoprotein A-I antibodies confirmed its identity as apolipoprotein A-I. Photoaffinity labeling and fluorescence quenching experiments demonstrated that binding of retinoic acid to apolipoprotein A-I is 1) concentration-dependent, 2) selective for all-trans-retinoic acid, and 3) requires the presence of apolipoprotein A-I-associated lipids for retinoid binding. Expression of apolipoprotein A-I mRNA and protein synthesis were markedly up-regulated in choroids of chick eyes during the recovery from induced myopia, and apolipoprotein A-I mRNA was significantly increased in choroids following retinoic acid treatment. Together, these data suggest that apolipoprotein A-I may participate in a regulatory feedback mechanism with retinoic acid to control the action of retinoic acid on ocular targets during postnatal ocular growth.

  9. 22 CFR 214.3 - A.I.D. Advisory Committee Management Officer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false A.I.D. Advisory Committee Management Officer. 214.3 Section 214.3 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ADVISORY COMMITTEE MANAGEMENT General § 214.3 A.I.D. Advisory Committee Management Officer. The Advisory Committee...

  10. Identification of Apolipoprotein A-I as a Retinoic Acid-binding Protein in the Eye.

    PubMed

    Summers, Jody A; Harper, Angelica R; Feasley, Christa L; Van-Der-Wel, Hanke; Byrum, Jennifer N; Hermann, Marcela; West, Christopher M

    2016-09-01

    All-trans-retinoic acid may be an important molecular signal in the postnatal control of eye size. The goal of this study was to identify retinoic acid-binding proteins secreted by the choroid and sclera during visually guided ocular growth. Following photoaffinity labeling with all-trans-[11,12-(3)H]retinoic acid, the most abundant labeled protein detected in the conditioned medium of choroid or sclera had an apparent Mr of 27,000 Da. Following purification and mass spectrometry, the Mr 27,000 band was identified as apolipoprotein A-I. Affinity capture of the radioactive Mr 27,000 band by anti-chick apolipoprotein A-I antibodies confirmed its identity as apolipoprotein A-I. Photoaffinity labeling and fluorescence quenching experiments demonstrated that binding of retinoic acid to apolipoprotein A-I is 1) concentration-dependent, 2) selective for all-trans-retinoic acid, and 3) requires the presence of apolipoprotein A-I-associated lipids for retinoid binding. Expression of apolipoprotein A-I mRNA and protein synthesis were markedly up-regulated in choroids of chick eyes during the recovery from induced myopia, and apolipoprotein A-I mRNA was significantly increased in choroids following retinoic acid treatment. Together, these data suggest that apolipoprotein A-I may participate in a regulatory feedback mechanism with retinoic acid to control the action of retinoic acid on ocular targets during postnatal ocular growth. PMID:27402828

  11. 22 CFR 214.13 - Responsibilities within A.I.D.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 214.13 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ADVISORY COMMITTEE MANAGEMENT... committee to the satisfaction of the A.I.D. Advisory Committee Management Officer, the A.I.D. Administrator, and the OMB Secretariat. (2) Prepares, clears with the Advisory Committee Management Officer and...

  12. 22 CFR 214.13 - Responsibilities within A.I.D.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 214.13 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ADVISORY COMMITTEE MANAGEMENT... committee to the satisfaction of the A.I.D. Advisory Committee Management Officer, the A.I.D. Administrator, and the OMB Secretariat. (2) Prepares, clears with the Advisory Committee Management Officer and...

  13. 22 CFR 214.13 - Responsibilities within A.I.D.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 214.13 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ADVISORY COMMITTEE MANAGEMENT... committee to the satisfaction of the A.I.D. Advisory Committee Management Officer, the A.I.D. Administrator, and the OMB Secretariat. (2) Prepares, clears with the Advisory Committee Management Officer and...

  14. 22 CFR 204.33 - A.I.D. approval of acceleration of notes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false A.I.D. approval of acceleration of notes. 204.33 Section 204.33 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Covenants § 204.33 A.I.D. approval of acceleration of notes. Without the...

  15. 22 CFR 204.33 - A.I.D. approval of acceleration of notes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false A.I.D. approval of acceleration of notes. 204.33 Section 204.33 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Covenants § 204.33 A.I.D. approval of acceleration of notes. Without the...

  16. 22 CFR 204.33 - A.I.D. approval of acceleration of notes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false A.I.D. approval of acceleration of notes. 204.33 Section 204.33 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Covenants § 204.33 A.I.D. approval of acceleration of notes. Without the...

  17. 22 CFR 204.33 - A.I.D. approval of acceleration of notes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false A.I.D. approval of acceleration of notes. 204.33 Section 204.33 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Covenants § 204.33 A.I.D. approval of acceleration of notes. Without the...

  18. 22 CFR 204.33 - A.I.D. approval of acceleration of notes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false A.I.D. approval of acceleration of notes. 204.33 Section 204.33 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Covenants § 204.33 A.I.D. approval of acceleration of notes. Without the...

  19. Simultaneous Quantification of Apolipoprotein A-I and Apolipoprotein B by Liquid-Chromatography–Multiple-Reaction–Monitoring Mass Spectrometry

    PubMed Central

    Agger, Sean A.; Marney, Luke C.; Hoofnagle, Andrew N.

    2011-01-01

    BACKGROUND If liquid-chromatography–multiple-reaction–monitoring mass spectrometry (LC-MRM/MS) could be used in the large-scale preclinical verification of putative biomarkers, it would obviate the need for the development of expensive immunoassays. In addition, the translation of novel biomarkers to clinical use would be accelerated if the assays used in preclinical studies were the same as those used in the clinical laboratory. To validate this approach, we developed a multiplexed assay for the quantification of 2 clinically well-known biomarkers in human plasma, apolipoprotein A-I and apolipoprotein B (apoA-I and apoB). METHODS We used PeptideAtlas to identify candidate peptides. Human samples were denatured with urea or trifluoroethanol, reduced and alkylated, and digested with trypsin. We compared reversed-phase chromatographic separation of peptides with normal flow and microflow, and we normalized endogenous peptide peak areas to internal standard peptides. We evaluated different methods of calibration and compared the final method with a nephelometric immunoassay. RESULTS We developed a final method using trifluoroethanol denaturation, 21-h digestion, normal flow chromatography-electrospray ionization, and calibration with a single normal human plasma sample. For samples injected in duplicate, the method had intraassay CVs <6% and interassay CVs <12% for both proteins, and compared well with immunoassay (n = 47; Deming regression, LC-MRM/MS = 1.17 × immunoassay – 36.6; Sx|y = 10.3 for apoA-I and LC-MRM/MS = 1.21 × immunoassay + 7.0; Sx|y = 7.9 for apoB). CONCLUSIONS Multiplexed quantification of proteins in human plasma/serum by LC-MRM/MS is possible and compares well with clinically useful immunoassays. The potential application of single-point calibration to large clinical studies could simplify efforts to reduce day-to-day digestion variability. PMID:20923952

  20. Quantification of serum apolipoproteins A-I and B-100 in clinical samples using an automated SISCAPA-MALDI-TOF-MS workflow.

    PubMed

    van den Broek, Irene; Nouta, Jan; Razavi, Morteza; Yip, Richard; Bladergroen, Marco R; Romijn, Fred P H T M; Smit, Nico P M; Drews, Oliver; Paape, Rainer; Suckau, Detlev; Deelder, André M; van der Burgt, Yuri E M; Pearson, Terry W; Anderson, N Leigh; Cobbaert, Christa M

    2015-06-15

    A fully automated workflow was developed and validated for simultaneous quantification of the cardiovascular disease risk markers apolipoproteins A-I (apoA-I) and B-100 (apoB-100) in clinical sera. By coupling of stable-isotope standards and capture by anti-peptide antibodies (SISCAPA) for enrichment of proteotypic peptides from serum digests to matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS detection, the standardized platform enabled rapid, liquid chromatography-free quantification at a relatively high throughput of 96 samples in 12h. The average imprecision in normo- and triglyceridemic serum pools was 3.8% for apoA-I and 4.2% for apoB-100 (4 replicates over 5 days). If stored properly, the MALDI target containing enriched apoA-1 and apoB-100 peptides could be re-analyzed without any effect on bias or imprecision for at least 7 days after initial analysis. Validation of the workflow revealed excellent linearity for daily calibration with external, serum-based calibrators (R(2) of 0.984 for apoA-I and 0.976 for apoB-100 as average over five days), and absence of matrix effects or interference from triglycerides, protein content, hemolysates, or bilirubins. Quantification of apoA-I in 93 normo- and hypertriglyceridemic clinical sera showed good agreement with immunoturbidimetric analysis (slope = 1.01, R(2) = 0.95, mean bias = 4.0%). Measurement of apoB-100 in the same clinical sera using both methods, however, revealed several outliers in SISCAPA-MALDI-TOF-MS measurements, possibly as a result of the lower MALDI-TOF-MS signal intensity (slope = 1.09, R(2) = 0.91, mean bias = 2.0%). The combination of analytical performance, rapid cycle time and automation potential validate the SISCAPA-MALDI-TOF-MS platform as a valuable approach for standardized and high-throughput quantification of apoA-I and apoB-100 in large sample cohorts.

  1. The Effect of Preoperative Apolipoprotein A-I on the Prognosis of Surgical Renal Cell Carcinoma: A Retrospective Large Sample Study.

    PubMed

    Guo, Shengjie; He, Xiaobo; Chen, Qian; Yang, Guangwei; Yao, Kai; Dong, Pei; Ye, Yunlin; Chen, Dong; Zhang, Zhiling; Qin, Zike; Liu, Zhuowei; Li, Zaishang; Xue, Yunfei; Zhang, Meng; Liu, Ruiwu; Zhou, Fangjian; Han, Hui

    2016-03-01

    The prognostic value of serum lipid-profile in renal cell cancer (RCC) remains unknown. The purpose of the study is to explore the association between the serum lipid-profile and RCC patients.The levels of preoperative serum lipid-profile (including cholesterol, triglycerides, high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], apolipoprotein A-I [ApoA-I], and apolipoprotein B [ApoB]) were retrospectively performed in 786 patients with RCC. The cutoff values of the lipids were determined by the receiver-operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic value of serum lipids in RCC.Combined ROC analysis and univariate and multivariate Cox regression analyses, for overall survival (OS), revealed patients with low ApoA-I (<1.04) had significantly lower OS than the high ApoA-I (≥1.04) group (multivariate Cox regression analyses, hazard ratio [HR], 0.57; P = 0.003). Not only in the whole RCC cohort but also in the subgroups stratified according to the pT1-2 (P = 0.002), pN0 (P < 0.001), and pM0 (P = 0.001) status, respectively. Moreover, in the 755 patients with nonmetastasis, the low ApoA-I group was also associated with shortened disease-free survival (DFS) time compared to the high ApoA-I group (multivariate Cox regression analyses, HR, 0.65; P = 0.033). However, the other lipids were not independent prognostic factors for surgical RCC.An elevated level of preoperative ApoA-I was demonstrated to be related with better survival in patients with surgical RCC. Measuring the preoperative ApoA-I might be a simple way for finding the poor prognostic patients who should enrolled in further clinical trials and management.

  2. Serum Apolipoprotein A-I and Large High-Density Lipoprotein Particles Are Positively Correlated with FEV1 in Atopic Asthma

    PubMed Central

    Kaler, Maryann; Cuento, Rosemarie A.; Gordon, Elizabeth M.; Weir, Nargues A.; Sampson, Maureen; Fontana, Joseph R.; MacDonald, Sandra; Moss, Joel; Manganiello, Vincent; Remaley, Alan T.; Levine, Stewart J.

    2015-01-01

    Rationale: Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. Objectives: To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects with atopy and asthma. Methods: Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma. Serum lipid and lipoprotein levels were quantified using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. Measurements and Main Results: Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA-I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. Conclusions: In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma. PMID:25692941

  3. Apolipoproteins A-I and A-II are potentially important effectors of innate immunity in the teleost fish Cyprinus carpio.

    PubMed

    Concha, Margarita I; Smith, Valerie J; Castro, Karina; Bastías, Adriana; Romero, Alex; Amthauer, Rodolfo J

    2004-07-01

    We have previously shown that high density lipoprotein is the most abundant protein in the carp plasma and displays bactericidal activity in vitro. Therefore the aim of this study was to analyze the contribution of its principal apolipoproteins, apoA-I and apoA-II, in defense. Both apolipoproteins were isolated by a two step procedure involving affinity and gel filtration chromatography and were shown to display bactericidal and/or bacteriostatic activity in the micromolar range against Gram-positive and Gram-negative bacteria, including some fish pathogens. In addition, a cationic peptide derived from the C-terminal region of carp apoA-I was synthesized and shown to possess antimicrobial activity (EC(50) = 3-6 micro m) against Planococcus citreus. This peptide was also able to potentiate the inhibitory effect of lysozyme in a radial diffusion assay at subinhibitory concentrations of both effectors. Finally, limited proteolysis of HDL-associated apoA-I with chymotrypsin in vitro was shown to generate a major truncated fragment, which indicates that apoA-I peptides liberated in vivo through a regulated proteolysis could also be involved in innate immunity.

  4. 10. Photographed 19131914 by L. M. Leisenring, F.A.I.A. Presented by ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. Photographed 1913-1914 by L. M. Leisenring, F.A.I.A. Presented by Mr. Leisenring 1959 - Dr. David Ross House, Annapolis Road (moved to Preservation Hill, Western Run Road, Cockeysville), Bladensburg, Prince George's County, MD

  5. 11. Photographed 19131914 by L. M. Leisenring, F.A.I.A. Presented by ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    11. Photographed 1913-1914 by L. M. Leisenring, F.A.I.A. Presented by Mr. Leisenring 1959 - Dr. David Ross House, Annapolis Road (moved to Preservation Hill, Western Run Road, Cockeysville), Bladensburg, Prince George's County, MD

  6. Curcumin induces ABCA1 expression and apolipoprotein A-I-mediated cholesterol transmembrane in the chronic cerebral hypoperfusion aging rats.

    PubMed

    Tian, Mingyuan; Zhang, Xiong; Wang, Linhui; Li, Yu

    2013-01-01

    Cerebral hypoperfusion or aging often results in the disturbances of cholesterol and lipoprotein, which have been well depicted as a common pathological status contributing to neurodegenerative diseases such as vascular dementia (VaD) and Alzheimer's dementia (AD). The pathway of the liver X receptor-β (LXR-β)/retinoic X receptor-α (RXR-α)/ABCA1 plays a vital role in lipoprotein metabolism. Curcumin, a kind of phenolic compound, has been widely used. It has been reported that curcumin can reduce the levels of cholesterol in serum, but the underlying mechanisms are poorly understood. In this study, we evaluated the effects of curcumin on the cholesterol level in brain, vascular cognitive impairment and explored whether the mechanisms for those effects are through activating LXR-β/RXR-α and ABCA1 expression and apoA-I. With a Morris water test, we found that curcumin treatment could attenuate cognitive impairment. With HE and Nissl staining, we found that curcumin could significantly ameliorate the abnormal changes of pyramidal neurons. Meanwhile, the expression of LXR-β, RXR-α, ABCA1 and apoA-I mRNA and protein were increased in a dose-dependent manner after curcumin treatment. Interestingly, both serum HDL cholesterol and total cholesterol levels were statistically higher in the curcumin treatment group than those other groups. We conclude that curcumin has the ability to activate permissive LXR-β/RXR-α signaling and thereby modulate ABCA1 and apoA-I-mediated cholesterol transmembrane transportation, which is a new preventive and therapeutic strategy for cerevascular diseases.

  7. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients; a meta-analysis

    PubMed Central

    Boekholdt, S. Matthijs; Arsenault, Benoit J.; Hovingh, G. Kees; Mora, Samia; Pedersen, Terje R.; LaRosa, John C.; Welch, K.M.A.; Amarenco, Pierre; DeMicco, David A.; Tonkin, Andrew M.; Sullivan, David R.; Kirby, Adrienne; Colhoun, Helen M.; Hitman, Graham A.; Betteridge, D. John; Durrington, Paul N.; Clearfield, Michael B.; Downs, John R.; Gotto, Antonio M.; Ridker, Paul M.; Kastelein, John J.P.

    2013-01-01

    Background It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol (LDL-C) on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and results We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio 0.83, 95%CI 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR 0.79, 95%CI 0.72–0.82). This association was also observed among patients achieving on-statin LDL-C levels < 50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR 0.98, 95%CI 0.94–1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR 0.93, 95%CI 0.90–0.97). Conclusions Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low LDL-C. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction. PMID:23965489

  8. Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization-International Federation of Clinical Chemistry First International Reference Materials.

    PubMed

    Jungner, I; Marcovina, S M; Walldius, G; Holme, I; Kolar, W; Steiner, E

    1998-08-01

    Serum concentrations of apolipoprotein (apo) B and apo A-I were measured from 1985-1996 in a Swedish population sample of 83 112 males and 64 464 females, ages <20 to >80 years, using an automated immunoturbidimetric method calibrated against fresh pools of human serum and commercial calibrators. All values were recalculated in 1997 after calibration against the WHO-IFCC First International Reference Materials. The recalculation factor was 1.059 for apo B, whereas for apo A-I, the correction was: y = 0.989x + 0.101. The total CVs for both apo B and A-I were generally <7%. The mean value (+/- SD) for apo B was 1.31 +/- 0.35 g/L in all males and 1.22 +/- 0.36 g/L in all females. The mean apo A-I concentration was 1.36 +/- 0.22 g/L in males-10% lower than in females (1.51 +/- 0.24 g/L). The mean value of apo B increased up to 60 years of age in males and up to 70 years of age in females. apo A-I concentrations changed only slightly with age in both males and females. apo A-I concentrations among Swedes are nearly identical to those reported recently by two American studies and those obtained in a Finnish population sample. Mean apo B concentrations differ somewhat between the populations but mirror-as expected-differences in total cholesterol concentrations. The highest values were noted in Swedish subjects. The Swedish sample population is, to our knowledge, the largest describing the distribution of apo B and A-I in a general population of adult males and females of all ages determined with procedures standardized and traceable to the WHO-IFCC First International Reference Materials.

  9. An Evaluation of the Crystal Structure of C-terminal Truncated Apolipoprotein A-I in Solution Reveals Structural Dynamics Related to Lipid Binding.

    PubMed

    Melchior, John T; Walker, Ryan G; Morris, Jamie; Jones, Martin K; Segrest, Jere P; Lima, Diogo B; Carvalho, Paulo C; Gozzo, Fábio C; Castleberry, Mark; Thompson, Thomas B; Davidson, W Sean

    2016-03-01

    Apolipoprotein (apo) A-I mediates many of the anti-atherogenic functions attributed to high density lipoprotein. Unfortunately, efforts toward a high resolution structure of full-length apoA-I have not been fruitful, although there have been successes with deletion mutants. Recently, a C-terminal truncation (apoA-I(Δ185-243)) was crystallized as a dimer. The structure showed two helical bundles connected by a long, curved pair of swapped helical domains. To compare this structure to that existing under solution conditions, we applied small angle x-ray scattering and isotope-assisted chemical cross-linking to apoA-I(Δ185-243) in its dimeric and monomeric forms. For the dimer, we found evidence for the shared domains and aspects of the N-terminal bundles, but not the molecular curvature seen in the crystal. We also found that the N-terminal bundles equilibrate between open and closed states. Interestingly, this movement is one of the transitions proposed during lipid binding. The monomer was consistent with a model in which the long shared helix doubles back onto the helical bundle. Combined with the crystal structure, these data offer an important starting point to understand the molecular details of high density lipoprotein biogenesis.

  10. Apolipoprotein A-I Mimetic Peptide D-4F Reduces Cardiac Hypertrophy and Improves Apolipoprotein A-I-Mediated Reverse Cholesterol Transport From Cardiac Tissue in LDL Receptor-null Mice Fed a Western Diet.

    PubMed

    Han, Jie; Zhang, Song; Ye, Ping; Liu, Yong-Xue; Qin, Yan-Wen; Miao, Dong-Mei

    2016-05-01

    Epidemiological studies have suggested that hypercholesterolemia is an independent determinant of increased left ventricular (LV) mass. Because high-density lipoprotein and its major protein apolipoprotein A-I (apoA-I) mediate reverse cholesterol transport (RCT) and have cardiac protective effects, we hypothesized that the apoA-I mimetic peptide D-4F could promote RCT in cardiac tissue and decrease cardiac hypertrophy induced by hypercholesterolemia. Low-density lipoprotein receptor-null mice were fed by a Western diet for 18 weeks and then randomized to receive water, or D-4F 0.3 mg/mL, or D-4F 0.5 mg/mL added to drinking water for 6 weeks. After D-4F administration, an increase in high-density lipoprotein cholesterol and a decrease in low-density lipoprotein cholesterol, total cholesterol, and triglyceride in a trend toward dose-responsivity were found in cardiac tissue. Ultrasound biomicroscopy revealed a reduction in LV posterior wall end-diastolic dimension, and an increase in mitral valve E/A ratio and LV ejection fraction. Hematoxylin-eosin staining showed reduced LV wall thickness and myocardial cell diameter. The protein levels of ABCA1 and LXRα were elevated in cardiac tissue of D-4F treated mice compared with the controls (P < 0.05). These results demonstrated that D-4F treatment reduced cardiac hypertrophy, and improved cardiac performance in low-density lipoprotein receptor-null mice fed a Western diet, presumably through the LXRα-ABCA1 pathway associated with enhanced myocardial RCT.

  11. In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I[S

    PubMed Central

    Zhao, Yannan; Black, Audrey S.; Bonnet, David J.; Maryanoff, Bruce E.; Curtiss, Linda K.; Leman, Luke J.; Ghadiri, M. Reza

    2014-01-01

    We have observed that molecular constructs based on multiple apoA-I mimetic peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic peptides, and were substantially atheroprotective. Surprisingly, these nanoparticles were also effective when administered orally at a dose of 75 mg/kg, despite the peptide construct being composed of l-amino acids and being undetectable in the plasma. The orally administered nanoparticles reduced whole aorta lesion areas by 55% and aortic sinus lesion volumes by 71%. Reductions in plasma cholesterol were due to the loss of non-HDL lipoproteins, while plasma HDL-cholesterol levels were increased. At a 10-fold lower oral dose, the nanoparticles were marginally effective in reducing atherosclerotic lesions. Intriguingly, analogous results were obtained with nanolipids of the corresponding monomeric peptide. These nanolipid formulations provide an avenue for developing orally efficacious therapeutic agents to manage atherosclerosis. PMID:24975585

  12. Hikiokoshins A-I, diterpenes from the leaves of Isodon japonicus.

    PubMed

    Tanaka, Naonobu; Tsuji, Eri; Sakai, Kanae; Gonoi, Tohru; Kobayashi, Jun'ichi

    2014-06-01

    Diterpenes, hikiokoshins A-I, and twelve known diterpenes were isolated from the leaves of Isodon japonicus (Burm. f.) H. Hara (Lamiaceae). The hikiokoshins A-I possess various skeletons such as ternifonane {hikiokoshin A}, ent-6,7:8,15-diseco-6,8-cyclokauran-7,20-olide {hikiokoshin B}, ent-6,7-secokauran-7,20-olide {hikiokoshin C}, and ent-7,20-epoxykaurane {hikiokoshins D-I}. Their structures were elucidated on the basis of spectroscopic analysis. Antimicrobial activities of hikiokoshins A and B were evaluated. PMID:24702849

  13. Molecular dynamics simulations of an apoliprotein A I derived peptide in explicit water

    NASA Astrophysics Data System (ADS)

    Stavrakoudis, Athanassios

    2008-08-01

    Molecular dynamics simulations have been performed for the 104-117 α-helical fragment of apoliprotein A-I using the CHARMM22 force field and the N AMD simulation engine. Simulation (50 ns in explicit water) resulted in significant appearance of π-helix conformation, which was totally diminished when the CMAP correction of the CHARMM force field was applied. This is consistent with other similar studies which suggest that the observation of π-helix in peptide conformation was force field biased rather actually existed. This study suggests that the 104-117 fragment of apoliprotein A-I has a stable α-helical conformation in water.

  14. [To the history of Tretiyakov almshouse of the A.I. Vishnevskiy Institute of Surgery].

    PubMed

    Kuzybayeva, M P

    2014-01-01

    The article deals with reconstruction of history of building and functioning of Tretiyakov almshouse in the A.I. Vishnevskiy institute of surgery. The archive documents were used for exploration. The input of architect S.I. Soloviyev into formation of architectural complex is demonstrated. The significance of this object in the history of national architecture is established.

  15. Transcriptome-wide identification of A > I RNA editing sites by inosine specific cleavage.

    PubMed

    Cattenoz, Pierre B; Taft, Ryan J; Westhof, Eric; Mattick, John S

    2013-02-01

    Adenosine to inosine (A > I) RNA editing, which is catalyzed by the ADAR family of proteins, is one of the fundamental mechanisms by which transcriptomic diversity is generated. Indeed, a number of genome-wide analyses have shown that A > I editing is not limited to a few mRNAs, as originally thought, but occurs widely across the transcriptome, especially in the brain. Importantly, there is increasing evidence that A > I editing is essential for animal development and nervous system function. To more efficiently characterize the complete catalog of ADAR events in the mammalian transcriptome we developed a high-throughput protocol to identify A > I editing sites, which exploits the capacity of glyoxal to protect guanosine, but not inosine, from RNAse T1 treatment, thus facilitating extraction of RNA fragments with inosine bases at their termini for high-throughput sequencing. Using this method we identified 665 editing sites in mouse brain RNA, including most known sites and suite of novel sites that include nonsynonymous changes to protein-coding genes, hyperediting of genes known to regulate p53, and alterations to non-protein-coding RNAs. This method is applicable to any biological system for the de novo discovery of A > I editing sites, and avoids the complicated informatic and practical issues associated with editing site identification using traditional RNA sequencing data. This approach has the potential to substantially increase our understanding of the extent and function of RNA editing, and thereby to shed light on the role of transcriptional plasticity in evolution, development, and cognition.

  16. Lipids and apolipoproteins A-I, B and C-II and different rapid weight loss programs (weight lifters, wrestlers, boxers and judokas).

    PubMed

    Jauhiainen, M; Laitinen, M; Penttilä, I; Nousiainen, U; Ahonen, E

    1985-01-01

    Apolipoproteins A-I, B, C-II and lipids were studied before and after rapid weight loss schedules. The compared groups were all athletic. Apolipoproteins were determined by electroimmunoassay methods using apoproteins purified by chromatofocusing column method. Dextran T10 was shown to increase rocket height in ApoB assay. Over 1% Dextran concentrations gave poor response. The linearity during calibration was from 0.3 to 3.0 g ApoB/l. Baseline values of ApoA-I in wrestlers, weightlifters, boxers and judokas were slightly higher as compared to "normal" population; ApoB was clearly reduced (mean value of 690 mg/l). Weight-loss was significant in each experimental group; mean value of 4.1% in active exercise, sauna and diuretic groups together. Compared as the whole sportsmen group in passive weight loss (or sauna) and diuretic groups the most pronounced changes were seen to be elevated apoprotein concentrations, whereas weight-loss by active rapid exercise resulted no apoprotein changes, but instead an increment in HDL cholesterol and decrement in triglycerides, respectively. The present study was the first to evaluate baseline values of apoproteins A-I, B and C-II in first class athletes and also the possible changes in these and lipid values in rapid weight-loss practices.

  17. Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?

    PubMed

    Das, Madhurima; Wilson, Christopher J; Mei, Xiaohu; Wales, Thomas E; Engen, John R; Gursky, Olga

    2016-01-29

    ApoA-I, the major protein of plasma high-density lipoprotein, removes cellular cholesterol and protects against atherosclerosis. ApoA-I mutations can cause familial amyloidosis, a life-threatening disease wherein N-terminal protein fragments form fibrils in vital organs. To unveil the protein misfolding mechanism and to understand why some mutations cause amyloidosis while others do not, we analyzed the structure, stability, and lipid-binding properties of naturally occurring mutants of full-length human apoA-I causing either amyloidosis (G26R, W50R, F71Y, and L170P) or aberrant lipid metabolism (L159R). Global and local protein conformation and dynamics in solution were assessed by circular dichroism, fluorescence, and hydrogen-deuterium exchange mass spectrometry. All mutants showed increased deuteration in residues 14-22, supporting our hypothesis that decreased protection of this major amyloid "hot spot" can trigger protein misfolding. In addition, L159R showed local helical unfolding near the mutation site, consistent with cleavage of this mutant in plasma to generate the labile 1-159 fragment. Together, the results suggest that reduced protection of the major amyloid "hot spot", combined with the structural integrity of the native helix bundle conformation, shifts the balance from protein clearance to β-aggregation. A delicate balance between the overall structural integrity of a globular protein and the local destabilization of its amyloidogenic segments may be a fundamental determinant of this and other amyloid diseases. Furthermore, mutation-induced conformational changes observed in the helix bundle, which comprises the N-terminal 75% of apoA-I, and its flexible C-terminal tail suggest the propagation of structural perturbations to distant sites via an unexpected template-induced ensemble-based mechanism, challenging the classical structure-based view.

  18. Impact of corpulence parameters and haemoglobin A1c on metabolic control in type 2 diabetic patients: comparison of apolipoprotein B/A-I ratio with fasting and postprandial conventional lipid ratios

    PubMed Central

    Diaf, Mustapha; Khaled, Boumediene M.; Sellam, Fériel

    2015-01-01

    Background and objective The incidence of diabetes co-morbidities could probably be better assessed by studying its associations with major corpulence parameters and glycaemic control indicators. We assessed the utility of body mass index (BMI), waist circumference (WC), and glycosylated haemoglobin (HbA1c) levels in metabolic control for type 2 diabetic patients. Methods Fasting and postprandial blood samples were collected from 238 type 2 diabetic patients aged 57.4±11.9 years. The sera were analysed for glucose, HbA1c, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and apolipoproteins (apoA-I and apoB). Ratios of lipids and apolipoproteins were calculated and their associations with BMI, WC, and HbA1c levels were analysed. Results Our investigation showed increases in most fasting and postprandial lipid parameters according to BMI and WC. In men, postprandial HDL-c and TG levels were significantly higher (p<0.05) in overweight and obese patients, respectively, as well as in patients with abdominal obesity. Contrariwise, postprandial TC levels were significantly higher (p<0.01) in overweight and abdominal obese women. However, elevations of apoA-I and apoB levels were according to BMI and WC in both genders. There was a strong influence of BMI, WC, and HbA1c levels on the apoB/apoA-I ratio compared to traditional fasting and postprandial lipid ratios in both men and women. The apoB/apoA-I ratio was more correlated with postprandial TC/HDL and LDL-c/HDL-c ratios in men and with postprandial TG/HDL-c in women. Conclusion The apoB/apoA-I ratio is helpful in assessing metabolic risk caused by overall obesity, abdominal obesity and impaired glycaemia in type 2 diabetic patients. PMID:25959906

  19. Gene and gene-product variation in the apolipoprotein A-I/C-III/A-IV cluster in the Dogrib Indians of the Northwest Territories.

    PubMed Central

    Cole, S A; Szathmary, E J; Ferrell, R E

    1989-01-01

    The Dogrib, an Amerindian tribe residing in the Northwest Territories of Canada, were typed for DNA and protein polymorphism at the apolipoprotein A-I/C-III/A-IV gene cluster. Variation was seen at three previously described RFLPs detected with the enzymes SstI, PstI, and XmnI, though frequencies of these polymorphisms differ significantly from those reported in other populations. They exhibit no variation at two previously reported PvuII sites. No variation was seen in the APO A-I or APO A-IV gene products, with the Dogrib showing the most common isoelectric-focusing/immunoblot patterns of other world populations. Haplotype frequencies computed from inferred haplotypes and by maximum likelihood estimation did not differ significantly. The extent of nonrandom association of these sites is highly significant (P less than .00001), though pairwise analysis shows significance between the SstI and XmnI sites only. Levels of fasting triglyceride and fasting total cholesterol were determined for each individual. Analysis of covariance shows that fasting triglyceride levels in women vary significantly with the XmnI genotype. These results suggest that genetic variation at the APO A-I/C-III/A-IV gene cluster may be a useful tool for the study of quantitative lipoprotein variation in the Dogrib. PMID:2499188

  20. 22 CFR 221.23 - Payment to A.I.D. of excess amounts received by a Noteholder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Payment to A.I.D. of excess amounts received by....I.D. of excess amounts received by a Noteholder. If a Noteholder shall, as a result of A.I.D. paying compensation under this Guarantee, receive an excess payment, it shall refund the excess to A.I.D....

  1. Francisella tularensis Subtype A.II Genomic Plasticity in Comparison with Subtype A.I

    PubMed Central

    Larson, Marilynn A.; Nalbantoglu, Ufuk; Sayood, Khalid; Zentz, Emily B.; Bartling, Amanda M.; Francesconi, Stephen C.; Fey, Paul D.; Dempsey, Michael P.; Hinrichs, Steven H.

    2015-01-01

    Although Francisella tularensis is considered a monomorphic intracellular pathogen, molecular genotyping and virulence studies have demonstrated important differences within the tularensis subspecies (type A). To evaluate genetic variation within type A strains, sequencing and assembly of a new subtype A.II genome was achieved for comparison to other completed F. tularensis type A genomes. In contrast with the F. tularensis A.I strains (SCHU S4, FSC198, NE061598, and TI0902), substantial genomic variation was observed between the newly sequenced F. tularensis A.II strain (WY-00W4114) and the only other publically available A.II strain (WY96-3418). Genome differences between WY-00W4114 and WY96-3418 included three major chromosomal translocations, 1580 indels, and 286 nucleotide substitutions of which 159 were observed in predicted open reading frames and 127 were located in intergenic regions. The majority of WY-00W4114 nucleotide deletions occurred in intergenic regions, whereas most of the insertions and substitutions occurred in predicted genes. Of the nucleotide substitutions, 48 (30%) were synonymous and 111 (70%) were nonsynonymous. WY-00W4114 and WY96-3418 nucleotide polymorphisms were predominantly G/C to A/T allelic mutations, with WY-00W4114 having more A+T enrichment. In addition, the A.II genomes contained a considerably higher number of intact genes and longer repetitive sequences, including transposon remnants than the A.I genomes. Together these findings support the premise that F. tularensis A.II may have a fitness advantage compared to the A.I subtype due to the higher abundance of functional genes and repeated chromosomal sequences. A better understanding of the selective forces driving F. tularensis genetic diversity and plasticity is needed. PMID:25918839

  2. Eucarobustols A-I, Conjugates of Sesquiterpenoids and Acylphloroglucinols from Eucalyptus robusta.

    PubMed

    Yu, Yang; Gan, Li-She; Yang, Sheng-Ping; Sheng, Li; Liu, Qun-Fang; Chen, Shao-Nong; Li, Jia; Yue, Jian-Min

    2016-05-27

    Nine new conjugates of sesquiterpenoids and acylphloroglucinols, named eucarobustols A-I (1-9), as well as 11 known analogues were isolated from the leaves of Eucalyptus robusta. The sesquiterpenoid motifs furnishing the new conjugates included four structural types of aristolane (1 and 2), guaiane (3), eudesmane (4), and aromadendrane (5-9) moieties. Compounds 1 and 2 were found to represent the first examples of conjugates of aristolane and acylphloroglucinol units. In turn, compound 3 features a new coupling model of guaiane and acylphloroglucinol via the C-4-C-7' bond. Compounds 1, 7, and 9 showed inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 1.3, 1.8, and 1.6 μM, respectively.

  3. Terpecurcumins A-I from the rhizomes of Curcuma longa: absolute configuration and cytotoxic activity.

    PubMed

    Lin, Xionghao; Ji, Shuai; Li, Rui; Dong, Yinhui; Qiao, Xue; Hu, Hongbo; Yang, Wenzhi; Guo, Dean; Tu, Pengfei; Ye, Min

    2012-12-28

    Terpecurcumins A-I (1-9), together with three known analogues (10-12), were isolated from the rhizomes of Curcuma longa (turmeric). They were derived from the hybridization of curcuminoids and bisabolanes. The structures and absolute configurations of 1-9 were elucidated on the basis of extensive spectroscopic data analysis, including NMR and electronic circular dichroism spectra. The configuration of 10 was further confirmed by X-ray crystallography. A plausible biogenetic relationship for 1-12 is proposed. Compounds 4, 6, 7, 10, and 11 showed higher cytotoxic activities (IC(50), 10.3-19.4 μM) than curcumin (IC(50), 31.3-49.2 μM) against human cancer cell lines (A549, HepG2, and MDA-MB-231).

  4. The specific amino acid sequence between helices 7 and 8 influences the binding specificity of human apolipoprotein A-I for high density lipoprotein (HDL) subclasses: a potential for HDL preferential generation.

    PubMed

    Carnemolla, Ronald; Ren, Xuefeng; Biswas, Tapan K; Meredith, Stephen C; Reardon, Catherine A; Wang, Jianjun; Getz, Godfrey S

    2008-06-01

    Humans have two major high density lipoprotein (HDL) sub-fractions, HDL(2) and HDL(3), whereas mice have a monodisperse HDL profile. Epidemiological evidence has suggested that HDL(2) is more atheroprotective; however, currently there is no direct experimental evidence to support this postulate. The amino acid sequence of apoA-I is a primary determinant of HDL subclass formation. The majority of the alpha-helical repeats in human apoA-I are proline-punctuated. A notable exception is the boundary between helices 7 and 8, which is located in the transitional segment between the stable N-terminal domain and the C-terminal hydrophobic domain. In this study we ask whether the substitution of a proline-containing sequence (PCS) separating other helices in human apoA-I for the non-proline-containing sequence (NPCS) between helices 7 and 8 (residues 184-190) influences HDL subclass association. The human apoA-I mutant with PCS2 replacing NPCS preferentially bound to HDL(2). In contrast, the mutant where PCS3 replaced NPCS preferentially associated with HDL(3). Thus, the specific amino acid sequence between helices 7 and 8 influences HDL subclass association. The wild-type and mutant proteins exhibited similar physicochemical properties except that the two mutants displayed greater lipid-associated stability versus wild-type human apoA-I. These results focus new attention on the influence of the boundary between helices 7 and 8 on the properties of apoA-I. The expression of these mutants in mice may result in the preferential generation of HDL(2) or HDL(3) and allow us to examine experimentally the anti-atherogenicity of the HDL subclasses.

  5. 30 CFR 57.22217 - Seals and stoppings (I-A, I-B, and I-C mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Seals and stoppings (I-A, I-B, and I-C mines... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22217 Seals and stoppings (I-A, I-B, and I-C mines). All seals, and those stoppings that separate main intake from...

  6. 30 CFR 57.22217 - Seals and stoppings (I-A, I-B, and I-C mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Seals and stoppings (I-A, I-B, and I-C mines... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22217 Seals and stoppings (I-A, I-B, and I-C mines). All seals, and those stoppings that separate main intake from...

  7. 30 CFR 57.22217 - Seals and stoppings (I-A, I-B, and I-C mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Seals and stoppings (I-A, I-B, and I-C mines... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22217 Seals and stoppings (I-A, I-B, and I-C mines). All seals, and those stoppings that separate main intake from...

  8. 30 CFR 57.22217 - Seals and stoppings (I-A, I-B, and I-C mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Seals and stoppings (I-A, I-B, and I-C mines... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22217 Seals and stoppings (I-A, I-B, and I-C mines). All seals, and those stoppings that separate main intake from...

  9. 30 CFR 57.22217 - Seals and stoppings (I-A, I-B, and I-C mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Seals and stoppings (I-A, I-B, and I-C mines... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22217 Seals and stoppings (I-A, I-B, and I-C mines). All seals, and those stoppings that separate main intake from...

  10. Apolipoprotein A-I and platelet factor 4 are biomarkers for infliximab response in rheumatoid arthritis

    PubMed Central

    Trocmé, Candice; Marotte, Hubert; Baillet, Athan; Pallot-Prades, Béatrice; Garin, Jérome; Grange, Laurent; Miossec, Pierre; Tebib, Jacques; Berger, François; Nissen, Michael J.; Juvin, Robert; Morel, Françoise; Gaudin, Philippe

    2009-01-01

    Objectives The use of biologics such as infliximab has dramatically improved the treatment of rheumatoid arthritis (RA). However, factors predictive of therapeutic response need to be identified. A proteomic study was performed prior to infliximab therapy to identify a panel of candidate protein biomarkers of RA predictive of treatment response. Methods Plasma profiles of 60 RA patients (28 non-responders ACR 20 negative and 32 responders ACR 70 positive to infliximab) were studied by SELDI-TOF-MS technology on two types of arrays, an anion exchange array (SAX2) and a nickel affinity array (IMAC3-Ni). Biomarker characterization was carried out using classical biochemical methods (purification by ammonium sulfate precipitation or metal affinity chromatography) and identification by MALDI-TOF analysis. Results Two distinct protein profiles were observed on both arrays and several proteins were differentially expressed in both patient populations. Five proteins at 3.86, 7.77, 7.97, 8.14 and 74.07 kDa were overexpressed in the non-responder group, whereas one at 28 kDa was increased in the responder population (sensitivity > 56%, specificity > 77.5%). Moreover combination of several biomarkers improved both the sensitivity and specificity of the detection of patient response to over 97%. The 28 kDa protein was characterized as apolipoprotein A-I and the 7.77 kDa biomarker was identified as platelet factor 4. Conclusions We characterized six plasma biomarkers, enabling the detection of patient response to infliximab with high sensitivity and specificity. Apolipoprotein A-1 was predictive of a good response to infliximab, whereas platelet factor 4 was associated with non-responders. PMID:18664547

  11. Proceedings of the XXII A.I.VE.LA. National Meeting

    NASA Astrophysics Data System (ADS)

    Primo Tomasini, Enrico

    2015-11-01

    A.I.VE.LA. - the Italian Association of Laser Velocimetry and non-invasive diagnostics - is a non-profit cultural association whose objective is to promote and support research in the field of non-contact or minimally invasive measurement techniques, particularly electromagnetic-based techniques and optical techniques. Through its Annual Meeting, AIVELA aims to create an active and stimulating forum where current research results and technical advances can be exchanged and the development of new systems for laboratory use, field testing and industrial application can be promoted. The techniques covered include Laser Doppler Anemometry - LDA, Phase Doppler Anemometry - PDA, Image Velocimetry - PIV, Flow visualization techniques, Spectroscopic measurement techniques (LIF, Raman, etc.), Laser Doppler Vibrometry - LDV, Speckle Pattern Interferometry - ESPI, Holographic techniques, Shearography, Digital Image Correlation - DIC, Moiré techniques, Structured light techniques, Infrared imaging, Photoelasticity, Image based measurement techniques, Ultrasonic sensing, Acoustic and Aeroacoustic measurements, etc. The first Annual Meeting was held back in October 1992 and since then there has been a large consensus among the research and scientific communities that the papers presented at the event are of a high scientific interest. The XXII AIVELA Annual Meeting was held at the Faculty of Engineering of University of Rome Tor Vergata on 15-16 December 2014 and was organised in collaboration with the International Master Courses in "Protection Against CBRNe Events". This volume contains a selection of the papers presented at the event. The detailed Programme of the Meeting can be found at: http://www.aivela.org/XXII_Convegno/index.html Trusting our Association and its initiatives will meet your interest, I wish to thank you in advance for your kind attention and hope to meet you soon at one of our events.

  12. Theoretical modeling of planet-induced stellar activity using A.I.K.E.F. simulations

    NASA Astrophysics Data System (ADS)

    Riousset, J. A.; Motschmann, U.; Reiners, A.; Marvin, C.

    2015-12-01

    Plasma flows and turbulences in stellar atmospheres and chromospheres can be disturbed by the presence of a planet in close orbit around the star. Such disturbances can be generated through tidal interactions between the two bodies, or through direct magnetic interaction between the magnetic fields of the star and the planet. The presence of an outer disturber and its influence on the generation of stellar activity, together with the knowledge about stars with no close planets, provide a unique laboratory for the investigation of plasma turbulence in stellar atmospheres. In this work we develop an integrated model covering the star and the planet as an interacting system where gravitational and electromagnetic forces are implemented self-consistently. The model is based on A.I.K.E.F. hybrid code for simulating stellar wind interaction with astronomical bodies. Compared to previous studies, the solar wind is no longer modeled as inflow/outflow boundary conditions, but created instead by a second body representing a star inside the simulation domain. The incorporation of the star is carried out based on Parker (1952) model for slow rotating stars with moderate stellar magnetic fields or on the sophisticated stellar wind model of Weber and Davis (1967) for fast rotators with strong stellar magnetic fields. Such an approach is not without scaling constraints, which will be discussed in this paper. Here, we present the first results for a configuration where the planet is within the star's Alfven radius, i.e., where the stellar wind flow velocity is subcritical. In this case, the resulting current system is extended and may even propagate against the inflowing stellar wind with possible consequences for the stellar activity.

  13. Association of a DNA polymorphism of the apolipoprotein A-I/C-III/A-IV gene cluster with hypertriglyceridemia in obese people.

    PubMed

    Oppert, J M; Fumeron, F; Moreel, J F; Apfelbaum, M

    1992-11-01

    Hypertriglyceridemia is frequently associated with obesity. In the general Caucasian population, an association of the uncommon S2 allele of a DNA polymorphism of the apolipoprotein (apo) A-I/C-III/A-IV gene cluster with hypertriglyceridemia has been reported. To assess the risk of hypertriglyceridemia associated with the S2 allele in obesity, lipid status and apo A-I/C-III/A-IV genotypes were studied in 90 unrelated Caucasian obese subjects. Age, body mass index, percentage body fat and waist-hip ratio were comparable between genotypes. The frequency of S1/S2 genotype was 35% in the hypertriglyceridemic group versus 11.4% in the normotriglyceridemic group (P < 0.05). The odds ratio of hypertriglyceridemia was 3.7 for obese subjects with the S2 allele and 26.7% of hypertriglyceridemias could be attributed to the S2 allele. Women with the S1/S2 genotype had also significantly higher VLDL- and LDL-cholesterol concentrations. These results suggest that the S2 allele modulates the effects of obesity on lipoproteins and increases the risk of hypertriglyceridemia when obese.

  14. Epigenetic effectiveness of complete carcinogens: specific interactions of polycyclic aromatic hydrocarbons and aminoazo dyes with cholesterol and apolipoprotein A-I.

    PubMed

    Contag, Bodo

    2005-01-01

    During a co-precipitation of cholesterol (Chol) and slight amounts of polycyclic aromatic hydrocarbons (PAHs) or aminoazo dyes (AZOs) in aqueous albumin solution, complex particles are formed; on their surfaces apolipoproteins with an amphipathic alpha-helix (e.g. apoA-I) are more or less firmly adsorbed. An efficacy index can be calculated from the strength of the hydrophobic interactions between apoA-I and the [Chol/PAH]- or [Chol/AZO]-complex, and the solubility of the PAH or AZO in an aqueous medium, which correlates to the carcinogenicity of these compounds. A short-term test for PAHs and AZOs is described, in which the efficacy index can be determined in the simplest manner without any great expenditure on equipment. The previous results suggest that the parent compounds of the PAHs and AZOs can be involved in a specific interaction with cholesterol-domains of the plasma membrane of a cell. The changes in membrane fluidity and architecture caused by these specific interactions could modulate the distribution and/or activity of membrane proteins which are critical to the regulation of cellular proliferation.

  15. 22 CFR 204.23 - Payment to A.I.D. of excess amounts received by the lender of any assignee.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Payment to A.I.D. of excess amounts received by... Payment to A.I.D. of excess amounts received by the lender of any assignee. If the Lender or Assignee shall, as a result of A.I.D. paying compensation under this Guaranty, receive an excess payment,...

  16. 78 FR 46807 - Mixed Straddles; Straddle-by-Straddle Identification Under Section 1092(b)(2)(A)(i)(I)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-02

    ... rulemaking by cross-reference to temporary regulations (50 FR 3351, January 24, 1985). Included in the... Under Section 1092(b)(2)(A)(i)(I) AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Temporary.... Applicability Date: For the date of applicability, see Sec. 1.1092(b)-6T(c). FOR FURTHER INFORMATION...

  17. 78 FR 46854 - Mixed Straddles; Straddle-by-Straddle Identification Under Section 1092(b)(2)(A)(i)(I)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-02

    ... Under Section 1092(b)(2)(A)(i)(I) AGENCY: Internal Revenue Service (IRS), Treasury. ACTION: Notice of... Federal Register amend the Income Tax Regulations (26 CFR part 1) relating to section 1092(b). First, the temporary regulations limit the application of Sec. 1.1092(b)-3T(b)(6) to section 1092(b)(2)...

  18. 78 FR 64396 - Mixed Straddles; Straddle-by-Straddle Identification Under Section 1092(b)(2)(A)(i)(I); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ... (78 FR 46807). The temporary regulations applied to all identified mixed straddles established after... Under Section 1092(b)(2)(A)(i)(I); Correction AGENCY: Internal Revenue Service (IRS), Treasury. ACTION..., 2013. Applicability Date: As corrected, Sec. 1.1092(b)-6T applies to identified mixed...

  19. 78 FR 64430 - Mixed Straddles; Straddle-by-Straddle Identification Under Section 1092(b)(2)(A)(i)(I); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ...), published in the Federal Register on Friday, August 2, 2013 (78 FR 46807), serves as the text of the... Friday, August 2, 2013 (78 FR 46854). The proposed regulations were proposed to apply to all identified... Under Section 1092(b)(2)(A)(i)(I); Correction AGENCY: Internal Revenue Service (IRS), Treasury....

  20. A proteoliposome containing apolipoprotein A-I mutant (V156K) enhances rapid tumor regression activity of human origin oncolytic adenovirus in tumor-bearing zebrafish and mice.

    PubMed

    Seo, Juyi; Yun, Chae-Ok; Kwon, Oh-Joon; Choi, Eun-Jin; Song, Jae-Young; Choi, Inho; Cho, Kyung-Hyun

    2012-08-01

    We recently reported that the efficiency of adenoviral gene delivery and virus stability are significantly enhanced when a proteoliposome (PL) containing apolipoprotein (apo) A-I is used in an animal model. In the current study, we tested tumor removal activity of oncolytic adenovirus (Ad) using PL-containing wildtype (WT) or V156K. Oncolytic Ad with or without PL was injected into tumors of zebrafish and nude mice as a Hep3B tumor xenograft model. The V156K-PL-Ad-injected zebrafish, group showed the lowest tumor tissue volume and nucleic acids in the tumor area, whereas injection of Ad alone did not result in adequate removal of tumor activity. Reactive oxygen species (ROS) contents increased two-fold in tumor-bearing zebrafish; however, the V156K-PL-Ad injected group showed a 40% decrease in ROS levels compared to that in normal zebrafish. After reducing the tumor volume with the V156K-PL-Ad injection, the swimming pattern of the zebrafish changed to be more active and energetic. The oncolytic effect of PL-Ad containing either V156K or WT was about two-fold more enhanced in mice than that of Ad alone 34 days after the injection. Immunohistochemical analysis revealed that the PL-Ad-injected groups showed enhanced efficiency of viral delivery with elevated Ad-E1A staining and a diminished number of proliferating tumor cells. Thus, the antitumor effect of oncolytic Ad was strongly enhanced by a PL-containing apoA-I and its mutant (V156K) without causing side effects in mice and zebrafish models. PMID:22851220

  1. Macrophage metalloproteinases degrade high-density-lipoprotein-associated apolipoprotein A-I at both the N- and C-termini.

    PubMed Central

    Eberini, Ivano; Calabresi, Laura; Wait, Robin; Tedeschi, Gabriella; Pirillo, Angela; Puglisi, Lina; Sirtori, Cesare R; Gianazza, Elisabetta

    2002-01-01

    Atheromatous plaques contain various cell types, including macrophages, endothelial cells and smooth-muscle cells. To investigate the possible interactions between secreted matrix metalloproteinases and high-density lipoprotein (HDL) components, we tested the above cell types by culturing them for 24 h. HDL(3) (HDL subfractions with average sizes of between 8.44 nm for HDL(3A) and 7.62 nm for HDL(3C)) were then incubated in their cell-free conditioned media. Proteolytic degradation of apolipoprotein A-I was observed with macrophages, but not with endothelial-cell- or muscle-cell-conditioned supernatant. Absence of calcium or addition of EDTA to incubation media prevented all proteolytic processes. The identified apolipoprotein A-I fragments had sizes of 26, 22, 14 and 9 kDa. Two-dimensional electrophoresis and MS resolved the 26 and the 22 kDa components and identified peptides resulting from both N- and C-terminal cleavage of apolipoprotein A-I. The higher abundance of C- than N-terminally cleaved peptides agrees with data in the literature for a fully structured alpha-helix around Tyr(18) compared with an unstructured region around Gly(185) and Gly(186). The flexibility in the latter region of apolipoprotein A-I may explain its susceptibility to proteolysis. In our experimental set-up, HDL(3C) was more extensively degraded than the other HDL(3) subclasses (HDL(3A) and HDL(3B)). Proteolytic fragments produced by metalloproteinase action were shown by gel filtration and electrophoresis to be neither associated with lipids nor self-associated. PMID:11879189

  2. Extended-release niacin alters the metabolism of plasma apolipoprotein (apo) A-I- and apoB-containing lipoproteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Extended-release niacin effectively lowers plasma TG levels and raises plasma HDL cholesterol levels, but the mechanisms responsible for these effects are unclear. We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to pl...

  3. Cytotoxicity and structure activity relationship studies of maplexins A-I, gallotannins from red maple (Acer rubrum).

    PubMed

    González-Sarrías, Antonio; Yuan, Tao; Seeram, Navindra P

    2012-05-01

    Maplexins A-I are a series of structurally related gallotannins recently isolated from the red maple (Acer rubrum) species. They differ in number and location of galloyl derivatives attached to 1,5-anhydro-glucitol. Here, maplexins A-I were evaluated for anticancer effects against human tumorigenic (colon, HCT-116; breast, MCF-7) and non-tumorigenic (colon, CCD-18Co) cell lines. The maplexins which contained two (maplexins C-D) or three (maplexins E-I) galloyl derivatives each, inhibited cancer cell growth while those with only one galloyl group (maplexins A-B) did not. Moreover, maplexins C-D showed greater antiproliferative effects than maplexins E-I (IC(50)=59.8-67.9 and 95.5-108.5 μM vs. 73.7-165.2 and 115.5-182.5 μM against HCT-116 and MCF-7 cells, respectively). Notably, the cancer cells were up to 2.5-fold more sensitive to the maplexins than the normal cells. In further mechanistic studies, maplexins C-D (at 75 μM concentrations) induced apoptosis and arrested cell cycle (in the S-phase) of the cancer cells. These results suggest that the number of galloyl groups attached to the 1,5-anhydro-glucitol moiety in these gallotannins are important for antiproliferative activity. Also, this is the first in vitro anticancer study of maplexins. PMID:22387705

  4. Cytotoxicity and structure activity relationship studies of maplexins A-I, gallotannins from red maple (Acer rubrum).

    PubMed

    González-Sarrías, Antonio; Yuan, Tao; Seeram, Navindra P

    2012-05-01

    Maplexins A-I are a series of structurally related gallotannins recently isolated from the red maple (Acer rubrum) species. They differ in number and location of galloyl derivatives attached to 1,5-anhydro-glucitol. Here, maplexins A-I were evaluated for anticancer effects against human tumorigenic (colon, HCT-116; breast, MCF-7) and non-tumorigenic (colon, CCD-18Co) cell lines. The maplexins which contained two (maplexins C-D) or three (maplexins E-I) galloyl derivatives each, inhibited cancer cell growth while those with only one galloyl group (maplexins A-B) did not. Moreover, maplexins C-D showed greater antiproliferative effects than maplexins E-I (IC(50)=59.8-67.9 and 95.5-108.5 μM vs. 73.7-165.2 and 115.5-182.5 μM against HCT-116 and MCF-7 cells, respectively). Notably, the cancer cells were up to 2.5-fold more sensitive to the maplexins than the normal cells. In further mechanistic studies, maplexins C-D (at 75 μM concentrations) induced apoptosis and arrested cell cycle (in the S-phase) of the cancer cells. These results suggest that the number of galloyl groups attached to the 1,5-anhydro-glucitol moiety in these gallotannins are important for antiproliferative activity. Also, this is the first in vitro anticancer study of maplexins.

  5. 49 CFR Appendix A-I to Part 541 - Lines With Antitheft Devices Which Are Exempted From the Parts-Marking Requirements of This...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 A Appendix A-I to Part.... 541, App. A-1 Appendix A-I to Part 541—Lines With Antitheft Devices Which Are Exempted From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 Manufacturer Subject lines BMW MINI....

  6. 49 CFR Appendix A-I to Part 541 - Lines With Antitheft Devices Which Are Exempted From the Parts-Marking Requirements of This...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... Dodge Magnum (2008). Ford Motor Co Escape. Explorer.1 Ford Five-Hundred (2007). Ford Focus. Lincoln Town... From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 A Appendix A-I to Part.... 541, App. A-1 Appendix A-I to Part 541—Lines With Antitheft Devices Which Are Exempted From the...

  7. 26 CFR 1.1092(b)-3T - Mixed straddles; straddle-by-straddle identification under section 1092(b)(2)(A)(i)(I) (temporary).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... identification under section 1092(b)(2)(A)(i)(I) (temporary). 1.1092(b)-3T Section 1.1092(b)-3T Internal Revenue... section 1092(b)(2)(A)(i)(I) (temporary). (a) In general. Except as otherwise provided, a taxpayer shall... constitute independent verification: (i) Separate account. Placement of one or more positions of a......

  8. 49 CFR Appendix A-I to Part 541 - Lines With Antitheft Devices Which Are Exempted From the Parts-Marking Requirements of This...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... Edge. Escape. Explorer. Fiesta.1 Focus. Fusion. Lincoln Town Car. Mustang. Mercury Mariner. Mercury... CFR part 1.95. ... From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 A Appendix A-I to...

  9. 77 FR 44677 - Quad/Graphics Inc., Including On-Site Leased Workers From Staff Mart and A.I.D., Jonesboro, AR...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-30

    ... of determination was published in the Federal Register on July 10, 2012 (77 FR 40641). At the request... and A.I.D.,Jonesboro, AR; Amended Certification Regarding EligibilityTo Apply for Worker...

  10. 49 CFR Appendix A-I to Part 541 - Lines With Antitheft Devices Which are Exempted From the Parts-Marking Requirements of This...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 A Appendix A-I to Part.... 541, App. A-1 Appendix A-I to Part 541—Lines With Antitheft Devices Which are Exempted From the Parts-Marking Requirements of This Standard Pursuant to 49 CFR Part 543 ER12AP11.002 ER12AP11.003...

  11. 30 CFR 57.22222 - Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and ventilation tubing shall be approved by MSHA in accordance with 30 CFR part 7, or shall bear a BC or...

  12. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  13. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  14. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  15. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  16. 26 CFR 1.1092(b)-3T - Mixed straddles; straddle-by-straddle identification under section 1092(b)(2)(A)(i)(I) (temporary).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... commission merchant (as defined in 7 U.S.C. 2 and 17 CFR 1.3(p)), or similar person and in which notations... identification under section 1092(b)(2)(A)(i)(I) (temporary). 1.1092(b)-3T Section 1.1092(b)-3T Internal Revenue... identification under section 1092(b)(2)(A)(i)(I) (temporary). (a) In general. Except as otherwise......

  17. 26 CFR 1.1092(b)-3T - Mixed straddles; straddle-by-straddle identification under section 1092(b)(2)(A)(i)(I) (temporary).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... commission merchant (as defined in 7 U.S.C. 2 and 17 CFR 1.3(p)), or similar person and in which notations... identification under section 1092(b)(2)(A)(i)(I) (temporary). 1.1092(b)-3T Section 1.1092(b)-3T Internal Revenue... identification under section 1092(b)(2)(A)(i)(I) (temporary). (a) In general. Except as otherwise......

  18. 26 CFR 1.1092(b)-3T - Mixed straddles; straddle-by-straddle identification under section 1092(b)(2)(A)(i)(I) (temporary).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... commission merchant (as defined in 7 U.S.C. 2 and 17 CFR 1.3(p)), or similar person and in which notations... identification under section 1092(b)(2)(A)(i)(I) (temporary). 1.1092(b)-3T Section 1.1092(b)-3T Internal Revenue... identification under section 1092(b)(2)(A)(i)(I) (temporary). (a) In general. Except as otherwise......

  19. The forgotten dispute: A.I. Oparin and H.J. Muller on the origin of life.

    PubMed

    Falk, Raphael; Lazcano, Antonio

    2012-01-01

    The debate between A.I. Oparin's heterotrophic proposal of the origin of life and H.J. Muller's suggestion that what may be considered a posteriori the beginning of life, was an autocatalytic, replicative gene, is analyzed. Although both recognized that what was needed was an interacting system contiguous in space and time, it is now rarely mentioned that this scientific confrontation went on for several decades against the background of intense ideological issues, political tensions, and scientific developments that include the rise and demise of Lysenkoism, on the one hand, and, on the other, the establishment of neoDarwinism and the birth of molecular biology. Whereas for Oparin life was the outcome of the step-wise slow process of precellular evolution in which membrane-bounded polymolecular systems played a key role, Muller argued that life started with the appearance of the first nucleic-acid (DNA) molecule in the primitive oceans. Oparin and Muller came from different scientific backgrounds and almost opposite intellectual traditions, so their common interest in the origin of life did nothing to assuage their opposing views, which as argued soon became part of the debates that took place within the framework of intense ideological confrontations.

  20. The neoplastic potential of rat tracheal epithelial cell lines induced by dibenzo(a, i)pyrene and 1-nitropyrene

    SciTech Connect

    Xiang, M.; Ong, T. |; Nath, J.

    1997-10-01

    The rat tracheal epithelial (RTE) cell transformation system is an important short-term assay for respiratory carcinogenesis. In our laboratories, studies have been performed using this assay system to determine the carcinogenic potential of dibenzo(a,i)pyrene (DBP) and 1-nitropyrene (1-NP), two compounds commonly contaminating occupational and environmental settings. RTE cells were exposed in vivo to DBP or 1-NP by intertracheal instillation. RTE cells were then isolated and plated on a medium for determination of cloning and transformation frequencies. Cell lines established from transformed cells induced by DBP and 1-NP were analyzed for their neoplastic potential with the soft agar cloning and the athymic nude mouse tumorigenicity assays. Results showed that: (1) incidence of transformed foci in cultures treated with DBP or 1-NP in vivo was significantly higher than that in the control cultures; (2) 8 and 25 cell lines were established from 28 and 48 transformed foci induced by DBP and 1-NP, respectively; (3) 3 of 5 cell lines from DBP and 5 anchorage independent growth in soft agar; (4) some of the cell lines from DBP and 1-NP induced transformed foci formed tumors after cells were injected in athymic nude mice. These results indicate that in vivo exposure to DBP and 1-NP can induce RTE cell transformation and that transformed cells induced by DBP and 1-NP may have neoplastic potential.

  1. Effects of weight-loss by exercise and by diet on apolipoproteins A-I and A-II and the particle-size distribution of high-density lipoproteins in men.

    PubMed

    Williams, P T; Krauss, R M; Vranizan, K M; Albers, J J; Wood, P D

    1992-04-01

    We studied separately the effects of weight-loss by dieting or by running on apolipoprotein (apo) A-I, apo A-II, and high-density lipoprotein (HDL) subfractions in sedentary, moderately overweight men assigned at random into three groups: exercise without calorie restriction, calorie restriction without exercise, and control. The absorbance of protein-stained polyacrylamide gradient gels was used as an index of mass concentrations for five HDL subclasses that have been identified by their particle sizes: HDL3c (7.2 to 7.8 nm), HDL3b (7.8 to 8.2 nm), HDL3a (8.2 to 8.8 nm), HDL2a (8.8 to 9.7 nm), and HDL2b (9.7 to 12.9 nm). During the 1-year trial, the exercisers ran (mean +/- SD) 15.6 +/- 9.1 km/wk, and the dieters reported eating 340 +/- 71 fewer calories per day than at baseline. Total body weight and fat weight were both reduced significantly more in dieters (-7.2 +/- 4.1 and -6.2 +/- 4.1 kg, respectively) and in exercisers (-4.0 +/- 3.9 and -4.6 +/- 3.5 kg) than in controls (0.6 +/- 3.7 and -0.7 +/- 2.7 kg). As compared with mean changes in controls, exercisers and dieters each decreased HDL3b and increased HDL2b. Exercisers also significantly increased plasma apo A-I concentrations. Analysis of covariance was used to statistically adjust the mean lipoprotein changes for the effects of weight-loss. The adjustment eliminated the significant reductions in HDL3b and the significant increases in HDL2b in exercisers and dieters, and it eliminated the significant increase in apo A-I in exercisers. When adjusted, the dieters' mean changes in HDL2b had significantly decreased relative to those of both exercisers and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. The I.A.G. / A.I.G. SEDIBUD (Sediment Budgets in Cold Environments) Programme: Current and future activities

    NASA Astrophysics Data System (ADS)

    Beylich, Achim A.; Lamoureux, Scott; Decaulne, Armelle

    2013-04-01

    Projected climate change in cold regions is expected to alter melt season duration and intensity, along with the number of extreme rainfall events, total annual precipitation and the balance between snowfall and rainfall. Similarly, changes to the thermal balance are expected to reduce the extent of permafrost and seasonal ground frost and increase active layer depths. These effects will undoubtedly change surface environments in cold regions and alter the fluxes of sediments, nutrients and solutes, but the absence of quantitative data and coordinated geomorphic process monitoring and analysis to understand the sensitivity of the Earth surface environment is acute in cold climate environments. The International Association of Geomorphologists (I.A.G. / A.I.G. ) SEDIBUD (Sediment Budgets in Cold Environments) Programme was formed in 2005 to address this existing key knowledge gap. SEDIBUD currently has about 400 members worldwide and the Steering Committee of this international programme is composed of ten scientists from eight different countries: Achim A. Beylich (Chair) (Norway), Armelle Decaulne (Secretary) (France), John C. Dixon (USA), Scott F. Lamoureux (Vice-Chair) (Canada), John F. Orwin (Canada), Jan-Christoph Otto (Austria), Irina Overeem (USA), Thorsteinn Sæmundsson (Iceland), Jeff Warburton (UK) and Zbigniew Zwolinski (Poland). The central research question of this global group of scientists is to: Assess and model the contemporary sedimentary fluxes in cold climates, with emphasis on both particulate and dissolved components. Initially formed as European Science Foundation (ESF) Network SEDIFLUX (Sedimentary Source-to-Sink Fluxes in Cold Environments) (2004 - ), SEDIBUD has further expanded to a global group of researchers with field research sites located in polar and alpine regions in the northern and southern hemisphere. Research carried out at each of the close to 50 defined SEDIBUD key test sites varies by programme, logistics and available

  3. Texas A & I University Child Development Associate Training Materials: Book C. Competency C: Building Positive Self-Concept and Individual Strength in Young Children.

    ERIC Educational Resources Information Center

    Texas A and I Univ., Kingsville.

    This volume, the fourth in a series of seven, contains the two learning modules which focus on the third Child Development Associate (CDA) competency, building positive self-concept and individual strength in young children, in the performance based curriculum of the Texas A & I Bilingual Bicultural Child Development Associate Training Program.…

  4. 30 CFR 57.22234 - Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... areas, except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR..., except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Actions at 1.0 percent methane (I-A, I-B,...

  5. 30 CFR 57.22234 - Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... areas, except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR..., except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Actions at 1.0 percent methane (I-A, I-B,...

  6. 30 CFR 57.22234 - Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... areas, except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR..., except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Actions at 1.0 percent methane (I-A, I-B,...

  7. apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Vezeridis, Alexander; Dafnis, Ioannis; Chroni, Angeliki; Kardassis, Dimitris; Zannis, Vassilis I

    2014-07-01

    The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE-deficient (apoE(-/-)) or apoA-I-deficient (apoA-I(-/-))×apoE(-/-) mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE(-/-) mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE(-/-) mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE(-/-) mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full-length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL. PMID:24776540

  8. 30 CFR 57.22234 - Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines). 57.22234 Section 57.22234 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Safety...

  9. Relationship between Tobacco, cagA and vacA i1 Virulence Factors and Bacterial Load in Patients Infected by Helicobacter pylori

    PubMed Central

    Aguirre, Estefanía; Aragones, Nuria; Saez, Jesús; Galiana, Antonio; Sola-Vera, Javier; Ruiz-García, Montserrat; Paz-Zulueta, María; Sarabia-Lavín, Raquel; Brotons, Alicia; López-Girona, Elena; Pérez, Estefanía; Sillero, Carlos

    2015-01-01

    Background and Aim Several biological and epidemiological studies support a relationship between smoking and Helicobacter pylori (H. pylori) to increase the risk of pathology. However, there have been few studies on the potential synergistic association between specific cagA and vacA virulence factors and smoking in patients infected by Helicobacter pylori. We studied the relationship between smoking and cagA, vacA i1 virulence factors and bacterial load in H. pylori infected patients. Methods Biopsies of the gastric corpus and antrum from 155 consecutive patients in whom there was clinical suspicion of infection by H. pylori were processed. In 106 patients H. pylori infection was detected. Molecular methods were used to quantify the number of microorganisms and presence of cagA and vacA i1 genes. A standardized questionnaire was used to obtain patients’ clinical data and lifestyle variables, including tobacco and alcohol consumption. Adjusted Odds Ratios (ORadjusted) were estimated by unconditional logistic regression. Results cagA was significantly associated with active-smoking at endoscope: ORadjusted 4.52. Evidence of association was found for vacA i1 (ORadjusted 3.15). Bacterial load was higher in active-smokers, although these differences did not yield statistical significance (median of 262.2 versus 79.4 copies of H. pylori per cell). Conclusions The association between smoking and a higher risk of being infected by a virulent bacterial population and with higher bacterial load, support a complex interaction between H. pylori infection and environmental factors. PMID:25794002

  10. Helicobacter pylori vacA i region polymorphism but not babA2 status associated to gastric cancer risk in northwestern Iran.

    PubMed

    Mottaghi, Batool; Safaralizadeh, Reza; Bonyadi, Morteza; Latifi-Navid, Saeid; Somi, Mohammad Hossein

    2016-02-01

    Helicobacter pylori-specific genotypes have been strongly associated with an increased risk of gastric cancer (GC). The aim of the present work was to study the associations of H. pylori virulence factors, vacA i region polymorphisms and babA2 status with GC risk in Azerbaijan patients. The DNA extracted from gastric biopsy specimens was used to access the babA2 and vacA genotypes. Overall, babA2 was present in 85.39 % (76/89) of H. pylori strains: 19 out of 24 (79.16 %) strains from GC, 16 out of 17 (94.14 %) strains from peptic ulcer disease (PUD) and 41 out of 48 (85.14 %) strains from chronic gastritis. No significant association was found between babA2 genotype and clinical outcomes (P > 0.05). i1 vacA polymorphism was detected in 46/89 (51.68 %) strains: in 21/24 (87.5 %), 6/17 (35.29 %) and 19/48 (39.58 %) patients with GC, PUD and chronic gastritis, respectively. i2 allele was detected in 43 (48.31 %) out of all 89 strains examined: 3 (14.28 %) of 24 strains from GC, 11 (64.71 %) of 17 from PUD, and 29 (60.42 %) of 48 strains from chronic gastritis. In this study, multiple linear regression analysis confirmed the strong association of i1 allele with GC (partial regression correlation 0.455 ± 0.101; P = 0). Results of multiple logistic regression analysis showed that vacA i1 genotype was significantly associated with GC compared with a control group (gastritis) (odds ratio 13.142, 95 % CI 3.116-55.430; P = 0). Findings from the measurement of H. pylori babA2 and vacA genotypes indicate a strong correlation between the vacA i1 allele and GC risk in the Azerbaijan area of Iran.

  11. Giffonins A-I, antioxidant cyclized diarylheptanoids from the leaves of the hazelnut tree (Corylus avellana), source of the Italian PGI product "Nocciola di Giffoni".

    PubMed

    Masullo, Milena; Cerulli, Antonietta; Olas, Beata; Pizza, Cosimo; Piacente, Sonia

    2015-01-23

    Eight new diaryl ether heptanoids, giffonins A-H (1-8), and one diaryl heptanoid, giffonin I (9), were isolated from the methanol extract of the leaves of Corylus avellana. Its hazelnut is the PGI product of the Campania region (Italy) known as "Nocciola di Giffoni". The MeOH extract of C. avellana leaves and giffonins A-I (1-9) were evaluated for their inhibitory effects on human plasma lipid peroxidation induced by H2O2 and H2O2/Fe(2+), by measuring the concentration of TBARS (thiobarbituric acid reactive substances). Compounds 4 and 8 at 10 μM reduced both H2O2- and H2O2/Fe(2+)-induced lipid peroxidation by more than 60% and 50%, respectively, indicating higher activity than curcumin used as reference compound.

  12. Giffonins A-I, antioxidant cyclized diarylheptanoids from the leaves of the hazelnut tree (Corylus avellana), source of the Italian PGI product "Nocciola di Giffoni".

    PubMed

    Masullo, Milena; Cerulli, Antonietta; Olas, Beata; Pizza, Cosimo; Piacente, Sonia

    2015-01-23

    Eight new diaryl ether heptanoids, giffonins A-H (1-8), and one diaryl heptanoid, giffonin I (9), were isolated from the methanol extract of the leaves of Corylus avellana. Its hazelnut is the PGI product of the Campania region (Italy) known as "Nocciola di Giffoni". The MeOH extract of C. avellana leaves and giffonins A-I (1-9) were evaluated for their inhibitory effects on human plasma lipid peroxidation induced by H2O2 and H2O2/Fe(2+), by measuring the concentration of TBARS (thiobarbituric acid reactive substances). Compounds 4 and 8 at 10 μM reduced both H2O2- and H2O2/Fe(2+)-induced lipid peroxidation by more than 60% and 50%, respectively, indicating higher activity than curcumin used as reference compound. PMID:25420236

  13. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  14. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  15. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  16. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  17. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  18. Gravity-dependent differentiation and root coils in Arabidopsis thaliana wild type and phospholipase-A-I knockdown mutant grown on the International Space Station.

    PubMed

    Scherer, G F E; Pietrzyk, P

    2014-01-01

    Arabidopsis roots on 45° tilted agar in 1-g grow in wave-like figures. In addition to waves, formation of root coils is observed in several mutants compromised in gravitropism and/or auxin transport. The knockdown mutant ppla-I-1 of patatin-related phospholipase-A-I is delayed in root gravitropism and forms increased numbers of root coils. Three known factors contribute to waving: circumnutation, gravisensing and negative thigmotropism. In microgravity, deprivation of wild type (WT) and mutant roots of gravisensing and thigmotropism and circumnutation (known to slow down in microgravity, and could potentially lead to fewer waves or increased coiling in both WT and mutant). To resolve this, mutant ppla-I-1 and WT were grown in the BIOLAB facility in the International Space Station. In 1-g, roots of both types only showed waving. In the first experiment in microgravity, the mutant after 9 days formed far more coils than in 1-g but the WT also formed several coils. After 24 days in microgravity, in both types the coils were numerous with slightly more in the mutant. In the second experiment, after 9 days in microgravity only the mutant formed coils and the WT grew arcuated roots. Cell file rotation (CFR) on the mutant root surface in microgravity decreased in comparison to WT, and thus was not important for coiling. Several additional developmental responses (hypocotyl elongation, lateral root formation, cotyledon expansion) were found to be gravity-influenced. We tentatively discuss these in the context of disturbances in auxin transport, which are known to decrease through lack of gravity.

  19. ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma.

    PubMed

    Lin, Chao; Wu, Wen-Chuan; Zhao, Guo-Chao; Wang, Dan-Song; Lou, Wen-Hui; Jin, Da-Yong

    2016-08-01

    Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19-9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC.A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens.Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118-0.774; P = 0.013) of patients with PDAC after curative surgery.ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers.

  20. Intake of cooked tomato sauce preserves coronary endothelial function and improves apolipoprotein A-I and apolipoprotein J protein profile in high-density lipoproteins.

    PubMed

    Vilahur, Gemma; Cubedo, Judit; Padró, Teresa; Casaní, Laura; Mendieta, Guiomar; González, Alicia; Badimon, Lina

    2015-07-01

    Intake of tomatoes has been linked with healthy diets (eg, Mediterranean diet). However, it remains unknown whether tomato intake exerts protective effects on the vasculature. The aim of this study was to determine whether medium-term supplementation with cooked tomato sauce (CTS) Mediterranean style (sofrito) attenuates diet-induced coronary endothelial dysfunction in an animal model with clinical impact and explore the mechanisms behind the effects. Pigs (N = 18) were fed a 10-day hypercholesterolemic diet. Half of the animals were given a supplement of 100 g/d of CTS (21.5 mg lycopene per day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide synthase [eNOS] inhibitor) were measured using flow Doppler. In the coronary arteries, we investigated eNOS gene expression and activation, monocyte chemoattractant protein 1 (MCP-1) expression, and oxidative DNA damage. In the circulation, we investigated lipoprotein resistance to oxidation and the differential proteomic protein profile. In dyslipidemic animals, CTS intake prevented diet-induced impairment of receptor-operated and nonreceptor-operated endothelial-dependent coronary vasodilation. These beneficial effects were associated with enhanced eNOS transcription and activation and diminished DNA damage in the coronary arteries. CTS-fed animals showed lower lipid peroxidation, higher high-density lipoprotein (HDL) antioxidant potential and plasma lycopene levels of 0.16 mg/L. Interestingly, improved HDL functionality was associated with protein profile changes in apolipoprotein A-I and apolipoprotein J. Lipids levels and MCP-1 expression were not affected by CTS. We report that CTS intake protects against low-density lipoprotein-induced coronary endothelial dysfunction by reducing oxidative damage, enhancing eNOS expression and activity, and improving HDL functionality.

  1. Hepatocyte-specific Dyrk1a gene transfer rescues plasma apolipoprotein A-I levels and aortic Akt/GSK3 pathways in hyperhomocysteinemic mice.

    PubMed

    Tlili, Asma; Jacobs, Frank; de Koning, Leanne; Mohamed, Sirine; Bui, Linh-Chi; Dairou, Julien; Belin, Nicole; Ducros, Véronique; Dubois, Thierry; Paul, Jean-Louis; Delabar, Jean-Maurice; De Geest, Bart; Janel, Nathalie

    2013-06-01

    Hyperhomocysteinemia, characterized by high plasma homocysteine levels, is recognized as an independent risk factor for cardiovascular diseases. The increased synthesis of homocysteine, a product of methionine metabolism involving B vitamins, and its slower intracellular utilization cause increased flux into the blood. Plasma homocysteine level is an important reflection of hepatic methionine metabolism and the rate of processes modified by B vitamins as well as different enzyme activity. Lowering homocysteine might offer therapeutic benefits. However, approximately 50% of hyperhomocysteinemic patients due to cystathionine-beta-synthase deficiency are biochemically responsive to pharmacological doses of B vitamins. Therefore, effective treatments to reduce homocysteine levels are needed, and gene therapy could provide a novel approach. We recently showed that hepatic expression of DYRK1A, a serine/threonine kinase, is negatively correlated with plasma homocysteine levels in cystathionine-beta-synthase deficient mice, a mouse model of hyperhomocysteinemia. Therefore, Dyrk1a is a good candidate for gene therapy to normalize homocysteine levels. We then used an adenoviral construct designed to restrict expression of DYRK1A to hepatocytes, and found decreased plasma homocysteine levels after hepatocyte-specific Dyrk1a gene transfer in hyperhomocysteinemic mice. The elevation of pyridoxal phosphate was consistent with the increase in cystathionine-beta-synthase activity. Commensurate with the decreased plasma homocysteine levels, targeted hepatic expression of DYRK1A resulted in elevated plasma paraoxonase-1 activity and apolipoprotein A-I levels, and rescued the Akt/GSK3 signaling pathways in aorta of mice, which can prevent homocysteine-induced endothelial dysfunction. These results demonstrate that hepatocyte-restricted Dyrk1a gene transfer can offer a useful therapeutic targets for the development of new selective homocysteine lowering therapy. PMID:23429073

  2. ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma

    PubMed Central

    Lin, Chao; Wu, Wen-Chuan; Zhao, Guo-Chao; Wang, Dan-Song; Lou, Wen-Hui; Jin, Da-Yong

    2016-01-01

    Abstract Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19-9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC. A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens. Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118–0.774; P = 0.013) of patients with PDAC after curative surgery. ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers. PMID:27495108

  3. Gravity-dependent differentiation and root coils in Arabidopsis thaliana wild type and phospholipase-A-I knockdown mutant grown on the International Space Station.

    PubMed

    Scherer, G F E; Pietrzyk, P

    2014-01-01

    Arabidopsis roots on 45° tilted agar in 1-g grow in wave-like figures. In addition to waves, formation of root coils is observed in several mutants compromised in gravitropism and/or auxin transport. The knockdown mutant ppla-I-1 of patatin-related phospholipase-A-I is delayed in root gravitropism and forms increased numbers of root coils. Three known factors contribute to waving: circumnutation, gravisensing and negative thigmotropism. In microgravity, deprivation of wild type (WT) and mutant roots of gravisensing and thigmotropism and circumnutation (known to slow down in microgravity, and could potentially lead to fewer waves or increased coiling in both WT and mutant). To resolve this, mutant ppla-I-1 and WT were grown in the BIOLAB facility in the International Space Station. In 1-g, roots of both types only showed waving. In the first experiment in microgravity, the mutant after 9 days formed far more coils than in 1-g but the WT also formed several coils. After 24 days in microgravity, in both types the coils were numerous with slightly more in the mutant. In the second experiment, after 9 days in microgravity only the mutant formed coils and the WT grew arcuated roots. Cell file rotation (CFR) on the mutant root surface in microgravity decreased in comparison to WT, and thus was not important for coiling. Several additional developmental responses (hypocotyl elongation, lateral root formation, cotyledon expansion) were found to be gravity-influenced. We tentatively discuss these in the context of disturbances in auxin transport, which are known to decrease through lack of gravity. PMID:24373011

  4. The I.A.G. / A.I.G. SEDIBUD Book Project: Source-to-Sink Fluxes in Undisturbed Cold Environments

    NASA Astrophysics Data System (ADS)

    Beylich, Achim A.; Dixon, John C.; Zwolinski, Zbigniew

    2015-04-01

    The currently prepared SEDIBUD Book on "Source-to-Sink Fluxes in Undisturbed Cold Environments" (edited by Achim A. Beylich, John C. Dixon and Zbigniew Zwolinski and published by Cambridge University Press) is summarizing and synthesizing the achievements of the International Association of Geomorphologists` (I.A.G./A.I.G.) Working Group SEDIBUD (Sediment Budgets in Cold Environments), which has been active since 2005 (http://www.geomorph.org/wg/wgsb.html). Amplified climate change and ecological sensitivity of largely undisturbed polar and high-altitude cold climate environments have been highlighted as key global environmental issues. The effects of projected climate change will change surface environments in cold regions and will alter the fluxes of sediments, nutrients and solutes, but the absence of quantitative data and coordinated geomorphic process monitoring and analysis to understand the sensitivity of the Earth surface environment in these largely undisturbed environments is acute. Our book addresses this existing key knowledge gap. The applied approach of integrating comparable and longer-term field datasets on contemporary solute and sedimentary fluxes from a number of different defined cold climate catchment geosystems for better understanding (i) the environmental drivers and rates of contemporary denudational surface processes and (ii) possible effects of projected climate change in cold regions is unique in the field of geomorphology. Largely undisturbed cold climate environments can provide baseline data for modeling the effects of environmental change. The book synthesizes work carried out by numerous SEDIBUD Members over the last decade in numerous cold climate catchment geosystems worldwide. For reaching a global cover of different cold climate environments the book is - after providing an introduction part and a basic part on climate change in cold environments and general implications for solute and sedimentary fluxes - dealing in different

  5. 2011-12 National Postsecondary Student Aid Study (NPSAS:12). Data File Documentation. Appendix A-I. NCES 2014-182_1

    ERIC Educational Resources Information Center

    Wine, Jennifer; Bryan, Michael; Siegel, Peter

    2013-01-01

    The National Postsecondary Student Aid Study (NPSAS) helps fulfill the U.S. Department of Education&apos;s National Center for Education Statistics (NCES) mandate to collect, analyze, and publish statistics related to education. The purpose of NPSAS is to compile a comprehensive research dataset, based on student-level records, on financial aid…

  6. 30 CFR 57.22501 - Personal electric lamps (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Personal electric lamps (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22501 Section 57.22501 Mineral Resources MINE SAFETY AND... Illumination § 57.22501 Personal electric lamps (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B...

  7. ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT.

    PubMed

    Duka, Adelina; Fotakis, Panagiotis; Georgiadou, Dimitra; Kateifides, Andreas; Tzavlaki, Kalliopi; von Eckardstein, Leonard; Stratikos, Efstratios; Kardassis, Dimitris; Zannis, Vassilis I

    2013-01-01

    The objective of this study was to establish the role of apoA-IV, ABCA1, and LCAT in the biogenesis of apoA-IV-containing HDL (HDL-A-IV) using different mouse models. Adenovirus-mediated gene transfer of apoA-IV in apoA-I(-/-) mice did not change plasma lipid levels. ApoA-IV floated in the HDL2/HDL3 region, promoted the formation of spherical HDL particles as determined by electron microscopy, and generated mostly α- and a few pre-β-like HDL subpopulations. Gene transfer of apoA-IV in apoA-I(-/-) × apoE(-/-) mice increased plasma cholesterol and triglyceride levels, and 80% of the protein was distributed in the VLDL/IDL/LDL region. This treatment likewise generated α- and pre-β-like HDL subpopulations. Spherical and α-migrating HDL particles were not detectable following gene transfer of apoA-IV in ABCA1(-/-) or LCAT(-/-) mice. Coexpression of apoA-IV and LCAT in apoA-I(-/-) mice restored the formation of HDL-A-IV. Lipid-free apoA-IV and reconstituted HDL-A-IV promoted ABCA1 and scavenger receptor BI (SR-BI)-mediated cholesterol efflux, respectively, as efficiently as apoA-I and apoE. Our findings are consistent with a novel function of apoA-IV in the biogenesis of discrete HDL-A-IV particles with the participation of ABCA1 and LCAT, and may explain previously reported anti-inflammatory and atheroprotective properties of apoA-IV. PMID:23132909

  8. Full-length apolipoprotein E protects against the neurotoxicity of an apoE-related peptide

    PubMed Central

    Crutcher, K.A.; Lilley, H.N.; Anthony, S. R.; Zhou, W.; Narayanaswami, V.

    2009-01-01

    Apolipoprotein E was found to protect against the neurotoxic effects of a dimeric peptide derived from the receptor-binding region of this protein (residues 141–149). Both apoE3 and apoE4 conferred protection but the major N-terminal fragment of each isoform did not. Nor was significant protection provided by bovine serum albumin or apoA-I. Full-length apoE3 and apoE4 also inhibited the uptake of a fluorescent-labeled derivative of the peptide, suggesting that the mechanism of inhibition might involve competition for cell surface receptors/proteoglycans that mediate endocytosis and/or signaling pathways. These results might bear on the question of the role of apoE in neuronal degeneration, such as occurs in Alzheimer’s disease where apoE4 confers a significantly greater risk of pathology. PMID:19836363

  9. CagA phosphorylation EPIYA-C motifs and the vacA i genotype in Helicobacter pylori strains of asymptomatic children from a high-risk gastric cancer area in northeastern Brazil

    PubMed Central

    Braga, Lucia Libanez Bessa Campelo; de Oliveira, Maria Aparecida Alves; Gonçalves, Maria Helane Rocha Batista; Chaves, Fernando Kennedy; Benigno, Tiago Gomes da Silva; Gomes, Adriana Dias; Silva, Cícero Igor Simões Moura; Anacleto, Charles; Batista, Sérgio de Assis; Queiroz, Dulciene Maria Magalhães

    2014-01-01

    Helicobacter pylori infection is one of the most common infections worldwide and is associated with gastric diseases. Virulence factors such as VacA and CagA have been shown to increase the risk of these diseases. Studies have suggested a causal role of CagA EPIYA-C in gastric carcinogenesis and this factor has been shown to be geographically diverse. We investigated the number of CagA EPIYA motifs and the vacA i genotypes in H. pylori strains from asymptomatic children. We included samples from 40 infected children (18 females and 22 males), extracted DNA directly from the gastric mucus/juice (obtained using the string procedure) and analysed the DNA using polymerase chain reaction and DNA sequencing. The vacA i1 genotype was present in 30 (75%) samples, the i2 allele was present in nine (22.5%) samples and both alleles were present in one (2.5%) sample. The cagA-positive samples showed distinct patterns in the 3’ variable region of cagA and 18 of the 30 (60%) strains contained 1 EPIYA-C motif, whereas 12 (40%) strains contained two EPIYA-C motifs. We confirmed that the studied population was colonised early by the most virulent H. pylori strains, as demonstrated by the high frequency of the vacA i1 allele and the high number of EPIYA-C motifs. Therefore, asymptomatic children from an urban community in Fortaleza in northeastern Brazil are frequently colonised with the most virulent H. pylori strains. PMID:25494468

  10. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.

    PubMed

    Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok; Alexander, Veronica J; Digenio, Andres; Yang, Qingqing; Miller, Yury I; Witztum, Joseph L; Tsimikas, Sotirios

    2016-04-01

    Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

  11. The association between serum ApoE genetic polymorphism and serum lipid level in hemodialysis patients.

    PubMed

    Zhang, Yong; Zhang, Linlin; Cao, Bo

    2015-02-01

    Growing evidence indicates that apolipoprotein E (ApoE) is one of the most important candidate genes for influencing the development of hemodialysis (HD). This study aims to detect the potential association between serum ApoE genetic polymorphism and serum lipid level in HD. A total of 485 subjects were enrolled in this case-control study. The created restriction site polymerase chain reaction and DNA sequencing methods were used to investigate ApoE c.109G>A genetic polymorphism. Our data suggested that there were significant differences in the distribution of allelic and genotypic frequencies between HD patients and healthy controls. The levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, ApoA-I, ApoB, ApoE, and lipoprotein (a) for genotype AA were different from genotype GG in HD patients and healthy controls. Our findings support that the ApoE c.109G>A genetic polymorphism might influence the development of HD and could be a risk factor for assessing HD.

  12. An experimental study on amelioration of dyslipidemia-induced atherosclesis by Clematichinenoside through regulating Peroxisome proliferator-activated receptor-α mediated apolipoprotein A-I, A-II and C-III.

    PubMed

    Liu, Chao; Guo, Qianqian; Lu, Mengchen; Li, Yunman

    2015-08-15

    Prevention or amelioration the prevalence of atherosclerosis has been an effective strategy in the management of cardiovascular diseases. The aim of the study was to scrutinize the effect of Clematichinenoside (AR) on dyslipidemia-induced atherosclerosis and explore its capability on expression of Peroxisome proliferator-activated receptor-α (PPAR-alpha), apolipoprotein A-I (APOA1) and A-II (APOA2), and suppression of apolipoprotein C-III (APOC3) genes and proteins. In the present study, we investigated atherosclerosis effect of AR using a combination of high-fat diet and balloon injury model in rabbits. The levels of biochemical indicators were evaluated in plasma, liver and HepG2 cells using immunoassay technology. In order to expose the underlying mechanism, we evaluated the regulation of PPAR-alpha, APOA1, APOA2 and APOC3 expressions by AR, and we further evaluated the interactions between them after transfection with shRNA (shPPAR-alpha) and, the action of PPAR-alpha in HepG2 cells. We could find that AR markedly promoted the PPAR-alpha transfer from cytoplasm to nucleus which resulted in the alteration of APOA1, APOA2 and APOC3 expressions in HepG2 cells. Moreover, AR significantly reduced total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) levels, and elevated high-density lipoprotein cholesterol (HDL-C) level, which play an important role in dyslipidemia-induced atherosclerosis. In conclusion, AR ameliorated atherosclerosis via the regulation of hepatic lipid metabolism, and AR also contributed to the activation of PPAR-alpha, APOA1, APOA2 and APOC3. Therefore, AR could be a potential therapeutic agent in the treatment of atherosclerosis.

  13. Comparative antiatherogenic effects of intravenous AAV8- and AAV2-mediated ApoA-IMilano gene transfer in hypercholesterolemic mice.

    PubMed

    Tian, Fang; Wang, Lai; Arias, Ana; Yang, Mingjie; Sharifi, Behrooz G; Shah, Prediman K

    2015-01-01

    Apolipoprotein A-IMilano (ApoA-IM), a naturally occurring Arg173 to Cys mutant of ApoA-I, has been shown to reduce atherosclerosis in animal models and in a small phase 2 human trial. We have shown superior atheroprotective effects of ApoA-IM gene compared with wild-type ApoA-I gene using transplantation of retrovirally transduced bone marrow in ApoA-I/ApoE null mice. In this study, we compared the antiatherogenic efficacy of ApoA-IM gene transfer using Recombinant adeno-associated virus (rAAV) 2 or rAAV8 as vectors in ApoA-I/ApoE null mice. Mice received a single intravenous injection of 1.2 × 10(12) vector genomes of AAV2 or AAV8 vectors expressing ApoA-IM or control empty vectors (12 mice/group). Circulating levels of ApoA-IM were higher in recipients of AAV8 compared with AAV2 at 4, 12, and 20 weeks postinjection. Qualitative polymerase chain reaction analysis of RNA collected from different tissues showed that the AAV8-mediated gene transfer resulted in a more efficient transgene expression in the heart, brain, liver, lung, spleen, and kidney of the recipient mice compared with AAV2. Intravenous AAV8-ApoA-IM injection reduced atherosclerosis in the whole aorta (P < .01), aortic sinuses (P < .05), and brachiocephalic arteries (P < .05) compared with the vector control, whereas there was no statistically significant reduction in atherosclerosis in mice receiving intravenous AAV2-ApoA-IM. The ApoA-IM gene was expressed in the aortic tissue of mice receiving AAV8 ApoA-IM but not in those receiving AAV2 ApoA-IM. Immunostaining showed that compared with the vector control, there was reduced macrophage content in the brachiocephalic (P < .05) and aortic sinus plaques (P < .05) of AAV8 ApoA-IM recipients but not in the recipients of AAV2 ApoA-IM. Thus, intravenous injection of AAV8 is more effective than intravenous injection of AAV2 in the expression of ApoA-IM gene. These data provide support for the potential feasibility of this approach for atheroprotection in

  14. FIRST Quantum-(1980)-Computing DISCOVERY in Siegel-Rosen-Feynman-...A.-I. Neural-Networks: Artificial(ANN)/Biological(BNN) and Siegel FIRST Semantic-Web and Siegel FIRST ``Page''-``Brin'' ``PageRank'' PRE-Google Search-Engines!!!

    NASA Astrophysics Data System (ADS)

    Rosen, Charles; Siegel, Edward Carl-Ludwig; Feynman, Richard; Wunderman, Irwin; Smith, Adolph; Marinov, Vesco; Goldman, Jacob; Brine, Sergey; Poge, Larry; Schmidt, Erich; Young, Frederic; Goates-Bulmer, William-Steven; Lewis-Tsurakov-Altshuler, Thomas-Valerie-Genot; Ibm/Exxon Collaboration; Google/Uw Collaboration; Microsoft/Amazon Collaboration; Oracle/Sun Collaboration; Ostp/Dod/Dia/Nsa/W.-F./Boa/Ubs/Ub Collaboration

    2013-03-01

    Belew[Finding Out About, Cambridge(2000)] and separately full-decade pre-Page/Brin/Google FIRST Siegel-Rosen(Machine-Intelligence/Atherton)-Feynman-Smith-Marinov(Guzik Enterprises/Exxon-Enterprises/A.-I./Santa Clara)-Wunderman(H.-P.) [IBM Conf. on Computers and Mathematics, Stanford(1986); APS Mtgs.(1980s): Palo Alto/Santa Clara/San Francisco/...(1980s) MRS Spring-Mtgs.(1980s): Palo Alto/San Jose/San Francisco/...(1980-1992) FIRST quantum-computing via Bose-Einstein quantum-statistics(BEQS) Bose-Einstein CONDENSATION (BEC) in artificial-intelligence(A-I) artificial neural-networks(A-N-N) and biological neural-networks(B-N-N) and Siegel[J. Noncrystalline-Solids 40, 453(1980); Symp. on Fractals..., MRS Fall-Mtg., Boston(1989)-5-papers; Symp. on Scaling..., (1990); Symp. on Transport in Geometric-Constraint (1990)

  15. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice.

    PubMed

    Jahagirdar, Ravi; Zhang, Haiyan; Azhar, Salman; Tobin, Jennifer; Attwell, Sarah; Yu, Raymond; Wu, Jin; McLure, Kevin G; Hansen, Henrik C; Wagner, Gregory S; Young, Peter R; Srivastava, Rai Ajit K; Wong, Norman C W; Johansson, Jan

    2014-09-01

    Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ∼50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin, a proinflammatory protein, known to bind with HDL/apoA-I, decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10, MIP1(®) and MDC. These results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities.

  16. Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys.

    PubMed

    Kempen, Herman J; Gomaraschi, Monica; Bellibas, S Eralp; Plassmann, Stephanie; Zerler, Brad; Collins, Heidi L; Adelman, Steven J; Calabresi, Laura; Wijngaard, Peter L J

    2013-09-01

    MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation. PMID:23828780

  17. Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys[S

    PubMed Central

    Kempen, Herman J.; Gomaraschi, Monica; Bellibas, S. Eralp; Plassmann, Stephanie; Zerler, Brad; Collins, Heidi L.; Adelman, Steven J.; Calabresi, Laura; Wijngaard, Peter L. J.

    2013-01-01

    MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation. PMID:23828780

  18. V.A. I Animal Science Technical Information.

    ERIC Educational Resources Information Center

    Texas A and M Univ., College Station. Vocational Instructional Services.

    This packet contains two units of informational materials and transparency masters, with accompanying scripts, for teachers to use in an animal science course in vocational agriculture. Unit A on breeds and selection of livestock and poultry includes 13 topics covering beef cattle, dairy cattle, swine, horses, goats, sheep, and poultry. Unit B on…

  19. Corneal crosslinking with riboflavin and ultraviolet A. I. Principles.

    PubMed

    Raiskup, Frederik; Spoerl, Eberhard

    2013-04-01

    Changes in the biomechanical properties of the human cornea play an important role in the pathogenesis of corneal ectatic diseases. Biomechanical investigation shows significant differences between human ectatic corneas and normal corneas, including decreased stiffness and reduction of collagen crosslinks in the ectatic cornea. Induction of crosslinks is a well-established procedure in polymer chemistry to increase the elastic modulus of materials. Crosslinking (CXL) in connective tissue can occur during aging and as a side effect of diabetes mellitus. CXL has been used medically to increase stability and reduce the biodegradation of collagen-based biomaterials for bioprostheses. CXL of the cornea using riboflavin and UVA light with a wavelength of 370 nm and a dosage of 5.4 J/cm² is a new approach that increases the mechanical and biochemical stability of stromal tissue. This technique combines the principles of CXL (chemical and nonenzymatic) and the biochemical mechanisms of photo-oxidative CXL with riboflavin as a photosensitizer. In this review, the enrichment of riboflavin in the stroma by standard (epi-off) and transepithelial (epi-on) CXL is discussed. The theoretical and experimental measurements of the absorption of UV light explain the stronger CXL effect in the anterior stroma and its importance for the prevention of damage to the endothelial cells. UV devices are described. Changes of the physical properties after CXL, as well as the cellular changes, are discussed. From these basic investigations, treatment parameters for effective and safe CXL are identified.

  20. A.I.e. in-flight blood collection system

    NASA Technical Reports Server (NTRS)

    Hank, J. M.

    1977-01-01

    The hardware selected to obtain and partially process human blood samples during the Skylab missions is described and consists of the following three major items: a centrifuge, an evacuation regulator, and a Beta cloth bag.

  1. Improved rocket ozonesonde (ROCOZ-A). I - Demonstration of precision

    NASA Technical Reports Server (NTRS)

    Holland, A. C.; Barnes, R. A.; Lee, H. S.

    1985-01-01

    Measurements of the daytime ozone distribution in the stratosphere have been made with an improved rocket ozonesonde (ROCOZ-A). Vertical cumulative ozone as a function of geometric altitude is the basic information content of these measurements. The instrument-to-instrument repeatability of the ozonesonde was determined by two series of four soundings each. At one standard deviation the instrument repeatability averages from 2.0 to 2.5 percent over the entire altitude range of the instrument. The worst measured repeatability is 3.7 percent at 55 km for one of the flight series.

  2. Artificial Intelligence: Is the Future Now for A.I.?

    ERIC Educational Resources Information Center

    Ramaswami, Rama

    2009-01-01

    In education, artificial intelligence (AI) has not made much headway. In the one area where it would seem poised to lend the most benefit--assessment--the reliance on standardized tests, intensified by the demands of the No Child Left Behind Act of 2001, which holds schools accountable for whether students pass statewide exams, precludes its use.…

  3. A.I.D. Economic Data Book: Latin America.

    ERIC Educational Resources Information Center

    Agency for International Development (Dept. of State), Washington, DC.

    This data book, updating a December 1968 publication, is designed to serve the internal program and operational needs of the Agency for International Development. More than 19 Latin American republics are referred to in major sections on: (1) Latin America in the Free World: population and production, (2) summary of basic data, (3) population…

  4. Importance of Apolipoprotein A-I in Multiple Sclerosis

    PubMed Central

    Gardner, Lidia A.; Levin, Michael C.

    2015-01-01

    Jean-Martin Charcot has first described multiple sclerosis (MS) as a disease of the central nervous system (CNS) over a century ago. MS remains incurable today, and treatment options are limited to disease modifying drugs. Over the years, significant advances in understanding disease pathology have been made in autoimmune and neurodegenerative components. Despite the fact that brain is the most lipid rich organ in human body, the importance of lipid metabolism has not been extensively studied in this disorder. In MS, the CNS is under attack by a person’s own immune system. Autoantigens and autoantibodies are known to cause devastation of myelin through up regulation of T-cells and cytokines, which penetrate through the blood–brain barrier to cause inflammation and myelin destruction. The anti-inflammatory role of high-density lipoproteins (HDLs) has been implicated in a plethora of biological processes: vasodilation, immunity to infection, oxidation, inflammation, and apoptosis. However, it is not known what role HDL plays in neurological function and myelin repair in MS. Understanding of lipid metabolism in the CNS and in the periphery might unveil new therapeutic targets and explain the partial success of some existing MS therapies. PMID:26635608

  5. Comparison of anti-endotoxin activity of apoE and apoA mimetic derivatives of a model amphipathic peptide 18A.

    PubMed

    Sharifov, Oleg F; Nayyar, Gaurav; Ternovoy, Vladimir V; Palgunachari, Mayakonda N; Garber, David W; Anantharamaiah, Gm; Gupta, Himanshu

    2014-11-01

    Endotoxemia is a major cause of chronic inflammation, and is an important pathogenic factor in the development of metabolic syndrome and atherosclerosis. Human apolipoprotein E (apoE) and apoA-I are protein components of high-density lipoprotein, which have strong anti-endotoxin activity. Here, we compared anti-endotoxin activity of Ac-hE18A-NH2 and 4F peptides, modified from model amphipathic helical 18A peptide, to mimic, respectively, apoE and apoA-I properties. Ac-hE18A-NH2, stronger than 4F, inhibited endotoxin activity and disaggregated Escherichia coli 055:B5 (wild smooth serotype). Ac-hE18A-NH2 and 4F inhibited endotoxin activity of E. coli 026:B6 (rough-like serotype) to a similar degree. This suggests that Ac-hE18A-NH2 as a dual-domain molecule might interact with both the lipid A and headgroup of smooth LPS, whereas 4F binds lipid A. In C57BL/6 mice, Ac-hE18A-NH2 was superior to 4F in inhibiting the inflammatory responses mediated by E. coli 055:B5, but not E. coli 026:B6. However, in THP-1 cells, isolated human primary leukocytes, and whole human blood, Ac-hE18A-NH2 reduced responses more strongly than 4F to both E. coli serotypes either when peptides were pre-incubated or co-incubated with LPS, indicating that Ac-hE18A-NH2 also has strong anti-inflammatory effects independent of endotoxin-neutralizing properties. In conclusion, Ac-hE18A-NH2 is more effective than 4F in inhibiting LPS-mediated inflammation, which opens prospective clinical applications for Ac-hE18A-NH2.

  6. Application of Multianalyte Microphysiometry to Characterize Macrophage Metabolic Responses to Oxidized LDL and Effects of an ApoA-1 Mimetic

    PubMed Central

    Kimmel, Danielle W.; Dole, William P.; Cliffel, David E.

    2013-01-01

    Although the interaction of macrophages with oxidized low density liopoprotein (oxLDL) is critical to the pathogenesis of atherosclerosis, relatively little is known about their metabolic response to oxLDL. Our development of the multianalyte microphysiometer (MAMP) allows for simultaneous measurement of extracellular metabolic substrates and products in real-time. Here, we use the MAMP to study changes in the metabolic rates of RAW-264.7 cells undergoing respiratory burst in response to oxLDL. These studies indicate that short duration exposure of macrophages to oxLDL results in time-dependent increases in glucose and oxygen consumption and in lactate production and extracellular acidification rate. Since apolipoprotein A-I (apoA-I) and apoA-I mimetics prevent experimental atherosclerosis, we hypothesized that the metabolic response of the macrophage during respiratory burst can be modulated by apoA-I mimetics. We tested this hypothesis by examining the effects of the apoA-I peptide mimetic, L-4F, alone and complexed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) on the macrophage metabolic response to oxLDL. L-4F and the DMPC/L-4F complexes attenuated the macrophage respiratory burst in response to oxLDL. The MAMP provides a novel approach for studying macrophage ligand-receptor interactions and cellular metabolism and our results provide new insights into the metabolic effects of oxLDL and mechanism of action of apoA-I mimetics. PMID:23313489

  7. Incubation of MDCO-216 (ApoA-IMilano/POPC) with Human Serum Potentiates ABCA1-Mediated Cholesterol Efflux Capacity, Generates New Prebeta-1 HDL, and Causes an Increase in HDL Size.

    PubMed

    Kempen, Herman J; Schranz, Dorota B; Asztalos, Bela F; Otvos, James; Jeyarajah, Elias; Drazul-Schrader, Denise; Collins, Heidi L; Adelman, Steven J; Wijngaard, Peter L J

    2014-01-01

    MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance ((1)H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12-15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. (1)H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the

  8. Incubation of MDCO-216 (ApoA-IMilano/POPC) with Human Serum Potentiates ABCA1-Mediated Cholesterol Efflux Capacity, Generates New Prebeta-1 HDL, and Causes an Increase in HDL Size

    PubMed Central

    Schranz, Dorota B.; Asztalos, Bela F.; Otvos, James; Drazul-Schrader, Denise; Wijngaard, Peter L. J.

    2014-01-01

    MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance (1H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12–15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. 1H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the results

  9. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro

    DOE PAGES

    Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques; Zhu, Xuewei

    2015-07-24

    Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from themore » carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are

  10. Teacher Education: A Selected List of References for A.I.D. Technicians. A.I.D. Bibliography Series: Education and Human Resources No. 3.

    ERIC Educational Resources Information Center

    Agency for International Development (Dept. of State), Washington, DC. Office of Education and Human Resources.

    This annotated bibliography is one of a series designed to provide a guide to the publications of the Agency for International Development (AID) and other agencies working in the field of development assistance. While AID reports and documents are the primary focus of the bibliography, other materials covering the work of international agencies,…

  11. ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia.

    PubMed

    Cubedo, Judit; Padró, Teresa; Alonso, Rodrigo; Mata, Pedro; Badimon, Lina

    2016-06-01

    HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFEHEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum and in HDL3 of patients that will suffer an adverse cardiac event within 3 years. PMID:27112635

  12. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro

    SciTech Connect

    Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques; Zhu, Xuewei

    2015-07-24

    Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These

  13. Plant Science. IV-A-1 to IV-F-2. Basic V.A.I.

    ERIC Educational Resources Information Center

    Texas A and M Univ., College Station. Vocational Instructional Services.

    This packet contains six units of informational materials and transparency masters, with accompanying scripts, for teachers to use in a plant science course in vocational agriculture. Designed especially for use in Texas, the first unit introduces the course through the following topics: economic importance of major crops, major areas of…

  14. The Spitzer Infrared Spectrograph Survey of Protoplanetary Disks in Orion A. I. Disk Properties

    NASA Astrophysics Data System (ADS)

    Kim, K. H.; Watson, Dan M.; Manoj, P.; Forrest, W. J.; Furlan, Elise; Najita, Joan; Sargent, Benjamin; Hernández, Jesús; Calvet, Nuria; Adame, Lucía; Espaillat, Catherine; Megeath, S. T.; Muzerolle, James; McClure, M. K.

    2016-09-01

    We present our investigation of 319 Class II objects in Orion A observed by Spitzer/IRS. We also present the follow-up observations of 120 of these Class II objects in Orion A from the Infrared Telescope Facility/SpeX. We measure continuum spectral indices, equivalent widths, and integrated fluxes that pertain to disk structure and dust composition from IRS spectra of Class II objects in Orion A. We estimate mass accretion rates using hydrogen recombination lines in the SpeX spectra of our targets. Utilizing these properties, we compare the distributions of the disk and dust properties of Orion A disks with those of Taurus disks with respect to position within Orion A (Orion Nebular Cluster [ONC] and L1641) and with the subgroups by the inferred radial structures, such as transitional disks (TDs) versus radially continuous full disks (FDs). Our main findings are as follows. (1) Inner disks evolve faster than the outer disks. (2) The mass accretion rates of TDs and those of radially continuous FDs are statistically significantly displaced from each other. The median mass accretion rate of radially continuous disks in the ONC and L1641 is not very different from that in Taurus. (3) Less grain processing has occurred in the disks in the ONC compared to those in Taurus, based on analysis of the shape index of the 10 μm silicate feature (F 11.3/F 9.8). (4) The 20–31 μm continuum spectral index tracks the projected distance from the most luminous Trapezium star, θ 1 Ori C. A possible explanation is UV ablation of the outer parts of disks.

  15. Educational Planning: A Critical Review and Recommendations for A.I.D.

    ERIC Educational Resources Information Center

    Daniere, A.

    Directed toward personnel in the Agency for International Development (AID), this document reviews the planning of AID educational assistance programs in developing nations. The report recommends that AID personnel should be in a position (a) to assign, organize, and monitor the planning of their own activities in the field of education; (b) to…

  16. A new antitumor antibiotic, chounghwamycin A. I. Taxonomy, isolation and characterization.

    PubMed

    Liu, Y T; Ho, T I; Lee, A R; Chen, C F; Chen, H Y; Chen, C J

    1986-04-01

    Chounghwamycin A, a new antitumor antibiotic produced by a strain of Streptomyces sp. No. PL-D-5, was isolated and characterized. It appeared to belong to the actinomycin group of antibiotics from physico-chemical studies and has an empirical formula of C63H88N11O21. The antibiotic is extractable into an organic solvent from the fermentation broth, possessing potent antileukemic activity against P388 mouse leukemia in mice and antimicrobial activity against Gram-positive bacteria with MIC values about 0.1-0.4 microgram/ml, but showed no activity on Gram-negative bacteria, yeast and fungi tested. PMID:2428073

  17. [P.A.I.S., a personal medical information system. A comprehensive medical knowledge base].

    PubMed

    Münch, E

    1994-06-01

    The electronic medical knowledge data base DOPIS is a compliation of knowledge from various special fields of medicine. Using uniform nomenclature, the data are presented on demand as they would be in a book chapter. Concise updates can be performed at low cost. The primary structure of the concept is the division of medical knowledge into data banks on diagnosis, literature, medication and pharmacology, as well as so-called electronic textbooks. All data banks and electronic textbooks are connected associatively. Visual information is obtained via the image data bank connected to the diagnosis data bank and the electronic books. Moreover, DOPIS has an integrated patient findings system, as well as an image processing and archiving system with research values enabling research functions. The diagnosis and literature data banks can be modified by the user or author, or fed with their own data (a so-called Expert System Shell). For authors from special fields working on the project, an extra Medical Electronic Publishing System has been developed and made available for the electronic textbooks. The model for the knowledge data base has been developed in the field of ENT, the programme implemented and initially ENT data have been stored.

  18. Project Profiles. A.I.D. Studies in Educational Technology and Development Communications.

    ERIC Educational Resources Information Center

    Agency for International Development (Dept. of State), Washington, DC. Clearinghouse on Development Communication.

    These profiles contain brief case studies showing how communication media are successfully used to support development projects in a variety of fields and international settings. Projects listed emphasize agriculture, health, nutrition, population, education (primary and middle grades, adult, and distance), and integrated development. Project…

  19. The Spitzer Infrared Spectrograph Survey of Protoplanetary Disks in Orion A. I. Disk Properties

    NASA Astrophysics Data System (ADS)

    Kim, K. H.; Watson, Dan M.; Manoj, P.; Forrest, W. J.; Furlan, Elise; Najita, Joan; Sargent, Benjamin; Hernández, Jesús; Calvet, Nuria; Adame, Lucía; Espaillat, Catherine; Megeath, S. T.; Muzerolle, James; McClure, M. K.

    2016-09-01

    We present our investigation of 319 Class II objects in Orion A observed by Spitzer/IRS. We also present the follow-up observations of 120 of these Class II objects in Orion A from the Infrared Telescope Facility/SpeX. We measure continuum spectral indices, equivalent widths, and integrated fluxes that pertain to disk structure and dust composition from IRS spectra of Class II objects in Orion A. We estimate mass accretion rates using hydrogen recombination lines in the SpeX spectra of our targets. Utilizing these properties, we compare the distributions of the disk and dust properties of Orion A disks with those of Taurus disks with respect to position within Orion A (Orion Nebular Cluster [ONC] and L1641) and with the subgroups by the inferred radial structures, such as transitional disks (TDs) versus radially continuous full disks (FDs). Our main findings are as follows. (1) Inner disks evolve faster than the outer disks. (2) The mass accretion rates of TDs and those of radially continuous FDs are statistically significantly displaced from each other. The median mass accretion rate of radially continuous disks in the ONC and L1641 is not very different from that in Taurus. (3) Less grain processing has occurred in the disks in the ONC compared to those in Taurus, based on analysis of the shape index of the 10 μm silicate feature (F 11.3/F 9.8). (4) The 20-31 μm continuum spectral index tracks the projected distance from the most luminous Trapezium star, θ 1 Ori C. A possible explanation is UV ablation of the outer parts of disks.

  20. Some Emphases and Resources for the A.I.D. Education Sector. Network Series: EHR-01.

    ERIC Educational Resources Information Center

    Agency for International Development (Dept. of State), Washington, DC. Office of Education and Human Resources.

    This paper elaborates on the Agency for International Development's (AID) new strategies for educational assistance to developing nations, with special reference to available, centrally funded technical assistance resources and the means for procuring them. Section one provides a brief introduction and lists the kinds of resources available and…

  1. Metabolism of cyclosporin A. I. Study in freshly isolated rabbit hepatocytes

    SciTech Connect

    Fabre, G.; Bertault-Peres, P.; Fabre, I.; Maurel, P.; Just, S.; Cano, J.P.

    1987-05-01

    The metabolism of cyclosporin A (CsA), a widely used immunosuppressive agent, was evaluated in freshly isolated rabbit hepatocytes by HPLC which separated CsA from its major group of derivatives, e.g. first generation metabolites (monohydroxylated and N-demethylated) and second generation derivatives (dihydroxylated and dihydroxy-N-demethylated). After exposure of hepatocytes to radiolabeled CsA (0.5 mg/liter), CsA was rapidly accumulated inside the cells and metabolized. The dihydroxylated metabolites represent the major intracellular forms after 1 hr. CsA metabolites synthesized inside the cells are then rapidly detected in the extracellular compartment. Unchanged drug and the various metabolites are concentrated inside the cells with transmembrane chemical gradients ranging between 20:1 and 40:1. Transport and metabolic processes for CsA have been evaluated over the following CsA extracellular concentration range, 0.1-10 mg/liter. Metabolism appears to be the rate-limiting step. The apparent affinity constant of CsA for the enzyme system involved in its metabolism is approximately 15 microM. Besides the lipophilicity of the molecule, which is responsible for the retention of CsA and its metabolites in the intracellular compartment, the presence of a binding component(s) in the hepatocytes was also demonstrated. CsA and its metabolites seem to have similar affinities for this binding site. These studies demonstrate that CsA is rapidly transformed inside the hepatocytes to various metabolites which may play an important role in the pharmacological activity of the drug and/or in its clinical toxicity.

  2. Soil Science. III-A-1 to III-D-4. Basic V.A.I.

    ERIC Educational Resources Information Center

    Texas A and M Univ., College Station. Vocational Instructional Services.

    This packet contains four units of informational materials and transparency masters, with accompanying scripts, for teachers to use in a soil science course in vocational agriculture. Designed especially for use in Texas, the first unit discusses the importance of soils. In the second unit, the nature and properties of soils are discussed,…

  3. Lipoprotein remodeling generates lipid-poor apolipoprotein A-I particles in human interstitial fluid

    PubMed Central

    Olszewski, Waldemar L.; Hattori, Hiroaki; Miller, Irina P.; Kujiraoka, Takeshi; Oka, Tomoichiro; Iwasaki, Tadao; Nanjee, M. Nazeem

    2013-01-01

    Although much is known about the remodeling of high density lipoproteins (HDLs) in blood, there is no information on that in interstitial fluid, where it might have a major impact on the transport of cholesterol from cells. We incubated plasma and afferent (prenodal) peripheral lymph from 10 healthy men at 37°C in vitro and followed the changes in HDL subclasses by nondenaturing two-dimensional crossed immunoelectrophoresis and size-exclusion chromatography. In plasma, there was always initially a net conversion of small pre-β-HDLs to cholesteryl ester (CE)-rich α-HDLs. By contrast, in lymph, there was only net production of pre-β-HDLs from α-HDLs. Endogenous cholesterol esterification rate, cholesteryl ester transfer protein (CETP) concentration, CE transfer activity, phospholipid transfer protein (PLTP) concentration, and phospholipid transfer activity in lymph averaged 5.0, 10.4, 8.2, 25.0, and 82.0% of those in plasma, respectively (all P < 0.02). Lymph PLTP concentration, but not phospholipid transfer activity, was positively correlated with that in plasma (r = +0.63, P = 0.05). Mean PLTP-specific activity was 3.5-fold greater in lymph, reflecting a greater proportion of the high-activity form of PLTP. These findings suggest that cholesterol esterification rate and PLTP specific activity are differentially regulated in the two matrices in accordance with the requirements of reverse cholesterol transport, generating lipid-poor pre-β-HDLs in the extracellular matrix for cholesterol uptake from neighboring cells and converting pre-β-HDLs to α-HDLs in plasma for the delivery of cell-derived CEs to the liver. PMID:23233540

  4. Jet-intracluster medium interaction in Hydra A - I. Estimates of jet velocity from inner knots

    NASA Astrophysics Data System (ADS)

    Nawaz, M. A.; Wagner, A. Y.; Bicknell, G. V.; Sutherland, R. S.; McNamara, B. R.

    2014-10-01

    We present the first stage of an investigation of the interactions of the jets in the radio galaxy Hydra A with the intracluster medium. We consider the jet kinetic power, the galaxy and cluster atmosphere and the inner structure of the radio source. Analysing radio observations of the inner lobes of Hydra A by Taylor et al. we confirm the jet power estimates ˜1045 erg s-1 derived by Wise et al. from dynamical analysis of the X-ray cavities. With this result and a model for the galaxy halo, we explore the jet-intracluster medium interactions occurring on a scale of 10 kpc using two-dimensional, axisymmetric, relativistic pure hydrodynamic simulations. A key feature is that we identify the three bright knots in the northern jet as biconical reconfinement shocks, which result when an overpressured jet starts to come into equilibrium with the galactic atmosphere. Through an extensive parameter space study we deduce that the jet velocity is approximately 0.8c at a distance 0.5 kpc from the black hole. The combined constraints of jet power, the observed jet radius profile along the jet and the estimated jet pressure and jet velocity imply a value of the jet density parameter χ ≈ 13 for the northern jet. We show that for a jet β = 0.8 and θ = 42°, an intrinsic asymmetry in the emissivity of the northern and southern jet is required for a consistent brightness ratio ≈7 estimated from the 6-cm Very Large Array image of Hydra A.

  5. Core III Materials for Metropolitan Agriculture/Horticulture Programs. Units A-I.

    ERIC Educational Resources Information Center

    Biondo, Ron; And Others

    This first volume of a two-volume curriculum guide contains 11 problem areas selected for study to be included in a core curriculum for 11th-grade or third-year students enrolled in a metropolitan agricultural program. The 11 problem areas are divided into eight units: Orientation to Agricultural Occupations (Gaining Employment), Supervised…

  6. Evaluation of new techniques to enhance the use of A.I. on farm.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Artificial insemination (AI) has played a seminal role in facilitating genetic improvement in dairy, beef and swine industries. The technology has not been routinely employed by the sheep industry and as a result genetic improvement has not been fully realized. The University of Wyoming and the US...

  7. A I-V analysis of irradiated Gallium Arsenide solar cells

    NASA Technical Reports Server (NTRS)

    Heulenberg, A.; Maurer, R. H.; Kinnison, J. D.

    1991-01-01

    A computer program was used to analyze the illuminated I-V characteristics of four sets of gallium arsenide (GaAs) solar cells irradiated with 1-MeV electrons and 10-MeV protons. It was concluded that junction regions (J sub r) dominate nearly all GaAs cells tested, except for irradiated Mitsubishi cells, which appear to have a different doping profile. Irradiation maintains or increases the dominance by J sub r. Proton irradiation increases J sub r more than does electron irradiation. The U.S. cells were optimized for beginning of life (BOL) and the Japanese for end of life (EOL). I-V analysis indicates ways of improving both the BOL and EOL performance of GaAs solar cells.

  8. 22 CFR 224.39 - Appeal to A.I.D. Administrator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... Administrator in accordance with this section. (b)(1) A notice of appeal may be filed at any time within 30 days....D. Administrator, and the time for filing motions for reconsideration under § 224.38 has expired... causing the failure to raise the objection. (i) If any party demonstrates to the satisfaction of the...

  9. A <i>NuSTAR observation of the center of the Coma Cluster

    SciTech Connect

    Gastaldello, Fabio; Wik, Daniel R.; Molendi, S.; Westergaard, N. J.; Hornstrup, A.; Madejski, G.; Ferreira, D. D. M.; Boggs, S. E.; Christensen, F. E.; Craig, W. W.; Grefenstette, B. W.; Hailey, C. J.; Harrison, F. A.; Madsen, K. K.; Stern, D.; Zhang, W. W.

    2015-02-20

    We present the results of a 55 ks NuSTAR observation of the core of the Coma Cluster. The global spectrum can be explained by thermal gas emission, with a conservative 90% upper limit to non-thermal inverse Compton (IC) emission of 5.1 × 10–12 erg cm–2 s–1 in a 12' × 12' field of view. The brightness of the thermal component in this central region does not allow more stringent upper limits on the IC component when compared with non-imaging instruments with much larger fields of view where claims of detections have been made. Future mosaic NuSTAR observations of Coma will further address this issue. In addition, the temperature map shows a relatively uniform temperature distribution with a gradient from the hot northwest side to the cooler southeast, in agreement with previous measurements. The temperature determination is robust given the flat effective area and low background in the 3-20 keV band, making NuSTAR an ideal instrument to measure high temperatures in the intracluster medium.

  10. The Challenge of Connecting the Dots in the B.R.A.I.N

    PubMed Central

    Devor, Anna; Bandettini, Peter A.; Boas, David A.; Bower, James M.; Buxton, Richard B.; Cohen, Lawrence B.; Dale, Anders M.; Einevoll, Gaute T.; Fox, Peter T.; Franceschini, Maria Angela; Friston, Karl J.; Fujimoto, James G.; Geyer, Marc A.; Greenberg, Joel H.; Halgren, Eric; Hämäläinen, Matti S.; Helmchen, Fritjof; Hyman, Bradley T.; Jasanoff, Alan; Jernigan, Terry L.; Judd, Lewis L.; Kim, Seong-Gi; Kleinfeld, David; Kopell, Nancy J.; Kutas, Marta; Kwong, Kenneth K.; Larkum, Matthew E.; Lo, Eng H.; Magistretti, Pierre J.; Mandeville, Joseph B.; Masliah, Eliezer; Mitra, Partha P.; Mobley, William C.; Moskowitz, Michael A.; Nimmerjahn, Axel; Reynolds, John H.; Rosen, Bruce R.; Salzberg, Brian M.; Schaffer, Chris B.; Silva, Gabriel A.; So, Peter T. C.; Spitzer, Nicholas C.; Tootell, Roger B.; Van Essen, David C.; Vanduffel, Wim; Vinogradov, Sergei A.; Wald, Larry L.; Wang, Lihong V.; Weber, Bruno; Yodh, Arjun G.

    2013-01-01

    The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts, and discuss likely technological deliverables and neuroscience progress. PMID:24139032

  11. Try P.R.A.I.S.E. - Positive Reinforcement And Individualized Systematic Economics.

    ERIC Educational Resources Information Center

    Wollam, Scott

    Described is a multi-faceted money system which utilizes positive and negative reinforcement while at the same time incorporating peer pressure and reinforcement for behavior modification. The system uses such items as money, checks, deposit slips, and bank books. Children have jobs such as pencil sellers, banker, or door monitor, and receive pay…

  12. Agricultural Mechanics. V-A-1 to V-E-1. Basic V.A.I.

    ERIC Educational Resources Information Center

    Texas A and M Univ., College Station. Vocational Instructional Services.

    This packet contains five units of informational materials and transparency masters with accompanying scripts, skill sheets, and safety tests for teacher and student use in an agricultural mechanics course in vocational agriculture. The first unit introduces the agricultural mechanics shop, covering the following topics: importance of agricultural…

  13. Optical Study of Interactions in a <i>d-Electron Kondo Lattice with Ferromagnetism

    SciTech Connect

    Burch, K. S.; Schafgans, A.; Butch, N. P.; Sayles, T. A.; Maple, M. B.; Sales, Brian C; Mandrus, David; Basov, D. N.

    2005-01-01

    We report on a comprehensive optical, transport, and thermodynamic study of the Zintl compound Yb{sub 14}MnSb{sub 11}, demonstrating that it is the first ferromagnetic Kondo lattice compound in the underscreened limit. We propose a scenario whereby the combination of Kondo and Jahn-Teller effects provides a consistent explanation of both transport and optical data.

  14. Pu'a i ka 'Olelo, Ola ka 'Ohana: Three Generations of Hawaiian Language Revitalization

    ERIC Educational Resources Information Center

    Kawai'ae'a, Keiki K. C.; Housman, Alohalani Kaluhiokalani; Alencastre, Makalapua

    2007-01-01

    In the early 1980s, the Hawaiian language had reached its low point with fewer than 50 native speakers of Hawaiian under the age of 18. Outside of the Ni'ihau community, a small group of families in Honolulu and Hilo were raising their children through Hawaiian. This article shares the perspectives of three pioneering families of the Hawaiian…

  15. A.I.-based real-time support for high performance aircraft operations

    NASA Technical Reports Server (NTRS)

    Vidal, J. J.

    1985-01-01

    Artificial intelligence (AI) based software and hardware concepts are applied to the handling system malfunctions during flight tests. A representation of malfunction procedure logic using Boolean normal forms are presented. The representation facilitates the automation of malfunction procedures and provides easy testing for the embedded rules. It also forms a potential basis for a parallel implementation in logic hardware. The extraction of logic control rules, from dynamic simulation and their adaptive revision after partial failure are examined. It uses a simplified 2-dimensional aircraft model with a controller that adaptively extracts control rules for directional thrust that satisfies a navigational goal without exceeding pre-established position and velocity limits. Failure recovery (rule adjusting) is examined after partial actuator failure. While this experiment was performed with primitive aircraft and mission models, it illustrates an important paradigm and provided complexity extrapolations for the proposed extraction of expertise from simulation, as discussed. The use of relaxation and inexact reasoning in expert systems was also investigated.

  16. Popular discourse on expert systems: communication patterns in the acculturation of an A. I. innovation

    SciTech Connect

    Opt, S.K.

    1987-01-01

    This study offers an organicist, trialectical communication perspective for analyzing the assumed relationship between technology and society. Other persons who have examined this relationship primarily have construed it as one in which (1) technology drives social change or (2) society drives technological change. Unanswered, though, is: what drives the relationship. This becomes the focus of this study. The study argues that understanding communication patterns about a technology (1) shows the processes by which human beings constitute sense-making scenarios about a technology, (2) makes salient the scenarios' implications for human needs, relationships, and worldview, and (3) provides an alternative approach to thinking about intervention into and side effects arising from the symbolic constitution of the future. The technology considered as case study is expert systems, and, by extension, artificial intelligence. The study focuses on the communication system of AI researchers, business persons, critics, and writers and their roles in inventing pasts, presents, and futures for the technology. The study finds that participants in discourse constitute names for expert systems in relation to the overarching ideology - the American dream.

  17. The challenge of connecting the dots in the B.R.A.I.N.

    PubMed

    Devor, Anna; Bandettini, Peter A; Boas, David A; Bower, James M; Buxton, Richard B; Cohen, Lawrence B; Dale, Anders M; Einevoll, Gaute T; Fox, Peter T; Franceschini, Maria Angela; Friston, Karl J; Fujimoto, James G; Geyer, Mark A; Greenberg, Joel H; Halgren, Eric; Hämäläinen, Matti S; Helmchen, Fritjof; Hyman, Bradley T; Jasanoff, Alan; Jernigan, Terry L; Judd, Lewis L; Kim, Seong-Gi; Kleinfeld, David; Kopell, Nancy J; Kutas, Marta; Kwong, Kenneth K; Larkum, Matthew E; Lo, Eng H; Magistretti, Pierre J; Mandeville, Joseph B; Masliah, Eliezer; Mitra, Partha P; Mobley, William C; Moskowitz, Michael A; Nimmerjahn, Axel; Reynolds, John H; Rosen, Bruce R; Salzberg, Brian M; Schaffer, Chris B; Silva, Gabriel A; So, Peter T C; Spitzer, Nicholas C; Tootell, Roger B; Van Essen, David C; Vanduffel, Wim; Vinogradov, Sergei A; Wald, Lawrence L; Wang, Lihong V; Weber, Bruno; Yodh, Arjun G

    2013-10-16

    The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.

  18. The National Comorbidity Survey Adolescent Supplement (NCS-A): I. Background and Measures

    PubMed Central

    Merikangas, Kathleen R.; Avenevoli, Shelli; Costello, E. Jane; Koretz, Doreen; Kessler, Ronald C.

    2009-01-01

    Objective This paper presents an overview of the background and measures used in the National Comorbidity Survey Replication Adolescent Supplement (NCS-A). Methods The NCS-A is a national psychiatric epidemiological survey of adolescents ages 13–17. Results The NCS-A was designed to provide the first nationally representative estimates of the prevalence, correlates and patterns of service use for DSM-V mental disorders among US adolescents and to lay the groundwork for follow-up studies of risk-protective factors, consequences, and early expressions of adult mental disorders. The core NCS-A diagnostic interview, the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), is a fully-structured research diagnostic interview designed for use by trained lay interviewers. A multi-construct, multi-method, multi-informant battery was also included to assess risk and protective factors and barriers to service use. Design limitations due to the NCS-A evolving as a supplement to an ongoing survey of mental disorders of US adults include restricted age range of youth, cross-sectional assessment, and lack of full parental/surrogate informant reports on youth mental disorders and correlates. Conclusions Despite these limitations, the NCS-A contains unparalleled information that can be used to generate national estimates of prevalence and correlates of adolescent mental disorders, risk and protective factors, patterns of service use, and barriers to receiving treatment for these disorders. The retrospective NCS-A data on the development of psychopathology can additionally complement data from longitudinal studies based on more geographically restricted samples and serve as a useful baseline for future prospective studies of the onset and progression of mental disorders in adulthood. PMID:19242382

  19. Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake

    PubMed Central

    Otis, Jessica P.; Zeituni, Erin M.; Thierer, James H.; Anderson, Jennifer L.; Brown, Alexandria C.; Boehm, Erica D.; Cerchione, Derek M.; Ceasrine, Alexis M.; Avraham-Davidi, Inbal; Tempelhof, Hanoch; Yaniv, Karina; Farber, Steven A.

    2015-01-01

    Improved understanding of lipoproteins, particles that transport lipids throughout the circulation, is vital to developing new treatments for the dyslipidemias associated with metabolic syndrome. Apolipoproteins are a key component of lipoproteins. Apolipoproteins are proteins that structure lipoproteins and regulate lipid metabolism through control of cellular lipid exchange. Constraints of cell culture and mouse models mean that there is a need for a complementary model that can replicate the complex in vivo milieu that regulates apolipoprotein and lipoprotein biology. Here, we further establish the utility of the genetically tractable and optically clear larval zebrafish as a model of apolipoprotein biology. Gene ancestry analyses were implemented to determine the closest human orthologs of the zebrafish apolipoprotein A-I (apoA-I), apoB, apoE and apoA-IV genes and therefore ensure that they have been correctly named. Their expression patterns throughout development were also analyzed, by whole-mount mRNA in situ hybridization (ISH). The ISH results emphasized the importance of apolipoproteins in transporting yolk and dietary lipids: mRNA expression of all apolipoproteins was observed in the yolk syncytial layer, and intestinal and liver expression was observed from 4–6 days post-fertilization (dpf). Furthermore, real-time PCR confirmed that transcription of three of the four zebrafish apoA-IV genes was increased 4 hours after the onset of a 1-hour high-fat feed. Therefore, we tested the hypothesis that zebrafish ApoA-IV performs a conserved role to that in rat in the regulation of food intake by transiently overexpressing ApoA-IVb.1 in transgenic larvae and quantifying ingestion of co-fed fluorescently labeled fatty acid during a high-fat meal as an indicator of food intake. Indeed, ApoA-IVb.1 overexpression decreased food intake by approximately one-third. This study comprehensively describes the expression and function of eleven zebrafish apolipoproteins

  20. Students&apos;, Guardians&apos;, and Teachers&apos; Perceptions of Student-Led Conferences

    ERIC Educational Resources Information Center

    Orso, Charlotte Lindsey

    2013-01-01

    The purpose of the study was to examine the ELL and non-ELL students&apos;, guardians&apos;, and the English as a second language (ESL) teachers&apos; perceptions of student-led conferences. Specifically, the study examined if ELL students&apos; and guardians&apos; preferences were similar to non-ELL students&apos; and guardians&apos; preferences…

  1. ApoE (Apolipoprotein E) Genotyping

    MedlinePlus

    ... There are no clear-cut tests to diagnose Alzheimer disease during life. Health practitioners can, however, make a reasonably accurate clinical diagnosis of AD by ruling out other potential causes of dementia and checking for a genetic predisposition to AD with APOE genotyping as supplemental ...

  2. HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

    PubMed Central

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2015-01-01

    Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that

  3. Parents&apos; Views of Schools&apos; Involvement Efforts

    ERIC Educational Resources Information Center

    Rodriguez, Raymond J.; Blatz, Erin T.; Elbaum, Batya

    2014-01-01

    Individual and focus group interviews were conducted with 96 parents of students with disabilities in 18 schools to explore parents&apos; views of schools&apos; efforts to engage them in their child&apos;s education. A mixed-methods approach was used to identify and evaluate the relative importance of eight themes related to schools&apos; efforts…

  4. APOE Genotyping, Cardiovascular Disease

    MedlinePlus

    ... Risk Assessment ; HDL Cholesterol ; LDL Cholesterol ; Lipid Profile ; Triglycerides Were you looking instead for APOE genotyping ordered ... the skin called xanthomas, a high level of triglycerides in the blood, and atherosclerosis that develops at ...

  5. ApoE isoform-dependent changes in hippocampal synaptic function.

    PubMed

    Korwek, Kimberly M; Trotter, Justin H; Ladu, Mary Jo; Sullivan, Patrick M; Weeber, Edwin J

    2009-05-27

    The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR) mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure.

  6. HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective.

    PubMed

    Chu, Qian; Diedrich, Jolene K; Vaughan, Joan M; Donaldson, Cynthia J; Nunn, Michael F; Lee, Kuo-Fen; Saghatelian, Alan

    2016-08-01

    Apolipoprotein E (ApoE) belongs to a large class of proteins that solubilize lipids for physiological transport. Humans have three different APOE alleles, APOE ε2, APOE ε3, and APOE ε4, and genetic studies identified ApoE4 as the strongest genetic risk factor for Alzheimer's disease (AD). People who are homozygous for ApoE4 (i.e., ApoE4/E4) are an order of magnitude more likely to develop late-onset AD (LOAD) than ApoE3/E3 carriers. Several differences between ApoE3 and ApoE4 may contribute to AD including the observation that ApoE4 is degraded to a greater extent than ApoE3 in the human brain. Experiments with high-temperature requirement serine peptidase A1 (HtrA1), which is found in the nervous system, demonstrate that HtrA1 is an allele-selective ApoE-degrading enzyme that degrades ApoE4 more quickly than ApoE3. This activity is specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4 proteolysis and trypsin had no preference between ApoE4 and ApoE3. HtrA1 has also been reported to cleave the tau protein (Tau) and the amyloid protein precursor (APP) to hinder the formation of toxic amyloid deposits associated with AD. Competition assays with ApoE4, ApoE3, and Tau revealed that ApoE4 inhibits Tau degradation. Thus, the identification of ApoE4 as an in vitro HtrA1 substrate suggests a potential biochemical mechanism that links ApoE4 regulation of AD proteins such as Tau.

  7. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis.

    PubMed

    Zhu, Li; Zhong, Minghao; Elder, Gregory A; Sano, Mary; Holtzman, David M; Gandy, Sam; Cardozo, Christopher; Haroutunian, Vahram; Robakis, Nikolaos K; Cai, Dongming

    2015-09-22

    The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

  8. Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models.

    PubMed

    Huang, Yadong

    2011-08-01

    ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.

  9. Interviewing Children--A Checklist for the I.A.I. Interview. Learning in Science Project. Working Paper 45.

    ERIC Educational Resources Information Center

    Bell, Beverley; Osborne, Roger

    The Learning in Science Project (1979-1981) studied the problems and difficulties of learning science at the 10-14 year old level in New Zealand to provide insights into the world of the science learner and provide an alternative perspective of the science classroom to that currently held by teachers and others. This paper offers practical…

  10. AID and Education: A Sector Report on Lessons Learned. A.I.D. Program Evaluation Report No. 12.

    ERIC Educational Resources Information Center

    Warren, Marion Kohashi

    Twelve United States Agency for International Development (AID) education projects were evaluated between 1980 and 1981. Four were in Asia (Philippines, Nepal, Thailand, Korea), two in Africa (Kenya, Nigeria), four in Latin America (Colombia, Brazil, Paraguay, Ecuador), and two in the Near East (Jordan, Afghanistan). The evaluations measured the…

  11. 38 CFR 3.809 - Specially adapted housing under 38 U.S.C. 2101(a)(2)(A)(i).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... service-connected amyotrophic lateral sclerosis rated 100 percent disabling under 38 CFR 4.124a..., having only light perception, plus the anatomical loss or loss of use of one lower extremity, (3)...

  12. CRITERIA POLLUTANT EMISSIONS FROM INTERNAL COMBUSTION ENGINES IN THE NATURAL GAS INDUSTRY VOLUME II. APPENDICES A-I

    EPA Science Inventory

    The report summarizes emission factors for criteria pollutants (NOx, CO, CH4, C2H6, THC, NMHC, and NMEHC) from stationary internal combustion engines and gas turbines used in the natural gas industry. The emission factors were calculated from test results from five test campaigns...

  13. A>N in inclusive lepton-proton collisions: TMD and twist-3 approaches

    SciTech Connect

    Prokudin, Alexei

    2015-01-23

    We consider the inclusive production of hadrons in lepton-nucleon scattering. For a transversely polarized nucleon this reaction shows a left-right azimuthal asymmetry, which we compute this asymmetry in both TMD and in twist-3 collinear factorization formalisms. All non-perturbative parton correlators of the calculation are fixed through information from other hard processes. Our results for the left-right asymmetry agree in sign with recent data for charged pion production from the HERMES Collaboration and from Jefferson Lab. As a result, we discuss similarities and differences of two formalisms.

  14. Pandemics: waves of disease, waves of hate from the Plague of Athens to A.I.D.S.*

    PubMed Central

    Cohn, Samuel K.

    2015-01-01

    This article briefly surveys the history of pandemics in the West, contesting long-held assumptions that epidemics sparked hatred and blame of the ‘Other’, and that it was worse when diseases were mysterious as to their causes and cures. The article finds that blame and hate were rarely connected with pandemics in history. In antiquity, epidemics more often brought societies together rather than dividing them as continued to happen with some diseases such as influenza in modernity. On the other hand, some diseases such as cholera were more regularly blamed than others and triggered violence even after their agents and mechanisms of transmission had become well known. PMID:25960572

  15. VEGF Mediates ApoE4-Induced Neovascularization and Synaptic Pathology in the Choroid and Retina.

    PubMed

    Antes, Ran; Salomon-Zimri, Shiran; Beck, Susanne C; Garcia Garrido, Marina; Livnat, Tami; Maharshak, Idit; Kadar, Tamar; Seeliger, Mathias; Weinberger, Dov; Michaelson, Daniel M

    2015-01-01

    Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. Recent findings suggest that retina of apoE4 mice have synaptic and functional impairments. We presently investigated the effects of apoE4 on retinal and choroidal vasculature and the possible role of VEGF in these effects. There were no histological differences between the retinal and choroidal vasculatures of naïve apoE3 and apoE4 mice. In contrast, laserdriven choroidal injury induced higher levels of choroidal neovascularization (CNV) in apoE4 than in apoE3 mice. These effects were associated with an inflammatory response and with activation of the Muller cells and asrocytic markers gluthatione synthetase and GFAP, all of which were more pronounced in the apoE4 mice. CNV also induced a transient increase in the levels of the synaptic markers synaptophysin and PSD95 which were however similar in the apoE4 and apoE3 naive mice. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation

  16. No association between ApoE polymorphism and febrile seizures.

    PubMed

    Lavenex, Pierre; Lavenex, Pamela Banta; Cachat, François; Gehri, Mario; Juvet, Typhaine

    2016-01-01

    Seizures associated with fever are a common pediatric problem, affecting about 2-7 % of children between 3 months and 5 years of age. Differentiation of febrile seizures from acute symptomatic seizures secondary to central nervous system infections or seizures associated with fever in children with epilepsy is essential to provide appropriate treatment and follow-up care. Here, we tested the hypothesis that children who exhibit simple febrile seizures during early childhood, but do not develop epileptic seizures later in life, might preferentially carry the ApoE2 allele of the gene coding for the apolipoprotein E. We did not find any differences in the distribution of ApoE alleles or genotypes between individuals who exhibited simple febrile seizures (n = 93) and age-matched, typically developing subjects (n = 80). We found that the observed allele and genotype frequencies did not deviate from Hardy-Weinberg equilibrium, which suggests that the frequencies of ApoE alleles and genotypes are stable in the Swiss population from which our samples were derived. Across both groups of subjects (n = 173), we found an ApoE2 allele frequency of 0.064, an ApoE3 frequency of 0.829 and an ApoE4 frequency of 0.107. Our findings are consistent with previous reports of the distribution of ApoE polymorphism for European subjects free of any neurological disorders, and show that the different alleles of the gene coding for the apolipoprotein E are not associated with the occurrence of simple febrile seizures. PMID:26233231

  17. An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo.

    PubMed

    Luz, Ishai; Liraz, Ori; Michaelson, Daniel M

    2016-06-01

    ApolipoproteinE4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and as such is a promising therapeutic target. This study examined the extent to which the pathological effects of apoE4 can be counteracted in vivo utilizing an immunological approach in which anti-apoE4 antibodies are applied peripherally by i.p. injections into apoE4-targeted replacement mice. Prerequisites for the successful pursuit of this objective are the availability of antibodies that specifically bind brain apoE4 and not apoE3, and demonstrating that direct application of these antibodies into the brain can counteract the effects of apoE4. Accordingly, it was shown that the antiapoE4 monoclonal antibody (mAb) 9D11 binds specifically to brain apoE4 and not apoE3. Direct i.c.v. application of mAb 9D11 prevented the apoE4-driven accumulation of Aβ in hippocampal neurons following activation of the amyloid cascade by inhibiting the Aβ-degrading enzyme neprilysin. These findings provide a proof-of-concept that anti-apoE4 mAb 9D11, when introduced into the brain, can counteract the apoE4 effects in vivo. Subsequent experiments, utilizing repeated i.p. injections of mAb 9D11, resulted in the formation of apoE/IgG complexes specifically in apoE4 mice. This was associated with reversal of the cognitive impairments of apoE4 in the Morris water maze and the novel object recognition test as well as with reversal of key apoE4-driven pathologies including the hyperphosphorylated tau and the reduced levels of the apoER2 receptor. These results indicate that anti-apoE4 immunotherapy counteracts the cognitive and brain pathological effects of apoE4, and suggest that such an approach could also benefit human apoE4 carriers.

  18. S-Nitrosylation of ApoE in Alzheimer’s Disease

    PubMed Central

    Abrams, Alexander J.; Farooq, Amjad; Wang, Gaofeng

    2011-01-01

    The mechanism by which apolipoprotein E (ApoE) isoforms functionally influence the risk and progression of late-onset Alzheimer’s disease (LOAD) remains hitherto unknown. Herein, we present evidence that all ApoE isoforms bind to nitric oxide synthase 1 (NOS1) and that such protein-protein interaction results in S-nitrosylation of ApoE2 and ApoE3 but not ApoE4. Our structural analysis at atomic level reveals that S-nitrosylation of ApoE2 and ApoE3 proteins may lead to conformational changes resulting in the loss of binding to low-density lipoprotein (LDL) receptors. Collectively, our data suggest that S-nitrosylation of ApoE proteins may play an important role in regulating lipid metabolism and in the pathogenesis of LOAD. PMID:21443265

  19. Impaired Autophagy in APOE4 Astrocytes.

    PubMed

    Simonovitch, Shira; Schmukler, Eran; Bespalko, Alina; Iram, Tal; Frenkel, Dan; Holtzman, David M; Masliah, Eliezer; Michaelson, Danny M; Pinkas-Kramarski, Ronit

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

  20. Gove&apos;s War

    ERIC Educational Resources Information Center

    Yarker, Patrick

    2013-01-01

    Policy pursued by Education Secretary Michael Gove promises to bring about the first national teachers&apos; strike for a generation. This article reviews the nature and effect of Gove&apos;s intensification of academisation, and outlines ways in which edu-business is involved.

  1. Deleuze&apos;s Children

    ERIC Educational Resources Information Center

    Hickey-Moody, Anna Catherine

    2013-01-01

    Children, the image of the child, and the gendered figures of the girl and the boy are thematics that run through the work of Deleuze and feature prominently in his joint writing with Guattari. However, there are many different children in Deleuze&apos;s writings. Various child figures do distinct things in Deleuze&apos;s work. In this article, I…

  2. ApoE: In Vitro Studies of a Small Molecule Effector.

    PubMed

    Mondal, Tridib; Wang, Hanliu; DeKoster, Gregory T; Baban, Berevan; Gross, Michael L; Frieden, Carl

    2016-05-10

    Apolipoprotein E4 (apoE4), one of three isoforms of apoE, is the major risk factor for developing late onset Alzheimer's disease. The only differences among these isoforms (apoE2, apoE3, and apoE4) are single amino acid changes. Yet these proteins are functionally very different. One approach to ameliorating the effect of apoE4 with respect to Alzheimer's disease would be to find small molecular weight compounds that affect the behavior of apoE4. Few studies of this approach have been carried out in part because there was no complete structure of any full-length apoE isoform until 2011. Here, we focus on one small molecular weight compound, EZ-482, and explore the effects of its binding to apoE. Using hydrogen-deuterium exchange, we determined that EZ-482 binds to the C-terminal domains of both apoE3 and apoE4. The binding to apoE4, however, is accompanied by a unique N-terminal allosteric effect. Using fluorescence methods, we determined an apparent dissociation constant of approximately 8 μM. Although EZ-482 binds to the C-terminal domain, it blocks heparin binding to the N-terminal domain. The residues of apoE that bind heparin are the same as those involved in apoE binding to LDL and LRP-1 receptors. The methods and the data presented here may serve as a template for future studies using small molecular weight compounds to modulate the behavior of apoE.

  3. ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice

    PubMed Central

    2013-01-01

    Background Recent findings suggest that the pathological effects of apoE4, the most prevalent genetic risk factor for Alzheimer’s disease (AD), start many years before the onset of the disease and are already detectable at a young age. In the present study we investigated the extent to which such pathological and cognitive impairments also occur in young apoE4 mice. Results This study revealed that the levels of the presynaptic glutamatergic vesicular transporter, VGlut, in the CA3, CA1, and DG hippocampal subfields were lower in hippocampal neurons of young (4-month-old) apoE4-targeted replacement mice than in those of the apoE3 mice. In contrast, the corresponding inhibitory GABAergic nerve terminals and perikarya were not affected by apoE4. This synaptic effect was associated with hyperphosphorylation of tau in these neurons. In addition, apoE4 increased the accumulation of neuronal Aβ42 and induced mitochondrial changes, both of which were specifically pronounced in CA3 neurons. Spatial navigation behavioral studies revealed that these hippocampal pathological effects of apoE4 are associated with corresponding behavioral impairments. Time-course studies revealed that the effects of apoE4 on tau hyperphosphorylation and the mitochondria were already apparent at the age of 1 month and that the apoE4-driven accumulation of neuronal Aβ and reduced VGlut levels evolve later and are apparent at the age of 2–4 months. Furthermore, the levels of tau phosphorylation decrease in apoE3 mice and increase in apoE4 mice between 1 and 4 months, whereas the levels of Aβ42 decrease in apoE3 mice and are not affected in apoE4 mice over the same time period. Conclusions These findings show that apoE4 stimulates the accumulation of Aβ42 and hyperphosphorylated tau and reduces the levels of VGlut in hippocampal neurons of young apoE4-targeted replacement mice and that these neurochemical effects are associated with cognitive impairments. This model is not associated with

  4. ApoE4 induces synaptic and ERG impairments in the retina of young targeted replacement apoE4 mice.

    PubMed

    Antes, Ran; Ezra-Elia, Raaya; Weinberger, Dov; Solomon, Arie; Ofri, Ron; Michaelson, Daniel M

    2013-01-01

    The vertebrate retina, which is part of the central nervous system, is a window into the brain. The present study investigated the extent to which the retina can be used as a model for studying the pathological effects of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD). Immunohistochemical studies of retinas from young (4 months old) apoE4-targeted replacement mice and from corresponding mice which express the AD benign apoE3 allele, revealed that the density of the perikarya of the different classes of retinal neurons was not affected by apoE4. In contrast, the synaptic density of the retinal synaptic layers, which was assessed immunohistochemically and by immunoblot experiments, was significantly lower in the apoE4 than in the apoE3 mice. This was associated with reduced levels of the presynaptic vesicular glutamatergic transporter, VGluT1, but not of either the GABAergic vesicular transporter, VGaT, or the cholinergic vesicular transporter, VAChT, suggesting that the glutamatergic nerve terminals are preferentially affected by apoE4. In contrast, the post synaptic scaffold proteins PSD-95 and Gephyrin, which reside in excitatory and inhibitory synapses, respectively, were both elevated, and their ratio was not affected by apoE4. Electroretinogram (ERG) recordings revealed significant attenuation of mixed rod-cone responses in dark-adapted eyes of apoE4 mice. These findings suggest that the reduced ERG response in the apoE4 mice may be related to the observed decrease in the retinal nerve terminals and that the retina could be used as a novel model for non-invasive monitoring of the effects of apoE4 on the CNS.

  5. Effects of simulated heat waves on ApoE-/- mice.

    PubMed

    Wang, Chunling; Zhang, Shuyu; Tian, Ying; Wang, Baojian; Shen, Shuanghe

    2014-02-01

    The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans. PMID:24477215

  6. Effects of simulated heat waves on ApoE-/- mice.

    PubMed

    Wang, Chunling; Zhang, Shuyu; Tian, Ying; Wang, Baojian; Shen, Shuanghe

    2014-02-01

    The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans.

  7. Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment.

    PubMed

    Salomon-Zimri, Shiran; Glat, Micaela Johanna; Barhum, Yael; Luz, Ishai; Boehm-Cagan, Anat; Liraz, Ori; Ben-Zur, Tali; Offen, Daniel; Michaelson, Daniel M

    2016-06-30

    Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.

  8. Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice.

    PubMed

    Klein, Rebecca C; Acheson, Shawn K; Mace, Brian E; Sullivan, Patrick M; Moore, Scott D

    2014-09-01

    The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Apolipoprotein E is secreted as part of a high-density lipoprotein-like particle by glial cells in the brain for the primary purpose of transport of lipophilic compounds involved in the maintenance of synapses. Previous studies examining synaptic integrity in the amygdala of human apoE targeted replacement (TR) mice showed a decrease in spontaneous excitatory synaptic activity, dendritic arbor, and spine density associated with apoE4 compared with apoE3 and apoE2 in adult male mice. In the present study, we assessed how APOE genotype affects synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in human apoE3, E4, and E2/4 TR mice at the age of 18-20 months. In contrast to adult mice, we found that aged apoE4 TR mice exhibited the highest level of excitatory synaptic activity compared with other cohorts. Additionally, apoE4 mice had significantly greater spontaneous inhibitory activity than all other cohorts. Taken together, there was a significant interaction between genotypes when comparing inhibition relative to excitation; there was a simple main effect of frequency type with an imbalance toward inhibition in apoE4 mice but not in apoE3 or apoE2/4 mice. These results suggest that apoE isoforms differentially influence synaptic transmission throughout the life span, where aging coupled with apoE4 expression, results in an imbalance in maintaining integrity of synaptic transmission.

  9. CSF Apo-E levels associate with cognitive decline and MRI changes

    PubMed Central

    Toledo, Jon B.; Da, Xiao; Weiner, Michael W.; Wolk, David A.; Xie, Sharon X.; Arnold, Steven E.; Davatzikos, Christos; Shaw, Leslie M.; Trojanowski, John Q.

    2014-01-01

    Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of the its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD Neuroimaging Initiative (ADNI) subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and grey matter atrophy rate in total tau/Aβ1–42 ratio and APOE genotype adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance. PMID:24385135

  10. The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice

    PubMed Central

    Janssen, Carola I. F.; Jansen, Diane; Mutsaers, Martina P. C.; Dederen, Pieter J. W. C.; Geenen, Bram; Mulder, Monique T.; Kiliaan, Amanda J.

    2016-01-01

    Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice. PMID:27171180

  11. The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice.

    PubMed

    Janssen, Carola I F; Jansen, Diane; Mutsaers, Martina P C; Dederen, Pieter J W C; Geenen, Bram; Mulder, Monique T; Kiliaan, Amanda J

    2016-01-01

    Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice. PMID:27171180

  12. The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice.

    PubMed

    Janssen, Carola I F; Jansen, Diane; Mutsaers, Martina P C; Dederen, Pieter J W C; Geenen, Bram; Mulder, Monique T; Kiliaan, Amanda J

    2016-01-01

    Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice.

  13. The effects of the apoE4 genotype on the developing mouse retina.

    PubMed

    Maharshak, Idit; Salomon-Zimri, Shiran; Antes, Ran; Liraz, Ori; Nisgav, Yael; Livnat, Tami; Weinberger, Dov; Colton, Carol A; Solomon, Arieh S; Michaelson, Daniel M

    2016-04-01

    Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. The retina, which is as an extension of the central nervous system (CNS), is a particularly suitable model for studying developmental and functional aspects of the neuronal and vascular systems. This study investigates the apoE4-dependent developmental effects on the retinal vasculature and neuronal systems and on the levels of apoE and the vascular endothelial growth factor (VEGF) in the retina. This was performed utilizing retinas of 4, 7, 12, and of 120-day-old human-apoE4-targeted replacement mice and of corresponding mice that express the AD benign isoform, apoE3. The results obtained revealed retinal vascular pathology in the apoE4 mice, which started on the early post-natal days. This includes transient increase in vascular branching, and vascular buds which are round vascular elements representing sprouting or retracting vessels. These effects peaked and ended during the neonatal period. Examination of the synaptic system utilizing the pre-synaptic marker synaptophysin revealed a significant decrease of retinal synaptic density in the apoE4 mice, which was detectable by post-natal day 12 (P12). These morphological changes are associated with neonatal age-dependent elevation in the apoE levels in both apoE3 and apoE4 retinas which is more profound in the apoE4 mice and a corresponding increase in VEGF levels, which is less profound in the apoE4 mice. Additionally, we observed lower levels of retinal VEGF in the apoE4 mice compared to the apoE3 mice retinas on P12. These results show that apoE4 has a transient vascular effect during retinal development that ends in the neonatal period, which is accompanied by a synaptic effect that begins at the end of the neonatal period. These findings show that the apoE4 genotype can have distinct developmental effects on both the retinal vasculature and on neurons and

  14. ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations.

    PubMed

    Williams, Benfeard; Convertino, Marino; Das, Jhuma; Dokholyan, Nikolay V

    2015-10-01

    The increased risk of developing Alzheimer's disease (AD) is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD-related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD.

  15. ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations

    PubMed Central

    Williams II, Benfeard; Convertino, Marino; Das, Jhuma; Dokholyan, Nikolay V.

    2015-01-01

    The increased risk of developing Alzheimer’s disease (AD) is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD-related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD. PMID:26506597

  16. The role of APOE in cerebrovascular dysfunction.

    PubMed

    Tai, Leon M; Thomas, Riya; Marottoli, Felecia M; Koster, Kevin P; Kanekiyo, Takahisa; Morris, Alan W J; Bu, Guojun

    2016-05-01

    The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells. PMID:26884068

  17. Binding of Pseudomonas aeruginosa Apo-Bacterioferritin Associated Ferredoxin to Bacterioferritin B Promotes Heme Mediation of Electron Delivery and Mobilization of Core Mineral Iron†

    PubMed Central

    Weeratunga, Saroja K.; Gee, Casey E.; Lovell, Scott; Zeng, Yuhong; Woodin, Carrie L.; Rivera, Mario

    2009-01-01

    The bfrB gene from Pseudomonas aeruginosa was cloned and expressed in E. coli. The resultant protein (BfrB), which assembles into a 445.3 kDa complex0020from 24 identical subunits, binds 12 molecules of heme axially coordinated by two Met residues. BfrB, isolated with 5–10 iron atoms per protein molecule, was reconstituted with ferrous ions to prepare samples with a core mineral containing 600 ± 40 ferric ions per BfrB molecule and approximately one phosphate molecule per iron atom. In the presence of sodium dithionite or in the presence of P. aeruginosa ferredoxin NADP reductase (FPR) and NADPH the heme in BfrB remains oxidized and the core iron mineral is mobilized sluggishly. In stark contrast, addition of NADPH to a solution containing BfrB, FPR and the apo-form of P. aeruginosa bacterioferritin associated ferredoxin (apo-Bfd) results in rapid reduction of the heme in BfrB and in the efficient mobilization of the core iron mineral. Results from additional experimentation indicate that Bfd must bind to BfrB to promote heme mediation of electrons from the surface to the core to support the efficient mobilization of ferrous ions from BfrB. In this context, the thus far mysterious role of heme in bacterioferritins has been brought to the front by reconstituting BfrB with its physiological partner, apo-Bfd. These findings are discussed in the context of a model for the utilization of stored iron in which the significant upregulation of the bfd gene under low-iron conditions [Ochsner, U.A., Wilderman, P.J., Vasil, A.I., and Vasil, M.L. (2002) Mol. Microbiol. 45, 1277–1287] ensures sufficient concentrations of apo-Bfd to bind BfrB and unlock the iron stored in its core. Although these findings are in contrast to previous speculations suggesting redox mediation of electron transfer by holo-Bfd, the ability of apo-Bfd to promote iron mobilization is an economical strategy used by the cell because it obviates the need to further deplete cellular iron levels to

  18. Attributional Gender Bias: Teachers&apos; Ability and Effort Explanations for Students&apos; Math Performance

    ERIC Educational Resources Information Center

    Espinoza, Penelope; Arêas da Luz Fontes, Ana B.; Arms-Chavez, Clarissa J.

    2014-01-01

    Research is presented on the attributional gender bias: the tendency to generate different attributions (explanations) for female versus male students&apos; performance in math. Whereas boys&apos; successes in math are attributed to ability, girls&apos; successes are attributed to effort; conversely, boys&apos; failures in math are attributed to a…

  19. Children&apos;s Talking and Listening within the Classroom: Teachers&apos; Insights

    ERIC Educational Resources Information Center

    Bosacki, Sandra; Rose-Krasnor, Linda; Coplan, Robert J.

    2014-01-01

    Research suggests that social communication (verbal and non-verbal) plays a key role in students&apos; and teachers&apos; elementary-school experiences. Within the framework of sociocognitive developmental theory, this qualitative study investigates teachers&apos; experiences and perceptions of children&apos;s talking and listening habits within…

  20. Jack Michael&apos;s Motivation

    ERIC Educational Resources Information Center

    Miguel, Caio F.

    2013-01-01

    Among many of Jack Michael&apos;s contributions to the field of behavior analysis is his behavioral account of motivation. This paper focuses on the concept of "motivating operation" (MO) by outlining its development from Skinner&apos;s (1938) notion of "drive." Conceptually, Michael&apos;s term helped us change our focus on…

  1. Pupils&apos; Voice: "My Primary School Teacher&apos;&apos;

    ERIC Educational Resources Information Center

    Alkan, Vesile

    2013-01-01

    This study aims to explore pupils&apos; views on how a teacher should be and the reasons for their decisions. Based on qualitative research design, focus group interviews were done with ten 5th graders from a public primary school in Turkey. These pupils were asked the following questions: "how do you think a teacher should be?" and…

  2. Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory.

    PubMed

    Biundo, Fabrizio; Ishiwari, Keita; Del Prete, Dolores; D'Adamio, Luciano

    2015-12-01

    Mutations in Amyloid β Precursor Protein (APP) and in genes that regulate APP processing--such as PSEN1/2 and ITM2b/BRI2--cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDDKI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDDKI/ApoE3, ApoE4, FDDKI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16-17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16-17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3-carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers.

  3. Mothers&apos; Beliefs about Children&apos;s Learning in Hong Kong and the United States: Implications for Mothers&apos; Child-Based Worth

    ERIC Educational Resources Information Center

    Ng, Florrie Fei-Yin; Pomerantz, Eva M.; Lam, Shui-fong

    2013-01-01

    Chinese and American mothers&apos; beliefs about children&apos;s learning and parents&apos; role in it were examined using notions salient in Chinese culture. Mothers from Hong Kong ("n" = 66) and the United States ("n" = 69) indicated their endorsement of the ideas that children&apos;s learning reflects children&apos;s…

  4. Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice.

    PubMed

    Jansen, Diane; Zerbi, Valerio; Janssen, Carola I F; van Rooij, Daan; Zinnhardt, Bastian; Dederen, Pieter J; Wright, Alan J; Broersen, Laus M; Lütjohann, Dieter; Heerschap, Arend; Kiliaan, Amanda J

    2014-09-01

    Lipid metabolism and genetic background together strongly influence the development of both cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). A non-pharmacological way to prevent the genotype-induced occurrence of these pathologies is given by dietary behavior. In the present study, we tested the effects of long-term consumption of a specific multi-nutrient diet in two models for atherosclerosis and vascular risk factors in AD: the apolipoprotein ε4 (apoE4) and the apoE knockout (apoE ko) mice. This specific multi-nutrient diet was developed to support neuronal membrane synthesis and was expected to contribute to the maintenance of vascular health. At 12 months of age, both genotypes showed behavioral changes compared to control mice and we found increased neurogenesis in apoE ko mice. The specific multi-nutrient diet decreased anxiety-related behavior in the open field, influenced sterol composition in serum and brain tissue, and increased the concentration of omega-3 fatty acids in the brain. Furthermore, we found that wild-type and apoE ko mice fed with this multi-nutrient diet showed locally increased cerebral blood volume and decreased hippocampal glutamate levels. Taken together, these data suggest that a specific dietary intervention has beneficial effects on early pathological consequences of hypercholesterolemia and vascular risk factors for AD. PMID:23832599

  5. Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice.

    PubMed

    Jansen, Diane; Zerbi, Valerio; Janssen, Carola I F; van Rooij, Daan; Zinnhardt, Bastian; Dederen, Pieter J; Wright, Alan J; Broersen, Laus M; Lütjohann, Dieter; Heerschap, Arend; Kiliaan, Amanda J

    2014-09-01

    Lipid metabolism and genetic background together strongly influence the development of both cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). A non-pharmacological way to prevent the genotype-induced occurrence of these pathologies is given by dietary behavior. In the present study, we tested the effects of long-term consumption of a specific multi-nutrient diet in two models for atherosclerosis and vascular risk factors in AD: the apolipoprotein ε4 (apoE4) and the apoE knockout (apoE ko) mice. This specific multi-nutrient diet was developed to support neuronal membrane synthesis and was expected to contribute to the maintenance of vascular health. At 12 months of age, both genotypes showed behavioral changes compared to control mice and we found increased neurogenesis in apoE ko mice. The specific multi-nutrient diet decreased anxiety-related behavior in the open field, influenced sterol composition in serum and brain tissue, and increased the concentration of omega-3 fatty acids in the brain. Furthermore, we found that wild-type and apoE ko mice fed with this multi-nutrient diet showed locally increased cerebral blood volume and decreased hippocampal glutamate levels. Taken together, these data suggest that a specific dietary intervention has beneficial effects on early pathological consequences of hypercholesterolemia and vascular risk factors for AD.

  6. ApoE genotypes are associated with age at natural menopause in Chinese females.

    PubMed

    Meng, Fan-Tao; Wang, Yan-Li; Liu, Ji; Zhao, Jun; Liu, Rong-Yu; Zhou, Jiang-Ning

    2012-08-01

    Ages at natural menarche and menopause are influenced by several genetic factors. This study aimed to investigate the possible relationship between the apolipoprotein E (ApoE) genotype and the age at menarche and natural menopause in Chinese females. In the current study, 398 (elderly group, aged 47-80 years) and 825 (young group, aged 15-25 years) Chinese females were enrolled under informed content. Ages at natural menarche and menopause were obtained by questionnaires. ApoE genotypes were identified by restriction fragment length polymorphism analysis. In the elderly group, the number of pregnancies and live births and breastfeeding were associated with the age at menopause (P = 0.008, P = 0.002, and P = 0.023, respectively). One-way ANOVA analysis revealed that the ApoE genotype was significantly associated with age at natural menopause (ANM; P = 0.010). Compared with ApoE ε3/3 carriers, ApoE ε3/4 females showed a 1.8-year delay in ANM (P = 0.002). Single ApoE allele-positive/allele-negative analysis also showed that the age at menopause of ApoE ε4 carriers was delayed compared with those who were not carriers (P = 0.023). In the young group, no statistical difference was found in the age of menarche between the carriers of ApoE ε3/3 and ε3/4. Single ApoE allele-positive/allele-negative analysis showed that the age at menarche in ApoE ε4 carriers was slightly earlier than in those who were not carriers (P = 0.048). Meanwhile, univariate association analysis revealed that the ApoE genotypes were not significantly associated with the age at menarche using age as a covariate in the pooled group (young + elderly) (P = 0.143). We demonstrated that the ApoE genotype is significantly linked to the age at natural menopause.

  7. Measuring Beliefs in Centimeters: Private Knowledge Biases Preschoolers&apos; and Adults&apos; Representation of Others&apos; Beliefs

    ERIC Educational Resources Information Center

    Sommerville, Jessica A.; Bernstein, Daniel M.; Meltzoff, Andrew N.

    2013-01-01

    A novel task, using a continuous spatial layout, was created to investigate the degree to which (in centimeters) 3-year-old children&apos;s ("N" = 63), 5-year-old children&apos;s ("N" = 60), and adults&apos; ("N" = 60) own privileged knowledge of the location of an object biased their representation of a…

  8. ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease.

    PubMed

    Sorbi, S; Nacmias, B; Forleo, P; Latorraca, S; Gobbini, I; Bracco, L; Piacentini, S; Amaducci, L

    1994-08-15

    Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD. PMID:7824157

  9. Broadening the Scope of PDS Liaisons&apos; Roles in Community Schools

    ERIC Educational Resources Information Center

    Ferrara, JoAnne; Gomez, Diane W.

    2014-01-01

    Professional Development School liaisons are accustomed to developing relationships between their respective universities and partner schools. When the partner school is also a &apos;&apos;full service&apos;&apos; or &apos;'community'&apos; school, the partnership&apos;s dynamics change. This article describes the expanded roles of two…

  10. Splicing defective mutants of the COXI gene of yeast mitochondrial DNA: initial definition of the maturase domain of the group II intron aI2.

    PubMed Central

    Moran, J V; Mecklenburg, K L; Sass, P; Belcher, S M; Mahnke, D; Lewin, A; Perlman, P

    1994-01-01

    Six mutations blocking the function of a seven intron form of the mitochondrial gene encoding subunit I of cytochrome c oxidase (COXI) and mapping upstream of exon 3 were isolated and characterized. A cis-dominant mutant of the group IIA intron 1 defines a helical portion of the C1 substructure of domain 1 as essential for splicing. A trans-recessive mutant confirms that the intron 1 reading frame encodes a maturase function. A cis-dominant mutant in exon 2 was found to have no effect on the splicing of intron 1 or 2. A trans-recessive mutant, located in the group IIA intron 2, demonstrates for the first time that intron 2 encodes a maturase. A genetic dissection of the five missense mutations present in the intron 2 reading frame of that strain demonstrates that the maturase defect results from one or both of the missense mutations in a newly-recognized conserved sequence called domain X. Images PMID:8029012

  11. Enhancing the Material Control & Accounting Measurement System at the State Scientific Center of the Russian Federation - Institute for Physics and Power Engineering named after A.I. Leypunsky

    SciTech Connect

    Scherer, Carolynn P.; Bezhunov, Gennady M.; Bogdanov, Sergey A.; Gorbachev, Vyacheslav M.; Ryazanov, Boris G.; Talanov, Vladimir V.

    2012-07-11

    Nuclear material control and accounting (NMCA) system is improving under cooperation with USA national laboratories. Standard reference materials (RMs) and measurement techniques certified at IPPE level are required for: instrument calibration, verification measurements of parameters of items and materials, measurement error estimation, and quality control measurements. We present the main results for development of nuclear RMs for two uranium strata and the results for certification of three measurement techniques (MT) for U-235 mass fraction in uranium and U-235 mass in items. We present the results for developing measurement techniques for Pu-239 in PuO{sub 2}.

  12. Genetic engineering and improvement of a <i>Zymomonas mobilis for arabinose utilization and its performance on pretreated corn stover hydrolyzate

    SciTech Connect

    Chou, Yat -Chen; Linger, Jeffrey; Yang, Shihui; Zhang, Min

    2015-04-28

    In this paper, a glucose, xylose and arabinose utilizing Zymomonas mobilis strain was constructed by incorporating arabinose catabolic pathway genes, araBAD encoding L-ribulokinase, L-arabinose isomerase and L-ribulose-5-phosphate- 4-epimerase in a glucose, xylose co-fermenting host, 8b, using a transposition integration approach. Further improvement on this arabinose-capable integrant, 33C was achieved by applying a second transposition to create a genomic knockout (KO) mutant library. Using arabinose as a sole carbon source and a selection pressure, the KO library was subjected to a growth-enrichment process involving continuous sub-culturing for over 120 generations. Strain 13-1-17, isolated from such process demonstrated significant improvement in metabolizing arabinose in a dilute acid pretreated, saccharified corn stover slurry. Through Next Generation Sequencing (NGS) analysis, integration sites of the transposons were identified. Furthermore, multiple additional point mutations (SNPs: Single Nucleotide Polymorphisms) were discovered in 13-1-17, affecting genes araB and RpiB in the genome. Finally, we speculate that these mutations may have impacted the expression of the enzymes coded by these genes, ribulokinase and Ribose 5-P-isomerase, thus attributing to the improvement of the arabinose utilization.

  13. An Analysis of U.S. Foreign Direct Investment Policy and Economic Development. A.I.D. Discussion Paper No. 36.

    ERIC Educational Resources Information Center

    Bergsten, C. Fred; De Castro, Bruce

    The purpose of the paper is to analyze U.S. policies toward financial investment in developing nations. The paper is presented in two sections. In section I, the controversial effects of direct foreign investment on development are discussed. Case studies of investment policies toward India, the Philippines, Ghana, Guatemala, and Argentina are…

  14. The Brookline LOGO Project. Final Report. Part II: Project Summary and Data Analysis. A.I. Memo No. 545. LOGO Memo No. 53.

    ERIC Educational Resources Information Center

    Papert, Seymour; And Others

    During the school year 1977/78 four computers equipped with LOGO and Turtle Graphics were installed in an elementary school in Brookline, Massachusetts. All sixth grade students in the school had between 20 and 40 hours of hands-on experience with the computers, and the work of 16 students ranging from intellectually gifted and average to learning…

  15. 30 CFR 57.22228 - Preshift examination (I-A, I-C, II-A, III, and V-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... requirements of 30 CFR parts 18 through 36. ... the beginning of a shift following an idle shift, a competent person shall test the mine atmosphere... immediately follows another, a competent person shall test the mine atmosphere at each active working face...

  16. Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a <i>Drosophila model of TPI deficiency

    SciTech Connect

    Roland, Bartholomew P.; Amrich, Christopher G.; Kammerer, Charles J.; Stuchul, Kimberly A.; Larsen, Samantha B.; Rode, Sascha; Aslam, Anoshe A.; Heroux, Annie; Wetzel, Ronald; VanDemark, Andrew P.; Palladino, Michael J.

    2014-10-16

    Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability. In this report, we genetically and physically characterize a human disease-associated TPI mutation caused by an I170V substitution. Human TPII170V elicits behavioral abnormalities in Drosophila. An examination of hTPII170V enzyme kinetics revealed this substitution reduced catalytic turnover, while assessments of thermal stability demonstrated an increase in enzyme stability. Furthermore, the crystal structure of the homodimeric I170V mutant reveals changes in the geometry of critical residues within the catalytic pocket. In the end, collectively these data reveal new observations of the structural and kinetic determinants of TPI deficiency pathology, providing new insights into disease pathogenesis.

  17. U.S. Aid to Education in Paraguay: The Rural Education Development Project. A.I.D. Project Impact Evaluation Report No. 46.

    ERIC Educational Resources Information Center

    Nicholson, Ronald; And Others

    Between 1970 and 1976, with continued funding and personnel support from the Agency for International Development (AID), Paraguay instituted major rural educational reforms encompassing curriculum revision, teacher training and retraining, training of administrators and supervisors, new school construction, and provision of teaching materials and…

  18. Biginkgosides A-I, Unexpected Minor Dimeric Flavonol Diglycosidic Truxinate and Truxillate Esters from Ginkgo biloba Leaves and Their Antineuroinflammatory and Neuroprotective Activities.

    PubMed

    Ma, Guang-Lei; Xiong, Juan; Yang, Guo-Xun; Pan, Li-Long; Hu, Chang-Ling; Wang, Wei; Fan, Hui; Zhao, Qiu-Hua; Zhang, Hai-Yan; Hu, Jin-Feng

    2016-05-27

    Nine unexpected new flavonol glycoside cyclodimers in the truxinate (1-7, biginkgosides A-G, respectively) or truxillate [biginkgosides H (8) and I (9)] forms were isolated as minor components from the extract of Ginkgo biloba leaves. The new dimers possess an unusual cyclobutane ring formed by a [2+2]-cycloaddition between two symmetric (for compounds 1-5 and 7-9) or nonsymmetric (for 6) flavonol coumaroyl glucorhamnosides. A plausible biosynthetic pathway for these new compounds based on the frontier molecular orbital theory of cycloaddition reactions is briefly discussed. An antineuroinflammatory screening revealed that biginkgosides E (5) and H (8) inhibited nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells, with IC50 values of 2.91 and 17.23 μM, respectively. Additionally, biginkgoside F (6) showed a significant neuroprotective effect (34.3% increase in cell viability at 1 μM) against Aβ25-35-induced cell viability decrease in SH-SY5Y neuroblastoma cells. PMID:27140807

  19. 30 CFR 57.22228 - Preshift examination (I-A, I-C, II-A, III, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... requirements of 30 CFR parts 18 through 36. ... the beginning of a shift following an idle shift, a competent person shall test the mine atmosphere... immediately follows another, a competent person shall test the mine atmosphere at each active working face...

  20. Animal Investigation Program (AIP), A.I.P. summary report on and around the Nevada Test Site from 1982--1995

    SciTech Connect

    Giles, K.R.

    1997-04-01

    This report describes the Animal Investigation Program conducted from 1982--1995 by the Environmental Protection Agency`s (EPA`s), Radiation and Indoor Environments National Laboratory (R and IE), formerly Radiation Sciences Laboratory-Las Vegas. This laboratory operates an environmental radiation monitoring program in the region surrounding the Nevada Test Site. The surveillance program was designed to measure levels and trends of radionuclides in animals on and around the Nevada Test Site to ascertain whether world-wide fallout, current radiation levels, and associated doses, to the general public were in compliance with existing radiation protection standards. The surveillance program additionally had the responsibility to take action to protect the health and well-being of the public in the event of any accidental release of radioactive contaminants. Comparison of the measurements and sample analysis results indicated that no significant amounts of biological radionuclides had been detected in the near offsite areas or on the NTS, except in animals drinking water that drains from tunnels in Area 12.

  1. 30 CFR 57.22228 - Preshift examination (I-A, I-C, II-A, III, and V-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... requirements of 30 CFR parts 18 through 36. ... the beginning of a shift following an idle shift, a competent person shall test the mine atmosphere... immediately follows another, a competent person shall test the mine atmosphere at each active working face...

  2. Polarization quantum beat spectroscopy of HCF(A1A"). I. 19F and 1H hyperfine structure and Zeeman effect.

    PubMed

    Fan, Haiyan; Ionescu, Ionela; Xin, Ju; Reid, Scott A

    2004-11-01

    To further investigate the (19)F and (1)H nuclear hyperfine structure and Zeeman effect in the simplest singlet carbene, HCF, we recorded polarization quantum beat spectra (QBS) of the pure bending levels 2(0) (n) with n = 0-7 and combination bands 1(0) (1)2(0) (n) with n = 1-6 and 2(0) (n)3(0) (1) with n = 0-3 in the HCF A(1)A(")<--X(1)A(') system. The spectra were measured under jet-cooled conditions using a pulsed discharge source, both at zero field and under application of a weak magnetic field (<30 G). Analysis yielded the nuclear spin-rotation constants C(aa) and weak field Lande g(aa) factors. Consistent with a two-state model, the majority of observed vibrational levels exhibit a linear correlation of C(aa) and g(aa), and our analysis yielded effective (a) hyperfine constants for the (19)F and (1)H nuclei (in MHz) of 728(23) and 55(2), respectively. The latter was determined here owing to the high resolving power of QBS. The vibrational state selectivity of the (19)F hyperfine constants is discussed, and we suggest that the underlying Renner-Teller interaction may play an important role.

  3. Educational Communication for the Deprived Child: Report and Suggestions. Texas A & I University, Kingsville, Texas, Teacher Corps Project Report. First Cycle Program 1966-1968.

    ERIC Educational Resources Information Center

    Elliott, Floyd W., Comp.; Cox, Robert L., Comp.

    The aims of the Teacher Corps are (1) to strengthen educational opportunities for children in areas with concentrations of low-income families; (2) to attract and prepare persons to become teachers in such areas through coordinated work-study experiences; and (3) to encourage colleges and universities, schools, and state departments of education…

  4. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-B mines). 57.22202 Section 57.22202 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation §...

  5. Pearson Syndrome: A Retrospective Cohort Study from the Marrow Failure Study Group of A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica).

    PubMed

    Farruggia, Piero; Di Cataldo, Andrea; Pinto, Rita M; Palmisani, Elena; Macaluso, Alessandra; Valvo, Laura Lo; Cantarini, Maria E; Tornesello, Assunta; Corti, Paola; Fioredda, Francesca; Varotto, Stefania; Martire, Baldo; Moroni, Isabella; Puccio, Giuseppe; Russo, Giovanna; Dufour, Carlo; Pillon, Marta

    2016-01-01

    Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis.

  6. 30 CFR 57.22234 - Actions at 1.0 percent methane (I-A, I-B, III, V-A, and V-B mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... changes shall be withdrawn from affected areas; (2) Electrical power shall be deenergized in affected areas, except power to monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR... methane reaches 1.0 percent at a main exhaust fan, electrical power underground shall be...

  7. PR-Set7 is degraded in a conditional Cul4A> transgenic mouse model of lung cancer

    SciTech Connect

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hsieh, David; Au, Alfred; Jablons, David M.; Li, Hui; You, Lian

    2015-06-01

    Background and objective. Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. Methods. We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. Results. The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. Conclusion. PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.

  8. B.A.I.L.A. - A Latin dance randomized controlled trial for older Spanish-speaking Latinos: Rationale, design, and methods

    PubMed Central

    Marquez, David X.; Wilbur, JoEllen; Hughes, Susan; Berbaum, Michael L.; Wilson, Robert; Buchner, David M.; McAuley, Edward

    2014-01-01

    Physical activity (PA) has documented health benefits, but older Latinos are less likely to engage in leisure time PA than older non-Latino whites. Dance holds promise as a culturally appropriate form of PA that challenges individuals physically and cognitively. This paper describes a randomized controlled trial that will test the efficacy of BAILAMOS©, a 4-month Latin dance program followed by a 4-month maintenance program, for improving lifestyle PA and health outcomes. Older adults (n = 332), aged 55+, Latino/Hispanic, Spanish speaking, with low PA levels, and at risk for disability will be randomized to one of two programs, a dance program or health education control group. BAILAMOS© is a 4-month program that meets two times per week for one hour per session. Dance sessions focus on instruction, including four styles of dance, and couples dancing. Bi-monthly “Fiestas de Baile” (dance parties) are also included, in which participants dance and practice what they have learned.. Monthly 1-hour discussion sessions utilize a Social Cognitive framework and focus on knowledge, social support, and self-efficacy to increase lifestyle PA. The health education control group will meet one time per week for two hours per session. Primary outcomes including PA changes and secondary outcomes including self-efficacy, physical function, cognitive function, and disability will be assessed at baseline, 4, and 8 months. It is hypothesized that PA, self-efficacy, physical function, cognitive function, and functional limitations and disability scores will be significantly better in the BAILAMOS© group at 4 and 8 months compared to the control group. PMID:24969395

  9. 30 CFR 57.22228 - Preshift examination (I-A, I-C, II-A, III, and V-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... requirements of 30 CFR parts 18 through 36. ... the beginning of a shift following an idle shift, a competent person shall test the mine atmosphere... immediately follows another, a competent person shall test the mine atmosphere at each active working face...

  10. Why Was Kelvin&apos;s Estimate of the Earth&apos;s Age Wrong?

    ERIC Educational Resources Information Center

    Lovatt, Ian; Syed, M. Qasim

    2014-01-01

    This is a companion to our previous paper in which we give a published example, based primarily on Perry&apos;s work, of a graph of ln "y" versus "t" when "y" is an exponential function of "t". This work led us to the idea that Lord Kelvin&apos;s (William Thomson&apos;s) estimate of the Earth&apos;s age was…

  11. The Impact of Adolescents&apos; Dyslexia on Parents&apos; and Their Own Educational Expectations

    ERIC Educational Resources Information Center

    Rimkute, Laura; Torppa, Minna; Eklund, Kenneth; Nurmi, Jari-Erik; Lyytinen, Heikki

    2014-01-01

    The present study examined the role that adolescents&apos; dyslexia plays in their educational expectations, as well as their parents&apos; expectations concerning their offspring&apos;s future education. To investigate this, 170 adolescents were asked to report their educational expectations on two occasions while they were still attending…

  12. Influence of Mothers&apos; Education on Children&apos;s Maths Achievement in Kenya

    ERIC Educational Resources Information Center

    Abuya, Benta A.; Oketch, Moses; Mutisya, Maurice; Ngware, Moses; Ciera, James

    2013-01-01

    Research shows that fathers&apos; level of education predicts achievement of both boys and girls, with significantly greater effect for boys. Similarly, mothers&apos; level of education predicts the achievement of girls but not boys. This study tests the mother-child education achievement hypothesis, by examining the effect of mothers&apos;…

  13. Critical Pedagogy&apos;s Problem with Changing Teachers&apos; Dispositions towards Critical Teaching

    ERIC Educational Resources Information Center

    Neumann, Jacob W.

    2013-01-01

    Increasing teachers&apos; dispositions towards critical teaching is a fundamental goal for critical pedagogy. Because critical educational change cannot occur without teachers&apos; "buy-in," developing teachers&apos; inclination to implement critical teaching into their classrooms is a prerequisite for any successful critical pedagogy…

  14. Individual Differences in Children&apos;s and Parents&apos; Generic Language

    ERIC Educational Resources Information Center

    Gelman, Susan A.; Ware, Elizabeth A.; Kleinberg, Felicia; Manczak, Erika M.; Stilwell, Sarah M.

    2014-01-01

    Generics ("&apos;Dogs&apos; bark") convey important information about categories and facilitate children&apos;s learning. Two studies with parents and their 2- or 4-year-old children (N = 104 dyads) examined whether individual differences in generic language use are as follows: (a) stable over time, contexts, and domains, and (b) linked…

  15. Japanese Children&apos;s Reactions to Family Photographs: Associations with Mothers&apos; Attachment Status

    ERIC Educational Resources Information Center

    Behrens, Kazuko Y.; Umemura, Tomo

    2013-01-01

    This study examined differences in children&apos;s responses to their family photographs within a sample of Japanese 6-year-olds ("N"?=?44), exploring associations with their mothers&apos; attachment status. The differences in children&apos;s photo reactions were captured by a 5-point continuous scale to rate how engaged children were…

  16. James Baldwin&apos;s "Everybody&apos;s Protest Novel": Educating Our Responses to Racism

    ERIC Educational Resources Information Center

    Frank, Jeff

    2014-01-01

    The aim of this article is to establish--and explore--James Baldwin&apos;s significance for educational theory. Through a close reading of "Everybody&apos;s Protest Novel", I show that Baldwin&apos;s thinking is an important (if unrecognized) precursor to the work of Stanley Cavell and Cora Diamond, and is relevant to a number of…

  17. Calculus Students&apos; and Instructors&apos; Conceptualizations of Slope: A Comparison across Academic Levels

    ERIC Educational Resources Information Center

    Nagle, Courtney; Moore-Russo, Deborah; Viglietti, Janine; Martin, Kristi

    2013-01-01

    This study considers tertiary calculus students&apos; and instructors&apos; conceptualizations of slope. Qualitative techniques were employed to classify responses to 5 items using conceptualizations of slope identified across various research settings. Students&apos; responses suggest that they rely on procedurally based conceptualizations of…

  18. Primary Health Care Providers&apos; Knowledge Gaps on Parkinson&apos;s Disease

    ERIC Educational Resources Information Center

    Thompson, Megan R.; Stone, Ramona F.; Ochs, V. Dan; Litvan, Irene

    2013-01-01

    In order to determine primary health care providers&apos; (PCPs) knowledge gaps on Parkinson&apos;s disease, data were collected before and after a one-hour continuing medical education (CME) lecture on early Parkinson&apos;s disease recognition and treatment from a sample of 104 PCPs participating at an annual meeting. The main outcome measure…

  19. Gene-Environment Interaction of ApoE Genotype and Combat Exposure on PTSD

    PubMed Central

    Lyons, Michael J.; Genderson, Margo; Grant, Michael D.; Logue, Mark; Zink, Tyler; McKenzie, Ruth; Franz, Carol E.; Panizzon, Matthew; Lohr, James B.; Jerskey, Beth; Kremen, William S.

    2015-01-01

    Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD. PMID:24132908

  20. White Teachers&apos; Racial Identities, Perceptions of Students&apos; Behaviors, and Symptoms of Burnout

    ERIC Educational Resources Information Center

    Chen, Cynthia E.

    2013-01-01

    Educational research has examined factors contributing to teachers&apos; burnout symptoms, including their perceptions of student behaviors (Ingersoll, 2003). Interestingly, teacher and students&apos; races have been differentially related to teachers&apos; perceptions of student behavior (Downey & Pribesh, 2004); this disparity in perceptions…

  1. Teaching Laura Kipnis&apos;s "Love&apos;s Labors" in "Ways of Reading"

    ERIC Educational Resources Information Center

    Fike, Matthew A.

    2013-01-01

    This essay describes a method of teaching a very challenging anthology piece: Laura Kipnis&apos;s "Love&apos;s Labors" (chapter 1 of her 2003 "Against Love: A Polemic"). The method, although designed for a critical thinking course, should also provide resources for those who teach Kipnis&apos;s work in writing courses. Using…

  2. On the Relations between Parents&apos; Ideals and Children&apos;s Autonomy

    ERIC Educational Resources Information Center

    de Ruyter, Doret J.; Schinkel, Anders

    2013-01-01

    In this article Doret J. de Ruyter and Anders Schinkel argue that parents&apos; ideals can enhance children&apos;s autonomy, but that they may also have a detrimental effect on the development of children&apos;s autonomy. After describing the concept of "ideals" and elucidating a systems theoretical conception of autonomy, de Ruyter and…

  3. Does Play Matter to Parents? Taiwanese Parents&apos; Perceptions of Child&apos;s Play

    ERIC Educational Resources Information Center

    Lin, Yen-Chun; Yawkey, Thomas D.

    2013-01-01

    The main purpose of this study was to gain an understanding of Taiwanese parents&apos; perceptions of child&apos;s play. Data were collected via parent questionnaires. To ensure greater variability in parents&apos; backgrounds, kindergartens with families from different social backgrounds were recruited. A total sample of 142 parents with…

  4. Master&apos;s Degree Learners&apos; Use of Theory in Designing Instructional Materials

    ERIC Educational Resources Information Center

    Wojtecki, John A.

    2012-01-01

    Educational institutions offering a master&apos;s degree program in instructional design incorporate instructional design theory into the master&apos;s degree course offerings. The responsibility for the student is to develop coursework. Master&apos;s degree learners will use instructional design theory to develop course materials. This study…

  5. Teachers&apos; Prestige in Spain: Probing the Public&apos;s and the Teachers&apos; Contrary Views

    ERIC Educational Resources Information Center

    Pérez-Díaz, Víctor; Rodríguez, Juan Carlos

    2014-01-01

    We use the results of a public opinion survey we carried out in 2012 on a sample of the Spanish adult population to offer a plausible explanation of one of the main conundrums of primary and secondary school teachers&apos; prestige, not only in Spain, i.e. that, contrary to public discourse and to teachers&apos; perceptions, this prestige has not…

  6. Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice

    PubMed Central

    Fitz, Nicholas F.; Cronican, Andrea A.; Saleem, Muzamil; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya

    2012-01-01

    ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOEε4 allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect of Abca1 deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1ΔE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examined Abca1 gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy of Abca1 significantly exacerbates memory deficits in APP/E4/Abca1−/+ but not in APP/E3/Abca1−/+ mice. The data for amyloid plaques and insoluble amyloid-β (Aβ) also show that Abca1 hemizygosity increases Aβ deposition only in APP/E4/Abca1−/+ but not in APP/E3/Abca1−/+ mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect of Abca1 on Aβ clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Aβ42 levels in APP/E4/Abca1−/+ mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in Aβ clearance. Overall, our results prove that the presence of functional Abca1 significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1–APOE regulatory axis. PMID:22993429

  7. Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?

    PubMed

    Jasienska, Grazyna; Ellison, Peter T; Galbarczyk, Andrzej; Jasienski, Michal; Kalemba-Drozdz, Malgorzata; Kapiszewska, Maria; Nenko, Ilona; Thune, Inger; Ziomkiewicz, Anna

    2015-03-22

    The alleles that are detrimental to health, especially in older age, are thought to persist in populations because they also confer some benefits for individuals (through antagonistic pleiotropy). The ApoE4 allele at the ApoE locus, encoding apolipoprotein E (ApoE), significantly increases risk of poor health, and yet it is present in many populations at relatively high frequencies. Why has it not been replaced by natural selection with the health-beneficial ApoE3 allele? ApoE is a major supplier of cholesterol precursor for the production of ovarian oestrogen and progesterone, thus ApoE has been suggested as the potential candidate gene that may cause variation in reproductive performance. Our results support this hypothesis showing that in 117 regularly menstruating women those with genotypes with at least one ApoE4 allele had significantly higher levels of mean luteal progesterone (144.21 pmol l(-1)) than women with genotypes without ApoE4 (120.49 pmol l(-1)), which indicates higher potential fertility. The hormonal profiles were based on daily data for entire menstrual cycles. We suggest that the finding of higher progesterone in women with ApoE4 allele could provide first strong evidence for an evolutionary mechanism of maintaining the ancestral and health-worsening ApoE4 allele in human populations.

  8. Role of leucine zipper motif in apoE3 N-terminal domain lipid binding activity.

    PubMed

    Yamamoto, Taichi; Ryan, Robert O

    2006-09-01

    The N terminal domain of human apolipoprotein E3 (apoE3-NT) functions as a ligand for members of the low-density lipoprotein receptor (LDLR) family. Whereas lipid-free apoE3-NT adopts a stable four-helix bundle conformation, a lipid binding induced conformational change is required for LDLR recognition. To investigate the role of a leucine zipper motif identified in the helix bundle on lipid binding activity, three leucine residues in helix 2 (Leu63, Leu71 and Leu78) were replaced by alanine. Recombinant "leucine to alanine" (LA) apoE3-NT was produced in E. coli, isolated and characterized. Stability studies revealed a transition midpoint of guanidine hydrochloride induced denaturation of 2.7 M and 2.1 M for wild type (WT) and LA apoE3-NT, respectively. Results from fluorescent dye binding assays revealed that, compared to WT apoE3-NT, LA apoE3-NT has an increased content of solvent exposed hydrophobic surfaces. In phospholipid vesicle solubilization assays, LA apoE3-NT was more effective than WT apoE3-NT at inducing a time-dependent decrease in dimyristoylphosphatidylglycerol vesicle light scattering intensity. Likewise, in lipoprotein binding assays, LA apoE3-NT protected human low-density lipoprotein from phospholipase C induced aggregation to a greater extent than WT apoE3-NT. On the other hand, LA apoE3-NT and WT apoE3-NT were equivalent in terms of their ability to bind a soluble LDLR fragment. The results suggest that the leucine zipper motif confers stability to the apoE3-NT helix bundle state and may serve to modulate lipid binding activity of this domain and, thereby, influence the conformational transition associated with manifestation of LDLR binding activity.

  9. Exploring Students&apos; Patterns of Reasoning

    ERIC Educational Resources Information Center

    Matloob Haghanikar, Mojgan

    2012-01-01

    As part of a collaborative study of the science preparation of elementary school teachers, we investigated the quality of students&apos; reasoning and explored the relationship between sophistication of reasoning and the degree to which the courses were considered inquiry oriented. To probe students&apos; reasoning, we developed open-ended written…

  10. Teaching the Writer&apos;s Craft

    ERIC Educational Resources Information Center

    Kittle, Penny

    2014-01-01

    "Writing is a core skill for living, not just for school," writes high school English teacher Penny Kittle. Although it&apos;s important to teach students the conventions of grammar, punctuation, and sentence structure, teachers don&apos;t need to approach this task "like scolds, red pens in hand, stamping out sin, and punishing…

  11. Omani Students&apos; Definitions of Geography

    ERIC Educational Resources Information Center

    Al-Nofli, Mohammed Abdullah

    2014-01-01

    Very few studies have been conducted on students&apos; definitions of geography. The purpose of the present study was to add to the existing literature by exploring Omani students&apos; definitions of geography. Participants were 477 students of grade 6 (ages 11-12) and grade 10 (ages 15-16) in one school district in Oman. They had been taught…

  12. Science Teachers&apos; Analogical Reasoning

    ERIC Educational Resources Information Center

    Mozzer, Nilmara Braga; Justi, Rosária

    2013-01-01

    Analogies can play a relevant role in students&apos; learning. However, for the effective use of analogies, teachers should not only have a well-prepared repertoire of validated analogies, which could serve as bridges between the students&apos; prior knowledge and the scientific knowledge they desire them to understand, but also know how to…

  13. Workers&apos; Education in Palestine

    ERIC Educational Resources Information Center

    Elayassa, Wajih

    2013-01-01

    Due to the political context and the restrictions placed on general freedoms and trade union activities, workers&apos; education in Palestine remained informal and largely reliant on oral memory until the early 1990s. For decades, it was an integral part of political education. Workers&apos; education only became a stand-alone field after the…

  14. Testing Bernoulli&apos;s Law

    ERIC Educational Resources Information Center

    Ivanov, Dragia; Nikolov, Stefan; Petrova, Hristina

    2014-01-01

    In this paper we present three different methods for testing Bernoulli&apos;s law that are different from the standard "tube with varying cross-section." They are all applicable to high-school level physics education, with varying levels of theoretical and experimental complexity, depending on students&apos; skills, and may even be…

  15. India&apos;s Higher Education Challenges

    ERIC Educational Resources Information Center

    Altbach, Philip G.

    2014-01-01

    India, with the world&apos;s second largest higher education system and a rapidly growing economy as one of the BRIC nations, faces significant challenges in building both capacity and excellence in higher education. India&apos;s higher education system is characterized by "islands of excellence in a sea of mediocrity." The mainstream…

  16. Measuring Master&apos;s Student Engagement

    ERIC Educational Resources Information Center

    O'Dair, Katherine G.

    2012-01-01

    Master&apos;s education is the largest segment of graduate education in the United States yet there is a paucity of research about how master&apos;s students experience their programs. Empirical research on student engagement--defined as the time and effort students devote to activities that are linked to educational outcomes and what institutions…

  17. Gene-Environment Interplay in the Link of Friends&apos; and Nonfriends&apos; Behaviors with Children&apos;s Social Reticence in a Competitive Situation

    ERIC Educational Resources Information Center

    Guimond, Fanny-Alexandra; Brendgen, Mara; Vitaro, Frank; Forget-Dubois, Nadine; Dionne, Ginette; Tremblay, Richard E.; Boivin, Michel

    2014-01-01

    This study used a genetically informed design to assess the effects of friends&apos; and nonfriends&apos; reticent and dominant behaviors on children&apos;s observed social reticence in a competitive situation. Potential gene-environment correlations (rGE) and gene-environment interactions (GxE) in the link between (a) friends&apos; and…

  18. The Influence of Teachers&apos; Conceptions on Their Students&apos; Learning: Children&apos;s Understanding of Sheet Music

    ERIC Educational Resources Information Center

    López-Íñiguez, Guadalupe; Pozo, Juan Ignacio

    2014-01-01

    Background: Despite increasing interest in teachers&apos; and students&apos; conceptions of learning and teaching, and how they influence their practice, there are few studies testing the influence of teachers&apos; conceptions on their students&apos; learning. Aims: This study tests how teaching conception (TC; with a distinction between…

  19. Effect of chronic ethanol on hepatic apolipoprotein (Apo)E glycosylation

    SciTech Connect

    Ghosh, P.; Okoh, C.; Chirtel, S.J.; Liu, Q.H.; Lakshman, M.R. George Washington Univ., Washington, DC )

    1991-03-15

    The authors have previously shown that chronic ethanol feeding significantly inhibits the secretion of ApoE in rats. Since many carbohydrate precursors are essential for the synthesis of mature ApoE before it is secreted, the authors have investigated the effects of chronic ethanol on the incorporation of these precursors into ApoE. Male Wistar rats were divided into groups and were pair-fed with Control and Ethanol liquid diets for a period of 8 weeks. At the end, hepatocytes were isolated from each group and {approximately}400 mg cells were incubated in 8 ml final volume of Krebs bicarbonate buffer, pH 7.4 for 30 min. at 37C with the following labeled precursors individually: (2-{sup 3}H)mannose, (6-{sup 3}H)N-acetyl mannosamine, (4,5-{sup 3}H)galactose, (5,6-{sup 3}H)fucose, and (4,5-{sup 3}H)leucine. The incorporation of each precursor into immunoprecipitable ApoE was measured in cell homogenate, microsome and the Golgi fractions. The results showed that chronic ethanol treatment did not significantly inhibit the incorporation of leucine, fucose and galactose into ApoE at any of the subcellular levels. In contrast, chronic ethanol inhibited the incorporation of: (a) mannose into ApoE by 38% both at whole cell and at microsomal level and (b) N-acetyl mannosamine by 26% at the whole cell level and at the Golgi level. Based on these results, it is concluded that chronic ethanol feeding impairs the mannosylation and sialylation of ApoE in rat liver probably by altering the structure and functions of hepatic microsome and Golgi.

  20. [Influence of genetic and environmental factors on lipid metabolism and cardiovascular risk associated with the apoE gene].

    PubMed

    Moreno, Juan Antonio; López-Miranda, José; Pérez-Jiménez, Francisco

    2006-09-01

    The apolipoprotein E (ApoE) plays an important role in lipid metabolism. This apoprotein presents three major isoforms (apoE2, apoE3 and apoE4) that modulate lipid levels. Carriers of the apoE4 allele have higher total and LDL-cholesterol plasma concentration and a greater coronary risk, particularly for myocardial infarction. Nevertheless, not all the people with this allele develop the disease, which suggests that other genetic or environmental factors are necessary for its total expression. In this review, we will analyze the importance of several polymorphisms in the apoE gene promoter region, as well as various environmental factors, including diet, in the association of this gene with lipid metabolism and cardiovascular risk.

  1. Gene-environment interaction of ApoE genotype and combat exposure on PTSD.

    PubMed

    Lyons, Michael J; Genderson, Margo; Grant, Michael D; Logue, Mark; Zink, Tyler; McKenzie, Ruth; Franz, Carol E; Panizzon, Matthew; Lohr, James B; Jerskey, Beth; Kremen, William S

    2013-10-01

    Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD. PMID:24132908

  2. Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy.

    PubMed

    Sakai, Kenji; Boche, Delphine; Carare, Roxana; Johnston, David; Holmes, Clive; Love, Seth; Nicoll, James A R

    2014-12-01

    Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.

  3. Proteomic analysis of changes in protein expression in liver mitochondria in apoE knockout mice.

    PubMed

    Suski, Maciej; Olszanecki, Rafał; Madej, Józef; Totoń-Żurańska, Justyna; Niepsuj, Anna; Jawień, Jacek; Bujak-Giżycka, Beata; Okoń, Krzysztof; Korbut, Ryszard

    2011-05-16

    The involvement of both apolipoprotein E (apoE) and mitochondria in lipid metabolism is widely recognized, however there is surprisingly scarce data about the putative mitochondrial action(s) of this protein. The aim of the study was to screen the alterations in liver mitochondrial proteome caused by apoE deficiency. We applied 2DE-LC-MS/MS methodology to investigate the changes in liver mitochondrial protein expression in 6-months old apoE(-/-) mice as compared to C57BL/6J controls. ApoE(-/-), but not C57BL/6J mice developed visible atherosclerotic changes in aorta and mild, diffuse steatosis of the liver. Collectively, 18 differentially expressed proteins were identified in mitochondria, related to apoptosis, antioxidant and detoxifying mechanisms of mitochondria, as well as lipid metabolism and transport. In conclusion, differential proteomic approach revealed several lines of proteomic evidence that mitochondrial function in the liver of apoE(-/-) mice could be altered as a result of overlapping of pathological and compensatory changes in expression of proteins.

  4. [ApoE polymorphisms and dopaminergic replacement therapy in Parkinson's disease].

    PubMed

    Cervantes-Arriaga, Amin; Rodríguez-Violante, Mayela; González-Latapí, Paulina; Dávila-Ortiz de Montellano, David José; Yescas, Petra; Alonso-Vilatela, Elisa

    2014-01-01

    INTRODUCCIÓN: se ha propuesto que la expresión de los polimorfismos de la apolipoproteína E (apoE) es un factor predisponente para el desarrollo temprano de psicosis en los pacientes con enfermedad de Parkinson. La relación entre el genotipo de la apoE y el desarrollo de complicaciones motoras es controvertida. El objetivo de esta investigación fue determinar la relación entre los polimorfismos de la apoE y su frecuencia alélica y el desarrollo de complicaciones secundarias al reemplazo dopaminérgico. MÉTODOS: se evaluaron 231 pacientes con diagnóstico de enfermedad de Parkinson. La presencia de complicaciones fue determinada por un neurólogo y se realizó la genotipificación de los polimorfismos de la apoE. Se utilizó la chi cuadrada para determinar la relación entre la presencia o ausencia de las complicaciones estudiadas y el genotipo de la apoE.

  5. Exercise, but not antioxidants, reversed ApoE4-associated motor impairments in adult GFAP-ApoE mice.

    PubMed

    Chaudhari, Kiran; Wong, Jessica M; Vann, Philip H; Sumien, Nathalie

    2016-05-15

    Motor dysfunction has been found to be predictive of cognitive dysfunction in Alzheimer's disease and to occur earlier than cognitive impairments. While apolipoprotein (Apo) E4 has been associated with cognitive impairments, it remains unclear whether it also increases risk for motor dysfunction. Exercise and antioxidants are often recommended to reduce cognitive declines, however it is unclear whether they can successfully improve motor impairments. This study was designed to determine the extent of the impact of apolipoprotein genotype on motor function, and whether interventions such as exercise and antioxidant intake can improve motor function. This study is the first to identify the nature of the interaction between antioxidant intake and exercise using a mouse model expressing either the human ApoE3 or ApoE4 isoforms under glial fibrillary acid protein promoter (GFAP-ApoE3 and GFAP-ApoE4 mice). The mice were fed either a control diet or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65mg/g ascorbic acid). Each genotype/diet group was further divided into a sedentary group or a group that followed a 6 days a week exercise regimen. After 8 weeks on their respective treatment, the mice were administered a battery of motor tests to measure reflexes, strength, coordination and balance. GFAP-ApoE4 mice exhibited impaired motor learning and diminished strength compared to the GFAP-ApoE3 mice. Exercise alone was more efficient at improving motor function and reversing ApoE4-associated impairments than antioxidants alone, even though improvements were rather subtle. Contrarily to expected outcomes, combination of antioxidants and exercise did not yield further improvements of motor function. Interestingly, antioxidants antagonized the beneficial effects of exercise on strength. These data suggest that environmental and genetic factors influence the outcome of interventions on motor function and should be investigated

  6. Serum cholesterol and expression of ApoAI, LXRbeta and SREBP2 in vitamin D receptor knock-out mice.

    PubMed

    Wang, Jing-Huan; Keisala, Tiina; Solakivi, Tiina; Minasyan, Anna; Kalueff, Allan V; Tuohimaa, Pentti

    2009-02-01

    Vitamin D insufficiency has been reported to be associated with increased blood cholesterol concentrations. Here we used two strains of VDR knock-out (VDR-KO) mice to study whether a lack of vitamin D action has any effect on cholesterol metabolism. In 129S1 mice, both in male and female VDR-KO mice serum total cholesterol levels were significantly higher than those in wild type (WT) mice (20.7% (P=0.05) and 22.2% (P=0.03), respectively). In addition, the serum high-density lipoprotein-bound cholesterol (HDL-C) level was 22% (P=0.03), respectively higher in male VDR-KO mice than in WT mice. The mRNA expression levels of five cholesterol metabolism related genes in livers of 129S1 mice were studied using quantitative real-time PCR (QRT-PCR): ATP-binding cassette transporter A1 (ABCA1), regulatory element binding protein (SREBP2), apolipoprotein A-I (ApoAI), low-density lipoprotein receptor (LDLR) and liver X receptor beta (LXRbeta). In the mutant male mice, the mRNA level of ApoAI and LXRbeta were 49.2% (P=0.005) and 38.8% (P=0.034) higher than in the WT mice. These changes were not observed in mutant female mice, but the female mutant mice showed 52.5% (P=0.006) decrease of SREBP2 mRNA expression compared to WT mice. Because the mutant mice were fed with a special rescue diet, we wanted to test whether the increased cholesterol levels in mutant mice were due to the diet. Both the WT and mutant NMRI mice were given the same diet for 3 weeks before the blood sampling. No difference in cholesterol or in HDL-C between WT and mutant mice was found. The results suggest that the food, gender and genetic background have an effect on the cholesterol metabolism. Although VDR seems to regulate some of the genes involved in cholesterol metabolism, its role in the regulation of serum cholesterol seems to be minimal.

  7. Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation.

    PubMed

    Huang, Zhi H; Reardon, Catherine A; Getz, Godfrey S; Maeda, Nobuyo; Mazzone, Theodore

    2015-02-01

    apoE is a multi-functional protein expressed in several cell types and in several organs. It is highly expressed in adipose tissue, where it is important for modulating adipocyte lipid flux and gene expression in isolated adipocytes. In order to investigate a potential systemic role for apoE that is produced in adipose tissue, mice were generated with selective suppression of adipose tissue apoE expression and normal circulating apoE levels. These mice had less adipose tissue with smaller adipocytes containing fewer lipids, but no change in adipocyte number compared with control mice. Adipocyte TG synthesis in the presence of apoE-containing VLDL was markedly impaired. Adipocyte caveolin and leptin gene expression were reduced, but adiponectin, PGC-1, and CPT-1 gene expression were increased. Mice with selective suppression of adipose tissue apoE had lower fasting lipid, insulin, and glucose levels, and glucose and insulin tolerance tests were consistent with increased insulin sensitivity. Lipid storage in muscle, heart, and liver was significantly reduced. Adipose tissue macrophage inflammatory activation was markedly diminished with suppression of adipose tissue apoE expression. Our results establish a novel effect of adipose tissue apoE expression, distinct from circulating apoE, on systemic substrate metabolism and adipose tissue inflammatory state.

  8. Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

    PubMed Central

    Ooi, Esther M. M.; Ng, Theodore W. K.; Watts, Gerald F.; Chan, Dick C.; Barrett, P. Hugh R.

    2012-01-01

    We examined the effects of fenofibrate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofibrate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations (P < 0.05). Fenofibrate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo (P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR (P < 0.05). Fenofibrate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofibrate was 22% less than that with atorvastatin (P < 0.01). With fenofibrate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofibrate decreased VLDL-apoE concentration by lowering VLDL-apoE production and increasing VLDL-apoE catabolism. By contrast, atorvastatin decreased VLDL-apoE concentration chiefly by increasing VLDL-apoE catabolism. Our study provides new insights into the mechanisms of action of two different lipid-lowering therapies on VLDL-apoE metabolism in MetS. PMID:22930812

  9. ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations.

    PubMed

    Johnson, Lance A; Zuloaga, Damian G; Bidiman, Erin; Marzulla, Tessa; Weber, Sydney; Wahbeh, Helane; Raber, Jacob

    2015-09-01

    Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.

  10. Infants&apos; Discrimination of Female Singing Voices

    ERIC Educational Resources Information Center

    Costa-Giomi, Eugenia; Davila, Yvonne

    2014-01-01

    There&apos;s extensive research on infant&apos;s discrimination of speaking voices but few studies have focused on infant&apos;s discrimination of singing voices. Most investigations on infants&apos; perception of timbre in music have been based on instrumental sounds. We completed an experiment with 7-and 13-month-olds (n = 16 and n = 17…

  11. Average Passenger Occupancy (APO) in Your Community.

    ERIC Educational Resources Information Center

    Stenstrup, Al

    1995-01-01

    Provides details of an activity in which students in grades 4-10 determine the Average Passenger Occupancy (APO) in their community and develop, administer, and analyze a survey to determine attitudes toward carpooling. (DDR)

  12. Effect of Diet and Age on Arterial Stiffening Due to Atherosclerosis in ApoE(-/-) Mice.

    PubMed

    Cilla, M; Pérez, M M; Peña, E; Martínez, M A

    2016-07-01

    This work analyzes the progressive stiffening of the aorta due to atherosclerosis development of both ApoE(-/-) and C57BL/6J mice fed on a Western (n = 5) and a normal (n = 5) chow diet for the ApoE(-/-) group and on a normal chow diet (n = 5) for the C57BL/6J group. Sets of 5 animals from the three groups were killed after 10, 20, 30 and 40 weeks on their respective diets (corresponding to 17, 27, 37 and 47 weeks of age). Mechanical properties (inflation test and axial residual stress measurements) and histological properties were compared for both strains, ApoE(-/-) on the hyper-lipidic diet and both ApoE(-/-) and C57BL/6J on the normal diet, after the same period and after different periods of diet. The results indicated that the aorta stiffness in the ApoE(-/-) and C57BL/6J mice under normal diet remained approximately constant irrespective of their age. However, the arterial stiffness in the ApoE(-/-) on the hyper-lipidic diet increased over time. Statistical differences were found between the group after 10 weeks and the groups after 30 and 40 weeks of a hyper-lipidic diet. Comparing the hyper-lipidic and normal diet mice, statistical differences were also found between both diets in all cases after 40 weeks of diet, frequently after 30 weeks, and in some cases after 20 weeks. The early stages of lesion corresponded to the first 2 weeks of diet. Advanced lesions were found at 30 weeks and, finally, the aorta was completely damaged after 40 weeks of diet. In conclusion, we found substantial changes in the mechanical properties of the aorta walls of the ApoE(-/-) mice fed with the hyper-lipidic diet compared to the normal chow diet groups for both the ApoE(-/-) and C57BL/6J groups. These findings could serve as a reference for the study of changes in the arterial wall properties in cases of atherosclerosis.

  13. Applications of Dweck&apos;s Model of Implicit Theories to Teachers&apos; Self-Efficacy and Emotional Experiences

    ERIC Educational Resources Information Center

    Williams, Alexis Ymon

    2012-01-01

    The current study explored Dweck&apos;s (1999; Dweck & Leggett, 1988) model of implicit theories in the context of teaching in order to establish its usefulness for describing teachers&apos; beliefs about students&apos; ability and social behavior. Further it sought to explain the connections between teachers&apos; implicit beliefs and their…

  14. The Role of Student-Teacher Ratio in Parents&apos; Perceptions of Schools&apos; Engagement Efforts

    ERIC Educational Resources Information Center

    Rodriguez, Raymond J.; Elbaum, Batya

    2014-01-01

    Research suggests a positive relationship between schools&apos; efforts to engage parents and parents&apos; involvement in their child&apos;s education. The authors investigated school socioeconomic status, school size, grade level, and student-teacher ratio as predictors of schools&apos; efforts to engage parents of students receiving special…

  15. How Do Teachers&apos; Beliefs Predict Children&apos;s Interest in Math from Kindergarten to Sixth Grade?

    ERIC Educational Resources Information Center

    Upadyaya, Katja; Eccles, Jacquelynne S.

    2014-01-01

    The present study investigated to what extent teachers&apos; beliefs about children&apos;s achievement contribute to the development of children&apos;s math interest. In addition, the extent to which other possible predictors, such as performance in math, gender, and race/ethnicity would contribute to the development of children&apos;s math…

  16. The Problem of Character Education and Kohlberg&apos;s Moral Education: Critique from Dewey&apos;s Moral Deliberation

    ERIC Educational Resources Information Center

    Liu, Xiangdong

    2014-01-01

    In this article, the author examines Dewey&apos;s moral deliberation. Liu argues that Dewey&apos;s work will enrich both character education and Kohlberg&apos;s moral education. Liu focuses on character education and on Kohlberg&apos;s moral education because these are the two dominant approaches. Character education seeks to cultivate good…

  17. Parents&apos; Views of the National Autistic Society&apos;s EarlyBird Plus Programme

    ERIC Educational Resources Information Center

    Cutress, Anna L.; Muncer, Steven J.

    2014-01-01

    Parent training interventions are recommended for parents soon after their child&apos;s autism spectrum condition diagnosis with the aim of improving parents&apos; psychological well-being and coping, as well as the child&apos;s behaviour. This report explores parents&apos; views of the EarlyBird Plus Programme through data collected routinely in…

  18. Family history and apoE genotype interaction in Alzheimer`s disease (AD)

    SciTech Connect

    Jarvik, G.P.; Kukull, W.A.; Goddards, K.

    1994-09-01

    The apoE {epsilon}4 allele is associated with increased risk and decreased age of onset of AD. The {epsilon}4 allele may have opposing effects. We determined that family history of a parent or sib with memory problems (famhx+) modified the effect of apoE genotype in a population-based, case (n=165, 72 famhx+)-control (n=233, 73 famhx+) sample. Logistic regression analyses detected a significant apoE genotype (E) by family history (F) by age (A) interaction (ExFxA, p=0.003) and ExF interaction (p=0.0001) in the prediction of AD. ExFxA remained significant when only {epsilon}4+ genotypes were included (p<0.01). ExFxSex (p=0.04) and ExF (p<0.0001) were significant when only {epsilon}4- genotypes were included. Similary, multiple regression detected significant ExF interaction in the prediction of age of AD onset for {epsilon}4+ genotypes (p=0.04) or {epsilon}4- genotypes (p=0.04). Sex did not interact in the prediction of age of onset. Famhx+ increased risk of AD differentially and reduced age of onset except in {epsilon}2+ genotypes. Family history modifies the apoE genotype influence on risk and onset age of AD, suggesting that non-apoE genetic effects interact with apoE in AD. It is most predictive of risk in those with the {epsilon}2{epsilon}3 genotype. Variation in risk and onset among both {epsilon}4+ and {epsilon}4- genotypes demonstrate that {epsilon}2 and {epsilon}3 mediate {epsilon}4 allele effects in AD.

  19. Higher Plasma ApoE Levels are Associated with Low-Normal Thyroid Function: Studies in Diabetic and Nondiabetic Subjects.

    PubMed

    van Tienhoven-Wind, L J N; Dallinga-Thie, G M; Dullaart, R P F

    2016-07-01

    Low-normal thyroid function within the euthyroid range may confer higher plasma triglycerides, but relationships with plasma apolipoprotein (apo) E, which plays an important role in the metabolism of triglyceride-rich apoB-containing lipoproteins, are unknown. We determined relationships of plasma apoE with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). TSH, free T4, lipids, and apoE were measured in fasting plasma from 72 T2DM subjects and 82 nondiabetic subjects. The APOE genotype was also determined. Free T4 was slightly higher in T2DM (p=0.030), but TSH levels were not different vs. nondiabetic subjects. The APOE genotype distribution was not different between the groups. None of the participants had the ε2/ε2 genotype. Plasma triglycerides were higher in T2DM (p=0.037). ApoB and apoE levels were not different between the groups. In all subjects combined, multivariable analysis showed that plasma triglycerides (p=0.039), non-high density lipoprotein (non-HDL) cholesterol (p=0.030), and apoE levels (p=0.002) were each independently and positively associated with TSH after adjustment for age, sex, T2DM and the presence of the APOE ε3 allele. Furthermore, the associations of TSH with apoE remained present after adjustment for either triglycerides, non-HDL cholesterol, or apoB (p=0.005 to 0.023). The presence of T2DM did not modify the relationships of TSH with these (apo) lipoprotein variables (p=0.11 to 0.36). In conclusion, low-normal thyroid function, as indicated by higher TSH levels within the euthyroid range, may influence the metabolism of triglyceride-rich lipoproteins by affecting apoE regulation.

  20. PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice.

    PubMed

    Segev, Yifat; Barrera, Iliana; Ounallah-Saad, Hadile; Wibrand, Karin; Sporild, Ida; Livne, Adva; Rosenberg, Tali; David, Orit; Mints, Meshi; Bramham, Clive R; Rosenblum, Kobi

    2015-09-23

    Sporadic Alzheimer's disease (AD) is an incurable neurodegenerative disease with clear pathological hallmarks, brain dysfunction, and unknown etiology. Here, we tested the hypothesis that there is a link between genetic risk factors for AD, cellular metabolic stress, and transcription/translation regulation. In addition, we aimed at reversing the memory impairment observed in a mouse model of sporadic AD. We have previously demonstrated that the most prevalent genetic risk factor for AD, the ApoE4 allele, is correlated with increased phosphorylation of the translation factor eIF2α. In the present study, we tested the possible involvement of additional members of the eIF2α pathway and identified increased mRNA expression of negative transcription factor ATF4 (aka CREB2) both in human and a mouse model expressing the human ApoE4 allele. Furthermore, injection of a PKR inhibitor rescued memory impairment and attenuated ATF4 mRNA increased expression in the ApoE4 mice. The results propose a new mechanism by which ApoE4 affects brain function and further suggest that inhibition of PKR is a way to restore ATF4 overexpression and memory impairment in early stages of sporadic AD. Significance statement: ATF4 mRNA relative quantities are elevated in ApoE4 allele carriers compared with noncarrier controls. This is true also for the ApoE ε4 human replacement mice. ApoE4 mice injected with PKR inhibitor (PKRi) demonstrate a significant reduction in ATF4 expression levels 3 h after one injection of PKRi. Treatment of ApoE4 human replacement mice with the PKRi before learning rescues the memory impairment of the ApoE4 AD model mice. We think that these results propose a new mechanism by which ApoE4 affects brain function and suggest that inhibition of PKR is a way to restore memory impairment in early stages of sporadic AD.

  1. Apo J and Apo D: Complementary or Antagonistic Roles in Alzheimer's Disease?

    PubMed

    Del Valle, Eva; Navarro, Ana; Martínez-Pinilla, Eva; Torices, Silvia; Tolivia, Jorge

    2016-05-17

    Apolipoprotein D (Apo D) and Apolipoprotein J (Apo J) are among the only nine apolipoproteins synthesized in the nervous system. Apart from development, these apolipoproteins are implicated in the normal aging process as well as in different neuropathologies as Alzheimer's disease (AD), where a neuroprotective role has been postulated. Different authors have proposed that Apo D and Apo J could be biomarkers for AD but as far as we know, there are no studies about the relationship between them as well as their expression pattern along the progression of the disease. In this paper, using double immunohistochemistry techniques, we have demonstrated that Apo D is mainly located in glial cells while Apo J expression preferentially occurs in neurons; both proteins are also present in AD diffuse and mature senile plaques but without signal overlap. In addition, we have observed that Apo J and Apo D immunostaining shows a positive correlation with the progression of the disease and the Braak's stages. These results suggest complementary and cell-dependent neuroprotective roles for each apolipoprotein during AD progress. PMID:27197790

  2. Students&apos; Perceptions of Their Science Teachers&apos; Pedagogical Content Knowledge

    ERIC Educational Resources Information Center

    Halim, Lilia; Abdullah, Sharifah Intan Sharina Syed; Meerah, T. Subahan Mohd

    2014-01-01

    Pedagogical content knowledge (PCK) is a type of teacher knowledge to be developed by a teacher. PCK is said to contribute to effective teaching. Most studies investigated the development of PCK and its influence on students&apos; learning from the teachers&apos; perspectives. Only a limited number of studies have investigated the components of…

  3. An Exploration of Mothers&apos; Attitudes towards Their Daughters&apos; Menarche

    ERIC Educational Resources Information Center

    Bennett, Clare; Harden, Jane

    2014-01-01

    Menarche is a significant milestone for young women, representing an important juncture between girlhood and maturation. The limited literature that exists suggests that a mother&apos;s reaction to her daughter&apos;s first periods can shape her experiences and perceptions of menstruation which, in turn, may impact on her self-image and,…

  4. Effects of Teachers&apos; Instructional Development on Students&apos; Study Approaches in Higher Education

    ERIC Educational Resources Information Center

    Stes, Ann; De Maeyer, Sven; Gijbels, David; Van Petegem, Peter

    2013-01-01

    Evidence regarding the impact of teachers&apos; instructional development on student learning in higher education is scarce. In this study the authors investigate the impact of an instructional development programme for beginning university teachers on students&apos; approach to studying. They also explore whether this impact is dependent on class…

  5. Extension&apos;s Role in Developing a Farmers&apos; Market

    ERIC Educational Resources Information Center

    Civittolo, David

    2012-01-01

    Interest in access to local food is increasing. Communities of all types and sizes have volunteers interested in creating farmers&apos; markets. Extension can play an important role in the development of farmers&apos; markets because it is ideally suited to organize and coordinate these volunteer energies. By helping community volunteers focus…

  6. Boys&apos; Music? School Context and Middle-School Boys&apos; Musical Choices

    ERIC Educational Resources Information Center

    Bennetts, Kathleen Scott

    2013-01-01

    This article focusses primarily on the findings relating to the musical participation of boys in one Melbourne school. As part of a project that investigated boys&apos; attitudes and participation at fifty-one schools, several contextual features were identified that set "Balton Boys" High School&apos; apart from other participating…

  7. Chilean Adolescents&apos; and Parents&apos; Views on Autonomy Development

    ERIC Educational Resources Information Center

    Martínez, M. Loreto; Pérez, J. Carola; Cumsille, Patricio

    2014-01-01

    This study aims to understand Chilean parents&apos; and adolescents&apos; conceptions of autonomy and whether they hold different expectations for autonomous behaviors by generation and socioeconomic level. A qualitative approach to data collection was used through separate focus groups of parents and adolescents from different socioeconomic…

  8. ApoE Genotype and Alzheimer's Disease in Adults with Down Syndrome: Meta-Analysis.

    ERIC Educational Resources Information Center

    Prashner, V. P.; Chowdhury, T. A.; Rowe, B. R.; Bain, S. C.

    1997-01-01

    ApoE gene polymorphism was examined in 100 adults with Down syndrome with and without dementia (Alzheimer's disease) and 346 control subjects. Additionally, a meta analysis of studies (total N=480 subjects) was performed. Results indicated a similar incidence of the gene across groups but subjects with the allele tended to an earlier onset of…

  9. Malaysian Primary Pre-Service Teachers&apos; Perceptions of Students&apos; Disruptive Behaviour

    ERIC Educational Resources Information Center

    Zakaria, Norzila; Reupert, Andrea; Sharma, Umesh

    2013-01-01

    The purpose of this paper was to investigate Malaysian primary pre-service teachers&apos; perceptions of students&apos; disruptive behaviour and their self-reported strategies to prevent and to manage such behaviours. Results indicate that Malaysian pre-service teachers understand disruptive behaviours to be those that disrupt the learning and…

  10. Parents&apos; and Teachers&apos; Perceptions of Standards-Based and Traditional Report Cards

    ERIC Educational Resources Information Center

    Swan, Gerry M.; Guskey, Thomas R.; Jung, Lee Ann

    2014-01-01

    The purpose of this study was to determine parents&apos; and teachers&apos; perceptions of standards-based and traditional report cards. Participants included 115 parents/guardians of students from a single, midsize school district that had implemented a standards-based report card. During the first two marking periods, all parents/guardians…

  11. The Relationship between Teacher&apos;s Autonomy Support and Students&apos; Autonomy and Vitality

    ERIC Educational Resources Information Center

    Núñez, Juan L.; Fernández, Celia; León, Jaime; Grijalvo, Fernando

    2015-01-01

    What makes a student feel vital and energetic? Using the self-determination framework, we analyzed how the behavior and feelings of students depend on social factors such as the teachers&apos; attitudes. The goal of the study was to test an integrated sequence over a semester in which teacher&apos;s autonomy support acts as a predictor of…

  12. Mapping of ApoE4 related white matter damage using diffusion MRI

    NASA Astrophysics Data System (ADS)

    Tsao, Sinchai; Gajawelli, Niharika; Hwang, Darryl H.; Kriger, Stephen; Law, Meng; Chui, Helena; Weiner, Michael; Lepore, Natasha

    2014-04-01

    ApoliopoproteinE Ɛ4 (ApoE-Ɛ4) polymorphism is the most well known genetic risk factor for developing Alzheimers Disease. The exact mechanism through which ApoE 4 increases AD risk is not fully known, but may be related to decreased clearance and increased oligomerization of Aβ. By making measurements of white matter integrity via diffusion MR and correlating the metrics in a voxel-based statistical analysis with ApoE-Ɛ4 genotype (whilst controlling for vascular risk factor, gender, cognitive status and age) we are able to identify changes in white matter associated with carrying an ApoE Ɛ4 allele. We found potentially significant regions (Puncorrected < 0:05) near the hippocampus and the posterior cingulum that were independent of voxels that correlated with age or clinical dementia rating (CDR) status suggesting that ApoE may affect cognitive decline via a pathway in dependent of normal aging and acute insults that can be measured by CDR and Framingham Coronary Risk Score (FCRS).

  13. Initiating Teachers&apos; Action Research: Empowering Teachers&apos; Voices

    ERIC Educational Resources Information Center

    Bognar, Branko

    2013-01-01

    The role of a teacher as an action researcher in Croatia is still insufficiently appreciated and promoted in initial teachers&apos; training, school students learning and in the employed teachers&apos; professional post-qualification development. In this country, teachers are most frequently perceived as mediators or technicians whose task is to…

  14. Examining the Relationship between Teachers&apos; Instructional Practices and Students&apos; Mathematics Achievement

    ERIC Educational Resources Information Center

    Firmender, Janine M.; Gavin, M. Katherine; McCoach, D. Betsy

    2014-01-01

    The purpose of this study was to determine whether relationships existed between teachers&apos; implementation of two specific discourse-related instructional practices and students&apos; mathematics achievement in geometry and measurement as part of a research study on the effectiveness of an advanced mathematics curriculum for kindergarten and…

  15. Teachers&apos; Perceptions Regarding School Principals&apos; Coaching Skills

    ERIC Educational Resources Information Center

    Yirci, Ramazan; Özdemir, Tuncay Yavuz; Kartal, Seçil Eda; Kocabas, Ibrahim

    2014-01-01

    The purpose of this study was to find out teachers&apos; perceptions about school principals&apos; coaching skills. The study was carried out within qualitative research methods. The study group included 76 teachers in Elazig and 73 teachers in Kahramanmaras provinces of Turkey. All the data were processed using Nvivo 9 software. The results…

  16. Teacher Educators&apos; Professional Development: Towards a Typology of Teacher Educators&apos; Researcherly Disposition

    ERIC Educational Resources Information Center

    Tack, Hanne; Vanderlinde, Ruben

    2014-01-01

    Since the beginning of the twenty-first century, the need for teacher educators&apos;--or those who teach the teachers--professional development became increasingly recognised in both policy and research literature. In this respect, a growing body of publications highly stress the teacher educators&apos; task of engaging in research and becoming a…

  17. Parallels in Preschoolers&apos; and Adults&apos; Judgments about Ownership Rights and Bodily Rights

    ERIC Educational Resources Information Center

    Van de Vondervoort, Julia W.; Friedman, Ori

    2015-01-01

    Understanding ownership rights is necessary for socially appropriate behavior. We provide evidence that preschoolers&apos; and adults&apos; judgments of ownership rights are related to their judgments of bodily rights. Four-year-olds (n = 70) and adults (n = 89) evaluated the acceptability of harmless actions targeting owned property and body…

  18. "Entre Familia": Immigrant Parents&apos; Strategies for Involvement in Children&apos;s Schooling

    ERIC Educational Resources Information Center

    Poza, Luis; Brooks, Maneka Deanna; Valdés, Guadalupe

    2014-01-01

    Teachers and administrators in schools with large, working-class Latino populations often complain of parents&apos; indifference or lack of involvement in children&apos;s schooling because of their low visibility at school events and relatively little face-to-face communication with teachers and school administration. In a series of…

  19. Reelin and apoE actions on signal transduction, synaptic function and memory formation.

    PubMed

    Rogers, Justin T; Weeber, Edwin J

    2008-08-01

    Low-density-lipoprotein receptors (LDLRs) are an evolutionarily ancient surface protein family with the ability to activate a diversity of extracellular signals across the cellular membrane in the adult central nervous system (CNS). Their intimate roles in modulating synaptic plasticity and their necessity in hippocampal-dependent learning and memory have only recently come to light. Two known LDLR ligands, specifically apolipoprotein E (apoE) and reelin, have been the most widely investigated in this regard. Most of our understanding of synaptic plasticity comes from investigation of both pre- and postsynaptic alterations. Therefore, it is interesting to note that neurons and glia that do not contribute to the synaptic junction in question can secrete signaling molecules that affect synaptic plasticity. Notably, reelin and apoE have been shown to modulate hippocampal long-term potentiation in general, and affect NMDA receptor and AMPA receptor regulation specifically. Furthermore, these receptors and signaling molecules have significant roles in neuronal degenerative diseases such as Alzheimer's disease. The recent production of recombinant proteins, knockout and transgenic mice for receptors and ligands and the development of human ApoE targeted replacement mice have significantly expanded our understanding of the roles LDLRs and their ligands have in certain disease states and the accompanying initiation of specific signaling pathways. This review describes the role LDLRs, apoE and reelin have in the regulation of hippocampal synaptic plasticity.

  20. Who&apos;s Really Struggling?: Middle School Teachers&apos; Perceptions of Struggling Readers

    ERIC Educational Resources Information Center

    Moreau, Leah K.

    2014-01-01

    This study explored middle school teachers&apos; perceptions of struggling readers, including influences such as: understandings of components and factors relating to reading difficulties; views of struggling readers&apos; behaviours and affect; classroom implications of their difficulties; and feelings of both competency and responsibility in the…

  1. Addressing K-5 Students&apos; and Preservice Elementary Teachers&apos; Conceptions of Seasonal Change

    ERIC Educational Resources Information Center

    Starakis, Ioannis; Halkia, Krystallia

    2014-01-01

    In this paper, primary school students&apos; and pre-service teachers&apos; ideas of seasonal change are investigated. The research was carried out in nine primary schools in Athens and in the Primary Education Department of the University of Athens. Written reports were used for gathering data while students also had the opportunity to support…

  2. A Class Act? Lecturers&apos; Views on Undergraduates&apos; Employability

    ERIC Educational Resources Information Center

    Morrison, Andrew

    2014-01-01

    This article details the findings of a study into lecturers&apos; perceptions of undergraduate employability. The investigation employed interviews with the staff on a BA (Hons) in Education Studies course at a post-1992 university. The aim was to examine staff beliefs regarding their students&apos; potential employability in the business and…

  3. Apo J and Apo D: Complementary or Antagonistic Roles in Alzheimer's Disease?

    PubMed

    Del Valle, Eva; Navarro, Ana; Martínez-Pinilla, Eva; Torices, Silvia; Tolivia, Jorge

    2016-05-17

    Apolipoprotein D (Apo D) and Apolipoprotein J (Apo J) are among the only nine apolipoproteins synthesized in the nervous system. Apart from development, these apolipoproteins are implicated in the normal aging process as well as in different neuropathologies as Alzheimer's disease (AD), where a neuroprotective role has been postulated. Different authors have proposed that Apo D and Apo J could be biomarkers for AD but as far as we know, there are no studies about the relationship between them as well as their expression pattern along the progression of the disease. In this paper, using double immunohistochemistry techniques, we have demonstrated that Apo D is mainly located in glial cells while Apo J expression preferentially occurs in neurons; both proteins are also present in AD diffuse and mature senile plaques but without signal overlap. In addition, we have observed that Apo J and Apo D immunostaining shows a positive correlation with the progression of the disease and the Braak's stages. These results suggest complementary and cell-dependent neuroprotective roles for each apolipoprotein during AD progress.

  4. The SAPO Campus Recommender System: A Study about Students&apos; and Teachers&apos; Opinions

    ERIC Educational Resources Information Center

    Pedro, Luís; Santos, Carlos; Almeida, Sara Filipa; Ramos, Fernando; Moreira, António; Almeida, Margarida; Antunes, Maria João

    2014-01-01

    This paper aims to assess the relevance and usefulness of the SAPO Campus recommender system, through the analysis of students&apos; and teachers&apos; opinions. Recommender systems, assuming a "technology-driven" approach, have been designed with the primary goal of predicting user interests based on the implicit analysis of their…

  5. Teachers&apos; Perceptions Based on Tenure Status and Gender about Principals&apos; Supervision

    ERIC Educational Resources Information Center

    Range, Bret G.; Finch, Kim; Young, Suzanne; Hvidston, David J.

    2014-01-01

    This descriptive study assessed teachers&apos; attitudes about their formative supervision and the observational ability of principals through the constructs of teacher tenure status and gender. In sum, 255 teachers responded to an online survey indicating teachers&apos; desired feedback focused on classroom climate, student engagement, and…

  6. Oxidative Stress Impairs Learning and Memory in apoE Knockout Mice

    PubMed Central

    Evola, Marianne; Hall, Allyson; Wall, Trevor; Young, Alice; Grammas, Paula

    2010-01-01

    Cardiovascular risk factors, such as oxidative stress and elevated lipids, are linked to the development of cognitive impairment. A mediator common to both stressors is the apolipoprotein E (apoE). The objectives of this study are to determine the effects of apoE deficiency and diet-induced systemic oxidative stress in mice on vascular expression of inflammatory proteins and on cognitive function. Mice are placed on a diet enriched in homocysteine for fifteen weeks and then assessed for spatial learning using an eight-arm radial maze and for inflammatory protein expression by immunohistochemistry. Our results show that diet-induced oxidative stress does not affect cognitive function in normal mice. In contrast, apoE−/− mice on the homocysteine diet show significantly impaired (p < 0. 001) maze performance. ApoE−/− mice also have high cholesterol levels. There is no expression of inflammatory proteins IL-6 and IL-8 in the vasculature of control mice on normal or homocysteine diet and little in apoE−/− mice on normal diet. In contrast, apoE−/− mice on homocysteine diet show pronounced vascular reactivity to IL-6 and IL-8 antibodies. These data show that systemic oxidative stress correlates with expression of inflammatory proteins in the cerebral vasculature and impaired cognitive function. These results are consistent with the hypothesis that an oxidative-inflammatory cycle in the cerebral vasculature could have deleterious consequences for cognition. PMID:20457176

  7. Let&apos;s Burn Them All: A Librarian&apos;s View

    ERIC Educational Resources Information Center

    Werner, Roye

    2014-01-01

    In this rejoinder to "Let&apos;s Burn Them All," a librarian supports the author&apos;s case for eliminating textbooks in the teaching of management and organizational behavior. A move away from textbooks would free libraries from worrying about whether and to what extent to provide expensive textbook access to students, a long-standing…

  8. Relations among Teachers&apos; Emotion Socialization Beliefs and Practices and Preschoolers&apos; Emotional Competence

    ERIC Educational Resources Information Center

    Morris, Carol A. S.; Denham, Susanne A.; Bassett, Hideko H.; Curby, Timothy W.

    2013-01-01

    Research Findings: Utilizing a 3-part model of emotion socialization that included modeling, contingent responding, and teaching, this study examined the associations between 44 teachers&apos; self-reported and observed emotion socialization practices and 326 preschoolers&apos; emotion knowledge and observed emotional behavior. Multilevel analyses…

  9. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice

    PubMed Central

    Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Haast, Roy; Lütjohann, Dieter; Broersen, Laus M.; Heerschap, Arend

    2016-01-01

    APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10–12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16–18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging. PMID:27034849

  10. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice.

    PubMed

    Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Haast, Roy; Lütjohann, Dieter; Broersen, Laus M; Heerschap, Arend; Kiliaan, Amanda J

    2016-01-01

    APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging. PMID:27034849

  11. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice.

    PubMed

    Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Haast, Roy; Lütjohann, Dieter; Broersen, Laus M; Heerschap, Arend; Kiliaan, Amanda J

    2016-01-01

    APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.

  12. "It&apos;s Not Them, It&apos;s Me": Competing Discourses in One Aspiring Teacher&apos;s Talk

    ERIC Educational Resources Information Center

    Gomez, Mary Louise; Carlson, James R.; Foubert, Jennifer; Powell, Shameka N.

    2014-01-01

    In this paper, we deploy M.M. Bakhtin&apos;s notions about how language works to understand aspiring teachers&apos; struggles about the intersecting roles race, class, gender, language background, and sexual orientation play in students&apos; school lives and learning. Through life-history interviews and document analysis, we investigated the…

  13. STEM High School Administrators&apos;, Teachers&apos;, and Students&apos; Perceptions of Curricular and Instructional Strategies and Practices

    ERIC Educational Resources Information Center

    Bruce-Davis, Micah N.; Gubbins, E. Jean; Gilson, Cindy M.; Villanueva, Merzili; Foreman, Jennifer L.; Rubenstein, Lisa DaVia

    2014-01-01

    The present qualitative study was conducted in response to federal initiatives aimed at increasing the number of science, technology, engineering, and mathematics (STEM) schools in the United States; and to better understand STEM high school administrators&apos;, teachers&apos;, and students&apos; perceptions of the characteristics of the…

  14. The Impact of Teachers&apos; and Supervisors&apos; Involvement on Students&apos; Skill and Affective Development in Service-Learning

    ERIC Educational Resources Information Center

    Leemen, Lee

    2013-01-01

    The study reported an assessment of a university-wide curriculum-based service learning program and, based on the assessment data, analyzed the impact of teachers&apos; and supervisors&apos; involvement on students&apos; skill and affective learning outcomes. The study (n=750) showed that in general the students agreed that their participation in…

  15. Fathers&apos; and Mothers&apos; Home Literacy Involvement and Children&apos;s Cognitive and Social Emotional Development: Implications for Family Literacy Programs

    ERIC Educational Resources Information Center

    Baker, Claire E.

    2013-01-01

    The relations between fathers&apos; and mothers&apos; home literacy involvement at 24 months and children&apos;s cognitive and social emotional development in preschool were examined using a large sample of African American and Caucasian families ("N" = 5190) from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B). Hierarchical…

  16. Living with Letters: An Exploration of Parents&apos;/Caregivers&apos; Perceptions of Shared Learning Activities, Socially Constructed Meaning, and Preschoolers&apos; Literacy Development

    ERIC Educational Resources Information Center

    Janaszak, Jaclyn

    2013-01-01

    The researcher&apos;s purpose in this descriptive case study, drawn from a suburban school population of pre-kindergarten children and their parents/caregivers was: (a) to explore parents&apos;/caregivers&apos; perceptions of the concept of emergent literacy and how their children develop the ability to read and write; (b) to document the ways in…

  17. Longitudinal Links between Fathers&apos; and Mothers&apos; Harsh Verbal Discipline and Adolescents&apos; Conduct Problems and Depressive Symptoms

    ERIC Educational Resources Information Center

    Wang, Ming-Te; Kenny, Sarah

    2014-01-01

    This study used cross-lagged modeling to examine reciprocal relations between maternal and paternal harsh verbal discipline and adolescents&apos; conduct problems and depressive symptoms. Data were from a sample of 976 two-parent families and their children (51% males; 54% European American, 40% African American). Mothers&apos; and fathers&apos;…

  18. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.

    PubMed

    Vandal, Milène; Alata, Wael; Tremblay, Cyntia; Rioux-Perreault, Christine; Salem, Norman; Calon, Frédéric; Plourde, Mélanie

    2014-05-01

    Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E ε4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [(14) C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4- and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r(2) = 0.21) and AD patients (r(2) = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD). PMID:24345162

  19. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.

    PubMed

    Vandal, Milène; Alata, Wael; Tremblay, Cyntia; Rioux-Perreault, Christine; Salem, Norman; Calon, Frédéric; Plourde, Mélanie

    2014-05-01

    Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E ε4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [(14) C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4- and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r(2) = 0.21) and AD patients (r(2) = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD).

  20. APOE related hippocampal shape alteration in geriatric depression.

    PubMed

    Qiu, Anqi; Taylor, Warren D; Zhao, Zheen; MacFall, James R; Miller, Michael I; Key, Cynthia R; Payne, Martha E; Steffens, David C; Krishnan, K Ranga R

    2009-02-01

    Late-onset depression often precedes the onset of dementia associated with the hippocampal degeneration. Using large deformation diffeomorphic metric mapping (LDDMM), we evaluated apolipoprotein E epsilon-4 allele (apoE E4) effects on hippocampal volume and shape in 38 depressed patients without the apoE E4, 14 depressed patients with one apoE E4, and 31 healthy comparison subjects without the apoE E4. The hippocampal volumes were manually assessed. We applied a diffeomorphic template generation procedure for creating the hippocampal templates based on a subset of the population. The LDDMM mappings were used to generate the hippocampal shape of each subject and characterize the surface deformation of each hippocampus relative to the template. Such deformation was modeled as random field characterized by the Laplace-Beltrami basis functions in the template coordinates. Linear regression was used to examine group differences in the hippocampal volume and shape. We found that there were significant hippocampal shape alternations in both depressed groups while the groups of depressed patients and the group of healthy subjects did not differ in the hippocampal volume. The depressed patients with one apoE E4 show more pronounced shape inward-compression in the anterior CA1 than the depressed patients without the apoE E4 when compared with the healthy controls without the apoE E4. Thus, hippocampal shape abnormalities in late-onset depressed patients with one apoE E4 may indicate future conversion of this group to AD at higher risk than depressed patients without the apoE E4. PMID:19010425

  1. Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE-/- Mice

    PubMed Central

    Lutgens, Suzanne P. M.; Wijnands, Erwin; Johnson, Jason; Schurgers, Leon J.; Liu, Cong-Lin; Daemen, Mat J. A. P.; Cleutjens, Kitty B. J. M.; Shi, Guo-Ping; Biessen, Erik A. L.; Heeneman, Sylvia

    2016-01-01

    Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response. PMID:27636705

  2. Influence of the APOE genotype on hepatic stress response: Studies in APOE targeted replacement mice and human liver cells.

    PubMed

    Dose, Janina; Nebel, Almut; Piegholdt, Stefanie; Rimbach, Gerald; Huebbe, Patricia

    2016-07-01

    Apolipoprotein E (APOE) is a multifunctional plasma protein mainly acting in lipid metabolism. Human APOE is polymorphic with three major isoforms (APOE2, APOE3 and APOE4). Up to 75% of the body's APOE is produced by the liver. There is increasing evidence from studies in brain-derived cells that APOE4 affects mitochondrial function and biogenesis as well as stress and inflammatory responses - processes, whose disturbances are considered hallmarks of the ageing process. However, although the liver is the main production site of APOE, knowledge about the impact of the APOE genotype on hepatic stress response-related processes is rather limited. Therefore, we studied biomarkers of oxidative status (glutathione levels, 3-nitrotyrosine adducts, protein carbonyl concentration), ER stress (XBP1(S), BiP, DDIT3), proteasome activity, mitochondrial function (respiratory complexes, ATP levels and mitochondrial membrane potential as well as biomarkers of mitochondrial biogenesis, fission and fusion), autophagy (LC3, LAMP2A), apoptosis (BCL2, BAX, CYCS) and DNA damage in the liver of APOE targeted replacement (TR) mice and in Huh7 hepatocytes overexpressing the APOE3 and the APOE4 isoform, respectively. APOE4 mice exhibited a lower chymotrypsin-like and a higher trypsin-like proteasome activity. Levels of protein carbonyls were moderately higher in liver tissue of APOE4 vs. APOE3 mice. Other biomarkers of oxidative stress were similar between the two genotypes. Under basal conditions, the stress-response pathways investigated appeared largely unaffected by the APOE genotype. However, upon stress induction, APOE4 expressing cells showed lower levels of adenosine triphosphate (ATP) and lower mRNA levels of the ATP-generating complex V of the mitochondrial respiratory chain. Overall, our findings provide evidence for a rather low influence of the APOE genotype on the hepatic stress response processes investigated in this study. PMID:27130033

  3. Effects of different isoforms of apoE on aggregation of the α-synuclein protein implicated in Parkinson's disease.

    PubMed

    Emamzadeh, Fatemeh Nouri; Aojula, Harmesh; McHugh, Patrick C; Allsop, David

    2016-04-01

    Parkinson's disease is a progressive brain disorder due to the degeneration of dopaminergic neurons in the substantia nigra. The accumulation of aggregated forms of α-synuclein protein into Lewy bodies is one of the characteristic features of this disease although the pathological role of any such protein deposits in causing neurodegeneration remains elusive. Here, the effects of different apolipoprotein E isoforms (apoE2, apoE3, apoE4) on the aggregation of α-synuclein in vitro were examined using thioflavin T assays and also an immunoassay to detect the formation of multimeric forms. Our results revealed that the aggregation of α-synuclein is influenced by apoE concentration. At low concentrations of apoE (<15nM), all of the isoforms were able to increase the aggregation of α-synuclein (50μM), with apoE4 showing the greatest stimulatory effect. This is in contrast to a higher concentration (>15nM) of these isoforms, where a decrease in the aggregation of α-synuclein was noted. The data show that exceptionally low levels of apoE may seed α-syn aggregation, which could potentially lead to the pathogenesis of α-synuclein-induced neurodegeneration. On the other hand, higher levels of apoE could potentially lower the degree of α-synuclein aggregation and confer protection. The differential effects noted with apoE4 could explain why this particular isoform results in an earlier age of onset for Parkinson's disease.

  4. Origin and heterogeneity of HDL subspecies

    SciTech Connect

    Nichols, A.V.; Gong, E.L.; Blanche, P.J.; Forte, T.M.; Shore, V.G.

    1987-09-01

    A major determinant of mature HDL particle size and apolar core content, in the absence of remodeling factors, is most likely the size and apolipoprotein content of the precursor particle. Depending on the number of apoA-I molecules per analog particle, the LCAT-induced transformation follows either a fusion pathway (for precursors with 2 apoA-I per particle) or a pathway (for precursors with more than 2 apoA-I per particle) that conserves the apolipoprotein number. According to our analog results, small nascent HDL probably serve as precursors to the major (apoA-I without apoA-II)-subpopulation in the size interval. Our studies with the large discoidal analog suggest that HDL/sub 2/ (apoA-I without apoA-II)-subpopulations probably originate from the large discoidal nascent HDL that contain a higher number of apolipoprotein molecules per particle than the small nascent HDL. Intermediate transformation products of the large discoidal analog, described in the present study, resemble deformable species found in human lymph and are characterized by a relatively high surface-to-core lipid ratio. Whether large discoidal precursors containing apoE transform in comparable manner but with eventual interchange of apoA-I for apoE (10,15) is under investigation in our laboratory. Likewise, detailed delineation of pathways whereby the (apoA-I with apoA-II)-HDL subpopulations are formed is yet to be accomplished. 23 refs., 6 figs., 2 tabs.

  5. Effect of plasma lipids and APOE genotype on cognitive decline.

    PubMed

    Yasuno, Fumihiko; Asada, Takashi

    2013-03-01

    A central tenet of brain aging is that "what is good for the heart is good for the brain." We examined the combined effect of plasma lipids and APOE genotype on cognitive function in elderly individuals. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein, triglyceride, total cholesterol, and apolipoprotein E (apoE) were evaluated in 622 community-dwelling individuals aged 65 years and older. We investigated the associations between plasma lipids and cognitive function in APOE4 carrier (E4+) and APOE4 noncarrier (E4-) groups using 3-year longitudinal data. At baseline and 3 years later, cognitive scores were correlated with plasma apoE levels in both E4- and E4+, and HDL level in E4-. Our findings suggest that an interaction between apoE and HDL is facilitated by APOE4, and is possibly linked with an enhancement of neuroplasticity and with resultant protective effects on cognitive function in later life. Preservation of higher plasma apoE and HDL from early life is proposed as a possible strategy for maintaining cognitive function in later life, especially for APOE4-positive individuals.

  6. Analysis of apoB and apoC-II gene polymorphism in random sample and CHD patients from Moscow

    SciTech Connect

    Pogoda, T.V.; Nikonova, A.; Perova, N.V.

    1994-09-01

    We have analyzed the allele frequency distributions of the 3{prime} apoB gene minisatellite and apoC-II gene microsatellite in random sample of coronary heart disease (CHD) patients. For this purpose we used the PCR technique followed by high-resolution PAGE. It was revealed that the apoB allele, harboring 30 repeats (apoB 30), as well as the apoC-II allele harboring 30 repeats (apoC-II 30), were less frequent in patients at the same time as the frequency of the apoB 32 and apoC-II 17 alleles was greater in patients. The greater frequency of apoB alleles which were larger in size than apoB 46 (defined as `long` - L) was observed in patients with high apoB levels (>160mg dl). The analysis of apoB genotype distribution showed that in a random sample the most common genotype was apoB 34,36 (a combination of the most frequent alleles in the random sample). In patients with high apoB levels, it was twice less frequent, and the most common genotype was apoB 36,L (43% versus 12% in the random sample). Analysis of data on a lipid spectrum of subjects from the random sample with different apoB and apoC-II 17 alleles were associated with atherogenic shifts in the lipid profile, at the same time as apoB 30 and apoC-II 30 alleles - with an apparently favorable lipid profile. The increment of the disease-related risk was observed for subjects with a combination of apoB 32 allele or apoB 36,L genotype with the apoC-11 17 allele. Alternatively, combination of these apoB variants with the apoC-II 30 allele resulted in decreased related risk. In conclusion, simultaneous analysis of two candidate gene variants demonstrated interaction in their influence on the lipid spectrum.

  7. A Study on Teachers&apos;, Students&apos; and Their Parents&apos; Views on the FATIH Project

    ERIC Educational Resources Information Center

    Sahin, Semsettin; Aktürk, Ahmet Oguz; Çelik, Ismail

    2013-01-01

    This study investigated the views of teachers, students and their parents on the FATIH (Movement of Enhancing Opportunities and Improving Technology) Project, which was put into service by the Ministry of National Education in cooperation with the Ministry of Transportation in Turkey in November 2010 for the purpose of increasing students&apos;…

  8. "It&apos;s All Shiny and There&apos;s No Pollution": "Barbapapa&apos;s Ark," Environmental Influences

    ERIC Educational Resources Information Center

    Lowe, Virginia

    2013-01-01

    The environmental picture book "Barbapapa&apos;s Ark" was published in 1974. I was keeping a parent-observer record of my two children at the time. The book had a strong influence on them from ages three to six, moving them to query pollution and hunting, in book and environment, and as adults, becoming committed activists for the…

  9. Exploring Primary School CLIL Perceptions in Catalonia: Students&apos;, Teachers&apos; and Parents&apos; Opinions and Expectations

    ERIC Educational Resources Information Center

    Pladevall-Ballester, Elisabet

    2015-01-01

    Analysing participants&apos; perceptions of a Content and Language Integrated Learning (CLIL) experience is essential in order to provide a clear picture of whether CLIL is effectively implemented. This becomes extremely relevant in primary school contexts, where the way the different groups involved in an educational experience feel tends to be…

  10. Responses to Children&apos;s Sadness: Mothers&apos; and Fathers&apos; Unique Contributions and Perceptions

    ERIC Educational Resources Information Center

    Cassano, Michael C.; Zeman, Janice L.; Sanders, Wesley M.

    2014-01-01

    Parental socialization of children&apos;s sadness was examined through self-report, spouse report, and a parent-child sadness discussion task. A total of 79 two-parent, predominantly White, middle-class families participated with one child in grades 2-5 (44 sons; M = 9 years, 8 months). Analyses revealed that mothers and fathers respond…

  11. Primary School Students&apos; Parents&apos; Level of Involvement into Their Children&apos;s Education

    ERIC Educational Resources Information Center

    Sad, Suleyman Nihat; Gurbuzturk, Oguz

    2013-01-01

    The aim of this study was to investigate the extent to which parents of elementary students (1st to 5th) participate in their children&apos;s education with regard to some variables. The study was designed based on descriptive survey model and comparative and correlational associative models. The sample of the research comprised 1252 parents whose…

  12. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    PubMed Central

    Jacobsen, Nicklas Raun; Møller, Peter; Jensen, Keld Alstrup; Vogel, Ulla; Ladefoged, Ole; Loft, Steffen; Wallin, Håkan

    2009-01-01

    Background The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid. Results Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE-/- mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE-/- mice. Thirdly, we compared effects of instillation in ApoE-/- mice of three carbonaceous particles; CB, fullerenes C60 (C60) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C60 particles caused much weaker inflammatory responses. Conclusion Our data suggest that ApoE-/- model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles. PMID:19138394

  13. Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease.

    PubMed

    Talayero, Beatriz; Wang, Liyun; Furtado, Jeremy; Carey, Vincent J; Bray, George A; Sacks, Frank M

    2014-10-01

    Human HDLs have highly heterogeneous composition. Plasma concentrations of HDL with apoC-III and of apoE in HDL predict higher incidence of coronary heart disease (CHD). The concentrations of HDL-apoA-I containing apoE, apoC-III, or both and their distribution across HDL sizes are unknown. We studied 20 normal weight and 20 obese subjects matched by age, gender, and race. Plasma HDL was separated by sequential immunoaffinity chromatography (anti-apoA-I, anti-apoC-III, anti-apoE), followed by nondenaturing-gel electrophoresis. Mean HDL-cholesterol concentrations in normal weight and obese subjects were 65 and 50 mg/dl (P = 0.009), and total apoA-I concentrations were 119 and 118 mg/dl, respectively. HDL without apoE or apoC-III was the most prevalent HDL type representing 89% of apoA-I concentration in normal weight and 77% in obese (P = 0.01) individuals; HDL with apoE-only was 5% versus 8% (P = 0.1); HDL with apoC-III-only was 4% versus 10% (P = 0.009); and HDL with apoE and apoC-III was 1.5% versus 4.6% (P = 0.004). Concentrations of apoE and apoC-III in HDL were 1.5-2× higher in obese subjects (P ≤ 0.004). HDL with apoE or apoC-III occurred in all sizes among groups. Obese subjects had higher prevalence of HDL containing apoE or apoC-III, subfractions associated with CHD, whereas normal weight subjects had higher prevalence of HDL without apoE or apoC-III, subfractions with protective association against CHD.

  14. Jacques Ranciere&apos;s Lesson on the Lesson

    ERIC Educational Resources Information Center

    Chambers, Samuel A.

    2013-01-01

    This article examines the significance of Jacques Ranciere&apos;s work on pedagogy, and argues that to make sense of Ranciere&apos;s "lesson on the lesson" one must do more but also less than merely explicate Ranciere&apos;s texts. It steadfastly refuses to draw out the lessons of Ranciere&apos;s writings in the manner of a series of…

  15. Teacher Educators&apos; Digital Competence

    ERIC Educational Resources Information Center

    Krumsvik, Rune Johan

    2014-01-01

    This position paper focuses on how the new national curriculum for school and the new general plan for teacher education in Norway change the underlying premises for teaching and learning in today&apos;s teacher education. This has become particularly pressing as a result of the new educational reform "Knowledge Promotion" in schools,…

  16. Students&apos; Differentiated Translation Processes

    ERIC Educational Resources Information Center

    Bossé, Michael J.; Adu-Gyamfi, Kwaku; Chandler, Kayla

    2014-01-01

    Understanding how students translate between mathematical representations is of both practical and theoretical importance. This study examined students&apos; processes in their generation of symbolic and graphic representations of given polynomial functions. The purpose was to investigate how students perform these translations. The result of the…

  17. Find Your School&apos;s Analemma

    ERIC Educational Resources Information Center

    Lough, Tom; Vanover, Courtney

    2014-01-01

    On any given sunny day, Courtney Vanover&apos;s third graders were like alarm clocks, making sure everyone in the room knew when 9:30 was approaching. Why? Because they were participating in a yearlong science project to answer the question, "Where is the tip of the shadow of the school flagpole each morning at 9:30?" Although they did…

  18. Site for Today&apos;s Teachers

    ERIC Educational Resources Information Center

    Brulles, Dina; Brown, Karen L.

    2013-01-01

    This article describes one school district department&apos;s efforts to train and support teachers in providing effective curriculum, instruction, and assessment methods to their students. This large, K-12 district embraces the spectrum of low to high SES schools, a large number of gifted students from diverse populations, and a variety of gifted…

  19. Dewey or Don&apos;t We?

    ERIC Educational Resources Information Center

    Pendergrass, Devona J.

    2013-01-01

    "Dewey or don&apos;t we?" is the question that hundreds, if not thousands, of school librarians across the country are currently asking themselves. Do they throw out what is old but trusted for new organizational systems, or do they continue using the Dewey Decimal Classification (DDC) system and make changes and adjustments to the…

  20. "Math for America" Isn&apos;t

    ERIC Educational Resources Information Center

    Wolfmeyer, Mark

    2014-01-01

    Aspects of the Math for America organization&apos;s actions, aims and affiliations are analyzed for their effects on urban schools and society at large. These aspects are argued as evidence to consider MfA as an agent working against democratic practice and in favor of furthering profit and its resultant inequitable resource distribution. The…