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Sample records for apo ai-ciii-aiv gene

  1. Genetics of coronary heart disease with reference to ApoAI-CIII-AIV gene region

    PubMed Central

    Agrawal, Suraksha; Mastana, Sarabjit

    2014-01-01

    Cardiovascular diseases are affected by multiple factors like genetic as well as environmental hence they reveal factorial nature. The evidences that genetic factors are susceptible for developing cardiovascular diseases come from twin studies and familial aggregation. Different ethnic populations reveal differences in the prevalence coronary artery disease (CAD) pointing towards the genetic susceptibility. With progression in molecular techniques different developments have been made to comprehend the disease physiology. Molecular markers have also assisted to recognize genes that may provide evidences to evaluate the role of genetic factors in causation of susceptibility towards CAD. Numerous studies suggest the contribution of specific “candidate genes”, which correlate with various roles/pathways that are involved in the coronary heart disease. Different studies have revealed that there are large numbers of genes which are involved towards the predisposition of CAD. However, these reports are not consistent. One of the reasons could be weak contribution of genetic susceptibility of these genes. Genome wide associations show different chromosomal locations which dock, earlier unknown, genes which may attribute to CAD. In the present review different ApoAI-CIII-AIV gene clusters have been discussed. PMID:25228954

  2. Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

    PubMed Central

    Kessling, A; Ouellette, S; Bouffard, O; Chamberland, A; Bétard, C; Selinger, E; Xhignesse, M; Lussier-Cacan, S; Davignon, J

    1992-01-01

    Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample. PMID:1346081

  3. Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster.

    PubMed Central

    Haviland, M B; Kessling, A M; Davignon, J; Sing, C F

    1991-01-01

    Departures from Hardy-Weinberg (HW) equilibria and pairwise disequilibria were estimated in a sample of unrelated healthy individuals typed for six RFLPs in the apo AI-CIII-AIV gene region. The sample was composed of males and females, selected for health, from two populations, those of exclusively French-Canadian (FC) and those of some non-French-Canadian (NFC) ancestry. An approach suggested by Weir and Cockerham, which includes estimates of nonrandom association (disequilibria) between three and four alleles at two loci as well as the traditional associations between two alleles, at two loci was used. The pattern of departures from HW equilibria suggested that the genetic structures of the FC and NFC are different. Departure from HW equilibrium at an RFLP locus could not be predicted from information about other loci in the same gene region. Nonrandom associations were also evident from the pairwise analyses. Two pairs of loci had significant diallelic disequilibria, while two other pairs had significant triallelic disequilibria. All of the RFLP pairs had at least one measure of disequilibrium at its maximum value determined by allele frequencies. Inferences about pairwise disequilibria depended on the statistical approach used. Sizes of the pairwise disequilibria were not correlated with the physical distance between loci. The impact of these disequilibria on RFLP-phenotype association studies is discussed. PMID:1678249

  4. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.

    PubMed Central

    Cohen, J C; Wang, Z; Grundy, S M; Stoesz, M R; Guerra, R

    1994-01-01

    Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci. PMID:7989594

  5. Mutilocus genetic determinants of LDL particle size in coronary artery disease families

    SciTech Connect

    Rotter, J.I.; Bu, X.; Cantor, R.M.

    1996-03-01

    Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (1) the association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (2) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair-analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P = .008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P = .06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P = .01) and the manganese superoxide dismutase locus (chromosome 6) (P = .001), thus indicating multilocus determination of this atherogenic trait. 73 refs., 3 figs., 4 tabs.

  6. LDLR, ApoB and ApoE genes polymorphisms and classical risk factors in premature coronary artery disease.

    PubMed

    Abd El-Aziz, Tarek A; Mohamed, Randa H

    2016-09-30

    Lipoproteins play a central role in the development of atherosclerotic disease. So, with their ability to affect lipid levels, the LDLR, ApoB and ApoE polymorphisms could be one of the factors influencing development of atherosclerosis. This hypothesis has been tested in different populations with conflicting results. The purpose of the present study was to investigate the association between the LDLR, ApoB and ApoE genes polymorphisms with premature CAD (PCAD) in Egyptians. One hundred thirty-five patients of PCAD and one hundred thirty-two ages and sex matched control subjects were included in the study. LDLR and ApoB genes polymorphisms were analyzed by polymerase chain reaction (PCR). The ApoE genotypes were identified by multiplex amplification refractory mutation system (multi-AMRS). We found that LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele increased the risk of PCAD by 1.8, 2.1 and 12.1 respectively. The present study proved that smoking, metabolic syndrome, ApoB X(+)X(+) genotype and ApoE E4 allele were independent risk factors for the development of PCAD. This is the first study investigate the association between low density lipoprotein receptor, apolipoprotein B and apolipoprotein E genes polymorphisms with PCAD and lipid levels in Egyptians and we concluded that the LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may be associated with an increased risk for development of PCAD by elevated levels of total cholesterol (TC) and low density lipoprotein (LDLc). The coexistence of CAD risk factors with LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may increase the risk of the development of PCAD in Egyptian patients. PMID:27236033

  7. 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

  8. Gene-Environment Interplay in the Link of Friends' and Nonfriends' Behaviors with Children'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' and nonfriends' reticent and dominant behaviors on children's observed social reticence in a competitive situation. Potential gene-environment correlations (rGE) and gene-environment interactions (GxE) in the link between (a) friends' and…

  9. Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein

    PubMed Central

    Papaioannou, Ioannis; Simons, J. Paul; Owen, James S.

    2012-01-01

    Cardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe atheroprotective properties of ApoE, though also potential proatherogenic actions, and the prevalence of dysfunctional isoforms, outline conventional gene transfer strategies, and then focus on gene correction therapeutics that can repair defective APOE alleles. In particular, we discuss the possibility and potential benefit of applying in combination two technical advances to repair aberrant APOE genes: (i) an engineered endonuclease to introduce a double-strand break (DSB) in exon 4, which contains the common, but dysfunctional, ε2 and ε4 alleles; (ii) an efficient and selectable template for homologous recombination (HR) repair, namely, an adeno-associated viral (AAV) vector, which harbours wild-type APOE sequence. This technology is applicable ex vivo, for example to target haematopoietic or induced pluripotent stem cells, and also for in vivo hepatic gene targeting. It is to be hoped that such emerging technology will eventually translate to patient therapy to reduce CVD risk. PMID:22645694

  10. The APOE Gene is Differentially Methylated in Alzheimer's Disease.

    PubMed

    Foraker, Jessica; Millard, Steven P; Leong, Lesley; Thomson, Zachary; Chen, Sunny; Keene, C Dirk; Bekris, Lynn M; Yu, Chang-En

    2015-01-01

    The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain. PMID:26402071

  11. Identification of a novel enhancer of brain expression near the apoE gene cluster by comparative genomics

    SciTech Connect

    Zheng, Ping; Pennacchio, Len A.; Goff, Wilfried Le; Rubin, Edward M.; Smith, Jonathan D.

    2003-10-01

    Comparative analysis of the human and mouse genomic sequences downstream of the apolipoprotein E gene (APOE) revealed a highly conserved element with previously undefined function. In reporter gene transfection studies, this element which is located f42 kb distal to APOE was found to have silencer activity in a subset of cell lines examined. Analysis of transgenic mice containing a fusion construct linking this distal 631 bp conserved element to a reporter gene comprised of the human APOE gene with its proximal promoter resulted in robust brain expression of the transgenic human apoE mRNA in three independent transgenic lines, supporting the identification of a novel brain controlling region (BCR). Further studies using immunohistochemistry revealed widespread human apoE localization throughout the brains of the BCR-apoE transgenic mice with prominent expression in the cortex and diencephalon. In addition, double-label immunofluorescence performed on brain sections and cultures of primary cortical cells localized human apoE protein to cortical neurons and microglia. These studies demonstrate that comparative sequence analysis is a successful strategy to predict candidate regulatory regions in vivo, although they do not imply that this element controls apoE expression physiologically.

  12. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  13. Cardiovascular protection by apoE and apoE-HDL linked to suppression of ECM gene expression and arterial stiffening

    PubMed Central

    Kothapalli, Devashish; Liu, Shu-Lin; Bae, Yong Ho; Monslow, James; Xu, Tina; Hawthorne, Elizabeth A.; Byfield, Fitzroy J.; Castagnino, Paola; Rao, Shilpa; Rader, Daniel J.; Puré, Ellen; Phillips, Michael C.; Lund-Katz, Sissel; Janmey, Paul A.; Assoian, Richard K.

    2012-01-01

    Summary Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing HDL maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop which increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE-null mice, this stiffening can be reduced by administration of the lysyl oxidase inhibitor, BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics, and this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol. PMID:23103162

  14. Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding

    PubMed Central

    Lazaris, Andreas; Hwang, Kristy S.; Goukasian, Naira; Ramirez, Leslie M.; Eastman, Jennifer; Blanken, Anna E.; Teng, Edmond; Gylys, Karen; Cole, Greg; Saykin, Andrew J.; Shaw, Leslie M.; Trojanowski, John Q.; Jagust, William J.; Weiner, Michael W.

    2015-01-01

    Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction. PMID:27066559

  15. Inducible Apoe Gene Repair in Hypomorphic ApoE Mice Deficient in the LDL Receptor Promotes Atheroma Stabilization with a Human-like Lipoprotein Profile

    PubMed Central

    Eberlé, Delphine; Luk, Fu Sang; Kim, Roy Y.; Olivas, Victor R.; Kumar, Nikit; Posada, Jessica M.; Li, Kang; Gaudreault, Nathalie; Rapp, Joseph H.; Raffai, Robert L.

    2013-01-01

    Objective To study atherosclerosis regression in mice following plasma lipid reduction to moderately elevated apolipoprotein B (apoB)-lipoprotein levels. Approach and Results Chow-fed hypomorphic Apoe mice deficient in LDL receptor expression (Apoeh/hLdlr−/−Mx1-cre mice) develop hyperlipidemia and atherosclerosis. These mice were studied before and after inducible cre-mediated Apoe gene repair. By 1 week, induced mice displayed a 2-fold reduction in plasma cholesterol and triglyceride levels and a decrease in the non-HDL:HDL-cholesterol ratio from 87%:13% to 60%:40%. This halted atherosclerotic lesion growth and promoted macrophage loss and accumulation of thick collagen fibers for up to 8 weeks. Concomitantly, blood Ly-6Chi monocytes were decreased by 2-fold but lesional macrophage apoptosis was unchanged. The expression of several genes involved in extra-cellular matrix remodeling and cell migration were changed in lesional macrophages 1 week after Apoe gene repair. However, mRNA levels of numerous genes involved in cholesterol efflux and inflammation were not significantly changed at this time point. Conclusions Restoring apoE expression in Apoeh/hLdlr−/−Mx1-cre mice resulted in lesion stabilization in the context of a human-like ratio of non-HDL:HDL-cholesterol. Our data suggest that macrophage loss derived in part from reduced blood Ly-6Chi monocytes levels and genetic reprogramming of lesional macrophages. PMID:23788760

  16. Identification of the human ApoAV gene as a novel ROR{alpha} target gene

    SciTech Connect

    Lind, Ulrika; Nilsson, Tina; McPheat, Jane; Stroemstedt, Per-Erik; Bamberg, Krister; Balendran, Clare; Kang, Daiwu . E-mail: Daiwu.Kang@astrazeneca.com

    2005-04-29

    Retinoic acid receptor-related orphan receptor-{alpha} (ROR{alpha}) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR{alpha} regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR{alpha} also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR{alpha} increased the endogenous expression of ApoAV in HepG2 cells and ROR{alpha} also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate ROR{alpha} transactivation, one of which overlaps with a previously identified binding site for PPAR{alpha}. Together, these results suggest a novel mechanism whereby ROR{alpha} modulates lipid metabolism and implies ROR{alpha} as a potential target for the treatment of dyslipidemia and atherosclerosis.

  17. Genetic association of the ApoB and ApoA1 gene polymorphisms with the risk for alcohol-induced osteonecrosis of femoral head

    PubMed Central

    Wang, Yuan; Cao, Yuju; Li, Yizhou; Guo, Yongchang; Wang, Quanjian; Yang, Min; Zhang, Ning; Jin, Tianbo; Wang, Jianzhong

    2015-01-01

    Polymorphisms of apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1) gene and ApoB/ApoA1 Ratio were associated with lipid metabolism disorders in previous reports. The aim of this study assess whether variation of ApoB, ApoA1 gene are associated or not with alcohol-induced osteonecrosis of femoral head (ONFH). In a case-control study, we genotyped 4 single-nucleotide polymorphisms (SNPs) in ApoB and ApoA1 genes in 209 alcohol-induced ONFH patients and 300 healthy control subjects in Han Chinese population using χ2 test and genetic model analysis. The analysis revealed that the frequencies of ApoB and ApoA1 genotypes were significantly different in alcohol-induced ONFH patients than in controls. We identified rs1042034, rs676210 and rs673548 in ApoB gene were associated with decreased risk of alcohol-induced ONFH using recessive model analysis (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.19-0.99; P = 0.042), the OR, CI, P value of three SNPs were the same after adjusted for gender + age. We also identified rs632153 in ApoA1 gene was associated with increased risk of alcohol-induced ONFH using allele model (OR, 1.83; 95% CI, 1.16-2.88; P = 0.008) and log-additive model (adjusted OR, 1.77; 95% CI, 1.00-3.14; P = 0.046), analysis respectively. Haplotype analysis demonstrated no difference between ApoB and alcohol-induced ONFH. Polymorphisms of the ApoB and ApoA1 gene are associated with alcohol-induced ONFH in the Han Chinese population. PMID:26617857

  18. Identification and characterization of novel Helicobacter pylori apo-fur-regulated target genes.

    PubMed

    Carpenter, Beth M; Gilbreath, Jeremy J; Pich, Oscar Q; McKelvey, Ann M; Maynard, Ernest L; Li, Zhao-Zhang; Merrell, D Scott

    2013-12-01

    In Helicobacter pylori, the ferric uptake regulator (Fur) has evolved additional regulatory functions not seen in other bacteria; it can repress and activate different groups of genes in both its iron-bound and apo forms. Because little is understood about the process of apo-Fur repression and because only two apo-Fur-repressed genes (pfr and sodB) have previously been identified, we sought to expand our understanding of this type of regulation. Utilizing published genomic studies, we selected three potential new apo-Fur-regulated gene targets: serB, hydA, and the cytochrome c553 gene. Transcriptional analyses confirmed Fur-dependent repression of these genes in the absence of iron, as well as derepression in the absence of Fur. Binding studies showed that apo-Fur directly interacted with the suspected hydA and cytochrome c553 promoters but not that of serB, which was subsequently shown to be cotranscribed with pfr; apo-Fur-dependent regulation occurred at the pfr promoter. Alignments of apo-regulated promoter regions revealed a conserved, 6-bp consensus sequence (AAATGA). DNase I footprinting showed that this sequence lies within the protected regions of the pfr and hydA promoters. Moreover, mutation of the sequence in the pfr promoter abrogated Fur binding and DNase protection. Likewise, fluorescence anisotropy studies and binding studies with mutated consensus sequences showed that the sequence was important for apo-Fur binding to the pfr promoter. Together these studies expand the known apo-Fur regulon in H. pylori and characterize the first reported apo-Fur box sequence. PMID:24097951

  19. Polymorphisms in ApoB gene are associated with risk of myocardial infarction and serum ApoB levels in a Chinese population

    PubMed Central

    Liu, Changqing; Yang, Jing; Han, Wei; Zhang, Qi; Shang, Xiaoming; Li, Xia; Lu, Feng; Liu, Xiaokun

    2015-01-01

    Myocardial infarction (MI) is a serious result of coronary artery disease. Recent data from clinical trials have showed that the risk of MI was associated with high plasma apolipoprotein B (apoB) levels. Mutations in ApoB gene were also found to be associated with plasma lipid levels. The aim of this study is to evaluate the effect of ApoB polymorphisms on the risk of MI and plasma apoB levels in a Chinese population. Eight polymorphisms (rs676210, rs679899, rs3791980, rs2854725, rs11676704, rs512535, rs12720841 and rs2678379) in ApoB gene were genotyped in a case-control study in China, including 550 MI cases and 550 healthy controls. Carriers of GG genotype of rs676210 had significant increased risk of MI [odd ratio (OR) = 1.93, 95% confidence interval (CI): 1.23-3.03] compared to carriers of AA genotype. Haplotype analysis also showed that GTTGG (rs676210-rs2854725-rs11676704-rs3791980-rs2678379) haplotype had significant increased risk of MI (OR = 2.82, 95% CI: 1.49-5.33) compared with ATTGA haplotype. Furthermore, apoB rs676210 and rs2678379 polymorphisms were significantly associated with plasma levels of apoB in healthy controls (P = 0.01 and 0.02). Our findings indicated that ApoB mutations may be associated with the risk of MI and plasma ApoB levels in healthy controls in Chinese population. PMID:26629186

  20. Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype

    SciTech Connect

    Allayee, H.; Aouizerat, B.E.; Lusis, A.J.; Cantor, R.M.; Lanning, C.D.; Rotter, J.I.; Dallinga-Thie, G.M.; Krauss, R.M.; Bruin, T.W.A. de

    1998-08-01

    Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, the authors have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl-transferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. The authors have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands than in the spouse controls. Evidence for linkage was observed at the MnSOD (P = .02), CETP/LCAT (P = .03), and apolipoprotein AI0CIII0AIV loci (P = .005) but not at the LDLR locus. The authors conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.

  1. Gene-Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene?

    PubMed

    Reynolds, Chandra A; Gatz, Margaret; Christensen, Kaare; Christiansen, Lene; Dahl Aslan, Anna K; Kaprio, Jaakko; Korhonen, Tellervo; Kremen, William S; Krueger, Robert; McGue, Matt; Neiderhiser, Jenae M; Pedersen, Nancy L

    2016-01-01

    Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE. PMID:26538244

  2. [Gene polymorphism at apoB locus and the serum lipids profile in children].

    PubMed

    Zhu, W; Feng, N; Wang, Y; Ye, G

    2001-09-01

    The relations of gene polymorphism at the apolipoprotein B locus and serum lipid profile in children was studied in 308 normal 7-11 year-old children, including 151 boys and 157 girls. Blood samples were collected for all subjects, and then the serum and blood clot were separated. Serum lipids, including TC, TG, LDL-C, HDL-C, apoB, apoA I and Lp(a) were detected. Genome DNA was extracted from blood clot, then apoB-Xba I gene polymorphism were tested by PCR-RFLP method. The results showed that the distribution of apoB-Xba I genotype in 308 children accorded with Hardy-Weiberg inheritance equilibrium law. The frequency of heterozygote(+/-) was 13.3%, allele(+) was 0.067. The frequency of allele(+) was closed to the internal and Japanese reports (0.033 and 0.04), but much less than the Caucasians (0.50). This showed a ethnic and population difference in the inheritance variation. The average LDL-C levels of the heterozygotes(+/-) were 2.17 mmol/L, no difference compared with homozygotes(-/-) (2.21 mmol/L, P > 0.05). There was also no difference for the genotype distribution between the hyperlipidemia group and control group, which may be the results of no enough sample size and the sample selection, and so on. On the other hand, in normal children, serum lipids controlled by many genes, the effect of a single gene might be small. More studies and analysis on the relationship between serum lipids and multiple genes in multisites should be the next step. PMID:12561593

  3. Impact of age and sex on the development of atherosclerosis and expression of the related genes in apoE deficient mice.

    PubMed

    Liu, Mengyang; Zhang, Wenwen; Li, Xiaoju; Han, Jihong; Chen, Yuanli; Duan, Yajun

    2016-01-15

    Development of atherosclerosis is a chronic pathological process. ApoE deficient (apoE(-/-)) mice spontaneously develop atherosclerotic lesions. However, the impact of age and sex on lesions and expression of the related genes have not been fully elucidated. In this study, we collected blood and tissue samples from normal chow fed male and female apoE(-/-) mice at different ages, and determined serum lipids, PCSK9 levels, en face aortic lesions and expression of some pro- or anti-atherogenic genes. We determined that lesion development was clearly associated with age, and more lesions in males than females (12.6 ± 1.7% vs. 8.9 ± 1.1% at 8 months old, P < 0.05). Associated with age, serum total, LDL- and HDL-cholesterol and PCSK9 levels increased with more PCSK9 in females than males (313 ± 31 ng/mL vs. 239 ± 28 ng/mL at 8 months old, P < 0.05); expression of liver LDLR and ABCA1 decreased while of SR-BI increased; expression of macrophage ABCA1 and SR-BI decreased but of CD36 increased. Estrogen and tamoxifen induced ABCA1 and SR-BI expression, respectively, in macrophages isolated from female mice at the different age. Taken together, our study suggests that aging facilitates lesion development in apoE(-/-) mice with greater effect on male mice. The lesion development is also related to expression of pro- or anti-atherogenic genes in tissues, particularly in macrophages. PMID:26592663

  4. APOE and LDLR Gene Polymorphisms and Dyslipidemia Tracking. Rio de Janeiro Study

    PubMed Central

    de Freitas, Rossana Ghessa Andrade; Campana, Erika Maria Gonçalves; Pozzan, Roberto; Brandão, Andréa Araujo; Brandão, Ayrton Pires; Magalhães, Maria Eliane Campos; da Silva, Dayse Aparecida

    2015-01-01

    Background Studies show an association between changes in apolipoprotein E (ApoE) and LDLR receptor with the occurrence of dyslipidemia. Objectives To investigate the association between polymorphisms of the APOE (ε2, ε3, ε4) and LDLR (A370T) genes with the persistence of abnormal serum lipid levels in young individuals followed up for 17 years in the Rio de Janeiro Study. Methods The study included 56 individuals (35 males) who underwent three assessments at different ages: A1 (mean age 13.30 ± 1.53 years), A2 (22.09 ± 1.91 years) and A3 (31.23 ± 1.99 years). Clinical evaluation with measurement of blood pressure (BP) and body mass index (BMI) was conducted at all three assessments. Measurement of waist circumference (WC) and serum lipids, and analysis of genetic polymorphisms by PCR-RFLP were performed at A2 and A3. Based on dyslipidemia tracking, three groups were established: 0 (no abnormal lipid value at A2 and A3), 1 (up to one abnormal lipid value at A2 or A3) and 2 (one or more abnormal lipid values at A2 and A3). Results Compared with groups 0 and 1, group 2 presented higher mean values of BP, BMI, WC, LDL-c and TG (p < 0.01) and lower mean values of HDL-c (p = 0.001). Across the assessments, all individuals with APOE genotypes ε2/ε4 and ε4/ε4 maintained at least one abnormal lipid variable, whereas those with genotype ε2/ε3 did not show abnormal values (χ2 = 16.848, p = 0.032). For the LDLR genotypes, there was no significant difference among the groups. Conclusions APOE gene polymorphisms were associated with dyslipidemia in young individuals followed up longitudinally from childhood. PMID:26131702

  5. Adeno-associated virus serotype 8 ApoA-I gene transfer reduces progression of atherosclerosis in ApoE-KO mice: comparison of intramuscular and intravenous administration.

    PubMed

    Cimmino, Giovanni; Giannarelli, Chiara; Chen, Wei; Alique, Matilde; Santos-Gallego, Carlos G; Fuster, Valentin; Hajjar, Roger J; Walsh, Christopher E; Badimon, Juan J

    2011-03-01

    Apolipoprotein A-I (ApoA-I)/high-density lipoprotein (HDL)-raising treatments are effective antiatherosclerotic strategies. We have compared the antiatherogenic effects of human ApoA-I (hApoA-I) overexpression by intraportal and intramuscular gene transfer in atherosclerotic ApoE-knockout mice. Atherosclerotic lesions were induced by atherogenic diet. After atherosclerosis induction, a group of animals was killed and served as atherosclerosis baseline-control group. The remaining animals were randomized into the following groups: (1) atherosclerosis-progression-control, (2) intraportal/vector administration, and (3) intramuscular/vector administration. Aortas and hearts were processed for atherosclerotic quantification by en face Sudan IV and Oil Red-O, respectively. Liver and muscle specimens were processed for protein/gene expression analysis. A sustained increase in hApoA-I/HDL plasma levels was observed in both transduced groups. hApoA-I overexpression abolished plaque progression versus progression-control group. hApoA-I overexpression significantly reduced lesion macrophage, feature indicative of plaque stabilization. Scavenger receptor class-B type I (SR-BI), but not ATP-binding cassette, sub-family A (ABCA), member 1 (ABCA-1), was significantly upregulated in treated groups versus progression-controls. The results of this study show a similar effect of hApoA-I/HDL overexpression on plaque progression/stabilization by 2 different routes of administration. Our results showing similar effects using either intramuscular administration and intraportal route of administration may have significant clinical implications, given the reduced medical risk to patient and cost of intramuscular injections. PMID:21164355

  6. Identification of ApoA1, HPX and POTEE genes by omic analysis in breast cancer.

    PubMed

    Cine, Naci; Baykal, Ahmet Tarik; Sunnetci, Deniz; Canturk, Zafer; Serhatli, Muge; Savli, Hakan

    2014-09-01

    Breast cancer is the most common cancer among women and accounts for 23% of all female types of cancers. It is well recognized that breast cancer represents a heterogeneous group of tumors, and the molecular events involved in the progression to cancer remain undetermined. Moreover, available prognostic and predictive markers are not sufficient for the accurate determination of the risk for many breast cancer patients. Thus, it is necessary to discover new molecular markers for accurate prediction of clinical outcome and individualized therapy. In the present study, we performed omics-based whole-genome trancriptomic and whole proteomic profiling with network and pathway analyses of breast tumors to identify gene expression patterns related to clinical outcome. A total of 20 samples from tumors and 14 normal appearing breast tissues were analyzed using both gene expression microarrays and LC-MS/MS. We identified 585 downregulated and 413 upregulated genes by gene expression microarrays. Among these genes, HPX, POTEE and ApoA1 were the most significant genes correlated with the proteomic profile. Our data revealed that these identified genes are closely related to breast cancer and may be involved in robust detection of disease progression. PMID:24969553

  7. Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN beta-1b.

    PubMed

    Lanzillo, Roberta; Prinster, Anna; Scarano, Valentina; Liuzzi, Raffaele; Coppola, Giovanni; Florio, Ciro; Salvatore, Elena; Schiavone, Vittorio; Brunetti, Arturo; Muto, Mario; Orefice, Giuseppe; Alfano, Bruno; Bonavita, Vincenzo; Brescia Morra, Vincenzo

    2006-06-15

    Few trials issued the effect of disease-modifying medications on cognitive functions in multiple sclerosis. We designed an open-label longitudinal study to evaluate, during 2 years, cognitive performance and its relationship with MRI data and ApoE polymorphism findings in a group of relapsing-remitting (RR) multiple sclerosis (MS) Interferon (IFN) beta-1b-treated patients (median age 30 years, median disease duration 3.4 years). Complete neuropsychological battery was grouped into attention, information learning/memory, language and visuo-spatial functions. Fifty-two patients (33 females) were enrolled in the study. Six patients (11.5%) dropped out, mainly due to side effects. At baseline neuropsychological evaluation, we found 54% normal, 42% mildly impaired and 4% moderately impaired patients. At 2 years follow-up, cognitive status was stable in 65%, improved in 33% and worsened in 2% of patients. No significant relations were found between global cognitive outcome vs. EDSS change, clinical disease activity, MRI data or ApoE gene polymorphisms over the 2 years follow-up. EDSS and MRI fractional volumes were found to correlate with the performance at single tests. Twenty-one patients (45.6%) showed active MRI scans throughout the study, without any worsening at the corresponding neuropsychological examination. This ongoing trial suggests a possible beneficial effect of IFN beta-1b treatment on cognitive functions in RRMS patients. Extension of follow-up and further data analyses are needed to confirm and clarify these findings. PMID:16626758

  8. Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.

    PubMed

    Galinsky, D; Tysoe, C; Brayne, C E; Easton, D F; Huppert, F A; Dening, T R; Paykel, E S; Rubinsztein, D C

    1997-03-21

    Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study

  9. APOE, CETP and LPL genes show strong association with lipid levels in Greek children☆

    PubMed Central

    Smart, M.C.; Dedoussis, G.; Louizou, E.; Yannakoulia, M.; Drenos, F.; Papoutsakis, C.; Maniatis, N.; Humphries, S.E.; Talmud, P.J.

    2010-01-01

    Background and aims Studies have consistently demonstrated that variants in a number of candidate genes are significant determinants of lipid levels in adults. However, few studies have investigated the impact of these variants in children. Therefore, in the present investigation we examined the influence of ten common variants in the genes for lipoprotein lipase (LPL – S447X), cholesterol ester transfer protein (CETP – Taq1B) apolipoprotein (APO) E (ɛ2, ɛ3, ɛ4), APOA5 (−1131C > T and S19W), APOA4 (S347T) and APOC3 (−482C > T; 1100C > T and 3238G > C) on lipoprotein levels children from the Gene–Diet Attica Investigation on childhood obesity (GENDAI). Methods and results The ten variants selected were genotyped in 882 Greek children, mean age: 11.2 ± 0.7 years (418 females and 464 males). Genotypes were assessed using TaqMan technology. Significantly higher total cholesterol (TC) (p = 0.0001) and low-density lipoprotein cholesterol (LDL-C) (p < 0.0001) were observed in APOE ɛ4 carriers compared to ɛ3/ɛ3 homozygotes and ɛ2 carriers. The association of APOE genotype with TC and high-density lipoprotein cholesterol (HDL-C) ratio (p = 0.0008) was further modulated by body mass index. Carriers of the CETP TaqIB B2 allele had significantly higher HDL-C (p < 0.0001) and significantly lower TC: HDL-C ratio (p < 0.0001) compared to B1/B1 individuals. No significant associations were observed between APOA4, APOA5 and APOC3 variants and serum lipids. Conclusion This study demonstrates that these common variants are associated with lipid levels in this healthy paediatric cohort, suggesting that even in these young children there may be potential in predicting their lifelong exposure to an adverse lipid profile. PMID:19403283

  10. Genes required for formation of the apoMoFe protein of Klebsiella pneumoniae nitrogenase in Escherichia coli.

    PubMed

    Harris, G S; White, T C; Flory, J E; Orme-Johnson, W H

    1990-09-15

    A binary plasmid system was used to produce nitrogenase components in Escherichia coli and subsequently to define a minimum set of nitrogen fixation (nif) genes required for the production of the iron-molybdenum cofactor (FeMoco) reactivatable apomolybdenum-iron (apoMoFe) protein of nitrogenase. The active MoFe protein is an alpha 2 beta 2 tetramer containing two FeMoco clusters and 4 Fe4S4 P centers (for review see, Orme-Johnson, W.H. (1985) Annu. Rev. Biophys. Biophys. Chem. 14, 419-459). The plasmid pVL15, carrying a tac-promoted nifA activator gene, was coharbored in E. coli with the plasmid pGH1 which contained nifHDKTYENXUSVWZMF' derived from the chromosome of the nitrogen fixing bacterium Klebsiella pneumoniae. The apoMoFe protein produced in E. coli by pGH1 + VL15 was identical to the apoprotein in derepressed cells of the nifB- mutant of K. pneumoniae (UN106) in its electrophoretic properties on nondenaturing polyacrylamide gels as well as in its ability to be activated by FeMoco. The constituent peptides migrated identically to those from purified MoFe protein during electrophoresis on denaturing gels. The concentrations of apoMoFe protein produced in nif-transformed strains of E. coli were greater than 50% of the levels of MoFe protein observed in derepressed wild-type K. pneumoniae. Systematic deletion of individual nif genes carried by pGH1 has established the requirements for the maximal production of the FeMoco-reactivatable apoMoFe protein to be the following gene products, NifHDKTYUSWZM+A. It appears that several of the genes (nifT, Y, U, W, and Z) are only required for maximal production of the apoMoFe protein, while others (nifH, D, K, and S) are absolutely required for synthesis of this protein in E. coli. One curious result is that the nifH gene product, the peptide of the Fe protein, but not active Fe protein itself, is required for formation of the apoMoFe protein. This suggests the possibility of a ternary complex of the NifH, D, and K

  11. Associations of APOE gene polymorphisms with bone mineral density and fracture risk: a meta-analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Apolipoprotein E (APOE) has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at common APOE loci, known as E2, E3, and E4, may modulate bone mineral density (BMD) through its effects on lipoproteins and vitamin K transport. To determine the associa...

  12. Variants in the APOE Gene Are Associated with Improved Outcome after Anti-VEGF Treatment for Neovascular AMD

    PubMed Central

    Xie, Jing; Lim, Jonathan; Chauhan, Devinder S.; Robman, Luba; Richardson, Andrea J.; Hageman, Gregory; Baird, Paul N.; Guymer, Robyn

    2011-01-01

    Purpose. Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately 30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene. Methods. One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients. Results. The presence of the APOE ε4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the ε2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE ε4 allele had an odds ratio (OR) of 4.04 (95% confidence interval [CI], 1.11–14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61–10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis. Conclusions. In patients with neovascular AMD, the presence of the APOE ε4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the ε2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF. PMID:21245410

  13. 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. PMID:26813964

  14. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

    PubMed Central

    Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L

    1995-01-01

    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600

  15. 8-gene Panel for Barrett&apos;s Esophagus — EDRN Public Portal

    Cancer.gov

    Eight methylation biomarkers - p16, RUNX3, HPP1 (HGNC name TMEFF2), NELL1, TAC1, SST, AKAP12 and CDH13 - were tested in a restrospective multicenter double-blinded validation study for their accuracy in predicting neoplastic progression in Barrett&apos;s Esophagus. Hypermethylation of p16, RUNX3 and HPP1 has been show to occur in early Barrett&apos;s Esophagus-related neoplastic progression and predicts progression risk. Several of the panel (NELL1, TAC1, SST, AKAP12 and CDH13) were also shown to be methylated early and often in Barrett&apos;s Esophagus-related neoplastic progression.

  16. Impact of APOE gene polymorphisms on the lipid profile in an Algerian population

    PubMed Central

    2013-01-01

    Background The importance of apolipoprotein E (APOE) in lipid and lipoprotein metabolism is well established. However, the impact of APOE polymorphisms has never been investigated in an Algerian population. This study assessed, for the fist time, the relationships between three APOE polymorphisms (epsilon, rs439401, rs4420638) and plasma lipid concentrations in a general population sample from Algeria. Methods The association analysis was performed in the ISOR study, a representative sample of the population living in Oran (787 subjects aged between 30 and 64). Polymorphisms were considered both individually and as haplotypes. Results In the ISOR sample, APOE ϵ4 allele carriers had higher plasma triglyceride (p=0.0002), total cholesterol (p=0.009) and LDL-cholesterol (p=0.003) levels than ϵ3 allele carriers. No significant associations were detected for the rs4420638 and rs439401 SNPs. Linkage disequilibrium and haplotype analyses confirmed the respectively deleterious and protective impacts of the ϵ4 and ϵ2 alleles on LDL-cholesterol levels and showed that the G allele of the rs4420638 polymorphism may exert a protective effect on LDL-cholesterol levels in subjects bearing the APOE epsilon 4 allele. Conclusion Our results showed that (i) the APOE epsilon polymorphism has the expected impact on the plasma lipid profile and (ii) the rs4420638 G allele may counterbalance the deleterious effect of the ϵ4 allele on LDL-cholesterol levels in an Algerian population. PMID:24160669

  17. Increased effect of the ApoE gene on survival at advanced age in healthy and long-lived Danes: two nationwide cohort studies

    PubMed Central

    Jacobsen, Rune; Martinussen, Torben; Christiansen, Lene; Jeune, Bernard; Andersen-Ranberg, Karen; Vaupel, James W.; Christensen, Kaare

    2010-01-01

    Summary Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a ‘frail’ or ‘risky’ genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE ε4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE ε4 allele on survival in a sample of the healthiest and long-lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE ε4 allele were followed from 1998 until death or end of follow-up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE ε4 status in 1998, 1546 had died at the end of the 10-year follow-up. Carriers of the ApoE ε4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92–103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE ε4 allele on mortality with age do not support previous findings of decreased influence ApoE ε4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age. PMID:20849521

  18. Deletion of Tenascin-C gene Exacerbates Atherosclerosis and Induces Intraplaque Hemorrhage in Apo E Deficient Mice

    PubMed Central

    Wang, Lai; Wang, Wei; Shah, Prediman K.; Song, Lei; Yang, Mingjie; Sharifi, Behrooz G.

    2012-01-01

    Aims Tenascin-C (TNC), a matricellular protein, is upregulated in atherosclerotic plaques. We investigated whether the deletion of TNC gene affects the development of atherosclerosis in a murine model. Methods TNC−/−/apo E−/− mice were generated and used for atherosclerosis studies. We compared these results to those observed in control groups of apo E−/− mice. Results The en face analysis of aortic area showed that the mean aortic lesion area of the double KO mice was significantly higher than control mice at different times after feeding of atherogenic diet; the accumulation of lesional macrophages and lipids were significantly higher, respectively. Analysis of cell adhesion molecules revealed that VCAM-1, but not ICAM-1, was upregulated 1 week after feeding of atherogenic diet in the double KO mouse as compared to apo E−/− mouse. Cell culture studies revealed that the expression of VCAM-1 in endothelial cells isolated from the double KO mouse is more sensitive to the TNFα stimulation than the cells isolated from apo E−/− mice. Cell adhesion studies showed that the adherence of RAW monocytic cells to the endothelial cells was significantly enhanced in the cultured endothelial cells from the TNC gene-deleted cells. Following the prolonged feeding of an atherogenic diet (28–30 weeks), the aortic and carotid atherosclerotic lesions frequently demonstrated large grossly visible areas of intraplaque hemorrhage in the double KO mice compared to control. Conclusions These data unveil a protective role for TNC in atherosclerosis and suggest that TNC signaling may have the potential to reduce atherosclerosis, in part by modulating VCAM-1 expression. PMID:22300502

  19. 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

  20. Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

    PubMed Central

    Ruiz, Jonatan R; Labayen, Idoia; Ortega, Francisco B; Moreno, Luis A; González-Lamuño, Domingo; Martí, Amelia; Nova, Esther; Fuentes, Miguel García; Redondo-Figuero, Carlos; Martínez, J Alfredo; Sjöström, Michael; Castillo, Manuel J

    2008-01-01

    Background There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-γ-2 (PPARγ2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13–18.5 years. Methods A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated. Results Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE ε3ε4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPARγ2 genotypes. Conclusion The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE ε3/ε4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life. PMID:19000312

  1. SPECTRAL GRAPH THEORY AND GRAPH ENERGY METRICS SHOW EVIDENCE FOR THE ALZHEIMER’S DISEASE DISCONNECTION SYNDROME IN APOE-4 RISK GENE CARRIERS

    PubMed Central

    Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Hibar, Derrek P.; Nir, Talia M.; Jack, Clifford R.; Weiner, Michael W.; Bernstein, Matt A.; Thompson, Paul M.

    2015-01-01

    Our understanding of network breakdown in Alzheimer’s disease (AD) is likely to be enhanced through advanced mathematical descriptors. Here, we applied spectral graph theory to provide novel metrics of structural connectivity based on 3-Tesla diffusion weighted images in 42 AD patients and 50 healthy controls. We reconstructed connectivity networks using whole-brain tractography and examined, for the first time here, cortical disconnection based on the graph energy and spectrum. We further assessed supporting metrics - link density and nodal strength - to better interpret our results. Metrics were analyzed in relation to the well-known APOE-4 genetic risk factor for late-onset AD. The number of disconnected cortical regions increased with the number of copies of the APOE-4 risk gene in people with AD. Each additional copy of the APOE-4 risk gene may lead to more dysfunctional networks with weakened or abnormal connections, providing evidence for the previously hypothesized “disconnection syndrome”. PMID:26413205

  2. Students&apos; Ontological Security and Agency in Science Education--An Example from Reasoning about the Use of Gene Technology

    ERIC Educational Resources Information Center

    Lindahl, Mats Gunnar; Linder, Cedric

    2013-01-01

    This paper reports on a study of how students&apos; reasoning about socioscientific issues is framed by three dynamics: societal structures, agency and how trust and security issues are handled. Examples from gene technology were used as the forum for interviews with 13 Swedish high-school students (year 11, age 17-18). A grid based on modalities…

  3. Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common "null" allele at the apo(a) locus.

    PubMed Central

    Gaw, A; Boerwinkle, E; Cohen, J C; Hobbs, H H

    1994-01-01

    Distributions of plasma lipoprotein(a) (Lp[a]) concentrations exhibit marked interracial differences. Apolipoprotein(a) (apo[a]), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4(K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the interracial variation in plasma Lp(a) levels, we compared apo(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese, and African Americans. Caucasians and African Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their apo(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African Americans than in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations but significantly different apo(a) allele size distributions. Therefore, interracial differences in the plasma concentrations of Lp(a) are not due to differences in the frequency distributions of apo(a) alleles. We also examined the relationship between apo(a) allele size and the presence of detectable plasma apo(a) protein in plasma. Apo(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, we conclude that there is no common "null" allele at the apo(a) locus. Images PMID:8200989

  4. Relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effects of pravastatin in patients with hyperlipidemia.

    PubMed

    Liu, T N; Wu, C T; He, F; Yuan, W; Li, S X; Li, H W; Yu, H Y; Wu, M

    2016-01-01

    In this study, we investigated the relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effect of pravastatin in patients with hyperlipidemia. A total of 179 patients were divided into two groups: the pravastatin (N = 97) and policosanol (N = 82) treatment groups. The total cholesterol (TC), triglyceride, low-density lipoprotein (LDL-c), high-density lipoprotein, ApoA, and ApoB concentrations in the serum were measured using an automatic biochemical analyzer before and after treatment for 12 weeks. The genotypes of the ApoA1 G75A SNP were detected by polymerase chain reaction-restriction fragment length polymorphism, and were subsequently statistically analyzed. Pravastatin treatment induced a significant decrease in the TC, LDL-c, and ApoB levels in patients expressing the ApoA1 AA+GA genotype (P < 0.05), and not in those expressing the GG genotype (P > 0.05). However, policosanol treatment induced a non-significant decrease in the serum TC levels (P > 0.05) and a significant decrease in the ApoB levels (P < 0.05), and did not induce a decrease in the LDL-c (P > 0.05) levels in patients with the AA+GA genotype. Policosanol also induced a significant decrease in the TC and LDL-c levels in patients with the GG genotype (P < 0.05). The various genotypes of the ApoA1 G75A SNP influence the efficacy of lipid regulation by pravastatin and policosanol in patients with hyperlipidemia. PMID:27323196

  5. Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice.

    PubMed

    Sanoudou, D; Duka, A; Drosatos, K; Hayes, K C; Zannis, V I

    2010-06-01

    We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and beta-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes. PMID:19949424

  6. Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

    PubMed Central

    Sanoudou, D; Duka, A; Drosatos, K; Hayes, K C; Zannis, V I

    2009-01-01

    We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes. PMID:19949424

  7. DNA methylation in cystathionine-γ-lyase (CSE) gene promoter induced by ox-LDL in macrophages and in apoE knockout mice.

    PubMed

    Du, Hua-Ping; Li, Jiaojiao; You, Shou-Jiang; Wang, Ya-Li; Wang, Fen; Cao, Yong-Jun; Hu, Li-Fang; Liu, Chun-Feng

    2016-01-15

    Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine γ-lyase (CSE) -hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE(-/-)) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE(-/-) mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development. PMID:26692478

  8. Effect of polymorphisms of the MTHFR and APOE genes on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian patients.

    PubMed

    Errera, F I V; Silva, M E R; Yeh, E; Maranduba, C M C; Folco, B; Takahashi, W; Pereira, A C; Krieger, J E; Passos-Bueno, M R

    2006-07-01

    Diabetes mellitus (DM) is a highly prevalent complex genetic disorder. There has been a worldwide effort in the identification of susceptibility genes for DM and its complications, and the 5-10-methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein-E (APOE) genes have been considered good candidate susceptibility genes to this condition. The objectives of the present study were to determine if the 677T MTHFR and epsilon2/epsilon3/epsilon4 APOE alleles are risk factors for DM and for severity of diabetic retinopathy (DR). A total of 248 individuals were studied: 107 healthy individuals and 141 diabetic patients (46 with type 1 diabetes and 95 with type 2 diabetes), who also had DR (81 with non-proliferative DR and 60 with proliferative DR). The polymorphisms were analyzed by PCR followed by digestion with restriction enzyme or the single-nucleotide primer extension method. No evidence of association between the 677TT genotype of MTHFR gene and DM [cases: TT = 10/95 (10.6%); controls: TT = 14/107 (13%)] or with severity of DR was observed [cases: TT = 5/60 (8.5%); controls: TT = 9/81 (11.1%); P > 0.05]. We also did not find evidence of an association between APOE alleles and proliferative DR (epsilon2, epsilon3 and epsilon4 in cases: 9, 76, and 15%, and in controls: 5, 88, and 12%, respectively) but the carriers of epsilon2 allele were more frequent among patients with type 2 DM and DR than in controls [cases: 15/95 (15.8%); controls: 7/107 (6.5%); P < 0.05]. Therefore, our results suggest that the epsilon2 allele/APOE might be a risk factor for diabetes in the Brazilian population. PMID:16862278

  9. 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

  10. The Role of Parenting and Dopamine D4 Receptor Gene Polymorphisms in Children&apos;s Inhibitory Control

    ERIC Educational Resources Information Center

    Smith, Heather J.; Kryski, Katie R.; Sheikh, Haroon I.; Singh, Shiva M.; Hayden, Elizabeth P.

    2013-01-01

    Temperamental effortful control has important implications for children&apos;s development. Although genetic factors and parenting may influence effortful control, few studies have examined interplay between the two in predicting its development. The current study investigated associations between parenting and a facet of children&apos;s effortful…

  11. Transcriptional regulation of the apolipoprotein F (ApoF) gene by ETS and C/EBPα in hepatoma cells.

    PubMed

    Shen, Xue-Bin; Huang, Ling; Zhang, Shao-Hong; Wang, De-Ping; Wu, Yun-Li; Chen, Wan-Nan; Xu, Shang-Hua; Lin, Xu

    2015-05-01

    Apolipoprotein F (ApoF) inhibits cholesteryl ester transfer protein (CETP) activity and plays an important role in lipid metabolism. In the present study, the full-length human ApoF promoter was cloned, and the molecular mechanism of the regulation of ApoF was investigated. The ApoF promoter displayed higher activities in hepatoma cell lines, and the -198 nt to +79 nt promoter region contained the maximum promoter activity. In the promoter region of -198 nt to -2 nt there were four putative binding sites for transcription factors ETS-1/ETS-2 (named EBS-1 to EBS-4) and one for C/EBP. Mutation of EBS-2, EBS4 and the C/EBP binding site abolished the promoter activity, and ETS-1/ETS-2 and C/EBPα could interact with corresponding binding sites. In addition, overexpression of ETS-1/2 or C/EBPα enhanced, while dominant-negative mutants of ETS-1/2 and knockdown of C/EBPα decreased, ApoF promoter activities. ETS-1 and C/EBPα associated physically, and acted synergistically to activate ApoF transcription. These results demonstrated combined activation of the ApoF promoter by liver-enriched and ubiquitous transcription factors. Direct interactions between C/EBPα and ETS-1 were important for high liver-specific expression of ApoF. PMID:25726912

  12. Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.

    PubMed

    Mahley, Robert W

    2016-07-01

    ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease. PMID:27174096

  13. Correlation of polymorphism of APOE and LRP genes to cognitive impairment and behavioral and psychological symptoms of dementia in Alzheimer’s disease and vascular dementia

    PubMed Central

    Mou, Chengzhi; Han, Tao; Wang, Min; Jiang, Meng; Liu, Bin; Hu, Jia

    2015-01-01

    Objective: To discuss the correlation of polymorphism of APOE and LRP genes to cognitive impairment and behavioral and psychological symptoms of dementia (BPSD) in Alzheimer’s disease (AD) and vascular dementia (VD). Method: AD cases, VD cases and healthy control cases totaling 237, 255 and 234 were recruited, respectively. The mini-mental state examination (MMSE) was performed to evaluate cognitive impairment. Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were adopted to evaluate BPSD. Apolipoprotein E (APOE) and Low-density lipoprotein receptor-related protein gene (LRP) genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: (1) Frequencies of APOEε4 allele in AD group and VD group were significantly higher than that of the control (P<0.05); (2) MMSE scores of APOEε4 carriers in AD group and VD group were lower than that of non-APOEε4 carriers in the same group (P<0.05); (3) The proportion of APOEε4 carriers presenting with BPSD in AD group was considerably higher that of non-APOEε4 carriers (P<0.05). Conclusion: APOEε4 may be the common risk factor for cognitive impairment in AD and VD and the risk factor for BPSD in AD. PMID:26885125

  14. 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

  15. 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

  16. Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention.

    PubMed

    Keeney, Jeriel Thomas-Richard; Ibrahimi, Shaher; Zhao, Liqin

    2015-01-01

    Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention. PMID:26402005

  17. Total ApoE and ApoE4 Isoform Assays in an Alzheimer's Disease Case-control Study by Targeted Mass Spectrometry (n = 669): A Pilot Assay for Methionine-containing Proteotypic Peptides*

    PubMed Central

    Simon, Romain; Girod, Marion; Fonbonne, Catherine; Salvador, Arnaud; Clément, Yohann; Lantéri, Pierre; Amouyel, Philippe; Lambert, Jean Charles; Lemoine, Jérôme

    2012-01-01

    Allelic polymorphism of the apolipoprotein E (ApoE) gene (ApoE ε2, ApoE ε3 and ApoE ε4 alleles) gives rise to three protein isoforms (ApoE2, ApoE3 and ApoE4) that differ by 1 or 2 amino acids. Inheritance of the ApoE ε4 allele is a risk factor for developing Alzheimer's disease (AD). The potential diagnostic value of ApoE protein levels in biological fluids (i.e. cerebrospinal fluid, plasma and serum) for distinguishing between AD patients and healthy elderly subjects is subject to great controversy. Although a recent study reported subnormal total ApoE and ApoE4 levels in the plasma of AD patients, other studies have found normal or even elevated protein levels (versus controls). Because all previously reported assays were based on immunoenzymatic techniques, we decided to develop an orthogonal assay based on targeted mass spectrometry by tracking (i) a proteotypic peptide common to all ApoE isoforms and (ii) a peptide that is specific for the ε4 allele. After trypsin digestion, the ApoE4-specific peptide contains an oxidation-prone methionine residue. The endogenous methionine oxidation level was evaluated in a small cohort (n = 68) of heterozygous ε3ε4 carriers containing both healthy controls and AD patients. As expected, the proportion of oxidized residues varied from 0 to 10%, with an average of 5%. We therefore developed a standardized strategy for the unbiased, absolute quantification of ApoE4, based on performic acid oxidization of methionine. Once the sample workflow had been thoroughly validated, it was applied to the concomitant quantification of total ApoE and ApoE4 isoform in a large case-control study (n = 669). The final measurements were consistent with most previously reported ApoE concentration values and confirm the influence of the different alleles on the protein expression level. Our results illustrate (i) the reliability of selected reaction monitoring-based assays and (ii) the value of the oxidization step for unbiased monitoring of

  18. 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

  19. How and Why Does the 5-HTTLPR Gene Moderate Associations between Maternal Unresponsiveness and Children&apos;s Disruptive Problems?

    ERIC Educational Resources Information Center

    Davies, Patrick T.; Cicchetti, Dante

    2014-01-01

    This study tested the 5-HTTLPR gene as a moderator in the relation between maternal unresponsiveness and child externalizing symptoms in a disadvantaged, predominantly Black sample of two hundred and one 2-year-old children and their mothers. Using a multimethod, prospective design, structural equation model analyses indicated that maternal…

  20. 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

  1. 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…

  2. APOE genotype alters glial activation and loss of synaptic markers in mice

    PubMed Central

    Zhu, Yuangui; Nwabuisi-Heath, Evelyn; Dumanis, Sonya B.; Tai, Leon; Yu, Chunjiang; Rebeck, G. William; Jo LaDu, Mary

    2011-01-01

    The E4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and affects clinical outcomes of chronic and acute brain damages. The mechanisms by which apoE affect diverse diseases and disorders may involve modulation of the glial response to various types of brain damages. We examined glial activation in a mouse model where each of the human APOE alleles are expressed under the endogenous mouse APOE promoter, as well as in APOE knock-out mice. APOE4 mice displayed increased glial activation in response to intracerebroventricular lipopolysaccharide (LPS) compared to APOE2 and APOE3 mice by several measures. There were higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in APOE4 mice. APOE4 mice also displayed greater and more prolonged increases of cytokines (IL-1β, IL-6, TNF-α) than APOE2 and APOE3 mice. We found that APOE4 mice had greater synaptic protein loss after LPS injection, as measured by three different markers: PSD-95, Drebin, and synaptophysin. In all assays, APOE knock-out mice responded similar to APOE4 mice, suggesting that the apoE4 protein may lack anti-inflammatory characteristics of apoE2 and apoE3. Together, these findings demonstrate that APOE4 predisposes to inflammation, which could contribute to its association with Alzheimer's disease and other disorders. PMID:22228589

  3. From Flavr Savr Tomatoes to STEM Cell Therapy: Young People&apos;s Understandings of Gene Technology, 15 Years On

    ERIC Educational Resources Information Center

    Lewis, Jenny

    2014-01-01

    This paper explores knowledge and understanding of basic genetics and gene technologies in school students who have been taught to a "science for all" National Curriculum and compares 482 students in 1995 (gene technology was a new and rapidly developing area of science with potential to impact on everyday life; the first cohort of…

  4. Blood and Bones: The Influence of the Mass Media on Australian Primary School Children&apos;s Understandings of Genes and DNA

    ERIC Educational Resources Information Center

    Donovan, Jenny; Venville, Grady

    2014-01-01

    Previous research showed that primary school children held several misconceptions about genetics of concern for their future lives. Included were beliefs that genes and DNA are separate substances, with genes causing family resemblance and DNA identifying suspects at crime scenes. Responses to this work "blamed" the mass media for these…

  5. ApoE type 4 allele affects cognitive function of aged population in Tianjin City, China.

    PubMed

    Sun, Shoudan; Fu, Jingming; Chen, Jun; Pang, Wei; Hu, Ruomei; Li, Haiqiang; Tan, Long; Jiang, Yugang

    2015-08-01

    Apolipoprotein E type 4 allele (ApoE∊4) is known as a risk gene for the late-onset Alzheimer's disease, and the relationship between ApoE∊4 and cognitive function of the elderly people has drawn the attention of the scientists. In this study, we investigated the relationship between ApoE∊4 and the cognitive function of the old people. A total of 156 old people were investigated, of whom 31 were ApoE∊4 carriers. The ApoE∊4 primarily influenced the global cognitive function, perceptual speed, and work memory. The results indicate that ApoE∊4 has significant negative effect on the cognitive function of the elderly people who are 60 years and older. PMID:25585996

  6. Association of APOE (E2, E3 and E4) gene variants and lipid levels in ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population.

    PubMed

    Das, Satrupa; Kaul, Subhash; Jyothy, Akka; Munshi, Anjana

    2016-08-15

    In the present study we evaluated the association of APOE (E2/E3/E4) polymorphism with ischemic stroke (n=620), its subtypes and hemorrhagic stroke (n=250) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP while lipid levels were measured using commercially available kits. We found significant difference in the genotypic distribution between hemorrhagic stroke patients and controls for certain genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3; E4/E4 vs.E2/E4 and E3 vs. E4]. However, no significant difference was observed in genotypic distribution between ischemic stroke patients and controls. On analysing the genotypic distribution between ischemic and hemorrhagic stroke patients, statistically significant difference was observed in specific genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3 and E4/E4 vs. E2/E4]. In ischemic stroke subtypes analysing for alleles E3 vs. E2 and E3 vs. E4, we found significant association with intracranial large artery (p=0.01), cardioembolic stroke (p=0.001 and p=0.0004) and lacunar stroke (p=0.02). Analysing the association of various genotypes with different lipid levels significant association was observed for VLDL (P=0.000) and for triglyceride (P=0.000) levels with E2/E4 and E3/E4 genotypes in ischemic stroke but not in hemorrhagic stroke. In conclusion, our results suggest that APOE polymorphism does seem to play a role in hemorrhagic stroke and also in the development of specific subtypes of ischemic stroke. Further, in ischemic stroke VLDL and triglycerides levels were found to be significantly associated with E2/E4 and E3/E4 genotypes. PMID:27329241

  7. Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation

    PubMed Central

    2012-01-01

    Background Inheritance of the human ϵ4 allele of the apolipoprotein (apo) E gene (APOE) significantly increases the risk of developing Alzheimer’s disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases. While apoE isoforms differentially interact with amyloid β (Aβ), a pleiotropic neurotoxin key to AD etiology, more recent work has focused on immune regulation in AD pathogenesis and on the mechanisms of innate immunomodulatory effects associated with inheritance of different APOE alleles. APOE genotype modulates expression of proximal genes including APOC1, which encodes a small apolipoprotein that is associated with Aβ plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I. Methods ApoC-I concentration in cerebrospinal fluid from control subjects of differing APOE genotypes was quantified by ELISA. Real-time PCR and ELISA were used to analyze apoC-I mRNA and protein expression, respectively, in liver, serum, cerebral cortex, and cultured primary astrocytes derived from mice with targeted replacement of murine APOE for human APOE ϵ3 or ϵ4. ApoC-I direct modulation of innate immune activity was investigated in cultured murine primary microglia and astrocytes, as well as human differentiated macrophages, using specific toll-like receptor agonists LPS and PIC as well as Aβ. Results ApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with ϵ4 carriers showing significantly less apoC-I in both species. ApoC-I potently reduced pro-inflammatory cytokine secretion from primary murine microglia and astrocytes, and human macrophages, stimulated with LPS, PIC, or Aβ. Conclusions ApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an ϵ4 allele have decreased expression of apoC-I resulting in increased innate immune activity. PMID

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

    PubMed Central

    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

  9. Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

    PubMed Central

    Ulrich, Victoria; Konaniah, Eddy S.; Herz, Joachim; Gerard, Robert D.; Jung, Eunjeong; Yuhanna, Ivan S.; Ahmed, Mohamed; Hui, David Y.; Mineo, Chieko; Shaul, Philip W.

    2014-01-01

    It is poorly understood why there is greater cardiovascular disease risk associated with the apolipoprotein E4 (apoE) allele vs. apoE3, and also greater risk with the LRP8/apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R952Q. Little is known about the function of the apoE–ApoER2 tandem outside of the central nervous system. We now report that in endothelial cells apoE3 binding to ApoER2 stimulates endothelial NO synthase (eNOS) and endothelial cell migration, and it also attenuates monocyte–endothelial cell adhesion. However, apoE4 does not stimulate eNOS or endothelial cell migration or dampen cell adhesion, and alternatively it selectively antagonizes apoE3/ApoER2 actions. The contrasting endothelial actions of apoE4 vs. apoE3 require the N-terminal to C-terminal interaction in apoE4 that distinguishes it structurally from apoE3. Reconstitution experiments further reveal that ApoER2-R952Q is a loss-of-function variant of the receptor in endothelium. Carotid artery reendothelialization is decreased in ApoER2−/− mice, and whereas adenoviral-driven apoE3 expression in wild-type mice has no effect, apoE4 impairs reendothelialization. Moreover, in a model of neointima formation invoked by carotid artery endothelial denudation, ApoER2−/− mice display exaggerated neointima development. Thus, the apoE3/ApoER2 tandem promotes endothelial NO production, endothelial repair, and endothelial anti-inflammatory properties, and it prevents neointima formation. In contrast, apoE4 and ApoER2-R952Q display dominant-negative action and loss of function, respectively. Thus, genetic variants of apoE and ApoER2 impact cardiovascular health by differentially modulating endothelial function. PMID:25197062

  10. 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…

  11. Additive genetic effect of APOE and BDNF on hippocampus activity.

    PubMed

    Kauppi, Karolina; Nilsson, Lars-Göran; Persson, Jonas; Nyberg, Lars

    2014-04-01

    Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF. PMID:24321557

  12. Novel action of apolipoprotein E (ApoE): ApoE isoform specifically inhibits lipid-particle-mediated cholesterol release from neurons

    PubMed Central

    Gong, Jian-Sheng; Morita, Shin-ya; Kobayashi, Mariko; Handa, Tetsurou; Fujita, Shinobu C; Yanagisawa, Katsuhiko; Michikawa, Makoto

    2007-01-01

    Background Since the majority of apolipoprotein E (apoE) existing in the cerebrospinal fluid is associated with high-density lipoprotein (HDL), one should focus on the role of the apoE-HDL complex rather than on that of free apoE in cholesterol metabolism in the central nervous system. However, the apoE-isoform-specific effect of apoE-HDL on cholesterol transport remains unclarified. Results Here we show that apoE3-HDL induced a marked cholesterol release from neurons, while apoE4-HDL induced little. To elucidate the mechanism underlying this phenomenon, we used a complex of lipid emulsion (EM) with recombinant apoE3 or apoE4 (apoE-EM) at various apoE concentrations. When a small number of apoE molecules were associated with EM, apoE3- and apoE4-EM, induced a marked cholesterol release to a level similar to that induced by EM alone. However, when apoE at given concentrations was incubated with EM, apoE3-EM induced a marked cholesterol release, while apoE4-EM induced little. Under these conditions, a greater number of apoE4 molecules were associated with EM than apoE3 molecules. When an increasing number of apoE molecules were associated with EM, both apoE3-EM and apoE4-EM induced little cholesterol release. Preincubation with β-mercaptoethanol increased the number of apoE3 molecules associated with EM similar to that of apoE4 molecules, indicating that the presence (apoE3) or absence (apoE4) of intermolecular disulfide bond formation is responsible for the association of a greater number of apoE4 molecules to EM than apoE3 molecules. Conclusion These results suggest that although apoE and a lipid particle are lipid acceptors, when apoE and a lipid particle form a complex, apoE on the particle surface inhibits the lipid particle-mediated cholesterol release from cells in an apoE-concentration-dependent manner. PMID:17504523

  13. 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 ...

  14. 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…

  15. 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 ...

  16. Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice

    PubMed Central

    Zhao, Yang; Dai, Xiao-yan; Zhou, Zhou; Zhao, Ge-xin; Wang, Xian; Xu, Ming-jiang

    2016-01-01

    Aim: Recent evidence suggests that the essential amino acid leucine may be involved in systemic cholesterol metabolism. In this study, we investigated the effects of leucine supplementation on the development of atherosclerosis in apoE null mice. Methods: ApoE null mice were fed with chow supplemented with leucine (1.5% w/v) in drinking water for 8 week. Aortic atherosclerotic lesions were examined using Oil Red O staining. Plasma lipoprotein-cholesterol levels were measured with fast protein liquid chromatography. Hepatic gene expression was detected using real-time PCR and Western blot analyses. Results: Leucine supplementation resulted in 57.6% reduction of aortic atherosclerotic lesion area in apoE null mice, accompanied by 41.2% decrease of serum LDL-C levels and 40.2% increase of serum HDL-C levels. The body weight, food intake and blood glucose level were not affected by leucine supplementation. Furthermore, leucine supplementation increased the expression of Abcg5 and Abcg8 (that were involved in hepatic cholesterol efflux) by 1.28- and 0.86-fold, respectively, and significantly increased their protein levels. Leucine supplementation also increased the expression of Srebf1, Scd1 and Pgc1b (that were involved in hepatic triglyceride metabolism) by 3.73-, 1.35- and 1.71-fold, respectively. Consequently, leucine supplementation resulted in 51.77% reduction of liver cholesterol content and 2.2-fold increase of liver triglyceride content. Additionally, leucine supplementation did not affect the serum levels of IL-6, IFN-γ, TNF-α, IL-10 and IL-12, but markedly decreased the serum level of MCP-1. Conclusion: Leucine supplementation effectively attenuates atherosclerosis in apoE null mice by improving the plasma lipid profile and reducing systemic inflammation. PMID:26687933

  17. 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. PMID:27379525

  18. Hypobetalipoproteinemic mice with a targeted apolipoprotein (Apo) B-27.6-specifying mutation: in vivo evidence for an important role of amino acids 1254-1744 of ApoB in lipid transport and metabolism of the apoB-containing lipoprotein.

    PubMed

    Chen, Zhouji; Fitzgerald, Robin L; Schonfeld, Gustav

    2002-04-19

    Carboxyl-terminal deletion of apoB-100 may impair its triglyceride (TG)-transporting capability and alter its catabolism. Here, we compare our newly generated apoB gene (Apob)-targeted apoB-27.6-bearing mice to our previously reported apoB-38.9 mice to understand further the relationship between the size of a truncated apoB variant and its function/metabolism in vivo. The apoB-27.6-specifying mutation produces a premature stop codon six amino acids (aa) downstream of the last codon of mouse Apob exon 24 (corresponding to aa 1254 of human apoB-100). ApoB-27.6 transcripts were 3- and 5-fold more abundant than apoB wild type and apoB-38.9 transcripts in the liver. Likewise, hepatic secretion rates of apoB-27.6 were 7-fold higher than those of apoB-48 and apoB-38.9. In contrast, apoB-27.6 heterozygotes (Apob(27.6/+)) had lower hepatic TG secretion rates and higher liver TG contents than both apoB-38.9 heterozygotes (Apob(38.9/+)) and apoB wild type mice (Apob(+/+)). ApoB-27.6 was secreted by Apob(27.6/+) hepatocytes as dense high density lipoprotein particles. Moreover, despite its high secretion rates, apoB-27.6 was barely detectable in plasma. Disruption of apoE gene in Apob(38.9/+) and Apob(27.6/+) dramatically increased plasma levels of apoB-38.9 as well as apoB-48 but caused no change in plasma apoB-27.6 concentrations. Finally, the birth rate of apoB-27.6 homozygotes (Apob(27.6/27.6)) from intercrosses of Apob(27.6/+) was 7-fold lower than that of Apob(38.9/38.9) from Apob(38.9/+) intercrosses (1.8% versus 12%). Crossbreeding of Apob(27.6/27.6) and Apob(38.9/38.9) produced viable Apob(27.6/38.9) offspring, but Apob(27.6/27.6) intercrosses produced no offspring. Together, these results demonstrate in vivo that the apoB-27.6-apoB-38.9 peptide segment (aa 1254-1744) plays a critical role, not only in supporting hepatic TG-secretion and in modulating catabolism of apoB-containing lipoproteins, but also in normal mouse embryonic development. PMID:11839763

  19. APOE3, but Not APOE4, Bone Marrow Transplantation Mitigates Behavioral and Pathological Changes in a Mouse Model of Alzheimer Disease

    PubMed Central

    Yang, Yue; Cudaback, Eiron; Jorstad, Nikolas L.; Hemingway, Jake F.; Hagan, Catherine E.; Melief, Erica J.; Li, Xianwu; Yoo, Tom; Khademi, Shawn B.; Montine, Kathleen S.; Montine, Thomas J.; Keene, C. Dirk

    2014-01-01

    Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset Alzheimer disease and confers a proinflammatory, neurotoxic phenotype to microglia. Here, we tested the hypothesis that bone marrow cell APOE genotype modulates pathological progression in experimental Alzheimer disease. We performed bone marrow transplants (BMT) from green fluorescent protein–expressing human APOE3/3 or APOE4/4 donor mice into lethally irradiated 5-month-old APPswe/PS1ΔE9 mice. Eight months later, APOE4/4 BMT–recipient APPswe/PS1ΔE9 mice had significantly impaired spatial working memory and increased detergent-soluble and plaque Aβ compared with APOE3/3 BMT–recipient APPswe/PS1ΔE9 mice. BMT-derived microglia engraftment was significantly reduced in APOE4/4 recipients, who also had correspondingly less cerebral apoE. Gene expression analysis in cerebral cortex of APOE3/3 BMT recipients showed reduced expression of tumor necrosis factor-α and macrophage migration inhibitory factor (both neurotoxic cytokines) and elevated immunomodulatory IL-10 expression in APOE3/3 recipients compared with those that received APOE4/4 bone marrow. This was not due to detectable APOE-specific differences in expression of microglial major histocompatibility complex class II, C-C chemokine receptor (CCR) type 1, CCR2, CX3C chemokine receptor 1 (CX3CR1), or C5a anaphylatoxin chemotactic receptor (C5aR). Together, these findings suggest that BMT-derived APOE3-expressing cells are superior to those that express APOE4 in their ability to mitigate the behavioral and neuropathological changes in experimental Alzheimer disease. PMID:23831297

  20. Apo-10’-lycopenoic acid induces Nrf2-mediated expression of phase II antioxidant genes and suppresses H2O2 induced oxidative damage in human bronchial epithelial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our previous study has demonstrated that apo-10’-lycopenoic acid (ALA), an enzymatic metabolite of lycopene, can suppress lung carcinogenesis in an animal model. However, the potential mechanism(s) underlying this protection is not well defined. It has been suggested that lycopene or its hydrophilic...

  1. Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice.

    PubMed

    Peris-Sampedro, Fiona; Cabré, Maria; Basaure, Pia; Reverte, Ingrid; Domingo, José L; Teresa Colomina, Maria

    2015-10-01

    Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Our recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Thus, we aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. We examined body weight status, food and water intake, lipid and glucose homeostasis, metabolic biomarkers concentrations, insulin levels and insulin resistance, and leptin and ghrelin profiles. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health. PMID:26162960

  2. Lipid transfer particle from the silkworm, Bombyx mori, is a novel member of the apoB/large lipid transfer protein family[S

    PubMed Central

    Yokoyama, Hiroshi; Yokoyama, Takeru; Yuasa, Masashi; Fujimoto, Hirofumi; Sakudoh, Takashi; Honda, Naoko; Fugo, Hajime; Tsuchida, Kozo

    2013-01-01

    Lipid transfer particle (LTP) is a high-molecular-weight, very high-density lipoprotein known to catalyze the transfer of lipids between a variety of lipoproteins, including both insects and vertebrates. Studying the biosynthesis and regulation pathways of LTP in detail has not been possible due to a lack of information regarding the apoproteins. Here, we sequenced the cDNA and deduced amino acid sequences for three apoproteins of LTP from the silkworm (Bombyx mori). The three subunit proteins of the LTP are coded by two genes, apoLTP-II/I and apoLTP-III. ApoLTP-I and apoLTP-II are predicted to be generated by posttranslational cleavage of the precursor protein, apoLTP-II/I. Clusters of amphipathic secondary structure within apoLTP-II/I are similar to Homo sapiens apolipoprotein B (apoB) and insect lipophorins. The apoLTP-II/I gene is a novel member of the apoB/large lipid transfer protein gene family. ApoLTP-III has a putative conserved juvenile hormone-binding protein superfamily domain. Expression of apoLTP-II/I and apoLTP-III genes was synchronized and both genes were primarily expressed in the fat body at the stage corresponding to increased lipid transport needs. We are now in a position to study in detail the physiological role of LTP and its biosynthesis and assembly. PMID:23812557

  3. Ictalurus punctatus apolipoprotein A-I (ApoA1) mRNA, complete cds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The complete coding sequence of channel catfish apolipoprotein A-I is 777 bp in length, encoding 258 amino acids. The publishing of this coding sequence will also allow phylogenetic comparison between catfish ApoAI and ApoAI genes from other species. The availability of this complete coding sequence...

  4. Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease.

    PubMed

    Tamboli, Irfan Y; Heo, Dongeun; Rebeck, G William

    2014-01-01

    Under normal conditions, brain apolipoprotein E (apoE) is secreted and lipidated by astrocytes, then taken up by neurons via receptor mediated endocytosis. Free apoE is either degraded in intraneuronal lysosomal compartments or released. Here we identified a novel way by which apoE undergoes proteolysis in the extracellular space via a secreted neuronal protease. We show that apoE is cleaved in neuronal conditioned media by a secreted serine protease. This apoE cleavage was inhibited by PMSF and α1-antichymotrypsin, but not neuroserpin-1 or inhibitors of thrombin and cathepsin G, supporting its identity as a chymotrypsin like protease. In addition, apoE incubation with purified chymotrypsin produced a similar pattern of apoE fragments. Analysis of apoE fragments by mass spectrometry showed cleavages occurring at the C-terminal side of apoE tryptophan residues, further supporting our identification of cleavage by chymotrypsin like protease. Hippocampal neurons were more efficient in mediating this apoE cleavage than cortical neurons. Proteolysis of apoE4 generated higher levels of low molecular weight fragments compared to apoE3. Primary glial cultures released an inhibitor of this proteolytic activity. Together, these studies reveal novel mechanism by which apoE can be regulated and therefore could be useful in designing apoE directed AD therapeutic approaches. PMID:24675880

  5. Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease

    PubMed Central

    Tamboli, Irfan Y.; Heo, Dongeun; Rebeck, G. William

    2014-01-01

    Under normal conditions, brain apolipoprotein E (apoE) is secreted and lipidated by astrocytes, then taken up by neurons via receptor mediated endocytosis. Free apoE is either degraded in intraneuronal lysosomal compartments or released. Here we identified a novel way by which apoE undergoes proteolysis in the extracellular space via a secreted neuronal protease. We show that apoE is cleaved in neuronal conditioned media by a secreted serine protease. This apoE cleavage was inhibited by PMSF and α1-antichymotrypsin, but not neuroserpin-1 or inhibitors of thrombin and cathepsin G, supporting its identity as a chymotrypsin like protease. In addition, apoE incubation with purified chymotrypsin produced a similar pattern of apoE fragments. Analysis of apoE fragments by mass spectrometry showed cleavages occuring at the C-terminal side of apoE tryptophan residues, further supporting our identification of cleavage by chymotrypsin like protease. Hippocampal neurons were more efficient in mediating this apoE cleavage than cortical neurons. Proteolysis of apoE4 generated higher levels of low molecular weight fragments compared to apoE3. Primary glial cultures released an inhibitor of this proteolytic activity. Together, these studies reveal novel mechanism by which apoE can be regulated and therefore could be useful in designing apoE directed AD therapeutic approaches. PMID:24675880

  6. ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA.

    PubMed

    Yajima, Ryuji; Tokutake, Takayoshi; Koyama, Akihide; Kasuga, Kensaku; Tezuka, Toshiyuki; Nishizawa, Masatoyo; Ikeuchi, Takeshi

    2015-01-01

    The formation of senile plaques composed of β-amyloid (Aβ) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aβ deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-β (Aβ) through the binding of Aβ to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of Aβ through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4>apoE3>apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled Aβ were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular Aβ into the recipient cells was most prominently accentuated when cocultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of Aβ mediated by LR11/SorLA. PMID

  7. No Association Between Apoε4 Alleles, HIV Infection, Age, Neuropsychological Outcome or Death

    PubMed Central

    Becker, James T.; Martinson, Jeremy J.; Penugonda, Sudhir; Kingsley, Lawrence; Molsberry, Samantha; Wolinsky, Steven; Reynolds, Sandra; Aronow, Aaron; Goodkin, Karl; Levine, Andrew; Martin, Eileen; Miller, Eric N.; Munro, Cynthia A.; Ragin, Ann; Sacktor, Ned

    2014-01-01

    The ε4 allele of the ApoE gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment and death in a large, well-characterized study sample. 2,846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range: 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus. PMID:25388225

  8. No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death.

    PubMed

    Becker, James T; Martinson, Jeremy J; Penugonda, Sudhir; Kingsley, Lawrence; Molsberry, Samantha; Reynolds, Sandra; Aronow, Aaron; Goodkin, Karl; Levine, Andrew; Martin, Eileen; Miller, Eric N; Munro, Cynthia A; Ragin, Ann; Sacktor, Ned

    2015-02-01

    The ε4 allele of the apolipoprotein E (ApoE) gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment, and death in a large, well-characterized study sample. A total of 2846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus. PMID:25388225

  9. Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

    PubMed Central

    Cacabelos, Ramón; Martínez, Rocío; Fernández-Novoa, Lucía; Carril, Juan C.; Lombardi, Valter; Carrera, Iván; Corzo, Lola; Tellado, Iván; Leszek, Jerzy; McKay, Adam; Takeda, Masatoshi

    2012-01-01

    Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics. PMID:22482072

  10. ApoE isoform-specific regulation of regeneration in the peripheral nervous system

    PubMed Central

    Comley, Laura H.; Fuller, Heidi R.; Wishart, Thomas M.; Mutsaers, Chantal A.; Thomson, Derek; Wright, Ann K.; Ribchester, Richard R.; Morris, Glenn E.; Parson, Simon H.; Horsburgh, Karen; Gillingwater, Thomas H.

    2011-01-01

    Apolipoprotein E (apoE) is a 34 kDa glycoprotein with three distinct isoforms in the human population (apoE2, apoE3 and apoE4) known to play a major role in differentially influencing risk to, as well as outcome from, disease and injury in the central nervous system. In general, the apoE4 allele is associated with poorer outcomes after disease or injury, whereas apoE3 is associated with better responses. The extent to which different apoE isoforms influence degenerative and regenerative events in the peripheral nervous system (PNS) is still to be established, and the mechanisms through which apoE exerts its isoform-specific effects remain unclear. Here, we have investigated isoform-specific effects of human apoE on the mouse PNS. Experiments in mice ubiquitously expressing human apoE3 or human apoE4 on a null mouse apoE background revealed that apoE4 expression significantly disrupted peripheral nerve regeneration and subsequent neuromuscular junction re-innervation following nerve injury compared with apoE3, with no observable effects on normal development, maturation or Wallerian degeneration. Proteomic isobaric tag for relative and absolute quantitation (iTRAQ) screens comparing healthy and regenerating peripheral nerves from mice expressing apoE3 or apoE4 revealed significant differences in networks of proteins regulating cellular outgrowth and regeneration (myosin/actin proteins), as well as differences in expression levels of proteins involved in regulating the blood–nerve barrier (including orosomucoid 1). Taken together, these findings have identified isoform-specific roles for apoE in determining the protein composition of peripheral nerve as well as regulating nerve regeneration pathways in vivo. PMID:21478199

  11. Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke

    PubMed Central

    Kim, Eunhee; Woo, Moon-Sook; Qin, Luye; Ma, Thong; Beltran, Cesar D.; Bao, Yi; Bailey, Jason A.; Corbett, Dale; Ratan, Rajiv R.; Lahiri, Debomoy K.

    2015-01-01

    Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect. SIGNIFICANCE STATEMENT There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long

  12. 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. PMID:27040139

  13. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation

    PubMed Central

    Marduel, Marie; Ouguerram, Khadija; Serre, Valérie; Bonnefont-Rousselot, Dominique; Marques-Pinheiro, Alice; Berge, Knut Erik; Devillers, Martine; Luc, Gérald; Lecerf, Jean-Michel; Tosolini, Laurent; Erlich, Danièle; Peloso, Gina M.; Stitziel, Nathan; Nitchké, Patrick; Jaïs, Jean-Philippe; Abifadel, Marianne; Kathiresan, Sekar; Leren, Trond Paul; Rabès, Jean-Pierre; Boileau, Catherine; Varret, Mathilde

    2013-01-01

    Apo E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal Dominant Hypercholesterolemia (ADH), due to mutations in the LDLR, APOB or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to high levels of low-density lipoproteins (LDL). We now report an exceptionally large family including 14 members with ADH. Through genome wide mapping, analysis of regional/functional candidate genes and whole exome sequencing, we identified a mutation in the APOE gene, p.Leu167del previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha-helix in the binding domain; (2) a decreased apo E level in LDL; and (3) a decreased catabolism of LDL. Our results show that mutations in the APOE gene can be associated with bona fide ADH. PMID:22949395

  14. Targeting ApoC-III to Reduce Coronary Disease Risk.

    PubMed

    Khetarpal, Sumeet A; Qamar, Arman; Millar, John S; Rader, Daniel J

    2016-09-01

    Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk. PMID:27443326

  15. Multiple members of the plasminogen-apolipoprotein(a) gene family associated with thrombosis

    SciTech Connect

    Ichinose, Akitada )

    1992-03-31

    Plasminogen and apolipoprotein(a) (apo(a)) are closely related plasma proteins that are associated with hereditary thrombophilia. Low plasminogen levels are found in some patients who developed venous thrombosis, while a population with high plasma concentrations of apo(a) have a higher incidence of arterial thrombosis. Two different gene coding for human apo(a) have been isolated and characterized in order to study and compare these genes with four other closely related genes in the plasminogen-apo(a) gene family. These include the gene coding for plasminogen, two unique plasminogen-related genes, and a gene coding for hepatocyte growth factor. Nucleotide sequence analysis of these genes revealed that the exons and their boundaries of these genes for plasminogen and apo(a), and the plasminogen-related genes, differ only 1-5% in sequence. The types of exon/intron junctions and positions of introns in the molecules are also exactly identical, suggesting that these genes have evolved from an ancestral plasminogen gene via duplication and exon shuffling. By utilizing these results, gene-specific probes have been designed for the analysis of each of the genes in this gene family. The plasminogen and two apo(a) genes were all localized to chromosome 6 by employing the gene-specific primers and genomic DNAs from human-hamster cell hybrids. These data also make it possible to characterize the apo(a) and plasminogen genes in individuals by in vitro amplification.

  16. Under-Threes&apos; Mathematical Learning--Teachers&apos; Perspectives

    ERIC Educational Resources Information Center

    Franzén, Karin

    2014-01-01

    This project highlights preschool teachers&apos; views of toddlers&apos; learning in mathematics. The Swedish national curriculum covers even the youngest children who are 1-3?years old. Interesting questions are thus: what should mathematics be for this age group and how should preschool teachers work with maths to achieve the curriculum…

  17. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.

    PubMed

    Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping; Ramms, Bastian; Lew, Irene; Gonzales, Jon C; Thacker, Bryan E; Basu, Debapriya; Lee, Richard G; Mullick, Adam E; Graham, Mark J; Goldberg, Ira J; Crooke, Rosanne M; Witztum, Joseph L; Esko, Jeffrey D

    2016-08-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis. PMID:27400128

  18. Novel mutations of APOB cause ApoB truncations undetectable in plasma and familial hypobetalipoproteinemia.

    PubMed

    Yue, Pin; Yuan, Bo; Gerhard, Daniela S; Neuman, Rosalind J; Isley, William L; Harris, William S; Schonfeld, Gustav

    2002-08-01

    Familial hypobetalipoproteinemia (FHBL) is a genetic disorder characterized by low levels of apoB-100 and LDL cholesterol. Truncation-producing mutations of apoB (chromosome 2) are among several potential causes of FHBL in patients. Ten new families with FHBL linked to chromosome 2 were identified. In Family 8, a 4432delT in exon 26 produces a frame-shift and a premature stop codon predicted to produce a truncated apoB-30.9. Even though this truncation is just 10 amino acid shorter than the well-documented apoB-31, which is readily detectable in plasma, apoB-30.9 is undetectable. Most truncations shorter than apoB-30 are not detectable in plasma. In Family 34, an acceptor splicing mutation at position -1 of exon 14 changes the acceptor splice site AG to AA. Two families (Family 50 and 52) had mutations (apoB-9 and apoB-29) reported previously. In Family 98, a novel point mutation in exon 26 (11163T>G) causes a premature stop codon, and produces a truncated apoB-80.5 readily detectable in plasma. Sequencing of the ApoB gene in families 1, 5, 18, 58, and 59 did not reveal mutations. PMID:12124991

  19. Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes.

    PubMed

    Roman, Corina; Fuior, Elena V; Trusca, Violeta G; Kardassis, Dimitris; Simionescu, Maya; Gafencu, Anca V

    Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341-488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5'- and 3'-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. PMID:26519880

  20. 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…

  1. 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.

  2. A Systems View of the Differences between APOE ε4 Carriers and Non-carriers in Alzheimer’s Disease

    PubMed Central

    Jiang, Shan; Tang, Ling; Zhao, Na; Yang, Wanling; Qiu, Yu; Chen, Hong-Zhuan

    2016-01-01

    APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and accounts for 50–65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers’ module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson’s disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes

  3. A Systems View of the Differences between APOE ε4 Carriers and Non-carriers in Alzheimer's Disease.

    PubMed

    Jiang, Shan; Tang, Ling; Zhao, Na; Yang, Wanling; Qiu, Yu; Chen, Hong-Zhuan

    2016-01-01

    APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes, whereas AD

  4. 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. PMID:27065061

  5. Invasion of oral and aortic tissues by oral spirochete Treponema denticola in ApoE(-/-) mice causally links periodontal disease and atherosclerosis.

    PubMed

    Chukkapalli, Sasanka S; Rivera, Mercedes F; Velsko, Irina M; Lee, Ju-Youn; Chen, Hao; Zheng, Donghang; Bhattacharyya, Indraneel; Gangula, Pandu R; Lucas, Alexandra R; Kesavalu, Lakshmyya

    2014-05-01

    Treponema denticola is a predominantly subgingival oral spirochete closely associated with periodontal disease and has been detected in atherosclerosis. This study was designed to evaluate causative links between periodontal disease induced by chronic oral T. denticola infection and atherosclerosis in hyperlipidemic ApoE(-/-) mice. ApoE(-/-) mice (n = 24) were orally infected with T. denticola ATCC 35404 and were euthanized after 12 and 24 weeks. T. denticola genomic DNA was detected in oral plaque samples, indicating colonization of the oral cavity. Infection elicited significantly (P = 0.0172) higher IgG antibody levels and enhanced intrabony defects than sham infection. T. denticola-infected mice had higher levels of horizontal alveolar bone resorption than sham-infected mice and an associated significant increase in aortic plaque area (P ≤ 0.05). Increased atherosclerotic plaque correlated with reduced serum nitric oxide (NO) levels and increased serum-oxidized low-density lipoprotein (LDL) levels compared to those of sham-infected mice. T. denticola infection altered the expression of genes known to be involved in atherosclerotic development, including the leukocyte/endothelial cell adhesion gene (Thbs4), the connective tissue growth factor gene (Ctgf), and the selectin-E gene (Sele). Fluorescent in situ hybridization (FISH) revealed T. denticola clusters in both gingival and aortic tissue of infected mice. This is the first study examining the potential causative role of chronic T. denticola periodontal infection and vascular atherosclerosis in vivo in hyperlipidemic ApoE(-/-) mice. T. denticola is closely associated with periodontal disease and the rapid progression of atheroma in ApoE(-/-) mice. These studies confirm a causal link for active oral T. denticola infection with both atheroma and periodontal disease. PMID:24566627

  6. Tenascin-C Deficiency in Apo E−/− Mouse Increases Eotaxin Levels: Implications for Atherosclerosis

    PubMed Central

    Wang, Lai; Shah, Prediman K.; Wang, Wei; Song, Lei; Yang, Mingjie; Sharifi, Behrooz G.

    2013-01-01

    Aim To investigate the potential role of inflammatory cytokines in apo E−/− mouse in response to deletion of Tenascin-C (TNC) gene. Methods and results We used antibody array and ELISA to compare the profile of circulating inflammatory cytokines in apo E−/− mice and apo E−/− TNC−/− double knockout mice. In addition, tissue culture studies were performed to investigate the activity of cells from each mouse genotype in vitro. Cytokine array analysis and subsequent ELISA showed that circulating eotaxin levels were selectively and markedly increased in response to TNC gene deletion in apo E−/− mice. In addition, considerable variation was noted in the circulating level of eotaxin among the control apo E−/− mouse group. Inbreeding of apo E−/− mice with high or low levels of plasma eotaxin showed that the level of eotaxin per se determines the extent of atherosclerosis in this mouse genotype. While endothelial cells from apo E−/− mice had low level of eotaxin expression, cells derived from apo E−/−TNC−/− mice expressed a high level of eotaxin. Transient transfection of eotaxin promoter-reporter constructs revealed that eotaxin expression is regulated at the transcriptional level by TNC. Histochemical analysis of aortic sections revealed the massive accumulation of mast cells in the adventitia of double KO mice lesions whereas no such accumulation was detected in the control group. Plasma from the apo E−/−TNC−/− mice markedly stimulated mast cell migration whereas plasma from the apo E−/− mice had no such effect. Conclusion These observations support the emerging hypothesis that TNC expression controls eotaxin level in apo E−/− mice and that this chemokine plays a key role in the development of atherosclerosis. PMID:23433402

  7. ApoE and Pulse Pressure Interactively Influence Level and Change in the Aging of Episodic Memory: Protective Effects Among ε2 Carriers

    PubMed Central

    McFall, G. Peggy; Wiebe, Sandra A.; Vergote, David; Westaway, David; Jhamandas, Jack; Bäckman, Lars; Dixon, Roger A.

    2014-01-01

    Objective We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. Method We assembled a sample of older adults (n=570, Baseline M age=71, Age range=53–95) and used latent growth modeling to test four research goals. Results First, the best fitting memory model was two single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles. Conclusions PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene. PMID:25436424

  8. 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

  9. Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice.

    PubMed

    Chukkapalli, Sasanka S; Velsko, Irina M; Rivera-Kweh, Mercedes F; Zheng, Donghang; Lucas, Alexandra R; Kesavalu, Lakshmyya

    2015-01-01

    Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal

  10. Genes and Gene Therapy

    MedlinePlus

    ... a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  11. Genes and Gene Therapy

    MedlinePlus

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  12. ApoA-I mimetics.

    PubMed

    Stoekenbroek, R M; Stroes, E S; Hovingh, G K

    2015-01-01

    A wealth of evidence indicates that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely related to the risk of cardiovascular disease (CVD). Consequently, HDL-C has been considered a target for therapy in order to reduce the residual CVD burden that remains significant, even after application of current state-of-the-art medical interventions. In recent years, however, a number of clinical trials of therapeutic strategies that increase HDL-C levels failed to show the anticipated beneficial effect on CVD outcomes. As a result, attention has begun to shift toward strategies to improve HDL functionality, rather than levels of HDL-C per se. ApoA-I, the major protein component of HDL, is considered to play an important role in many of the antiatherogenic functions of HDL, most notably reverse cholesterol transport (RCT), and several therapies have been developed to mimic apoA-I function, including administration of apoA-I, mutated variants of apoA-I, and apoA-I mimetic peptides. Based on the potential anti-inflammatory effects, apoA-I mimetics hold promise not only as anti-atherosclerotic therapy but also in other therapeutic areas. PMID:25523005

  13. 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

  14. Sterol-dependent nuclear import of ORP1S promotes LXR regulated trans-activation of apoE

    SciTech Connect

    Lee, Sungsoo; Wang, Ping-Yuan; Jeong, Yangsik; Mangelsdorf, David J.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041 ; Anderson, Richard G.W.; Michaely, Peter

    2012-10-01

    Oxysterol binding protein related protein 1S (ORP1S) is a member of a family of sterol transport proteins. Here we present evidence that ORP1S translocates from the cytoplasm to the nucleus in response to sterol binding. The sterols that best promote nuclear import of ORP1S also activate the liver X receptor (LXR) transcription factors and we show that ORP1S binds to LXRs, promotes binding of LXRs to LXR response elements (LXREs) and specifically enhances LXR-dependent transcription via the ME.1 and ME.2 enhancer elements of the apoE gene. We propose that ORP1S is a cytoplasmic sterol sensor, which transports sterols to the nucleus and promotes LXR-dependent gene transcription through select enhancer elements. -- Highlights: Black-Right-Pointing-Pointer ORP1S translocates to the nucleus in response to sterol binding. Black-Right-Pointing-Pointer The sterols that best promote nuclear import of ORP1S are LXR agonists. Black-Right-Pointing-Pointer ORP1S binds to LXRs, enhances binding of LXRs to LXREs and promotes LXR-dependent transcription of apoE.

  15. Using ApoE Genotyping to Promote Healthy Lifestyles in Finland - Psychological Impacts: Randomized Controlled Trial.

    PubMed

    Hietaranta-Luoma, H-L; Luomala, H T; Puolijoki, H; Hopia, A

    2015-12-01

    Common health recommendations often incite very little public response, as people instead require individualized information. The purpose of this study was to assess the psychological effects of personal genetic information, provided by different apoE genotypes, as a tool to promote lifestyle changes. This study was a one-year intervention study using healthy adults, aged 20-67 years (n = 107). Their experiences of state anxiety, threat and stage of change were measured three times over a 12 months period. These psychological experiences were assessed, during the genetic information gathering, for three groups: a high-risk group (Ɛ4+, n = 16); a low-risk group (Ɛ4-, n = 35); and a control group (n = 56). The psychological effects of personal genetic risk information were shown to be short-term, although the levels of state anxiety and threat experiences in the high-risk group both remained at a slightly higher level than in the baseline. Threat experiences differed almost significantly (alpha = 0.017) between the Ɛ4+ and Ɛ4- groups (p = 0.034). Information on the apoE genotype impacted the experience of cardiovascular threat; this effect was most intense immediately after genetic feedback was received. However, fears of threat and anxiety may not be an obstacle for using gene information to motivate healthy, stable adults towards making lifestyle changes. Further studies should thus focus on how to utilize genetic screening in prevention of lifestyle-related diseases. PMID:25735442

  16. 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

  17. 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

  18. Homozygous familial hypobetalipoproteinemia. Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, apo B-87Padova.

    PubMed

    Gabelli, C; Bilato, C; Martini, S; Tennyson, G E; Zech, L A; Corsini, A; Albanese, M; Brewer, H B; Crepaldi, G; Baggio, G

    1996-09-01

    Mutations on the apolipoprotein (apo) B gene that interfere with the full-length translation of the apoB molecule are associated with familial hypobetalipoproteinemia (FHBL), a disease characterized by the reduction of plasma apoB and LDL cholesterol. In this report, we describe an FHBL kindred carrying a unique truncated apoB form, apoB-87Padova. Sequence analysis of amplified genomic DNA identified a single G deletion at nucleotide 12032, which shifts the translation reading frame and causes a termination at amino acid 3978. Two homozygous subjects and seven heterozygous relatives were studied. Although homozygous individuals had only trace amounts of LDL, they were virtually free from the symptoms typical of homozygous FHBL subjects. We investigated the in vivo turnover of radiolabeled normal apoB-100 LDL and apoB-87 LDL in one homozygous patient and two normal control subjects. ApoB-87 LDL showed a similar metabolism in all three subjects, with a fractional catabolic rate more than double that of normal LDL. The rate of entry of apoB-87 in the LDL compartment was also markedly decreased compared with normal apoB-100. The increased in vivo catabolism of apoB-87 LDL was paralleled in vitro by a 2.5-fold increased ability of these particles to inhibit the uptake and degradation of normal apoB-100 LDL by normal human cultured fibroblasts. These results indicate that apoB-87 LDL has an enhanced ability to interact with the LDL receptor, the increased apoB catabolism contributes to the hypobetalipoproteinemia and may explain the mild expression of the disease in the two homozygous individuals. PMID:8792774

  19. Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

    SciTech Connect

    Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya; Gafencu, Anca V.

    2015-05-29

    The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metformin up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition.

  20. No differences in hippocampal volume between carriers and non-carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents.

    PubMed

    Khan, Wasim; Giampietro, Vincent; Ginestet, Cedric; Dell'Acqua, Flavio; Bouls, David; Newhouse, Steven; Dobson, Richard; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun L W; Büchel, Christian; Conrod, Patricia; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Anreas; Ittermann, Bernd; Lemaître, Hervé; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Smolka, Michael N; Ströhle, Andreas; Gallinat, Jean; Westman, Eric; Schumann, Gunther; Lovestone, Simon; Simmons, Andrew

    2014-01-01

    Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life. PMID:24326516

  1. Prevalence of the ApoE Arg145Cys Dyslipidemia At-risk Polymorphism in African-derived Populations

    PubMed Central

    Abou Ziki, Maen D.; Strulovici-Barel, Yael; Hackett, Neil R.; Rodriguez-Flores, Juan L.; Mezey, Jason G.; Salit, Jacqueline; Radisch, Sharon; Hollmann, Charleen; Chouchane, Lotfi; Malek, Joel; Zirie, Mahmoud A.; Jayyuosi, Amin; Gotto, Antonio M.; Crystal, Ronald G.

    2013-01-01

    Apolipoprotein E (ApoE), a protein component of blood lipid particles, plays an important role in lipid transport. Different mutations in the ApoE gene have been associated with various clinical phenotypes. In an initiated study of Qataris, we observed that 17% of the African-derived genetic subgroup were heterozygotes for a rare Arg145Cys (R145C) variant that functions as a dominant trait with incomplete penetrance associated with type III hyperlipoproteinemia. Based on this observation, we hypothesized that the R145C polymorphism may be common in African-derived populations. The prevalence of the R145C variant was assessed worldwide in the 1000 Genomes Project (1000G) and in 1012 Caucasians and 1226 African-Americans in New York City. The 1000G data demonstrated that the R145C polymorphism is rare in non-African derived populations, but present in 5–12% of sub-Saharan African-derived populations. The R145C polymorphism was also rare in New York City Caucasians (1/1012, 0.1%), but strikingly, 53 (4.3%) of 1226 New York City African-Americans were R145C heterozygotes. Lipid profiles of the Qatari and New York R145C were compared to controls. Qatari R145C had higher triglyceride levels compared to Qatari controls (p<0.007) and NY African-Americans R145C had an average of 52% higher fasting triglyceride levels compared to NY African-American controls (p<0.002). Based on these observations, there are likely millions of people worldwide derived from Sub-Saharan Africans that are ApoE R145C. In conclusion, while larger epidemiologic studies are necessary to determine the long-term consequences of this polymorphism, the available evidence suggests it is a common cause of a mild triglyceride dyslipidemia. PMID:24239320

  2. Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides.

    PubMed

    Hinrich, Anthony J; Jodelka, Francine M; Chang, Jennifer L; Brutman, Daniella; Bruno, Angela M; Briggs, Clark A; James, Bryan D; Stutzmann, Grace E; Bennett, David A; Miller, Steven A; Rigo, Frank; Marr, Robert A; Hastings, Michelle L

    2016-01-01

    Apolipoprotein E receptor 2 (ApoER2) is an apolipoprotein E receptor involved in long-term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for the receptor in the disease is not clear. ApoER2 signaling requires amino acids encoded by alternatively spliced exon 19. Here, we report that the balance of ApoER2 exon 19 splicing is deregulated in postmortem brain tissue from AD patients and in a transgenic mouse model of AD To test the role of deregulated ApoER2 splicing in AD, we designed an antisense oligonucleotide (ASO) that increases exon 19 splicing. Treatment of AD mice with a single dose of ASO corrected ApoER2 splicing for up to 6 months and improved synaptic function and learning and memory. These results reveal an association between ApoER2 isoform expression and AD, and provide preclinical evidence for the utility of ASOs as a therapeutic approach to mitigate Alzheimer's disease symptoms by improving ApoER2 exon 19 splicing. PMID:26902204

  3. Principals&apos; Views on Teachers&apos; Professional Development

    ERIC Educational Resources Information Center

    Nabhani, Mona; Nicolas, Maureen O'Day; Bahous, Rima

    2014-01-01

    This article is an account of a study that aimed to elicit the perceptions of school principals and middle managers in Lebanon on teachers&apos; professional development (PD) and to promote an understanding of PD that extends beyond workshops. The study was qualitative and exploratory and used online interviewing to collect data. Questions were…

  4. Relationship between Principals&apos; Sense of Achievement and Teachers&apos; Perceptions of Their Principals&apos; Leadership Behaviors

    ERIC Educational Resources Information Center

    Siddiqi, Javaid Edward

    2012-01-01

    The purpose of the study was to examine the relationship between principals&apos; sense of achievement and teachers&apos; perceptions of their principals&apos; leadership behaviors. This was determined by examining job satisfaction of principals and leadership style using the Minnesota Satisfaction Questionnaire (MSQ) and the School…

  5. The effects of apoA-I/C-III/A-IV, apoE and apoB polymorphisms on carotid artery intima-media thickness.

    PubMed

    Nieminen, Tuomo; Kähönen, Mika; Lehtimäki, Terho

    2006-03-01

    Different apolipoprotein combinations explain most of the functional differences between plasma lipoproteins. This emphasizes the pivotal role of apolipoproteins in the homeostasis and physiological control of lipid metabolism. Genetic polymorphisms of apolipoprotein (apo)A-I/C-III/A-IV, apoE and apoB have been suggested to modulate plasma lipid levels as well as the risk of coronary artery disease and stroke. Carotid artery intima-media thickness has been shown to represent preclinical atherosclerosis and has, therefore, been used as a surrogate in quantifying the early stages of atherosclerosis. The effects of the polymorphisms in apoA-I/C-III/A-IV and apoB on carotid intima-media thickness are poorly known. The corresponding influence of apoE polymorphisms has been studied more extensively, but the results are not yet conclusive. In this review, these results are presented in detail and the potential reasons and mechanisms for the discrepancies are discussed. PMID:19804074

  6. Krüppel-like factor 4 synergizes with CREB to increase the activity of apolipoprotein E gene promoter in macrophages.

    PubMed

    Stavri, Simona; Simionescu, Maya; Kardassis, Dimitris; Gafencu, Anca V

    Krüppel-like factor 4 (KLF4) is a critical regulator of monocyte differentiation and macrophage polarization, and it also plays an important role in several vascular diseases, including atherosclerosis. Apolipoprotein E (apoE) is an essential anti-atherosclerotic glycoprotein involved in lipid metabolism, expressed by the liver, macrophages and other cell types. We hypothesized that KLF4 is involved in apoE gene regulation in macrophages. Our experiments showed that differentiation of THP-1 monocytes to macrophages using PMA was associated with a robust induction of both KLF4 and apoE genes. KLF4 bound to the apoE promoter, as revealed by chromatin immunoprecipitation and DNA pull-down (DNAP) assays, and transactivated the apoE promoter in a dose-dependent manner. Using a series of apoE promoter deletion mutants we revealed the biological activity of multiple KLF4 binding sites located in the [-500/-100] region of apoE promoter. Moreover, overexpression of cAMP-response-element-binding protein (CREB) further increased KLF4 up-regulatory effect on apoE promoter. Despite the fact that no putative CREB binding sites were predicted in silico, we found that in macrophages CREB bound to apoE proximal promoter in the region -200/+4 and even more strongly on -350/-274 region. In similar DNAP experiments using cell extracts obtained from monocytes (lacking KLF4), a very weak binding of CREB was detected, indicating that interaction of CREB with apoE promoter takes place indirectly. In conclusion our results show: (i) a robust synchronized induction of KLF4 and apoE expression during differentiation of monocytes to macrophages; (ii) KLF4 up-regulates apoE gene in a dose-dependent manner; (iii) biologically active KLF4 binding sites are present on apoE promoter and (iv) the interaction of KLF4 with CREB results in an enhanced up-regulatory effect of KLF4 on apoE promoter. Taken together these data provide novel knowledge on apoE gene regulation mechanism in macrophages

  7. Relationships between Educators&apos; Organizational Commitment, Job Satisfaction, and Administrators&apos; Gender

    ERIC Educational Resources Information Center

    Potter, Stephanie Litton

    2012-01-01

    The purpose of this quantitative, causal-comparative study was to examine the differences between teachers&apos; mean job satisfaction scores based on the administrators&apos; gender and examine the relationship between the administrators&apos; gender and teachers&apos; organizational commitment plans in Tennessee middle schools. Job satisfaction…

  8. 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…

  9. 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…

  10. ApoE and the role of very low density lipoproteins in adipose tissue inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our goal was too identify the role of triglyceride-rich lipoproteins and apoE, a major apolipoprotein in triglyceride-rich lipoproteins, in adipose tissue inflammation with high-fat diet induced obesity. Male apoE-/- and C57BL/6J wild-type mice fed high fat diets for 12 weeks were assessed for metab...

  11. Childrens&apos; Conceptions of Nature

    ERIC Educational Resources Information Center

    Payne, Phillip

    2014-01-01

    This paper describes a study of sixth grade children&apos;s conceptions of nature and the environment. In so doing, it asks that environmental educators pay more attention to children&apos;s preconceived notions of environment and nature. Should this occur the theory-practice gap in environmental education may be diminished. Learners&apos; concept…

  12. 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…

  13. Molecular cloning and expression characterization of ApoC-I in the orange-spotted grouper.

    PubMed

    Wang, Y; Zhou, L; Li, Z; Gui, J F

    2008-12-01

    Endogenous yolk nutrients are crucial for embryo and larval development in fish, but developmental behavior of the genes that control yolk utilization remains unknown. Apolipoproteins have been shown to play important roles in lipid transport and uptake through the circulation system. In this study, EcApoC-I, the first cloned ApoC-I in teleosts, has been screened from pituitary cDNA library of female orange-spotted grouper (Epinephelus coioides), and the deduced amino acid sequence shows 43.5% identity to one zebrafish (Danio rerio) hypothetical protein similar to ApoC-I, and 21.2%, 21.7%, 22.5%, 20%, and 22.5% identities to Apo C-I of human (Homo sapiens), house mouse (Mus musculus), common tree shrew (Tupaia glis), dog (Canis lupus familiaris) and hamadryas baboon (Papio hamadryas), respectively. Although the sequence identity is low, amphipathic alpha-helices with the potential to bind to lipid were predicted to exist in the EcApoC-I. RT-PCR analysis revealed that it was first transcribed in gastrula embryos and maintained a relatively stable expression level during the following embryogenesis. During embryonic and early larval development, a very high level of EcApoC-I expression was in the yolk syncytial layer, indicating that it plays a significant role in yolk degradation and transfers nutrition to the embryo and early larva. By the day 7 after hatching, EcApoC-I transcripts were observed in brain. In adult, EcApoC-I mRNA was detected abundantly in brain and gonad. In transitional gonads, the EcApoC-I expression is restricted to the germ cells. The data suggested that EcApoC-I might play an important role in brain and gonad morphogenesis and growth. PMID:18958591

  14. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

    PubMed Central

    IFERE, GODWIN O.; DESMOND, RENEE; DEMARK-WAHNEFRIED, WENDY; NAGY, TIM R.

    High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID:23934233

  15. Reduced Physiological Complexity in Robust Elderly Adults with the APOE ε4 Allele

    PubMed Central

    Hong, Chen-Jee; Yang, Albert C.

    2009-01-01

    Background It is unclear whether the loss of physiological complexity during the aging process is due to genetic variations. The APOE gene has been studied extensively in regard to its relationship with aging-associated medical illness. We hypothesize that diminished physiological complexity, as measured by heart rate variability, is influenced by polymorphisms in the APOE allele among elderly individuals. Methodology/Principal Findings A total of 102 robust, non-demented, elderly subjects with normal functions of daily activities participated in this study (97 males and 5 females, aged 79.2±4.4 years, range 72–92 years). Among these individuals, the following two APOE genotypes were represented: ε4 non-carriers (n = 87, 85.3%) and ε4 carriers (n = 15, 14.7%). Multi-scale entropy (MSE), an analysis used in quantifying complexity for nonlinear time series, was employed to analyze heart-rate dynamics. Reduced physiological complexity, as measured by MSE, was significantly associated with the presence of the APOE ε4 allele in healthy elderly subjects, as compared to APOE ε4 allele non-carriers (24.6±5.5 versus 28.9±5.2, F = 9.429, p = 0.003, respectively). Conclusions/Significance This finding suggests a role for the APOE gene in the diminished physiological complexity seen in elderly populations. PMID:19890394

  16. Alterations in the hepatic transcriptional landscape after RNAi mediated ApoB silencing in cynomolgus monkeys.

    PubMed

    Hamza, M Sabry; Kumar, Chanchal; Chia, Ser Mien; Anandalakshmi, Vidhya; Boo, Nicole; Strapps, Walter; Robinson, Michael; Caguyong, Michelle; Bartz, Steven; Tadin-Strapps, Marija; van Gool, Alain; Shih, Shian-Jiun

    2015-10-01

    The greater genomic conservation between humans and non-human primates (NHP) enables target validation studies for developing of therapeutic strategies for human diseases. Together with predicting activity and potential adverse clinical signs, the inclusion of NHP testing bequeaths to efficacy models for dose titration and pharmacodynamic effects. We have used lipid nanoparticle encapsulated siRNA to silence ApoB in the liver and assessed the phenotypic effects on serum lipids with various levels of hepatic ApoB mRNA knockdown in healthy lean cynomolgus monkeys. ApoB siRNA dosed animals demonstrated significant reductions of hepatic ApoB mRNA and serum APOB protein, with a substantial lowering of plasma lipid levels without obvious signs of toxicity. Microarray based assessment of ApoB siRNA mediated effects revealed a number of differentially expressed genes which mapped onto biological pathways and processes related to lipid and cholesterol metabolism. Furthermore, we identified potential targets and cellular effects that could be studied for therapeutic benchmarking of APOB mediated effects. The network of ApoB regulated genes should be of significance for the understanding and development of novel hypercholesterolemia therapies. PMID:26275376

  17. Inflammatory Stress Sensitizes the Liver to Atorvastatin-Induced Injury in ApoE-/- Mice

    PubMed Central

    Wu, Wei; Zhao, Lei; Yang, Ping; Zhou, Wei; Li, Beibei; Moorhead, John F.; Varghese, Zac; Ruan, Xiong Z.; Chen, Yaxi

    2016-01-01

    Statins, which are revolutionized cholesterol-lowing agents, have been reported to have unfavorable effects on the liver. Inflammatory stress is a susceptibility factor for drug-induced liver injury. This study investigated whether inflammatory stress sensitized the liver to statin-induced toxicity in mice and explored the underlying mechanisms. We used casein injection in ApoE-/- mice to induce inflammatory stress. Half of the mice were orally administered atorvastatin (10mg/kg/d) for 8 weeks. The results showed that casein injection increased the levels of serum pro-inflammatory cytokines (IL-6 and TNFα). Atorvastatin treatment increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in casein injection mice. Moreover, atorvastatin treatment exacerbated hepatic steatosis, inflammation and fibrosis, as well as increased hepatic reactive oxygen species (ROS) and malondialdehyde in casein injection mice. However, above changes were not observed in atorvastatin treated alone mice. The protein expression of liver nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expressions of Nrf2 target genes were increased, together with the enhancement of activities of hepatic catalase and superoxide dismutase in atorvastatin treated alone mice, but these antioxidant responses were lost in mice treated with atorvastatin under inflammatory stress. This study demonstrates that atorvastatin exacerbates the liver injury under inflammatory stress, which may be associated with the loss of adaptive antioxidant response mediated by Nrf2. PMID:27428373

  18. Inflammatory Stress Sensitizes the Liver to Atorvastatin-Induced Injury in ApoE-/- Mice.

    PubMed

    Wu, Wei; Zhao, Lei; Yang, Ping; Zhou, Wei; Li, Beibei; Moorhead, John F; Varghese, Zac; Ruan, Xiong Z; Chen, Yaxi

    2016-01-01

    Statins, which are revolutionized cholesterol-lowing agents, have been reported to have unfavorable effects on the liver. Inflammatory stress is a susceptibility factor for drug-induced liver injury. This study investigated whether inflammatory stress sensitized the liver to statin-induced toxicity in mice and explored the underlying mechanisms. We used casein injection in ApoE-/- mice to induce inflammatory stress. Half of the mice were orally administered atorvastatin (10mg/kg/d) for 8 weeks. The results showed that casein injection increased the levels of serum pro-inflammatory cytokines (IL-6 and TNFα). Atorvastatin treatment increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in casein injection mice. Moreover, atorvastatin treatment exacerbated hepatic steatosis, inflammation and fibrosis, as well as increased hepatic reactive oxygen species (ROS) and malondialdehyde in casein injection mice. However, above changes were not observed in atorvastatin treated alone mice. The protein expression of liver nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expressions of Nrf2 target genes were increased, together with the enhancement of activities of hepatic catalase and superoxide dismutase in atorvastatin treated alone mice, but these antioxidant responses were lost in mice treated with atorvastatin under inflammatory stress. This study demonstrates that atorvastatin exacerbates the liver injury under inflammatory stress, which may be associated with the loss of adaptive antioxidant response mediated by Nrf2. PMID:27428373

  19. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

    PubMed

    Wintjens, René; Bozon, Dominique; Belabbas, Khaldia; MBou, Félicien; Girardet, Jean-Philippe; Tounian, Patrick; Jolly, Mathilde; Boccara, Franck; Cohen, Ariel; Karsenty, Alexandra; Dubern, Béatrice; Carel, Jean-Claude; Azar-Kolakez, Ahlam; Feillet, François; Labarthe, François; Gorsky, Anne-Marie Colin; Horovitz, Alice; Tamarindi, Catherine; Kieffer, Pierre; Lienhardt, Anne; Lascols, Olivier; Di Filippo, Mathilde; Dufernez, Fabienne

    2016-03-01

    Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function. PMID:26802169

  20. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

    PubMed

    Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J; Smith, Conor; LaDu, Mary Jo; Sullivan, Patrick M; Morgan, Todd E; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olof; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E

    2016-01-01

    The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. PMID:26686669

  1. Association of APOE Genotype with Bone Mineral Density in Men and Women: The Dong-gu and Namwon Studies.

    PubMed

    Kim, Sun A; Kweon, Sun-Seog; Choi, Jin-Su; Rhee, Jung-Ae; Lee, Young-Hoon; Nam, Hae-Sung; Jeong, Seul-Ki; Park, Kyeong-Soo; Ryu, So-Yeon; Choi, Seong-Woo; Kim, Hee Nam; Song, Hye-Rim; Oh, Su-Hyun; Cauley, Jane A; Shin, Min-Ho

    2016-01-01

    Many studies have investigated relationships between APOE genotype and bone mineral density (BMD). However, the results of these studies have been inconsistent. Few studies have been carried out in Asian populations. We studied the relationship of the APOE gene polymorphism and BMD in two large population-based studies. The datasets included the Dong-gu Study (3575 men and 5335 women) and the Namwon Study (2310 men, 3512 women). Lumbar spine and femoral neck BMD were measured by dual-energy X-ray absorptiometry. APOE genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The APOE genotypes were classified into APOE E2 (E2/E2 and E2/E3), APOE E3 (E3/E3), and APOE E4 (E3/E4 and E4/E4). The genotype distribution of the study population was in Hardy-Weinberg equilibrium. There were no significant differences among APOE genotype groups in lumbar and femoral neck BMD in either cohort. Our data do not support the hypothesis that the APOE genotype is associated with BMD. PMID:26866001

  2. Gene-Environment Correlation Underlying the Association between Parental Negativity and Adolescent Externalizing Problems

    ERIC Educational Resources Information Center

    Marceau, Kristine; Horwitz, Briana N.; Narusyte, Jurgita; Ganiban, Jody M.; Spotts, Erica L.; Reiss, David; Neiderhiser, Jenae M.

    2013-01-01

    Studies of adolescent or parent-based twins suggest that gene-environment correlation (rGE) is an important mechanism underlying parent-adolescent relationships. However, information on how parents&apos; and children&apos;s genes and environments influence correlated parent "and" child behaviors is needed to distinguish types of rGE. The…

  3. APOE, MAPT, SNCA, and Cognitive Performance in Parkinson Disease

    PubMed Central

    Mata, Ignacio F.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Hurtig, Howard I.; Van Deerlin, Vivianna M.; Ritz, Beate; Rausch, Rebecca; Rhodes, Shannon L; Factor, Stewart A.; Wood-Siverio, Cathy; Quinn, Joseph F.; Chung, Kathryn A.; Peterson, Amie L.; Espay, Alberto J.; Revilla, Fredy J.; Devoto, Johnna; Hu, Shu-Ching; Cholerton, Brenna A.; Wan, Jia Y.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.

    2014-01-01

    Importance Cognitive impairment (CI) is a common and disabling problem in Parkinson’s disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important non-motor feature. Objectives To determine if common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD. Design, Setting and Participants We studied 1,079 PD patients from six academic centers in the U.S. who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention/executive function (Letter-Number Sequencing and Trail Making Test), language processing (semantic and phonemic verbal fluency), visuospatial skills (Benton Judgment of Line Orientation) and global cognitive function (Montreal Cognitive Assessment [MoCA]). Subjects were genotyped for APOE ε2/ε3/ε4, MAPT H1/H2 haplotypes, and SNCA rs356219. Linear regression was used to test for association between genotype and baseline cognitive performance adjusting for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the nine comparisons that were performed for each gene. Main Outcomes and Measures Nine variables derived from seven psychometric tests. Results APOE ε4 was associated with lower performance on HVLT-R total learning (P=6.7×10−6; corrected P [Pc]=6.0×10−5), delayed recall (P=0.001; Pc=0.009), and recognition discrimination index (P=0.004; Pc=0.04), and semantic verbal fluency (P=0.002; Pc=0.018), Letter-Number sequencing (P=1 × 10−5; Pc=9 × 10−5), and Trails B-A (P=0.002; Pc=0.018). In a subset of 645 non-demented patients, APOE ε4 was associated with lower scores on HVLT-R total learning (P=0.005; Pc=0.045) and semantic verbal fluency (P=0.005; Pc=0.045). MAPT and SNCA variants were not

  4. Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

    PubMed Central

    Cacabelos, Ramón; Fernández-Novoa, Lucía; Martínez-Bouza, Rocío; McKay, Adam; Carril, Juan C.; Lombardi, Valter; Corzo, Lola; Carrera, Iván; Tellado, Iván; Nebril, Laura; Alcaraz, Margarita; Rodríguez, Susana; Casas, Ángela; Couceiro, Verónica; Álvarez, Antón

    2010-01-01

    About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

  5. 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…

  6. The Socio-Economic Gradient in Children&apos;s Reading Skills and the Role of Genetics

    ERIC Educational Resources Information Center

    Jerrim, John; Vignoles, Anna; Lingam, Raghu; Friend, Angela

    2015-01-01

    By the time children leave primary school there is a large socio-economic gap in their reading proficiency. There are a number of potential explanations for this socio-economic gap and in this paper we investigate the role of three particular genes and gene-environment interactions in determining children&apos;s reading skills, using the Avon…

  7. Molecular cloning and characterization of the promoter region of the porcine apolipoprotein E gene.

    PubMed

    Xia, Jihan; Hu, Bingjun; Mu, Yulian; Xin, Leilei; Yang, Shulin; Li, Kui

    2014-05-01

    Apolipoprotein E (APOE), a component of lipoproteins plays an important role in the transport and metabolism of cholesterol, and is associated with hyperlipoproteinemia and Alzheimer's disease. In order to further understand the characterization of APOE gene, the promoter of APOE gene of Landrace pigs was analyzed in the present study. The genomic structure and amino acid sequence in pigs were analyzed and found to share high similarity in those of human but low similarity in promoter region. Real-time PCR revealed the APOE gene expression pattern of pigs in diverse tissues. The highest expression level was observed in liver, relatively low expression in other tissues, especially in stomach and muscle. Furthermore, the promoter expressing in Hepa 1-6 was significantly better at driving luciferase expression compared with C2C12 cell. After analysis of porcine APOE gene promoter regions, potential transcription factor binding sites were predicted and two GC signals, a TATA box were indicated. Results of promoter activity analysis indicated that one of potential regulatory elements was located in the region -669 to -259, which was essential for a high expression of the APOE gene. Promoter mutation and deletion analysis further suggested that the C/EBPA binding site within the APOE promoter was responsible for the regulation of APOE transcription. Electrophoretic mobility shift assays also showed the binding site of the transcription factor C/EBPA. This study advances our knowledge of the promoter of the porcine APOE gene. PMID:24464129

  8. The association-dissociation behavior of the ApoE proteins: kinetic and equilibrium studies

    PubMed Central

    Garai, Kanchan; Frieden, Carl

    2010-01-01

    The apolipoprotein E family consists of three major protein isoforms: apolipoprotein E4 (ApoE4), ApoE3 and ApoE2. The isoforms, which contain 299 residues, differ only by single amino acid changes but of the three only ApoE4 is a risk factor for Alzheimer’s Disease. At μM concentrations lipid-free ApoE exists predominantly as tetramers. In more dilute solutions, lower molecular weight species predominate. Using Fluorescence Correlation Spectroscopy (FCS), intermolecular Fluorescence Resonance Energy Transfer (FRET) and sedimentation methods we find that the association-dissociation reaction of ApoE can be modeled with a monomer-dimer-tetramer process. Equilibrium constants have been determined from the sedimentation data while the individual rate constants for association and dissociation are determined by measuring the kinetics of dissociation of ApoE and are in agreement with the equilibrium constants. Dissociation kinetics as measured by intermolecular FRET show two phases reflecting the dissociation of tetramer to dimer and of dimer to monomer with dissociation from tetramer to dimer being more rapid than the dimer to monomer dissociation. The rate constants differ for the different ApoE isoforms showing that the association-dissociation process is isoforms specific. Strikingly, the association rate constants are almost two orders of magnitude slower than expected for a diffusion controlled process. Dissociation kinetics were also monitored by tryptophan fluorescence in presence of acrylamide and the data found to be consistent with the monomer-dimer-tetramer model. The approach combining multiple methods establishes the reaction scheme of ApoE self-association. PMID:20923231

  9. Liver X receptor agonist downregulates hepatic apoM expression in vivo and in vitro

    SciTech Connect

    Zhang Xiaoying; Zhu Zhaojin; Luo Guanghua; Zheng Lu; Nilsson-Ehle, Peter; Xu Ning

    2008-06-20

    It has been demonstrated that apolipoprotein M (apoM), a recently discovered HDL apolipoprotein, has antiatherosclerotic properties, which may be mediated by the enhancement of reversed cholesterol transportation and/or hepatic cholesterol catabolism. The detailed mechanisms are unknown yet. Liver X receptor (LXR) belongs to the nuclear receptor superfamily and is a ligand-activated transcription factor involved in the regulation of lipid metabolism and inflammation. Activation of LXR in the cell cultures results in an enhancement of cholesterol efflux to apoAI. In the present study, we investigated effects of the LXR agonist, T0901317 on hepatic apoM expression in vivo and in vitro. Serum apoM levels in mice given T0901317 at 10 mg or 100 mg/kg for 7 days were reduced by 12-17% (P < 0.05). In HepG2 cell cultures, apoM mRNA levels were significantly lower in presence of 25 {mu}M T0901317 (37.1%) than in control cells (P < 0.001). A similar reduction was found by the addition of 9-cis retinoic acid (RA). Twenty-five micromolar T0901317 together with 100 nM RA decreased apoM mRNA expression by 65% (P < 0.001). Thus, the LXR agonist T0901317 significantly downregulates apoM mRNA expression in vivo and in vitro, which indicates that apoM is another novel target gene regulated by the LXR. The combination of RA and T0901317 showed additive effects, which suggests that apoM expression can be modulated by LXR/RXR pathway.

  10. Linguistic Challenges in Mendelian Genetics: Teachers&apos; Talk in Action

    ERIC Educational Resources Information Center

    Thörne, Karin; Gericke, Niklas M.; Hagberg, Mariana

    2013-01-01

    This study investigates Swedish teachers&apos; use of language when teaching Mendelian genetics in compulsory school. The primary objective of the study is to explore how teachers use the related concepts "gene," "allele," and "anlag" (a Swedish variant of the German word "anlage") and how these are related…

  11. Teaching Genetics in Secondary Classrooms: A Linguistic Analysis of Teachers&apos; Talk about Proteins

    ERIC Educational Resources Information Center

    Thörne, Karin; Gericke, Niklas

    2014-01-01

    This study investigates Swedish biology teachers&apos; inclusion of proteins when teaching genetics in grade nine (students 15-16 years old). For some years, there has been a call to give attention to proteins when teaching genetics as a means of linking the concepts "gene" and "trait". Students are known to have problems with…

  12. 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…

  13. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    PubMed Central

    Zhu, Zhu; Hua, Bingxuan; Shang, Zhanxian; Yuan, Gongsheng; Xu, Lirong; Li, Ermin; Li, Xiaobo; Yan, Zuoqin; Qian, Ruizhe

    2016-01-01

    Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

  14. Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a).

    PubMed

    Scipione, Corey A; Sayegh, Sera E; Romagnuolo, Rocco; Tsimikas, Sotirios; Marcovina, Santica M; Boffa, Michael B; Koschinsky, Marlys L

    2015-12-01

    Elevated lipoprotein (a) [Lp(a)] levels are a causal risk factor for coronary heart disease. Accumulating evidence suggests that Lp(a) can stimulate cellular inflammatory responses through the kringle-containing apolipoprotein (a) [apo(a)] component. Here, we report that recombinant apo(a) containing 17 kringle (17K) IV domains elicits a dose-dependent increase in interleukin (IL)-8 mRNA and protein expression in THP-1 and U937 macrophages. This effect was blunted by mutation of the lysine binding site in apo(a) kringle IV type 10, which resulted in the loss of oxidized phospholipid (oxPL) on apo(a). Trypsin-digested 17K had the same stimulatory effect on IL-8 expression as intact apo(a), while enzymatic removal of oxPL from apo(a) significantly blunted this effect. Using siRNA to assess candidate receptors, we found that CD36 and TLR2 may play roles in apo(a)-mediated IL-8 stimulation. Downstream of these receptors, inhibitors of MAPKs, Jun N-terminal kinase and ERK1/2, abolished the effect of apo(a) on IL-8 gene expression. To assess the roles of downstream transcription factors, luciferase reporter gene experiments were conducted using an IL-8 promoter fragment. The apo(a)-induced expression of this reporter construct was eliminated by mutation of IL-8 promoter binding sites for either NF-κB or AP-1. Our results provide a mechanistic link between oxPL modification of apo(a) and stimulation of proinflammatory intracellular signaling pathways. PMID:26474593

  15. Renal ApoA-1 amyloidosis with Glu34Lys mutation and intra-amyloid lipid accumulation.

    PubMed

    Andeen, Nicole K; Lam, Daniel Y; de Boer, Ian H; Nicosia, Roberto F

    2014-12-01

    Apolipoprotein A-1 (ApoA-1) amyloidosis occurs as a nonhereditary condition in atherosclerotic plaques, but it can also manifest as a hereditary disorder caused by mutations of the APOA1 gene. Hereditary ApoA-1 amyloidosis presents with diverse organ involvement based on the position of the mutation. We describe a case of ApoA-1 amyloidosis with a Glu34Lys mutation; testicular, conjunctival, and renal involvement; and the notable finding of lipid deposition within the amyloid deposits. PMID:24925720

  16. Genome-wide screen for modulation of hepatic apolipoprotein A-I (ApoA-I) secretion.

    PubMed

    Miles, Rebecca R; Perry, William; Haas, Joseph V; Mosior, Marian K; N'Cho, Mathias; Wang, Jian W J; Yu, Peng; Calley, John; Yue, Yong; Carter, Quincy; Han, Bomie; Foxworthy, Patricia; Kowala, Mark C; Ryan, Timothy P; Solenberg, Patricia J; Michael, Laura F

    2013-03-01

    Control of plasma cholesterol levels is a major therapeutic strategy for management of coronary artery disease (CAD). Although reducing LDL cholesterol (LDL-c) levels decreases morbidity and mortality, this therapeutic intervention only translates into a 25-40% reduction in cardiovascular events. Epidemiological studies have shown that a high LDL-c level is not the only risk factor for CAD; low HDL cholesterol (HDL-c) is an independent risk factor for CAD. Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-c that mediates reverse cholesterol transport from tissues to the liver for excretion. Therefore, increasing ApoA-I levels is an attractive strategy for HDL-c elevation. Using genome-wide siRNA screening, targets that regulate hepatocyte ApoA-I secretion were identified through transfection of 21,789 siRNAs into hepatocytes whereby cell supernatants were assayed for ApoA-I. Approximately 800 genes were identified and triaged using a convergence of information, including genetic associations with HDL-c levels, tissue-specific gene expression, druggability assessments, and pathway analysis. Fifty-nine genes were selected for reconfirmation; 40 genes were confirmed. Here we describe the siRNA screening strategy, assay implementation and validation, data triaging, and example genes of interest. The genes of interest include known and novel genes encoding secreted enzymes, proteases, G-protein-coupled receptors, metabolic enzymes, ion transporters, and proteins of unknown function. Repression of farnesyltransferase (FNTA) by siRNA and the enzyme inhibitor manumycin A caused elevation of ApoA-I secretion from hepatocytes and from transgenic mice expressing hApoA-I and cholesterol ester transfer protein transgenes. In total, this work underscores the power of functional genetic assessment to identify new therapeutic targets. PMID:23322769

  17. 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…

  18. 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…

  19. Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer’s disease

    PubMed Central

    Caberlotto, Laura; Marchetti, Luca; Lauria, Mario; Scotti, Marco; Parolo, Silvia

    2016-01-01

    Among the genetic factors known to increase the risk of late onset Alzheimer’s diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer’s disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer’s disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer’s disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer’s disease. PMID:27585646

  20. Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer's disease.

    PubMed

    Caberlotto, Laura; Marchetti, Luca; Lauria, Mario; Scotti, Marco; Parolo, Silvia

    2016-01-01

    Among the genetic factors known to increase the risk of late onset Alzheimer's diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer's disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer's disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer's disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer's disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer's disease. PMID:27585646

  1. APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease

    PubMed Central

    Donix, Markus; Burggren, Alison C.; Scharf, Maria; Marschner, Kira; Suthana, Nanthia A.; Siddarth, Prabha; Krupa, Allison K.; Jones, Michael; Martin-Harris, Laurel; Ercoli, Linda M.; Miller, Karen J.; Werner, Annett; von Kummer, Rüdiger; Sauer, Cathrin; Small, Gary W.; Holthoff, Vjera A.; Bookheimer, Susan Y.

    2013-01-01

    Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology. PMID:24080518

  2. Influence of ApoB100 3′ hypervariable repeats on acute myocardial infarction

    PubMed Central

    Singh, Neha; Sinha, Nakul; Kumar, Sudeep; Pandey, Chandra M; Agrawal, Suraksha

    2014-01-01

    Background and objective The 3′ flanking region of apolipoprotein B (ApoB) 100 gene is known to contain short A+T-rich DNA sequences which are hypervariable in nature and called the variable number of tandem repeats (VNTRs). It results in different alleles of ApoB100. The present study extends the investigation of whether there is a correlation between the presence of these alleles and acute myocardial infarction (MI). Methods We examined ApoB genotypes in 230 acute MI patients and 300 healthy controls. PCR based genotyping was done for ApoB 3′ VNTRs. Results We recoded 3′ApoB-VNTR alleles through three- and five-allelic models based on different sizes and found that large repeats (>37) were significantly associated with acute MI (p<0.0001). These large repeats (>37) were also significantly associated with higher lipid levels in the MI group. Conclusion Patients with 3′ApoB-VNTR large repeats (>37) are more susceptible to acute MI development.

  3. Flaxseed Oil Containing α -Linolenic Acid Ester of Plant Sterol Improved Atherosclerosis in ApoE Deficient Mice.

    PubMed

    Han, Hao; Yan, Peipei; Chen, Li; Luo, Cheng; Gao, Hui; Deng, Qianchun; Zheng, Mingming; Shi, Yong; Liu, Liegang

    2015-01-01

    Plant sterols (PS) have potential preventive function in atherosclerosis due to their cholesterol-lowering ability. Dietary α-linolenic acid in flaxseed oil is associated with a reduction in cardiovascular events through its hypolipidemic and anti-inflammation properties. This study was designed to evaluate the effects of flaxseed oil containing α-linolenic acid ester of PS (ALA-PS) on atherosclerosis and investigate the underlying mechanisms. C57BL/6 mice were administered a regular diet and apoE knockout (apoE-KO) mice were given a high fat diet alone or supplemented with 5% flaxseed oil with or without 3.3% ALA-PS for 18 weeks. Results demonstrated that flaxseed oil containing ALA-PS was synergistically interaction in ameliorating atherosclerosis as well as optimizing overall lipid levels, inhibiting inflammation and reducing oxidative stress. These data were associated with the modification effects on expression levels of genes involved in lipid metabolism (PPARα, HMGCR, and SREBPs), inflammation (IL-6, TNF, MCP-1, and VCAM-1), and oxidative stress (NADPH oxidase). PMID:26180602

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. 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…

  9. 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…

  10. 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…

  11. 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…

  12. Head Teachers&apos; Experiences of School Inspection under Ofsted&apos;s January 2012 Framework

    ERIC Educational Resources Information Center

    Courtney, Steven J.

    2013-01-01

    This article focuses on head teachers&apos; experiences of inspection under Ofsted&apos;s revised school inspection framework, their views of its principles and its implications for school leaders and leadership. The article draws on findings from a mixed-methods study to show that inspections are more focused on pupils&apos; attainment and…

  13. 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…

  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. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice

    PubMed Central

    Stein, Sokrates; Schäfer, Nicola; Breitenstein, Alexander; Besler, Christian; Winnik, Stephan; Lohmann, Christine; Heinrich, Kathrin; Brokopp, Chad E.; Handschin, Christoph; Landmesser, Ulf; Tanner, Felix C.; Lüscher, Thomas F.; Matter, Christian M.

    2010-01-01

    Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-κB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-κB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation. PMID:20606253

  16. 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…

  17. 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;…

  18. 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…

  19. Genes and gene regulation

    SciTech Connect

    MacLean, N.

    1988-01-01

    Genetics has long been a central topic for biologists, and recent progress has captured the public imagination as well. This book addresses questions that are at the leading edge of this continually advancing discipline. In tune with the increasing emphasis on molecular biology and genetic engineering, this text emphasizes the molecular aspects of gene expression, and the evolution of gene sequence organization and control. It reviews the genetic material of viruses, bacteria, and of higher organisms. Cells and organisms are compared in terms of gene numbers, their arrangements within a cell, and the control mechanisms which regulate the activity of genes.

  20. APOE2 Is Associated with Spatial Navigational Strategies and Increased Gray Matter in the Hippocampus.

    PubMed

    Konishi, Kyoko; Bhat, Venkat; Banner, Harrison; Poirier, Judes; Joober, Ridha; Bohbot, Véronique D

    2016-01-01

    The Apolipoprotein E (APOE) gene has a strong association with Alzheimer's disease (AD). The ε4 allele is a well-documented genetic risk factor of AD. In contrast, the ε2 allele of the APOE gene is known to be protective against AD. Much of the focus on the APOE gene has been on the ε4 allele in both young and older adults and few studies have looked into the cognitive and brain structure correlates of the ε2 allele, especially in young adults. In the current study, we investigated the relationship between APOE genotype, navigation behavior, and hippocampal gray matter in healthy young adults. One-hundred and twenty-four healthy young adults were genotyped and tested on the 4on8 virtual maze, a task that allows for the assessment of navigation strategy. The task assesses the spontaneous use of either a hippocampus-dependent spatial strategy or a caudate nucleus-dependent response strategy. Of the 124 participants, 37 underwent structural magnetic resonance imaging (MRI). We found that ε2 carriers use a hippocampus-dependent spatial strategy to a greater extent than ε3 homozygous individuals and ε4 carriers. We also found that APOE ε2 allele carriers have more gray matter in the hippocampus compared to ε3 homozygous individuals and ε4 carriers. Our findings suggest that the protective effects of the ε2 allele may, in part, be expressed through increased hippocampus gray matter and increased use of hippocampus-dependent spatial strategies. The current article demonstrates the relationship between brain structure, navigation behavior, and APOE genotypes in healthy young adults. PMID:27468260

  1. APOE2 Is Associated with Spatial Navigational Strategies and Increased Gray Matter in the Hippocampus

    PubMed Central

    Konishi, Kyoko; Bhat, Venkat; Banner, Harrison; Poirier, Judes; Joober, Ridha; Bohbot, Véronique D.

    2016-01-01

    The Apolipoprotein E (APOE) gene has a strong association with Alzheimer’s disease (AD). The ε4 allele is a well-documented genetic risk factor of AD. In contrast, the ε2 allele of the APOE gene is known to be protective against AD. Much of the focus on the APOE gene has been on the ε4 allele in both young and older adults and few studies have looked into the cognitive and brain structure correlates of the ε2 allele, especially in young adults. In the current study, we investigated the relationship between APOE genotype, navigation behavior, and hippocampal gray matter in healthy young adults. One-hundred and twenty-four healthy young adults were genotyped and tested on the 4on8 virtual maze, a task that allows for the assessment of navigation strategy. The task assesses the spontaneous use of either a hippocampus-dependent spatial strategy or a caudate nucleus-dependent response strategy. Of the 124 participants, 37 underwent structural magnetic resonance imaging (MRI). We found that ε2 carriers use a hippocampus-dependent spatial strategy to a greater extent than ε3 homozygous individuals and ε4 carriers. We also found that APOE ε2 allele carriers have more gray matter in the hippocampus compared to ε3 homozygous individuals and ε4 carriers. Our findings suggest that the protective effects of the ε2 allele may, in part, be expressed through increased hippocampus gray matter and increased use of hippocampus-dependent spatial strategies. The current article demonstrates the relationship between brain structure, navigation behavior, and APOE genotypes in healthy young adults. PMID:27468260

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. 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…

  9. 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…

  10. 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…

  11. Studying Genes

    MedlinePlus

    ... Area What are genes? Genes are sections of DNA that contain instructions for making the molecules—many ... material in an organism. This includes genes and DNA elements that control the activity of genes. Does ...

  12. 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.

  13. 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.

  14. Increased expression of ApoE and protection from amyloid-beta toxicity in transmitochondrial cybrids with haplogroup K mtDNA.

    PubMed

    Thaker, Kunal; Chwa, Marilyn; Atilano, Shari R; Coskun, Pinar; Cáceres-Del-Carpio, Javier; Udar, Nitin; Boyer, David S; Jazwinski, S Michal; Miceli, Michael V; Nesburn, Anthony B; Kuppermann, Baruch D; Kenney, M Cristina

    2016-09-01

    Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNP) patterns, represent populations of diverse geographic origins and have been associated with increased risk or protection of many diseases. The H haplogroup is the most common European haplogroup while the K haplogroup is highly associated with the Ashkenazi Jewish population. Transmitochondrial cybrids (cell lines with identical nuclei, but mtDNA from either H (n=8) or K (n=8) subjects) were analyzed by the Seahorse flux analyzer, quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry (IHC). Cybrids were treated with amyloid-β peptides and cell viabilities were measured. Other cybrids were demethylated with 5-aza-2'-deoxycytidine (5-aza-dC) and expression levels for APOE and NFkB2 were measured. Results show K cybrids have (a) significantly lower mtDNA copy numbers, (b) higher expression levels for MT-DNA encoded genes critical for oxidative phosphorylation, (c) lower Spare Respiratory Capacity, (d) increased expression of inhibitors of the complement pathway and important inflammasome-related genes; and (e) significantly higher levels of APOE transcription that were independent of methylation status. After exposure to amyloid-β1-42 peptides (active form), H haplogroup cybrids demonstrated decreased cell viability compared to those treated with amyloid-β42-1 (inactive form) (p<0.0001), while this was not observed in the K cybrids (p=0.2). K cybrids had significantly higher total global methylation levels and differences in expression levels for two acetylation genes and four methylation genes. Demethylation with 5-aza-dC altered expression levels for NFkB2, while APOE transcription patterns were unchanged. Our findings support the hypothesis that mtDNA-nuclear retrograde signaling may mediate expression levels of APOE, a key factor in many age-related diseases. Future studies will focus on identification of the mitochondrial-nuclear retrograde signaling

  15. 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

  16. The Apolipoprotein E Gene, Attention, and Brain Function

    PubMed Central

    Parasuraman, Raja; Greenwood, Pamela M.; Sunderland, Trey

    2005-01-01

    The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer’s disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE–attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ɛ4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection. PMID:11949718

  17. Regulation of the promoter of rat apolipoprotein A-I gene in cultured cells

    SciTech Connect

    Chao, Y.; Pan, T.; Wu, T.; Hao, Q.; Yamin, T.; Kroon, P.A.

    1987-05-01

    In order to study the regulation of the promoter of apolipoprotein (apo) A-I gene, they joined the 5' end of rat apo A-I gene (1.9 Kb) to the coding region of bacterial chloramphenicol acetyltransferase (CAT) gene. The chimeric gene produced high levels of CAT activity in both mouse L cells and Hep G2 cells in transient expression assays. Ethanol increased the levels of rat apo A-I promoter activity in both cells. However, dexamethasone increased rat apo A-I promoter activity only in Hep G2 cells. Similar results were obtained in stable expression cell lines. Nucleotide deletion experiments showed DNA sequences between -149 and -469 base pairs upstream from the rat apo A-I transcription site are required for the high level of expression and that the regulatory sequences are located further upstream. These data demonstrated that the 5' end of rat apo A-I gene contains sequences which are responsible for the regulation of apo A-I expression by ethanol and dexamethasone and that the expression and regulation of rat apo A-I promoter are cell specific.

  18. The effect of ApoE e4 on blood pressure in patients with and without depression

    PubMed Central

    Hestad, Knut A; Engedal, Knut; Whist, Jon Elling; Farup, Per G

    2016-01-01

    Introduction Depression is considered an independent risk factor for hypertension, particularly for people with recurrent episodes or a long history of depression. Another risk factor for cardiovascular disease is the Apolipoprotein E e4 allele (ApoE e4). The aim of this study was to examine how ApoE e4 was related to blood pressure (BP) in patients with depression and a control group. Methods A total of 78 patients, 49 with depression and 29 without, all recruited from the same hospital, underwent ApoE e genotyping (24 had at least one ApoE e4 allele) and examination of BP. Results In the depression group, but not in the control group, both systolic and diastolic BP were significantly higher in patients with ApoE e4 than in those without. The effect of ApoE e4 on BP differed significantly between the two groups. Conclusion Our findings showed that the effect of ApoE e4 on BP differed between the patients with depression and the control group. In patients with depression, ApoE e4 was associated with an increase in BP. We suggest that patients with depression and ApoE e4-positive status are particularly prone to develop BP elevation. PMID:27366067

  19. Cardioprotective role of vitamin D receptor in circulating endothelial cells of ApoE-deficient mice

    PubMed Central

    Ding, Yan; Liao, Wang; Yi, Zhuwen; Xiang, Wei; He, Xiaojie

    2015-01-01

    Atherosclerosis is the key course of coronary heart disease. In this study, we investigated the effect of vitamin D receptor on serum 1,25-(OH)2D levels, lipid profiles, nitric oxide expression, apoptosis-related gene Bcl-2, fas protein levels, in ApoE-deficient mice. The proliferation activity of VDR-RNAi transfected endothelial cells was decreased, the ability of apoptosis was increased, nitric oxide concentration was decreased and eNOS protein level was significantly reduced. VDR-RNAi induced lipid metabolism abnormality, reduced eNOS and ApoE levels, promoted lipid peroxidation, damaged the endothelial function and accelerated the process of atheroscleros. Together, our data presented a novel role for VDR in the pathogenesis process of atheroscleros by up regulating eNOS protein expression which could lay a solid foundation of VDR-specific activator treatment for coronary artery disease. PMID:26131079

  20. Mass spectrometry analysis reveals non-mutated ApoA1 lumbosacral radiculoplexus amyloidoma

    PubMed Central

    Loavenbruck, Adam J.; Chaudhry, Vinay; Zeldenrust, Steven R.; Spinner, Robert J.; Theis, Jason D.; Klein, Christopher J.

    2012-01-01

    Introduction Rarely, amyloidosis presents as a focal, macroscopic lesion involving peripheral neural tissues (amyloidoma). In all known reported cases, peripheral nerve amyloidomas have immunoglobulin light chain fibril composition and occurred in the context of paraproteinemia. Methods A 46 y.o. man presented with progressive insidious onset right lumbosacral radiculoplexus neuropathy without paraproteinemia. MRI-targeted fascicular nerve biopsy was performed on an enlarged sciatic nerve after earlier distal fibular nerve biopsy was nondiagnostic. Laser dissected mass spectroscopy of the discovered amyloid protein was performed after immunohistochemistry failed to identify the specific amyloid protein. Complete gene sequencing of ApoA1 was performed. Results Only wild type ApoA1 amyloid was found in the congophilic component in the nerve. Discussion The case highlights the utility of MRI guided fascicular nerve biopsy combined with laser dissected mass spectrometric analysis. Importantly, the case expands the known causes of amyloidomas to include wild type ApoA1. PMID:23055319

  1. Homocysteine and cognitive performance: modification by the ApoE genotype.

    PubMed

    Elias, Merrill F; Robbins, Michael A; Budge, Marc M; Elias, Penelope K; Dore, Gregory A; Brennan, Suzanne L; Johnston, Carole; Nagy, Zsuzsanna

    2008-01-01

    We hypothesized that the magnitude of the association between plasma homocysteine concentration and cognitive performance is larger for ApoE-epsilon4 carriers than for non-carriers. Nine hundred eleven dementia-free and stroke-free subjects (59% women) from the Maine-Syracuse study (26-98 years old) were stratified into no-ApoE-epsilon4 (n=667) and ApoE-epsilon4 carrier (n=244) cohorts. Employing a cross-sectional design and multiple regression analyses, plasma homocysteine was related to multiple domains of cognitive performance within these cohorts. When unadjusted, and with adjustment for age, education, gender, ethnicity, and previous cognitive examinations, homocysteine concentrations were inversely related to cognitive performance within both ApoE cohorts, with higher magnitude of associations within the ApoE-epsilon4 cohort. With adjustment for cardiovascular disease risk factors, cardiovascular disease, and B-vitamin concentrations, the higher magnitude of associations between plasma homocysteine and cognitive performance within the ApoE-epsilon4 cohort relative to the no-ApoE-epsilon4 cohort persisted; but associations of plasma homocysteine and cognitive performance were attenuated and no longer significant within the no-ApoE-epsilon4 cohort. Presence of the ApoE-epsilon4 allele modifies the relation between plasma homocysteine and cognitive performance. PMID:18023533

  2. Association between APOE polymorphism and metabolic syndrome in Uyghur ethnic men

    PubMed Central

    Sun, YuPing; Wei, Rong; Yan, DanDan; Xu, FeiLi; Zhang, XiaoJin; Zhang, Bei; Yimiti, Delixiati; LI, Hui; Sun, HongYan; Hu, Cheng; Luo, Li; Yao, Hua

    2016-01-01

    Objectives This study aimed to examine the association between apolipoprotein E (APOE) polymorphism and metabolic syndrome (MetS) among Uyghur ethnic men in Xinjiang, China. Participants A total of 482 patients with MetS and 510 healthy sex-matched and age-matched controls were recruited from the Xinjiang Uyghur Autonomous Region of China. The participants were subjected to routine physical and blood biochemical tests, and APOE genotyping was performed. Results The APOE ε3/3 was the predominant type, with a frequency of 71.8%, while ε2/2 was less common than ε4/4 in Uyghur males. The frequencies of the APOE2, E3 and E4 alleles in Uyghur males were 8.5%, 80.0% and 11.5%, respectively. However, the distribution of APOE genotypes was significantly different between the MetS and control groups (p<0.001). In the MetS group, the frequencies of the ε2 and ε4 alleles and the frequencies of the ε2/2, ε2/3 and ε2/4 genotypes were significantly lower than those of the control group. Those individuals without the ε2 and ε4 alleles had higher MetS prevalence than the other gene carriers, and the ORs of these individuals developing MetS were 1.5 and 1.27 compared to the gene carriers. Triglyceride, serum total cholesterol and low-density lipoprotein cholesterol levels were lower and serum high-density lipoprotein was higher in the ε2 carriers than the ε3 carriers, and the prevalence of MetS, central obesity, high blood pressure, hypercholesterolaemia and hypertriglyceridaemia was lower in the APOE2 group than in the APOE4 group. The risks of these individuals with ε4 allele carriers getting these changes were 1.327, 1.780, 1.888, 1.428 and 2.571 times greater than those of ε2 allele carriers. Conclusions APOE4 is associated with many individual components of MetS, whereas APOE2 was associated with a reduced risk of MetS at the univariate level in Uyghur ethnic men. PMID:26739741

  3. Actions of β-Apo-Carotenoids in Differentiating Cells: Differential Effects in P19 Cells and 3T3-L1 Adipocytes

    PubMed Central

    Wang, Cynthia X.; Jiang, Hongfeng; Yuen, Jason J.; Lee, Seung-Ah; Narayanasamy, Sureshbabu; Curley, Robert W.; Harrison, Earl H.; Blaner, William S.

    2015-01-01

    β-Apo-carotenoids, including β-apo-13-carotenone and β-apo-14′-carotenal, are potent retinoic acid receptor (RAR) antagonists in transactivation assays. We asked how these influence RAR-dependent processes in living cells. Initially, we explored the effects of β-apo-13-carotenone and β-apo-14′-carotenal on P19 cells, a mouse embryonal carcinoma cell line that differentiates into neurons when treated with all-trans-retinoic acid. Treatment of P19 cells with either compound failed to block all-trans-retinoic acid induced differentiation. Liquid chromatography tandem mass spectrometry studies, however, established that neither of these β-apo-carotenoids accumulates in P19 cells. All-trans-retinoic acid accumulated to high levels in P19 cells. This suggests that the uptake and metabolism of β-apo-carotenoids by some cells does not involve the same processes used for retinoids and that these may be cell type specific. We also investigated the effects of two β-apo-carotenoids on 3T3-L1 adipocyte marker gene expression during adipocyte differentiation. Treatment of 3T3-L1 adipocytes with either β-apo-13-carotenone or β-apo-10′-carotenoic acid, which lacks RAR antagonist activity, stimulated adipocyte marker gene expression. Neither blocked the inhibitory effects of a relatively large dose of exogenous all-trans-retinoic acid on adipocyte differentiation. Our data suggest that in addition to acting as transcriptional antagonists, some β-apo-carotenoids act through other mechanisms to influence 3T3-L1 adipocyte differentiation. PMID:25602703

  4. The Association between Apolipoprotein E Gene Polymorphism and Mild Cognitive Impairment among Different Ethnic Minority Groups in China

    PubMed Central

    Wang, ZhiZhong; Ma, Wanrui; Liu, Lan

    2014-01-01

    The association, in different ethnic groups, of apolipoprotein E (apoE) gene polymorphism with mild cognitive impairment (MCI) has been unclear. Few studies have examined the association in Chinese minorities. The current study explores the association between apoE gene polymorphism and MCI in one of the biggest ethnic groups—the Hui—and compares it with the Han. The Minimental State Exam, Activities of Daily Living Scale, and Geriatric Depression Scale were administered to 306 ethnic Hui and 618 ethnic Han people aged ≥55 years. ApoE genotypes were determined using the high resolution melting curve method. The distribution of the apoE genotype and the frequency of alleles ε2, ε3, and ε4 were similar in the Hui and Han groups. In analyses adjusted for age, gender, and education level, the ε4 allele was a risk factor for MCI in both the Hui group (OR = 2.61, 95% CI: 1.02–6.66) and the Han group (OR = 2.36, 95% CI: 1.19–4.67), but the apoE ε2 allele was protective for MCI only in the Han group (OR = 0.48, 95% CI: 0.38–0.88). The association of some apoE genotypes with MCI may differ in different ethnic groups in China. Further studies are needed to explore this effect among different populations. PMID:25161798

  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. Longitudinal change in working memory as a function of APOE genotype in midlife and old age.

    PubMed

    Greenwood, Pamela M; Espeseth, Thomas; Lin, Ming-Kuan; Reinvang, Ivar; Parasuraman, Raja

    2014-06-01

    Previous investigations into whether the APOE-ε4 allele exerts cognitive effects at midlife have been inconclusive. We have advanced a "cognitive phenotype" hypothesis arguing that the ε4 allele of the apolipoprotein E gene (APOE) is associated with lower efficiency of neuronal plasticity thereby resulting in poorer cognitive performance independently of the pathology of Alzheimer's disease (Greenwood et al., ). This hypothesis is best tested at midlife, prior to the neuron loss associated with AD diagnosis. This hypothesis predicts that the ε4 allele would alter cognition regardless of age through plasticity mechanisms, but would not induce longitudinal decline in midlife. The alternative "prodrome" hypothesis predicts that the APOE-ε4 allele would be associated with longitudinal cognitive decline as early as midlife due to prodromal effects of AD. We tested these hypotheses with a working memory task in a large cross-sectional sample of cognitively screened APOE-ε4 carriers and non-carriers and also in a small longitudinal sample over 3 years. The sample was divided into middle-aged (mean age 50, range 40-59) and older (mean age 69, range 60-84) individuals. Cross-sectionally, we observed that older, but not middle-aged, APOE-ε4 carriers had lower accuracy than ε4 non-carriers, mainly under the hardest discrimination condition. Longitudinally, we observed increases in accuracy in middle-aged APOE-ε4 carriers, suggesting a cognitive phenotype that includes ability to benefit from experience. We observed a longitudinal decrease in older APOE-ε4 carriers, suggesting an AD prodrome. PMID:24853824

  7. Abeta, tau and ApoE4 in Alzheimer's disease: the axonal connection.

    PubMed

    Adalbert, Robert; Gilley, Jonathan; Coleman, Michael P

    2007-04-01

    Mutations in amyloid precursor protein (APP), tau and apolipoprotein E4 (ApoE4) lead to Alzheimer's disease (AD) or related pathologies. Pathogenesis and interactions between these pathways have been studied in mouse models. Here, we highlight the fact that axons are important sites of cellular pathology in each pathway and propose that pathway convergence at the molecular level might occur in axons. Recent developments suggest that axonal transport of APP influences beta-amyloid deposition and that tau regulates axonal transport. ApoE4 influences both axonal tau phosphorylation and amyloid-induced neurite pathology. Thus, a better understanding of axonal events in AD might help connect the pathogenic mechanisms of beta-amyloid, ApoE4 and tau, indicating the most important steps for therapeutic targeting. PMID:17344096

  8. APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer's disease.

    PubMed

    Reinvang, Ivar; Espeseth, Thomas; Westlye, Lars Tjelta

    2013-09-01

    Individuals carrying the *E4 allele of the apolipoprotein E gene (APOE) are at increased risk of developing Alzheimer's disease (AD). However, the biological mechanisms underlying this association are still unclear because of the complexity of the pathological processes that cause AD. Furthermore, the effect of APOE genotype on development, maintenance and aging of the normal brain is poorly understood because of the strong bias toward studying disease associations. In vivo techniques such as neuroimaging and cognitive testing offer valuable insights into the effects of APOE genotype on brain structure and function in healthy and clinical populations. We review the evidence from in vivo studies that APOE *E4, in addition to increasing the chance of age-related pathological events, is associated with age-independent non-pathological changes in brain physiology, some of which make the brain less resilient to neurodegenerative processes. We argue that the interaction between the APOE-dependent non-pathological vulnerabilities and age-related pathological changes is one mechanism that can trigger neurodegeneration, resulting in AD and other complex phenotypes. PMID:23701948

  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. PMID:25857685

  10. Fundamentalism or Pluralism: Iranian Youth&apos;s Orientation

    ERIC Educational Resources Information Center

    Pasha, Nourollah; Ahmad, Zaid

    2014-01-01

    Islamic fundamentalism is an extreme perception of Islam that views "the &apos;Other&apos; as the enemy demonized" against the "West", which also views the Muslim "enemy within". In contrast, pluralism perceives &apos;others&apos; as different people, with different values from us. While the fundamentalist seeks to…

  11. 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…

  12. Apolipoprotein gene involved in lipid metabolism

    DOEpatents

    Rubin, Edward; Pennacchio, Len A.

    2007-07-03

    Methods and materials for studying the effects of a newly identified human gene, APOAV, and the corresponding mouse gene apoAV. The sequences of the genes are given, and transgenic animals which either contain the gene or have the endogenous gene knocked out are described. In addition, single nucleotide polymorphisms (SNPs) in the gene are described and characterized. It is demonstrated that certain SNPs are associated with diseases involving lipids and triglycerides and other metabolic diseases. These SNPs may be used alone or with SNPs from other genes to study individual risk factors. Methods for intervention in lipid diseases, including the screening of drugs to treat lipid-related or diabetic diseases are also disclosed.

  13. 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. PMID:26502169

  14. Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome.

    PubMed

    Cavani, S; Tamaoka, A; Moretti, A; Marinelli, L; Angelini, G; Di Stefano, S; Piombo, G; Cazzulo, V; Matsuno, S; Shoji, S; Furiya, Y; Zaccheo, D; Dagna-Bricarelli, F; Tabaton, M; Mori, H

    2000-11-27

    In Down syndrome (DS) brain an early, selective accumulation of amyloid beta (Abeta) peptides ending at residue 42 (Abeta42) occurs. Whether this event depends on an altered processing of amyloid beta precursor protein (APP) or on defective clearance is uncertain. To investigate this issue, we measured Abeta species 40 and 42 in plasma from 61 patients with DS, 77 age-matched normal controls, and 55 mentally retarded subjects without chromosomal abnormalities. The Abeta 40 and 42 plasma levels were then correlated with apolipoprotein E (apoE) genotypes in all groups of cases, and with I. Q. and Mini Mental Status Examination values in DS subjects. Both Abeta species were significantly elevated in DS compared to control groups, and the extent of their increase reflects that expected from APP gene overexpression. Plasma levels of Abeta 40 and 42 did not correlate with apoE genotypes in DS and control cases, and with the extent of mental retardation in DS subjects. The results indicate that accumulation and clearance of plasma and cerebral Abeta are regulated by different and independent factors. PMID:11102927

  15. 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…

  16. 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…

  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. A Quest for Legitimacy: On the Professionalization Policies of Sweden&apos;s Teachers&apos; Unions

    ERIC Educational Resources Information Center

    Lilja, Peter

    2014-01-01

    The aim of this article is to contribute to the ongoing discussion on teacher professionalism by analyzing the professional strategies of Sweden&apos;s two teachers&apos; unions from an organizational perspective. Drawing on institutional theory, the article argues that the teachers&apos; unions&apos; focus on strategies of professionalization has…

  19. 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…

  20. APOLIPOPROTEIN E GENE POLYMORPHISMS ARE NOT ASSOCIATED WITH DIABETIC RETINOPATHY: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE: Polymorphism of the apolipoprotein E (APOE) gene has been associated with dyslipidemia and cardiovascular disease. This study examines the association of APOE polymorphisms and diabetic retinopathy. DESIGN: Population-based cross-sectional study. METHODS: We studied 1,398 people aged 49 to ...

  1. Modulation of miRNA Expression by Dietary Polyphenols in apoE Deficient Mice: A New Mechanism of the Action of Polyphenols

    PubMed Central

    Milenkovic, Dragan; Deval, Christiane; Gouranton, Erwan; Landrier, Jean-François; Scalbert, Augustin; Morand, Christine; Mazur, Andrzej

    2012-01-01

    Background Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee or wine. Epidemiological, clinical and animal studies support a role of polyphenols in the prevention of various diseases, such as cardiovascular diseases, cancers or neurodegenerative diseases. Recent findings suggest that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. However, the impact of polyphenol on the expression of microRNA, small non-coding RNAs, has not yet been studied. The aim of this study was to investigate the impact of dietary supplementation with polyphenols at nutritional doses on miRNA expression in the livers of apolipoprotein E-deficient mice (apoE−/−) jointly with mRNA expression profiling. Methodology/Principal Findings Using microarrays, we measured the global miRNA expression in the livers of wild-type (C57B6/J) mice or apoE−/− mice fed diets supplemented with one of nine different polyphenols or a control diet. This analysis revealed that knock-out of the apoE gene induced significant modulation in the expression of miRNA. Moreover, changes in miRNA expression were observed after polyphenol supplementation, and five miRNAs (mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1*, mmu-miR-467b* and mmu-miR-374*) were identified as being commonly modulated by these polyphenols. We also observed that these polyphenols counteracted the modulation of miRNA expression induced by apoE mutation. Pathway analyses on these five miRNA-target genes revealed common pathways, some of which were also identified from a pathway analysis on mRNA profiles. Conclusion This in vivo study demonstrated for the first time that polyphenols at nutritional doses modulate the expression of miRNA in the liver. Even if structurally different, all polyphenols induced a similar miRNA expression profile

  2. Determinants of ApoB, ApoA1, and the ApoB/ApoA1 ratio in healthy schoolgirls, prospectively studied from mean ages 10 to 19 years: the Cincinnati National Growth and Health Study.

    PubMed

    Morrison, John A; Glueck, Charles J; Daniels, Stephen R; Horn, Paul S; Wang, Ping

    2012-10-01

    The objectives were to prospectively assess determinants of apolipoproteins B (ApoB), A1 (ApoA1), and the ApoB/ApoA1 ratio in 797 healthy black and white schoolgirls from mean ages 10 to 19. There was prospective 9-year follow-up, with measures of ApoB at mean ages 10, 12, 14, 16 and 19, ApoA1 at mean ages 12, 14, 16, and 19, and assessment of annual reports of delayed menstrual cyclicity (≥42 days) from ages 14 to 19. Studies of 402 black and 395 white healthy schoolgirls were done in public and private schools, in urban and suburban Cincinnati. Black girls had lower ApoB, higher ApoA1, and lower ApoB/ApoA1. SHBG at age 14 in white and black girls was inversely correlated with the ApoB/ApoA1. At age 19, ≥3 annual reports of menstrual delay ≥42 days and metabolic syndrome were associated with higher ApoB and a higher ApoB/ApoA1 ratio. From ages 14 to 19, BMI and TG were independently positively associated with ApoB. Menstrual cyclicity ≥42 days, metabolic syndrome, BMI, and TG were independently positively associated with ApoB/ApoA1 ratios, while black race was negatively associated. The atherogenic ApoB/ApoA1 ratio from ages 14 to 19 is lower in black girls, and positively associated with hyperandrogenism, menstrual cyclicity ≥42 days, BMI, TG, and the metabolic syndrome, facilitating an adolescent approach to primary prevention of cardiovascular disease. PMID:22512822

  3. Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients

    PubMed Central

    Lehmann, Manja; Ghosh, Pia M.; Madison, Cindee; Karydas, Anna; Coppola, Giovanni; O’Neil, James P.; Huang, Yadong; Miller, Bruce L.; Jagust, William J.; Rabinovici, Gil D.

    2013-01-01

    Background ApoE4 has been associated with an increased risk of Alzheimer’s disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients. Methods Fifty-two patients with probable AD (NIA-AA) underwent [11C]Pittsburgh compound B (PIB) and [18F]fluorodeoxyglucose (FDG) PET scans. All patients had positive PIB-PET scans. 23 were ApoE4+ (14 heterozygous, 9 homozygous) and 29 were ApoE4−. Groups consisted of language-variant AD, visual-variant AD, and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions-of-interest. Results Whilst PIB patterns were diffuse in both patient groups, ApoE4− patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4− patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex, and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4− patients showed greater hypometabolism in cortical areas including supplementary motor cortex and superior frontal gyrus. Conclusions ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared to matched ApoE4− patients. These findings suggest that ApoE4 may increase susceptibility

  4. 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.

  5. 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. PMID:26916531

  6. 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,…

  7. "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…

  8. 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…

  9. 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…

  10. 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…

  11. 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…

  12. 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…

  13. 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…

  14. 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…

  15. 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…

  16. 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…

  17. 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).

  18. 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…

  19. 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…

  20. 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…

  1. 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…

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  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. Let&apos;s Talk! ESL Students&apos; Needs and Writing Centre Philosophy

    ERIC Educational Resources Information Center

    Moussu, Lucie

    2013-01-01

    When university/college faculty members believe that ESL students&apos; writing skills are not equivalent to those of native speakers, they frequently send these ESL students to their institution&apos;s writing centres (WCs). However, this often results in frustration for WC staff, the students, and faculty members. This article first describes…

  8. The Relationship between Instructors&apos; Professional Competencies and University Students&apos; School Engagement

    ERIC Educational Resources Information Center

    Sahin, Mehmet

    2014-01-01

    This study was conducted to explore the relationship between university students&apos; school engagement and instructors&apos; professional competencies. The study group consisted of 314 students from the Faculty of Art at Çankiri Karatekin University. The participants filled in the Scale for Professional Competence of Instructor (SPCI) and the…

  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. 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…

  11. Tumor necrosis factor-alpha modulates monocyte/macrophage apoprotein E gene expression.

    PubMed Central

    Duan, H; Li, Z; Mazzone, T

    1995-01-01

    apo E has been shown to modulate cholesterol balance in arterial wall cells. Production of apo E by macrophages in atherosclerotic plaques could thereby influence the development of the plaque lesion. Cytokines, including TNF alpha, have been identified in human lesions, therefore, we undertook a series of studies to evaluate the effect of TNF alpha on monocyte/macrophage apo E production. The addition of TNF alpha to freshly isolated human monocytes led to a four- to fivefold increase of apo E mRNA abundance. The addition of TNF alpha to fully differentiated macrophages either had no effect or modestly inhibited apo E mRNA expression. THP1 human monocytic cells also responded to TNF alpha in a phenotype-specific manner. Treatment of these cells with TNF alpha produced a dose- and time-dependent increase in apo E mRNA. This increase was reflected in apo E synthesis and was associated with inhibition of DNA synthesis, and with induction of c-fos and ICAM-1 gene expression. Cell-permanent analogues of ceramide did not reproduce TNF alpha effect on apo E, but antagonists of protein kinase C did inhibit its effect. TNF alpha induction of apo E mRNA abundance was associated with stimulation of apo E promoter-dependent gene transcription. In summary, TNF alpha stimulates apo E gene transcription, mRNA abundance, and protein synthesis in the monocyte/macrophage in a phenotype-specific manner. Such regulation could significantly modify the amount of apo E present in vessel wall lesions. Images PMID:7635986

  12. 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

  13. 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

  14. Association between apolipoprotein E gene polymorphism and depression.

    PubMed

    Feng, Fang; Lu, Shan-Shan; Hu, Cai-Yun; Gong, Feng-Feng; Qian, Zhen-Zhong; Yang, Hui-Yun; Wu, Yi-Le; Zhao, Yuan-Yuan; Bi, Peng; Sun, Ye-Huan

    2015-08-01

    We performed an updated meta-analysis to obtain a more precise estimation of the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility to depression, as previous reports have been inconsistent. Twenty studies with 2286 depression patients and 3845 controls were included. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between ApoE gene polymorphism and depression using a random effects model. Results showed a significant association between ApoE gene polymorphism and susceptibility to depression in the overall population (ε2/ε3 genotype versus ε3/ε3: OR 0.76, 95% CI 0.59-0.99). Subgroup analyses indicated an association in the Caucasian population (ε2 allele versus ε3: OR 0.75, 95% CI 0.58-0.97) as well as in late-life depression (LLD) patients (ε3/ε4 genotype versus ε3/ε3: OR 1.34, 95% CI 1.07-1.68, and ε4 allele versus ε3: OR 1.30, 95% CI 1.06-1.59). We concluded that the ε2/ε3 genotype likely provided a protective effect against depression in the overall population and the ε2 allele acted as a protective factor for depression in the Caucasian population while the ε4 allele and ε3/ε4 genotype were associated with an increased risk of depression in the LLD subjects. PMID:25979253

  15. Readers&apos; Responses When Characters Act on Completed Goals: Impact of Characters&apos; Mental States and Readers&apos; Task Focus

    ERIC Educational Resources Information Center

    Foy, Jeffrey E.; Gerrig, Richard J.

    2014-01-01

    Research has demonstrated that readers track the objective status of characters&apos; goals (i.e., whether the goals have been completed). We suggest that readers also use characters&apos; subjective representations--characters&apos; mental states with respect to goals--to comprehend actions. We explored circumstances in which local information…

  16. Mothers&apos; Attributions in Reminiscing Conversations about Children&apos;s Successes and Failures: Connections with Children&apos;s Self-Evaluations

    ERIC Educational Resources Information Center

    Goodvin, Rebecca; Rolfson, Jacqueline

    2014-01-01

    Effects of feedback on children&apos;s self-evaluations are well established, yet little is known about how parents talk with children about everyday successes and failures, despite the importance of parent-child reminiscing in children&apos;s psychological understanding. We examine mothers&apos; attributions and performance evaluations 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. 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…

  19. 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…

  20. 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…

  1. 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…

  2. "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…

  3. Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice123

    PubMed Central

    Jugdaohsingh, Ravin; Kessler, Katharina; Messner, Barbara; Stoiber, Martin; Pedro, Liliana D; Schima, Heinrich; Laufer, Günther; Powell, Jonathan J; Bernhard, David

    2015-01-01

    Background: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. Objectives: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. Methods: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10–15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (−Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15–19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). Results: The serum silicon concentration in the −Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the −Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. Conclusions: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol

  4. APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

    PubMed Central

    Berdnik, Daniela; Shen, Jadon C.; Bernstein, Jeffrey D.; Fenesy, Michelle C.; Deutsch, Gayle K.; Wyss-Coray, Tony; Rutt, Brian K.

    2014-01-01

    Objectives: Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory. Methods: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment. Results: We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory. Conclusions: The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation. PMID:24453080

  5. 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

  6. APOE genotype alters immunoglobulin subtypes in knock-in mice

    PubMed Central

    Zhou, Ye; Zhao, Wenjuan; Al-muhtasib, Nour; Rebeck, G. William

    2016-01-01

    Apolipoprotein E (APOE) alleles are strongly related to the risk of Alzheimer’s disease (AD). APOE genotype also affects inflammatory processes in response to damage. We tested whether APOE genotype affected the levels of specific immunoglobulins in healthy, uninfected APOE knock-in mice. We measured specific immunoglobulins in brain, spleen and plasma. Levels of total IgG in brain and spleen were highest in APOE-ε3 mice, significantly higher than in APOE-ε2 and APOE-ε4 mice; no differences were observed for levels of total IgG plasma. We also measured specific subtypes of IgG. IgG1 was only detectable in plasma, and did not differ by APOE genotype. IgG3 was detectable in plasma and spleen, and also did not differ by APOE genotype. IgG2b showed the same pattern as levels of total IgG by APOE genotype, with the highest levels of IgG2b in brain, spleen, and plasma of APOE-ε3 mice. IgG2a showed an entirely different pattern, with significantly higher levels in spleen and plasma of APOE-ε4 mice compared to APOE-ε2 and APOE-ε3 mice. We also measured IgM and IgA in spleens and plasma of these mice. In spleen, APOE-ε4 mice had the lowest IgA levels and the highest levels of IgM; both being significantly different from APOE-ε2 mice. In total, murine IgG2a and IgM were highest in APOE-ε4 mice, while total IgG and Ig2b were highest in APOE-ε3 mice. These dramatically different distributions of immunoglobulins could allow for human AD risk biomarkers based on specific immunoglobulin subtypes. PMID:25737044

  7. Genetic variation in lipoprotein (a) levels in families enriched for coronary artery disease is determined almost entirely by the apolipoprotein (a) gene locus

    SciTech Connect

    DeMeester, C.A.; Lusis, A.J.; Bu, X.; Gray, R.J.; Rotter, J.I.

    1995-01-01

    Lipoprotein (a) (Lp[a]) is a cholesterol-rich lipoprotein resembling LDL but also containing a large polypeptide designated apolipoprotein (a) (apo[a]). Its levels are highly variable among individuals and, in a number of studies, are strongly correlated with the risk of coronary artery disease (CAD). In an effort to determine which genes control Lp(a) levels, we have studied 25 multiplex families (comprising 298 members) enriched for CAD. The apo(a) gene was genotyped among the families, using a highly informative pulse-field gel electrophoresis procedure. In addition, polymorphisms of the gene for the other major protein of Lp(a), apolipoprotein B (apoB), were examined. Quantitative sib-pair linkage analysis indicates that apo(a) is the major gene controlling Lp(a) levels in this CAD population (P = .001; 99 sib pairs), whereas the apoB gene demonstrated no significant quantitative linkage effect. We estimate that the apo(a) locus accounts for {le}98% of variance of Lp(a) serum levels. Approximately 43% of this variation is explained by size polymorphisms within the apo(a) gene. These results indicate that the apo(a) gene is the major determinant of Lp(a) serum levels not only in the general population but also in a high-risk CAD population. 59 refs., 4 figs., 3 tabs.

  8. Reactivation of apolipoprotein II gene transcription by cycloheximide reveals two steps in the deactivation of estrogen receptor-mediated transcription.

    PubMed

    Sensel, M G; Binder, R; Lazier, C B; Williams, D L

    1994-03-01

    In this report, we describe apolipoprotein II (apoII) gene expression in cell lines derived by stable expression of the chicken estrogen receptor in LMH chicken hepatoma cells. In cell lines expressing high levels of receptor (LMH/2A), apoII gene expression is increased by estrogen 300-fold compared with levels in the receptor-deficient parent LMH line. LMH/2A cells show apoII mRNA induction and turnover kinetics similar to those in chicken liver. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin following estrogen withdrawal superinduces apoII mRNA without affecting apoII mRNA stability. Superinduction is due to an estrogen-independent reactivation of apoII gene transcription. The apoII gene can be reactivated by CHX for up to 24 h following hormone withdrawal, suggesting that the gene is in a repressed yet transcriptionally competent state. These results reveal two distinct events necessary for termination of estrogen receptor-mediated transcription. The first event, removal of hormone, is sufficient to stop transcription when translation is ongoing. The second event is revealed by the CHX-induced superinduction of apoII mRNA following hormone withdrawal. This superinduction suggests that deactivation of estrogen receptor-mediated transcription requires a labile protein. Furthermore, reactivation of apoII gene expression by CHX and estrogen is additive, suggesting that estrogen is unable to overcome repression completely. Thus, a labile protein may act to repress estrogen receptor-mediated transcription of the apoII gene. PMID:8114707

  9. Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo

    PubMed Central

    Gilat-Frenkel, Moran; Boehm-Cagan, Anat; Liraz, Ori; Xian, Xunde; Herz, Joachim; Michaelson, Daniel M.

    2014-01-01

    This study investigated the possible role of the ApoE receptors Lrp1 and Apoer2 in mediating the pathological effects of ApoE4 in ApoE-targeted-replacement mice expressing either the human ApoE3 or ApoE4 allele. In this study we show that activation of the amyloid cascade by inhibition of the Aβ-degrading enzyme neprilysin results in up-regulation of the ApoE receptor Lrp1 in the CA1 hippocampal neurons of 4-month-old ApoE4 mice, but not in the corresponding ApoE3 or ApoE-deficient (KO) mice. These results are in accordance with the previous findings that activation of the amyloid cascade induces Aβ accumulation in the CA1 neurons of ApoE4 mice, but not in ApoE3 or ApoE-KO mice. This suggests that the apoE4-driven elevation of Lrp1 is mediated via a gain of function mechanism and may play a role in mediating the effects of ApoE4 on Aβ. In contrast, no changes were observed in the levels of the corresponding Apoer2 receptor following the neprilysin inhibition. The ApoE receptors of naive ApoE4 mice were also affected differentially and isoform specifically by ApoE4. However, under these conditions, the effect was an ApoE4-driven reduction in the levels of Apoer2 in CA1 and CA3 pyramidal neurons, whereas the levels of Lrp1 were not affected. RT-PCR measurements revealed that the levels of Apoer2 and Lrp1 mRNA in the hippocampus of naïve and neprilysin-inhibited mice were not affected by ApoE4, suggesting that the observed effects of ApoE4 on the levels of these receptors is post-transcriptional. In conclusion, this study shows that the levels of hippocampal ApoE receptors Lrp1 and Apoer2 in vivo are affected isoform specifically by ApoE4 and that the type of receptor affected is context dependent. PMID:24251389

  10. Transgenic mouse model for estrogen-regulated lipoprotein metabolism: studies on apoVLDL-II expression in transgenic mice.

    PubMed

    Zsigmond, E; Nakanishi, M K; Ghiselli, F E; Chan, L

    1995-07-01

    We have produced transgenic mice that express an estrogen-responsive avian apolipoprotein, apoVLDL-II. An apoVLDL-II natural gene construct containing 4.7 kb of 5' flanking and 19 bp of 3' flanking sequences together with the 4 exon/3 intron structural gene was expressed in a liver-specific manner in transgenic mice. A single injection of estrogen caused a 5.9- to 7.5-fold stimulation of apoVLDL-II mRNA in the liver. The transgene mRNA had the same initiation sites of transcription as the native mRNA isolated from laying hen liver, and the same sites were used before and after estrogen treatment. The number of hepatocytes that stain positive for immunoreactive apoVLDL-II increased from < 1% to 40-60% in 24 h after estrogen treatment. Thus, in trangenic mice as in the cockerel, hepatocytes are biochemically heterogeneous and induction of apoVLDL-II synthesis occurs by recruitment of hepatocytes. In the plamsa compartment, compared to controls, transgenic mice have a 3- to 5-fold higher basal total plasma triglyceride which was accounted for by a 5.4-fold high basal VLDL triglyceride. Estrogen treatment results in a approximately 2-fold increase in the VLDL triglycerides over basal levels and 8.5-fold increase over nontransgenic mice, which did not show any change in VLDL in response to estrogen. Transgenic mice with the integrated apoVLDL-II gene provide a useful model for the study of the regulation of lipoprotein metabolism by estrogen. PMID:7595069

  11. 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

  12. 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…

  13. 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…

  14. 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…

  15. "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…

  16. ApoE4 effects on automated diagnostic classifiers for mild cognitive impairment and Alzheimer's disease.

    PubMed

    Apostolova, Liana G; Hwang, Kristy S; Kohannim, Omid; Avila, David; Elashoff, David; Jack, Clifford R; Shaw, Leslie; Trojanowski, John Q; Weiner, Michael W; Thompson, Paul M

    2014-01-01

    Biomarkers are the only feasible way to detect and monitor presymptomatic Alzheimer's disease (AD). No single biomarker can predict future cognitive decline with an acceptable level of accuracy. In addition to designing powerful multimodal diagnostic platforms, a careful investigation of the major sources of disease heterogeneity and their influence on biomarker changes is needed. Here we investigated the accuracy of a novel multimodal biomarker classifier for differentiating cognitively normal (NC), mild cognitive impairment (MCI) and AD subjects with and without stratification by ApoE4 genotype. 111 NC, 182 MCI and 95 AD ADNI participants provided both structural MRI and CSF data at baseline. We used an automated machine-learning classifier to test the ability of hippocampal volume and CSF Aβ, t-tau and p-tau levels, both separately and in combination, to differentiate NC, MCI and AD subjects, and predict conversion. We hypothesized that the combined hippocampal/CSF biomarker classifier model would achieve the highest accuracy in differentiating between the three diagnostic groups and that ApoE4 genotype will affect both diagnostic accuracy and biomarker selection. The combined hippocampal/CSF classifier performed better than hippocampus-only classifier in differentiating NC from MCI and NC from AD. It also outperformed the CSF-only classifier in differentiating NC vs. AD. Our amyloid marker played a role in discriminating NC from MCI or AD but not for MCI vs. AD. Neurodegenerative markers contributed to accurate discrimination of AD from NC and MCI but not NC from MCI. Classifiers predicting MCI conversion performed well only after ApoE4 stratification. Hippocampal volume and sex achieved AUC = 0.68 for predicting conversion in the ApoE4-positive MCI, while CSF p-tau, education and sex achieved AUC = 0.89 for predicting conversion in ApoE4-negative MCI. These observations support the proposed biomarker trajectory in AD, which postulates that amyloid markers

  17. Hypolipidemic effect of young persimmon fruit in C57BL/6.KOR-ApoEshl mice.

    PubMed

    Matsumoto, Kenji; Yokoyama, Shin-ichiro; Gato, Nobuki

    2008-10-01

    We investigated the hypolipidemic effects of young persimmon fruit (YP) on apolipoprotein E-deficient C57BL/6.KOR-ApoEshl mice. These mice exhibited higher plasma cholesterols, except for high-density lipoprotein (HDL), and lower plasma HDL cholesterol than C57BL/6.Cr mice that had the same genetic background as the C57BL/6.KOR-ApoEshl mice. Male C57BL/6.KOR-ApoEshl mice (n=5) were fed a diet supplemented with dry YP, Hachiya-kaki, at a concentration of 5% (w/w) for 10 weeks. YP treatment significantly lowered plasma chylomicron, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterols, and triglyceride, and this response was accompanied by an elevation of fecal bile acid excretion. In the liver, sterol regulatory element binding protein-2 gene expression was significantly higher in mice fed YP, while the mRNA and protein levels of the LDL receptor did not change. These results indicate that acceleration of fecal bile acid excretion is a major mechanism of the hypolipidemic effect induced by YP in C57BL/6.KOR-ApoEshl mice. PMID:18838807

  18. Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation in vitro.

    PubMed

    Gui, Yuyan; Duan, Zhongliang; Qiu, Xuemin; Tang, Wei; Gober, Hans-Jürgen; Li, Dajin; Wang, Ling

    2016-02-01

    Apolipoprotein E (ApoE) regulated bone metabolism in mice might mediate uptake of lipid particles into target cells such as osteoblasts via receptor-mediated endocytosis by apoE receptors, which includes the low-density lipoprotein receptor (LDLR) family and heparan sulfate proteoglycans (HSPGs). There is no report regarding the expression of ApoE receptors mRNA induced by estrogen during osteoblast differentiation in vitro. Primary osteoblasts were collected from the calvaria of newborn mice and were subjected to osteoblast mineralization culture with serial concentrations of 17-β-estradiol (E2) in vitro. RNA was isolated at days 0, 5 and 25 of differentiation. Real-time PCR was conducted to analyze apoE receptors mRNA levels. We found that most LDLR family members genes were induced during osteoblast differentiation in vitro. The effect of E2 on apoE receptors gene expression during osteoblast differentiation was multifarious. The most noted members of the LDLR family involved in the maintenance of bone metabolism were LRP5, LRP6, LRP4, and Apoer2. LRP6 was up-regulated, while LRP5, LRP4, and Apoer2 were down-regulated by E2. Given that LRP6 is required for early stages of differentiation, we speculate E2 promotes osteoblast differentiation mainly in the early stage. PMID:26924297

  19. What&apos;s in a Symbol?

    ERIC Educational Resources Information Center

    Leadstone, Stuart

    2013-01-01

    This "Science Note" explores the new adaptation of Newton&apos;s Second Law of Motion, "F = ma." In older physics and applied mathematics textbooks this expression appears as "P = mf." The author examines why "f" is now favored over "a" and why practitioners write "P = mf" rather than…

  20. Gutenberg&apos;s Effects on Universities

    ERIC Educational Resources Information Center

    Moodie, Gavin

    2014-01-01

    This article considers the effects on universities of Gutenberg&apos;s invention of printing. It considers four major effects: the gradual displacement of Latin as the language of scholarship with vernacular languages, the expansion and eventual opening of libraries, major changes to curriculum, and major changes to pedagogy including lectures.…

  1. Clustering Teachers&apos; Motivations for Teaching

    ERIC Educational Resources Information Center

    Visser-Wijnveen, Gerda J.; Stes, Ann; Van Petegem, Peter

    2014-01-01

    The motivation to teach is a powerful, yet neglected, force in teaching at institutes of higher education. A better understanding of academics&apos; motivations for teaching is necessary. The aim of this mixed-method study was to identify groups with distinctively different motivations for teaching. Six clusters were identified: expertise, duty,…

  2. Mathematics Teachers&apos; Criteria of Dimension

    ERIC Educational Resources Information Center

    Ural, Alattin

    2014-01-01

    The aim of the study is to determine mathematics teachers&apos; decisions about dimensions of the geometric figures, criteria of dimension and consistency of decision-criteria. The research is a qualitative research and the model applied in the study is descriptive method on the basis of general scanning model. 15 mathematics teachers attended the…

  3. 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…

  4. My Brother&apos;s Keeper

    ERIC Educational Resources Information Center

    Obama, Barack

    2014-01-01

    In a White House address, the president announced an initiative to reclaim young boys and men of color. The "My Brother&apos;s Keeper" initiative partners with businesses, foundations, and nonprofits to address disparities in education, justice, and employment. President Obama was introduced by Christian, one of a group of students from…

  5. Flip Your Students&apos; Learning

    ERIC Educational Resources Information Center

    Sams, Aaron; Bergmann, Jonathan

    2013-01-01

    Flipped learning is not about how to use videos in lessons. It&apos;s about how to best use in-class time with students. That insight is causing educators in classrooms from kindergarten to college to reevaluate how they teach. Flipped learning helps teachers move away from direct instruction as their primary teaching tool toward a more…

  6. What&apos;s a Learning Center?

    ERIC Educational Resources Information Center

    Brown, Wesley C.

    2014-01-01

    The purpose of this narrative is to describe and explain the function of learning centers in American colleges and universities. Since the early 1960&apos;s nearly every four-year institution has created or increased support for some kind of learning center with the ostensible aim of improving the academic performance of its enrolled students. In…

  7. "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…

  8. Students&apos; Images of Mathematics

    ERIC Educational Resources Information Center

    Martin, Lee; Gourley-Delaney, Pamela

    2014-01-01

    Students&apos; judgments about "what counts" as mathematics in and out of school have important consequences for problem solving and transfer, yet our understanding of the source and nature of these judgments remains incomplete. Thirty-five sixth grade students participated in a study focused on what activities students judge as…

  9. Quirks of Stirling&apos;s Approximation

    ERIC Educational Resources Information Center

    Macrae, Roderick M.; Allgeier, Benjamin M.

    2013-01-01

    Stirling&apos;s approximation to ln "n"! is typically introduced to physical chemistry students as a step in the derivation of the statistical expression for the entropy. However, naive application of this approximation leads to incorrect conclusions. In this article, the problem is first illustrated using a familiar "toy…

  10. Physical Education Teachers&apos; Organizational Commitment

    ERIC Educational Resources Information Center

    Demir, Hayri

    2013-01-01

    The aim of this study was to determine physical education teachers&apos; organizational commitment levels. The sample consisted of 204 physical education teachers working in the city center of Konya in the 2011 to 2012 academic year. The respondents were randomly selected in this research. Data collected for this research by using the Scale for…

  11. Ontario&apos;s Student Voice Initiative

    ERIC Educational Resources Information Center

    Courtney, Jean

    2014-01-01

    This article describes in some detail aspects of the Student Voice initiative funded and championed by Ontario&apos;s Ministry of Education since 2008. The project enables thousands of students to make their voices heard in meaningful ways and to participate in student-led research. Some students from grades 7 to 12 become members of the Student…

  12. 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…

  13. Text Complexity: Primary Teachers&apos; Views

    ERIC Educational Resources Information Center

    Fitzgerald, Jill; Hiebert, Elfrieda H.; Bowen, Kimberly; Relyea-Kim, E. Jackie; Kung, Melody; Elmore, Jeff

    2015-01-01

    The research question was, "What text characteristics do primary teachers think are most important for early grades text complexity?" Teachers from across the United States accomplished a two-part task. First, to stimulate teachers&apos; thinking about important text characteristics, primary teachers completed an online paired-text…

  14. 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…

  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. Kentucky&apos;s Urban Extension Focus

    ERIC Educational Resources Information Center

    Young, Jeffery; Vavrina, Charles

    2014-01-01

    Defining the success of Urban Extension units is sometimes challenging. For those Extension agents, specialists, administrators, and others who have worked to bring solid, research-based programming to urban communities, it is no surprise that working in these communities brings its own unique and sometimes difficult challenges. Kentucky&apos;s…

  17. Under Threes&apos; Mathematical Learning

    ERIC Educational Resources Information Center

    Franzén, Karin

    2015-01-01

    The article focuses on mathematics for toddlers in preschool, with the aim of challenging a strong learning discourse that mainly focuses on cognitive learning. By devoting more attention to other perspectives on learning, the hope is to better promote children&apos;s early mathematical development. Sweden is one of few countries to have a…

  18. Students&apos; Perceptions of Plagiarism

    ERIC Educational Resources Information Center

    Fish, Reva; Hura, Gerri

    2013-01-01

    While plagiarism by college students is a serious problem that must be addressed, students generally overestimate the frequency of plagiarism at their schools and blame students they do not know for the majority of incidents. This study looked at students&apos; estimations of the frequency of plagiarism at a large urban college and explored how…

  19. MFA Writers&apos; Relationships with Writing

    ERIC Educational Resources Information Center

    Olthouse, Jill M.

    2013-01-01

    Through a qualitative research design, I explored how eight talented masters in fine arts (MFA) writers related to their craft. The phenomenon "relationship with writing" includes writers&apos; goals, values, identity, and emotions as these relate to writing. I found that that these MFA writers experience compatibilities and conflicts…

  20. Inquiry on Teachers&apos; Emotion

    ERIC Educational Resources Information Center

    Schutz, Paul A.

    2014-01-01

    Teaching, like other caring professions, is emotional. These emotions tend to emerge as teachers&apos; goals, standards, and beliefs transact with other classroom stakeholders during everyday school activities. As such, for teachers, the classroom context involves both the extreme happiness and joy from a lesson that goes as planned to the intense…

  1. 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…

  2. Seniors&apos; Perspectives about Academic Reading

    ERIC Educational Resources Information Center

    Hooley, Diana S.; Tysseling, Lee Ann; Ray, Beverly

    2013-01-01

    Reports show that the reading proficiency scores for 17-year-olds have stagnated over the past several decades. In this study, the authors explored older students&apos; academic reading perceptions that might suggest links to proficiency. What do high school seniors really think about class reading? Do they understand what they read? How do they…

  3. The Apo Riboswitch as a Molecular Hydra

    PubMed Central

    Wedekind, Joseph E.

    2010-01-01

    Summary Riboswitches ‘sense’ metabolites but knowledge is sparse for structures without bound ligand. Stoddard et al. (2010) determined an apo riboswitch structure ‘closed’ to metabolite binding. Further SAXS, biochemical and computational analyses support ensemble behavior with interconverting open and closed conformations. PMID:20637410

  4. In Memory of Garth Boomer: "May He Not &apos;Rust Unburnished&apos; but &apos;Shine in Use&apos;"

    ERIC Educational Resources Information Center

    Brock, Paul

    2013-01-01

    This article is based on the authors&apos; own experience of Garth Boomer as a splendid friend, a superb colleague, and an inspirational leader. In September 2005 the author was invited to deliver the Garth Boomer Memorial Lecture at the Biennial International Conference of the Australian Curriculum Studies Association (ACSA). This article is…

  5. America&apos;s Descent into Madness

    ERIC Educational Resources Information Center

    Giroux, Henry A.

    2014-01-01

    This article describes America&apos;s descent into madness under the regime of neoliberalism that has emerged in the United States since the late 1970s. In part, this is due to the emergence of a public pedagogy produced by the corporate-owned media that now saturates Americans with a market-driven value system that undermines those formative…

  6. 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…

  7. ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer's disease mouse model.

    PubMed

    Chan, Elizabeth S; Shetty, Mahesh Shivarama; Sajikumar, Sreedharan; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

    2016-01-01

    The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice. PMID:27189808

  8. ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model

    PubMed Central

    Chan, Elizabeth S.; Shetty, Mahesh Shivarama; Sajikumar, Sreedharan; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

    2016-01-01

    The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice. PMID:27189808

  9. Studying the role of ApoE in Alzheimer's disease pathogenesis using a systems biology model.

    PubMed

    Kyrtsos, Christina Rose; Baras, John S

    2013-10-01

    Alzheimer's disease (AD) is the most common form of dementia. Even with its well-known symptoms of memory loss and well-characterized pathology of beta amyloid (Aβ) plaques and neurofibrillary tangles, the disease pathogenesis and initiating factors are still not well understood. To tackle this problem, a systems biology model has been developed and used to study the varying effects of variations in the ApoE allele present, as well as the effects of short term and periodic inflammation at low to moderate levels. Simulations showed a late onset peak of Aβ in the ApoE4 case that lead to localized neuron loss which could be ameliorated in part by application of short-term pro-inflammatory mediators. The model that has been developed herein represents one of the first attempts to model AD from a systems approach to study physiologically relevant parameters that may prove useful to physicians in the future. PMID:24131052

  10. APOE/TOMM 40 genetic loci, white matter hyperintensities, and cerebral microbleeds

    PubMed Central

    Lyall, Donald M.; Muñoz Maniega, Susana; Harris, Sarah E.; Bastin, Mark E.; Murray, Catherine; Lutz, Michael W.; Saunders, Ann M.; Roses, Allen D.; Valdés Hernández, Maria del C.; Royle, Natalie A.; Starr, John M.; Porteous, David J.; Deary, Ian J.

    2015-01-01

    Background Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease. Aim and/or hypothesis To test for independent associations between two Alzheimer's disease‐susceptibility gene loci – APOE ε and the TOMM 40 ‘523’ poly‐T repeat – and white matter hyperintensities/cerebral microbleed burden in community‐dwelling older adults. Methods Participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε and TOMM 40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74). Results No significant effects of APOE ε or TOMM 40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants. Conclusions Lack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature. PMID:26310205

  11. Interrogating Meanings of Work in Children&apos;s Literature

    ERIC Educational Resources Information Center

    Wieland, Stacey M. B.; Bauer, Janell C.

    2015-01-01

    In this article, Wieland and Bauer discuss a teaching activity that helps students understand how meanings of work (MOW) are socially constructed through commonplace texts: children&apos;s books. The activity helps students consider how children&apos;s books shape future workers&apos; understandings of what work is, what kinds of work are most…

  12. Asperger&apos;s in the Holmes Family

    ERIC Educational Resources Information Center

    Altschuler, Eric L.

    2013-01-01

    I show that Mycroft Holmes (Sherlock Holmes&apos; brother) is a formally described case of Asperger&apos;s syndrome a half century before Asperger&apos;s description of the syndrome. Further, given the genetic similarity and links between the brothers stated by Sherlock, this also cinches the same diagnosis for Sherlock.

  13. Revitalizing Ernst Mach&apos;s Popular Scientific Lectures

    ERIC Educational Resources Information Center

    Euler, Manfred

    2007-01-01

    Compared to Ernst Mach&apos;s influence on the conceptual development of physics, his efforts to popularize science and his reflections on science literacy are known to a much lesser degree. The approach and the impact of Mach&apos;s popular scientific lectures are discussed in view of today&apos;s problems of understanding science. The key issues…

  14. Chemistry Teachers&apos; Knowledge and Application of Models

    ERIC Educational Resources Information Center

    Wang, Zuhao; Chi, Shaohui; Hu, Kaiyan; Chen, Wenting

    2014-01-01

    Teachers&apos; knowledge and application of model play an important role in students&apos; development of modeling ability and scientific literacy. In this study, we investigated Chinese chemistry teachers&apos; knowledge and application of models. Data were collected through test questionnaire and analyzed quantitatively and qualitatively. The…

  15. Mencius&apos; Educational Philosophy and Its Contemporary Relevance

    ERIC Educational Resources Information Center

    Huang, Chun-chieh

    2014-01-01

    This article argues that Mencius&apos; education is "holistic education" that aims at igniting the "silent revolution" from within one&apos;s inner mind-heart to be unfolded in society, state, and the world. Mencius&apos; educational philosophy is based on his theory of human nature and his theory of self-cultivation. Mencius…

  16. First-Year Students&apos; Perspectives on Intercultural Learning

    ERIC Educational Resources Information Center

    Lee, Amy; Williams, Rhiannon D.; Shaw, Marta A.; Jie, Yiyun

    2014-01-01

    Faculty can play a critical role in supporting students&apos; intercultural development, but studies indicate that instructors report a lack of formal understanding about how to maximize this opportunity. Through the investigation of 115 first-year students&apos; written reflections, this study provides faculty with students&apos; perspectives on…

  17. Learning about Other People&apos;s Families

    ERIC Educational Resources Information Center

    Goldstein, Tara

    2014-01-01

    While the call for teacher education students to learn about their students&apos; family and community lives remains urgent and compelling, educating teachers about the Other is tricky business. In this article I discuss the use of two performed ethnographies, "Harriet&apos;s House" and "Ana&apos;s Shadow," to provide…

  18. Gaps in Alzheimer&apos;s Knowledge among College Students

    ERIC Educational Resources Information Center

    Eshbaugh, Elaine M.

    2014-01-01

    Despite the prevalence of the disease, it appears that there may be a need for increased education for formal and family caregivers of those with Alzheimer&apos;s disease and related dementias. Today&apos;s college students will be asked to fill both of these roles in the future. This study examined the level of knowledge of Alzheimer&apos;s…

  19. Using Computational Simulations to Confront Students&apos; Mental Models

    ERIC Educational Resources Information Center

    Rodrigues, R.; Carvalho, P. Simeão

    2014-01-01

    In this paper we show an example of how to use a computational simulation to obtain visual feedback for students&apos; mental models, and compare their predictions with the simulated system&apos;s behaviour. Additionally, we use the computational simulation to incrementally modify the students&apos; mental models in order to accommodate new data,…

  20. Connecting to Special Collections of Children&apos;s Literature

    ERIC Educational Resources Information Center

    Brodie, Carolyn S.

    2013-01-01

    The Kent State University School of Library and Information Science serves as the home for two children&apos;s literature special collections. The Reinberger Children&apos;s Library Center is located on the third floor of Kent State&apos;s University Library and includes the Marantz Picturebook Collection for the Study of Picturebook Art. The…

  1. Gifted Children&apos;s Relationships with Writing

    ERIC Educational Resources Information Center

    Olthouse, Jill M.

    2014-01-01

    This collective case study represents 10 gifted children&apos;s relationships with writing. The construct "relationship with writing" includes children&apos;s influences, goals, values, identity, and emotions connected to writing. Overall, these students&apos; relationships with writing can be described as creative, responsible, and…

  2. The Not-so-Random Drunkard&apos;s Walk

    ERIC Educational Resources Information Center

    Ehrhardt, George

    2013-01-01

    This dataset contains the results of a quasi-experiment, testing Karl Pearson&apos;s "drunkard&apos;s walk" analogy for an abstract random walk. Inspired by the alternate hypothesis that drunkards stumble to the side of their dominant hand, it includes data on intoxicated test subjects walking a 10&apos; line. Variables include: the…

  3. Feedback Dialogues That Stimulate Students&apos; Reflective Thinking

    ERIC Educational Resources Information Center

    Van der Schaaf, Marieke; Baartman, Liesbeth; Prins, Frans; Oosterbaan, Anne; Schaap, Harmen

    2013-01-01

    How can feedback dialogues stimulate students&apos; reflective thinking? This study aims to investigate: (1) the effects of feedback dialogues between teachers and students on students&apos; perceptions of teacher feedback and (2) the relation between features of feedback dialogues and students&apos; thinking activities as part of reflective…

  4. Towards a Sociocultural Understanding of Children&apos;s Voice

    ERIC Educational Resources Information Center

    Maybin, Janet

    2013-01-01

    While "voice" is frequently invoked in discussions of pupils&apos; agency and empowerment, less attention has been paid to the dialogic dynamics of children&apos;s voices and the sociocultural features shaping their emergence. Drawing on linguistic ethnographic research involving recent recordings of 10- and 11-year-old children&apos;s…

  5. ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-07-01

    Apolipoprotein A1 (ApoA1) is a main protein moiety in high-density lipoprotein (HDL) particles. Generally, ApoA1 and HDL are considered as atheroprotective. In prooxidant and inflammatory microenvironment in the vicinity to the atherosclerotic lesion, ApoA1/HDL are subjected to modification. The chemical modifications such as oxidation, nitration, etc result in altering native architecture of ApoA1 toward dysfunctionality and abnormality. Neutrophil myeloperoxidase has a prominent role in this mechanism. Neo-epitopes could be formed and then exposed that makes them immunogenic. Indeed, these epitopes may be recognized by immune cells and induce production of proatherogenic ApoA1-specific IgG antibodies. These antibodies are biologically relevant because they are able to react with Toll-like receptor (TLR)-2 and TLR4 in target cells and induce a variety of pro-inflammatory responses. Epidemiological and functional studies underline a prognostic value of ApoA1 self-antibodies for several cardiovascular diseases, including myocardial infarction, acute coronary syndrome, and severe carotid stenosis. PMID:27183204

  6. Reduced VLDL clearance in Apoe(-/-)Npc1(-/-) mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels.

    PubMed

    Ishibashi, Minako; Masson, David; Westerterp, Marit; Wang, Nan; Sayers, Scott; Li, Rong; Welch, Carrie L; Tall, Alan R

    2010-09-01

    Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver_X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe(-/-)Npc1(-/-) mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe(-/-)Npc1(-/-) liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 (Pcsk9) and inducible degrader of the LDL-R (Idol), both known to promote proteolytic degradation of LDL-R. While Pcsk9 is known to be an SREBP-2 target, marked upregulation of IDOL in Apoe(-/-)Npc1(-/-) liver was unexpected. However, several other LXR target genes also increased in Apoe(-/-)Npc1(-/-) liver, suggesting increased synthesis of endogenous LXR ligands secondary to activation of sterol biosynthesis. In conclusion, we demonstrate that NPC1 deficiency has a major impact on VLDL metabolism in Apoe(-/-) mice through modulation of hepatic LDL-R protein levels. In contrast to modest induction of hepatic IDOL with synthetic LXR ligands, a striking upregulation of IDOL in Apoe(-/-)Npc1(-/-) mice could indicate a role of endogenous LXR ligands in regulation of hepatic IDOL. PMID:20562239

  7. The Role of a Model&apos;s Age for Young Children&apos;s Imitation: A Research Review

    ERIC Educational Resources Information Center

    Zmyj, Norbert; Seehagen, Sabine

    2013-01-01

    The influence of a model&apos;s age on young children&apos;s behaviour has been a subject of considerable debate among developmental theorists. Despite the recent surge of interest, controversy remains about the nature of peer influence in early life. This article reviews studies that investigated the influence of a model&apos;s age on young…

  8. The Correlation of Students&apos; Views on Constructivist Teaching Environment and Teachers&apos; Student Control Ideologies

    ERIC Educational Resources Information Center

    Beyhan, Omer

    2013-01-01

    The purpose of this study is to examine the correlation between elementary teachers&apos; student control ideology and students&apos; views on constructivist learning environment. In this study, the correlation between the views of teachers working in elementary schools on student control ideology and students&apos; views on constructivist…

  9. The Relationship between Elementary School Teachers&apos; Perceptions of Principals&apos; Leadership Effectiveness and Teacher Burnout

    ERIC Educational Resources Information Center

    Owens, Sallye Applewhite

    2013-01-01

    Burnout, an ever-present concern in the teaching profession, is arguably related to principals&apos; leadership effectiveness. The purpose of this study was to investigate relationships between elementary school teachers&apos; levels of burnout and their perceptions of their principals&apos; leadership effectiveness. Data were gathered using the…

  10. The Impact of Teachers&apos; Characteristics and Self-Reported Practices on Students&apos; Algebra Achievement

    ERIC Educational Resources Information Center

    Cope, Liza M.

    2013-01-01

    This study examined the impact of teachers&apos; characteristics and self-reported practices on students&apos; Algebra achievement while controlling for students&apos; characteristics. This study is based on the secondary analysis of data collected from a nationally representative sample of 9 th grade students and their mathematics teachers during…

  11. "Yes, Master&apos;s": A Graduate Degree&apos;s Moment in the Age of Higher Education Innovation

    ERIC Educational Resources Information Center

    Gallagher, Sean

    2014-01-01

    Over the past decade, enrollment in professional master&apos;s degree programs has grown substantially, and this category has outpaced the overall recent flattening of college enrollment. Today, 5 million more U.S. adults hold a master&apos;s degree compared with a decade ago, and in some circles the master&apos;s is being referred to as "the…

  12. Using Video Analysis to Support Prospective K-8 Teachers&apos; Noticing of Students&apos; Multiple Mathematical Knowledge Bases

    ERIC Educational Resources Information Center

    Roth McDuffie, Amy; Foote, Mary Q.; Bolson, Catherine; Turner, Erin E.; Aguirre, Julia M.; Bartell, Tonya Gau; Drake, Corey; Land, Tonia

    2014-01-01

    As part of a larger research project aimed at transforming preK-8 mathematics teacher preparation, the purpose of this study was to examine the extent to which prospective teachers notice children&apos;s competencies related to children&apos;s mathematical thinking, and children&apos;s community, cultural, and linguistic funds of knowledge or what…

  13. Parents&apos; Emotion-Related Beliefs, Behaviours, and Skills Predict Children&apos;s Recognition of Emotion

    ERIC Educational Resources Information Center

    Castro, Vanessa L.; Halberstadt, Amy G.; Lozada, Fantasy T.; Craig, Ashley B.

    2015-01-01

    Children who are able to recognize others&apos; emotions are successful in a variety of socioemotional domains, yet we know little about how school-aged children&apos;s abilities develop, particularly in the family context. We hypothesized that children develop emotion recognition skill as a function of parents&apos; own emotion-related beliefs,…

  14. Mothers&apos; Beliefs about Risk and Risk-Taking in Children&apos;s Outdoor Play

    ERIC Educational Resources Information Center

    Little, Helen

    2015-01-01

    Changes to social and environmental contexts impact on children&apos;s opportunities for and the nature of outdoor play in many ways. A number of studies over the past decade have noted a trend towards over-protective parenting practices that restrict children&apos;s activities and limit children&apos;s independent mobility and engagement with…

  15. Teachers&apos; Behavior and Pupils&apos; Achievement Motivation as Determinants of Intended Helping Behavior in Physical Education

    ERIC Educational Resources Information Center

    Kokkonen, Juha A.; Kokkonen, Marja T.; Telama, Risto K.; Liukkonen, Jarmo O.

    2013-01-01

    The present two-wave longitudinal study examined the extent to which physical education (PE) teachers&apos; democratic and socially supportive behavior, pupils&apos; goal orientations, and the perceived motivational climate in PE explained differences in pupils&apos; intended helping behavior by gender in PE classes. The results of 105 boys and…

  16. The Intergenerational Congruence of Mothers&apos; and Preschoolers&apos; Narrative Affective Content and Narrative Coherence

    ERIC Educational Resources Information Center

    Sher-Censor, Efrat; Grey, Izabela; Yates, Tuppett M.

    2013-01-01

    Intergenerational congruence of mothers&apos; and preschoolers&apos; narratives about the mother-child relationship was examined in a sample of 198 Hispanic (59.1%), Black (19.2%), and White (21.7%) mothers and their preschool child. Mothers&apos; narratives were obtained with the Five Minute Speech Sample and were coded for negative and positive…

  17. Developing Intercultural Understanding for Study Abroad: Students&apos; and Teachers&apos; Perspectives on Pre-Departure Intercultural Learning

    ERIC Educational Resources Information Center

    Holmes, P.; Bavieri, L.; Ganassin, S.

    2015-01-01

    This study reports on students&apos; and teachers&apos; perspectives on a programme designed to develop Erasmus students&apos; intercultural understanding prior to going abroad. We aimed to understand how students and their teachers perceived pre-departure materials in promoting their awareness of key concepts related to interculturality (e.g.,…

  18. Genotype patterns at CLU, CR1, PICALM and APOE, cognition and Mediterranean diet: the PREDIMED-NAVARRA trial.

    PubMed

    Martínez-Lapiscina, Elena H; Galbete, Cecilia; Corella, Dolores; Toledo, Estefania; Buil-Cosiales, Pilar; Salas-Salvado, Jordi; Ros, Emilio; Martinez-Gonzalez, Miguel A

    2014-05-01

    The traditional Mediterranean diet (MedDiet) has shown beneficial effects on cognitive decline. Nevertheless, diet-gene interactions have been poorly evaluated. We aimed to investigate diet-gene interaction in the PREDIMED-NAVARRA randomized trial. A total of 522 participants (67 ± 6 years at baseline) enrolled in the PREDIMED-NAVARRA trial were randomly allocated to one of three diets: two MedDiets (supplemented with either extra-virgin olive oil or nuts) or a low-fat diet. They were evaluated with the Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT) after 6.5 years of intervention. Subjects were genotyped for CR1-rs3818361, CLU-rs11136000, PICALM-rs3851179 and Apolipoprotein E (ApoE) genes. We studied MedDiet-gene interactions for cognition and assessed the effect of the MedDiet on cognition across different genetic profiles. A significant interaction (p = 0.041) between CLU-rs11136000 and the MedDiet intervention on the MMSE was found with a beneficial effect of MedDiet among carriers of the T minor allele (B = 0.97, 95 % CI 0.45-1.49). Similar effect was observed for CR1-rs3818361, but no significant interaction was observed (p = 0.335). For PICALM-rs3851179, the MedDiet intervention showed a beneficial effect in both genotype groups. No apparent interaction was found for the CDT between intervention and gene variants. Similarly, participants randomly allocated to MedDiet groups, with favorable profiles of CR1, CLU and PICALM genes, significantly improved CDT scores compared to controls with the same genetic profile. Cognitive performance was better for non-ApoE4 and for ApoE4 carriers of MedDiet groups compared to controls, but for CDT performance, we only found statistical significant differences for non-ApoE4 carriers. A MedDiet intervention modulates the effect of genetic factors on cognition. The effect of MedDiet might be greater for subjects with a more favorable genetic profile. PMID:24643340

  19. Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.

    PubMed

    Roses, Allen; Sundseth, Scott; Saunders, Ann; Gottschalk, William; Burns, Dan; Lutz, Michael

    2016-06-01

    The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the "APOE" region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics. PMID:27154058

  20. Effects of Simulated Heat Waves with Strong Sudden Cooling Weather on ApoE Knockout Mice.

    PubMed

    Zhang, Shuyu; Kuang, Zhengzhong; Zhang, Xiakun

    2015-06-01

    This study analyzes the mechanism of influence of heat waves with strong sudden cooling on cardiovascular diseases (CVD) in ApoE-/- mice. The process of heat waves with strong sudden cooling was simulated with a TEM1880 meteorological-environment simulation chamber according to the data obtained at 5 a.m. of 19 June 2006 to 11 p.m. of 22 June 2006. Forty-eight ApoE-/- mice were divided into six blocks based on their weight. Two mice from each block were randomly assigned to control, heat wave, temperature drop, and rewarming temperature groups. The experimental groups were transferred into the climate simulator chamber for exposure to the simulated heat wave process with strong sudden temperature drop. After 55, 59, and 75 h of exposure, the experimental groups were successively removed from the chamber to monitor physiological indicators. Blood samples were collected by decollation, and the hearts were harvested in all groups. The levels of heat stress factors (HSP60, SOD, TNF, sICAM-1, HIF-1α), cold stress factors (NE, EPI), vasoconstrictor factors (ANGII, ET-1, NO), and four items of blood lipid (TC, TG, HDL-C, and LDL-C) were measured in each ApoE-/- mouse. Results showed that the heat waves increased the levels of heat stress factors except SOD decreased, and decreased the levels of vasoconstrictor factors and blood lipid factors except TC increased. The strong sudden temperature drop in the heat wave process increased the levels of cold stress factors, vasoconstrictor factors and four blood lipid items (except the level of HDL-C which decreased) and decreased the levels of heat stress factors (except the level of SOD which increased). The analysis showed that heat waves could enhance atherosclerosis of ApoE-/- mice. The strong sudden temperature drop during the heat wave process increased the plasma concentrations of NE and ANGII, which indicates SNS activation, and resulted in increased blood pressure. NE and ANGII are vasoconstrictors involved in systemic

  1. Genetic Contribution of Variants near SORT1 and APOE on LDL Cholesterol Independent of Obesity in Children

    PubMed Central

    Büttner, Petra; Weise, Sebastian; Schleinitz, Dorit; Kiess, Wieland; Scholz, Markus; Kovacs, Peter; Körner, Antje

    2015-01-01

    Objective To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. Results Expression of selected genes increased 101 to >104 fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. Conclusion We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants. PMID:26375028

  2. High-Fat Diet Changes Hippocampal Apolipoprotein E (ApoE) in a Genotype- and Carbohydrate-Dependent Manner in Mice

    PubMed Central

    Lane-Donovan, Courtney; Herz, Joachim

    2016-01-01

    Alzheimer’s disease is a currently incurable neurodegenerative disease affecting millions of individuals worldwide. Risk factors for Alzheimer’s disease include genetic risk factors, such as possession of ε4 allele of apolipoprotein E (ApoE4) over the risk-neutral ApoE3 allele, and lifestyle risk factors, such as diet and exercise. The intersection of these two sources of disease risk is not well understood. We investigated the impact of diet on ApoE levels by feeding wildtype, ApoE3, and ApoE4 targeted replacement (TR) mice with chow, high-fat, or ketogenic (high-fat, very-low-carbohydrate) diets. We found that high-fat diet affected both plasma and hippocampal levels of ApoE in an isoform-dependent manner, with high-fat diet causing a surprising reduction of hippocampal ApoE levels in ApoE3 TR mice. Conversely, the ketogenic diet had no effect on hippocampal ApoE. Our findings suggest that the use of dietary interventions to slow the progression AD should take ApoE genotype into consideration. PMID:26828652

  3. High-Fat Diet Changes Hippocampal Apolipoprotein E (ApoE) in a Genotype- and Carbohydrate-Dependent Manner in Mice.

    PubMed

    Lane-Donovan, Courtney; Herz, Joachim

    2016-01-01

    Alzheimer's disease is a currently incurable neurodegenerative disease affecting millions of individuals worldwide. Risk factors for Alzheimer's disease include genetic risk factors, such as possession of ε4 allele of apolipoprotein E (ApoE4) over the risk-neutral ApoE3 allele, and lifestyle risk factors, such as diet and exercise. The intersection of these two sources of disease risk is not well understood. We investigated the impact of diet on ApoE levels by feeding wildtype, ApoE3, and ApoE4 targeted replacement (TR) mice with chow, high-fat, or ketogenic (high-fat, very-low-carbohydrate) diets. We found that high-fat diet affected both plasma and hippocampal levels of ApoE in an isoform-dependent manner, with high-fat diet causing a surprising reduction of hippocampal ApoE levels in ApoE3 TR mice. Conversely, the ketogenic diet had no effect on hippocampal ApoE. Our findings suggest that the use of dietary interventions to slow the progression AD should take ApoE genotype into consideration. PMID:26828652

  4. Doing Good? Interpreting Teachers&apos; Given and Felt Responsibilities for Pupils&apos; Well-Being in an Age of Measurement

    ERIC Educational Resources Information Center

    Edling, Silvia; Frelin, Anneli

    2013-01-01

    The purpose of this study is to theoretically discuss a specific aspect of teachers&apos; responsibilities: their responsibility for pupils&apos; or children&apos;s well-being. We ask two interrelated questions: firstly, how might (Swedish) teachers&apos; sense of responsibilities for their pupils&apos; well-being be understood in relation to…

  5. Human serum amyloid A genes are expressed in monocyte/macrophage cell lines.

    PubMed Central

    Urieli-Shoval, S.; Meek, R. L.; Hanson, R. H.; Eriksen, N.; Benditt, E. P.

    1994-01-01

    Serum amyloid A (apoSAA) is a family of proteins found, mainly associated with high density lipoproteins, in the blood plasma of mammals and at least one avian species, the Pekin duck. These proteins are present in small amounts under normal circumstances, but their concentration is capable of rising 100- to 1,000-fold in situations involving tissue injury or infection. Like classic acute phase proteins they are produced in the liver; however, expression of one of the apoSAA genes is known to occur in activated macrophages of mice. We examined three human macrophage precursor cell lines (THP-1, U-937, and HL-60), before and after differentiation with phorbol 12-myristate 13-acetate or 1 alpha,25-dihydroxy-vitamin D3, for apoSAA messenger (m)-RNA expression and found that: 1) induction of steady-state apoSAA mRNA by lipopolysaccharide, interleukin-1, or interleukin-6 required the presence of the synthetic glucocorticoid dexamethasone; 2) the three known active genes, apoSAA1, apoSAA2, and apoSAA4, were induced in THP-1 cells, whereas the pseudogene apoSAA3 was not; 3) differentiated and undifferentiated THP-1 cells expressed apoSAA mRNA, but U-937 cells expressed apoSAA mRNA (low levels) only after phorbol 12-myristate 13-acetate differentiation and HL-60 cells did not express apoSAA mRNA whether differentiated or not; 4) apoSAA protein was detectable immunologically at a low level in lyophilized medium from induced THP-1 cells. Our findings are compatible with the hypotheses that 1) apoSAA gene expression in human monocytes/macrophages in vivo is differentiation dependent; 2) activated macrophages provide a local source of apoSAA at sites of tissue injury or inflammation; 3) apoSAA is induced in tissue macrophages by local stimuli, under conditions that may not evoke the systemic acute phase response. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8080047

  6. A Logistic Regression Analysis of Turkey&apos;s 15-Year-Olds&apos; Scoring above the OECD Average on the PISA&apos;09 Reading Assessment

    ERIC Educational Resources Information Center

    Kasapoglu, Koray

    2014-01-01

    This study aims to investigate which factors are associated with Turkey&apos;s 15-year-olds&apos; scoring above the OECD average (493) on the PISA&apos;09 reading assessment. Collected from a total of 4,996 15-year-old students from Turkey, data were analyzed by logistic regression analysis in order to model the data of students who were split…

  7. Nuclear apoJ: A low dose radiation inducible regulator of cell death. Final report for period September 15, 1998 - September 14, 2001

    SciTech Connect

    Aronow, Bruce J.

    2002-04-19

    This project was based on preliminary data that was published by Dr. Boothman (Yang et al. 2000) which indicated a strong induction of apoJ gene expression, increased secretion of the protein, and accumulation of an apparently somewhat different form of the apoJ protein in the nucleus of MCF-7 breast carcinoma cells undergoing response to DNA damage. A clone expressing apoJ protein was isolated that was capable of interacting with Ku80, a component of the double strand break repair complex that is essential for the successful repair of rearranging immunoglobulin and T-cell receptor genes as evidenced by failure to produce mature B and T cells in the absence of Ku70. ApoJ clones isolated and characterized by Dr. Boothman bound strongly to a Ku-70 ''bait'' protein. Over-expression of these same clones in a cell line was capable of killing the cell. ApoJ is very strongly induced in many instances of programmed cell death and has been proposed repeatedly to play some sort of effector role in the process. Our principle hypothesis for this study was that the strong induction of the apoJ gene and the particular expression of a nuclear form of the protein was potentially a causal factor in the decision point made by the cell as it attempts to repair double-strand breakage based DNA damage. The hypothesis was that if sufficiently high damage occurred, it would be deleterious to maintain the cell's viability through continued DNA repair. One method to inhibit DNA repair might be by inhibiting proteins such as Ku-70 that are necessary for double-strand break repair. If apoJ does play a critical role in tipping the decision balance over to cell death, we reasoned that deficiency of apoJ would cause increased accumulation of cells with DNA damage and that this might decrease cell death in response to DNA damage and increase tumor occurrence rates. To test this hypothesis and its potential implications, we exposed wildtype and apoJ deficient animals that we constructed through

  8. 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. PMID:26400930

  9. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

    SciTech Connect

    Corder, E.H.; Saunders, A.M.; Strittmatter, W.J.; Gaskell, P.C.; Roses, A.D.; Petricak-Vance, M.A. ); Schmechel, D.E. Durham VA Medical Center, CA ); Small, G.W. ); Haines, J.L. )

    1993-08-13

    The apolipoprotein E type 4 allele (APOE-[epsilon]4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-[epsilon]4 alleles in 42 families with late onset AD. Thus APOE-[epsilon]4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-[epsilon]4 was virtually sufficient to cause AD by age 80.

  10. Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression

    SciTech Connect

    Song, Kwang-Hoon

    2010-01-29

    The orphan nuclear receptor Nur77 (NR4A1) has been reported to play a crucial role in the modulation of diverse metabolic processes in liver. Here, we reported the identification of human apolipoprotein A5 (ApoA5), which implicated in lowering plasma triglyceride levels, as a novel target gene of Nur77. Nur77 induced the human ApoA5 promoter activity. Using 5'-deletion and mutagenesis of human ApoA5 promoter analysis and chromatin immunoprecipitation assays, it was shown that Nur77 directly regulated human ApoA5 gene expression by binding to a Nur77 response element (AAAGGTCA) located in the proximal human ApoA5 promoter region. In addition, we demonstrated that blocking of Nur77 transcriptional activity via overexpression of dominant negative Nur77 suppressed human ApoA5 promoter activity and mRNA expression in human hepatoma cells, HepG2. Taken together, our results demonstrated that Nur77 is a novel regulator of human ApoA5 gene expression and provide a new insight into the role of this orphan nuclear receptor in lipoprotein metabolism and triglyceride homeostasis.

  11. A Nontoxic Barlow&apos;s Wheel

    ERIC Educational Resources Information Center

    Daffron, John A.; Greenslade, Thomas B., Jr.

    2015-01-01

    Barlow&apos;s wheel has been a favorite demonstration since its invention by Peter Barlow (1776-1862) in 1822. In the form shown in Fig. 1, it represents the first electric motor. The interaction between the electric current passing from the axle of the wheel to the rim and the magnetic field produced by the U-magnet produces a torque that turns…

  12. The Mayors&apos; Charter Schools

    ERIC Educational Resources Information Center

    Magee, Michael

    2014-01-01

    In 2007, the case could be made that Rhode Island had, dollar for dollar, the worst-performing public education system in the United States. Despite per-pupil expenditures ranking in the top 10 nationally, the state&apos;s 8th graders fared no better than 40th in reading and 33rd in math on the National Assessment of Educational Progress (NAEP).…

  13. Effect of the APOE ε4 Allele and Combat Exposure on PTSD among Iraq/Afghanistan-Era Veterans

    PubMed Central

    Kimbrel, Nathan A.; Hauser, Michael A.; Garrett, Melanie; Ashley-Koch, Allison; Liu, Yutao; Dennis, Michelle F.; Klein, Rebecca C.; Beckham, Jean C.

    2015-01-01

    Background The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans. Method Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report. Results The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene x environment (GxE) interactions were observed for lifetime PTSD (p = .0029) and PTSD symptom severity (p = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5). Conclusions While preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans’ risk for developing PTSD. PMID:25709077

  14. p53 family members regulate the expression of the apolipoprotein D gene.

    PubMed

    Sasaki, Yasushi; Negishi, Hideaki; Koyama, Ryota; Anbo, Naoki; Ohori, Kanae; Idogawa, Masashi; Mita, Hiroaki; Toyota, Minoru; Imai, Kohzoh; Shinomura, Yasuhisa; Tokino, Takashi

    2009-01-01

    p73 and p63 are members of the p53 gene family that play an important role in development and homeostasis, mainly by regulating transcription of a variety of genes. We report here that apolipoprotein D (apoD), a member of the lipocalin superfamily of lipid transport proteins, is a direct transcriptional target of the p53 family member genes. We found that the expression of apoD was specifically up-regulated by either TAp73 or TAp63 but not significantly by p53. In addition, apoD transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abolishes induction of apoD transcription following cisplatin treatment. We also identified a p73/p63-binding site in the promoter of the apoD gene that is responsive to the p53 family members. The ectopic expression of TAp73 as well as the addition of recombinant human apoD to culture medium induced the osteoblastic differentiation of the human osteosarcoma cell line Saos-2, as assessed by alkaline phosphatase activity. Importantly, apoD knockdown abrogated p73-mediated alkaline phosphatase induction. Moreover, TAp73-mediated apoD expression was able to induce morphological differentiation, as well as expression of neuronal markers, in the human neuroblastoma cell line SH-SY5Y. These results suggest that apoD induction may mediate the activity of p73 in normal development. PMID:19001418

  15. Immunization with an ApoB-100 Related Peptide Vaccine Attenuates Angiotensin-II Induced Hypertension and Renal Fibrosis in Mice

    PubMed Central

    Honjo, Tomoyuki; Chyu, Kuang-Yuh; Dimayuga, Paul C.; Lio, Wai Man; Yano, Juliana; Trinidad, Portia; Zhao, Xiaoning; Zhou, Jianchang; Cercek, Bojan; Shah, Prediman K.

    2015-01-01

    Recent studies suggest the potential involvement of CD8+ T cells in the pathogenesis of murine hypertension. We recently reported that immunization with apoB-100 related peptide, p210, modified CD8+ T cell function in angiotensin II (AngII)-infused apoE (-/-) mice. In this study, we hypothesized that p210 vaccine modulates blood pressure in AngII-infused apoE (-/-) mice. Male apoE (-/-) mice were immunized with p210 vaccine and compared to unimmunized controls. At 10 weeks of age, mice were subcutaneously implanted with an osmotic pump which released AngII for 4 weeks. At 13 weeks of age, p210 immunized mice showed significantly lower blood pressure response to AngII compared to controls. CD8+ T cells from p210 immunized mice displayed a different phenotype compared to CD8+ T cells from unimmunized controls. Serum creatinine and urine albumin to creatinine ratio were significantly decreased in p210 immunized mice suggesting that p210 vaccine had renal protective effect. At euthanasia, inflammatory genes IL-6, TNF-α, and MCP-1 in renal tissue were down-regulated by p210 vaccine. Renal fibrosis and pro-fibrotic gene expression were also significantly reduced in p210 immunized mice. To assess the role of CD8+ T cells in these beneficial effects of p210 vaccine, CD8+ T cells were depleted by CD8 depleting antibody in p210 immunized mice. p210 immunized mice with CD8+ T cell depletion developed higher blood pressure compared to mice receiving isotype control. Depletion of CD8+ T cells also increased renal fibrotic gene expression compared to controls. We conclude that immunization with p210 vaccine attenuated AngII-induced hypertension and renal fibrosis. CD8+ T cells modulated by p210 vaccine could play an important role in the anti-hypertensive, anti-fibrotic and renal-protective effect of p210 vaccine. PMID:26121471

  16. Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice.

    PubMed

    Park, Tae-Sik; Panek, Robert L; Rekhter, Mark D; Mueller, Sandra Bak; Rosebury, Wendy S; Robertson, Andrew; Hanselman, Jeffrey C; Kindt, Erick; Homan, Reynold; Karathanasis, Sotirios K

    2006-12-01

    Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis. PMID:16458317

  17. Inhibitory effects of myricitrin on oxidative stress-induced endothelial damage and early atherosclerosis in ApoE −/− mice

    SciTech Connect

    Sun, Gui-bo; Qin, Meng; Ye, Jing-xue; Pan, Rui-le; Meng, Xiang-bao; Wang, Min; Luo, Yun; Li, Zong-yang; Wang, Hong-wei; Sun, Xiao-bo

    2013-08-15

    Atherosclerosis (AS) is a state of heightened oxidative stress characterized by lipid and protein oxidation in vascular walls. Oxidative stress-induced vascular endothelial cell (VEC) injury is a major factor in the pathogenesis of AS. Myricitrin, a natural flavonoid isolated from the root bark of Myrica cerifera, was recently found to have a strong antioxidative effect. However, its use for treating cardiovascular diseases, especially AS is still unreported. Consequently, we evaluated the cytoprotective effect of myricitrin on AS by assessing oxidative stress-induced VEC damage. The in vivo study using an ApoE −/− mouse model of AS demonstrated that myricitrin treatment protects against VEC damage and inhibits early AS plaque formation. This effect is associated with the antioxidative effect of myricitrin, as observed in a hydrogen peroxide (H{sub 2}O{sub 2})-induced rat model of artery endothelial injury and primary cultured human VECs. Myricitrin treatment also prevents and attenuates H{sub 2}O{sub 2}-induced endothelial injury. Further investigation of the cytoprotective effects of myricitrin demonstrated that myricitrin exerts its function by scavenging for reactive oxygen species, as well as reducing lipid peroxidation, blocking NO release, and maintaining mitochondrial transmembrane potential. Myricitrin treatment also significantly decreased H{sub 2}O{sub 2}-induced apoptosis in VECs, which was associated with significant inhibition of p53 gene expression, activation of caspase-3 and the MAPK signaling pathway, and alteration of the patterns of pro-apoptotic and anti-apoptotic gene expression. The resulting significantly increased bcl-2/bax ratio indicates that myricitrin may prevent the apoptosis induced by oxidative stress injury. - Highlights: • Myricitrin prevents early atherosclerosis in ApoE−/− mice. • Myricitrin protects endothelial cell from H{sub 2}O{sub 2} induced injury in rat and HUVECs. • Myricitrin enhanced NO release and up

  18. Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS deficient ApoE ko mice

    PubMed Central

    Kuhlencordt, Peter J.; Padmapriya, P.; Rützel, S.; Schödel, J.; Hu, K.; Schäfer, A.; Huang, P.L.; Ertl, G.; Bauersachs, J.

    2013-01-01

    Objective Hypercholesterolemia is associated with decreased vascular nitric oxide bioavailability and deletion of endothelial nitric oxide synthase (eNOS) markedly accelerates atherosclerosis development in apolipoprotein E knockout (apoE ko) mice. The current study tests whether atheroprotection provided by a lipid lowering therapy with Ezetimibe depends on eNOS. Methods/Results ApoE ko and apoE/eNOS double ko (dko) mice received a high fat diet with or without 0.05% Ezetimibe. Ezetimibe significantly reduced plasma cholesterol concentrations and atherogenic lipoproteins in both genotypes to a similar extent. Moreover, the drug reduced vascular inflammation, as it significantly reduced Vascular Cell Adhesion Molecule-1 (VCAM-1) expression and vascular CD14 expression, a marker for mononuclear cell infiltration, in both genotypes. Neither NOS protein expression nor vascular reactivity of aortic rings were changed in apoE ko mice following Ezetimibe treatment. Significant lesion reduction was seen in Ezetimibe treated male and female apoE ko and apoE/eNOS dko animals (p≤0.05). Interestingly, the drug mediated additional atheroprotection in male apoE ko, compared to male eNOS dko mice, suggesting that lipid lowering does provide additional eNOS dependent atheroprotection in this experimental group. Conclusion Lipid lowering with Ezetimibe potently reduces atherosclerosis and vascular inflammation independent of eNOS. Moreover, Ezetimibe did not exert any effects on eNOS protein expression or enzyme activity. However, additional atheroprotection by Ezetimibe was observed in eNOS competent apoE ko mice, suggesting that some of the drug's antiatherosclerotic effects are mediated by the eNOS pathway. PMID:18479686

  19. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress

    PubMed Central

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  20. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress.

    PubMed

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin; Liu, Enqi

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  1. The Distribution of Apolipoprotein E Gene Polymorphism and Apolipoprotein E Levels among Coronary Artery Patients Compared to Controls

    PubMed Central

    Atis, Omer; Sahin, Semsettin; Ceyhan, Koksal; Ozyurt, Huseyin; Akbas, Ali; Benli, Ismail

    2016-01-01

    Objective: Coronary artery disease (CAD) is a multifactorial disease that is caused by various genetics and environmental factors. Genetically, predisposition is an important component for CAD. The candidate apolipoprotein E (apoE) gene is the most studied one. ApoE is composed of e2, e3, e4 alleles and E2/2, E2/3, E2/4, E3/3, E3/4, E4/4 genotypes. In this study, the relationship between CAD and apoE polymorphism and apoE level has been studied in Tokat region. Materials and Methods: The study population is composed of 100 CAD patients diagnosed by coronary angiography and 100 control patients of whom fifty have normal coronary angiography and fifty did not have any CAD symptoms. The serum lipid and apoE levels and apoE genotypes of all participants have been measured, and the relationship between these parameters has been evaluated. Results: Apolipoprotein E, total cholesterol, HDL cholesterol and LDL cholesterol levels were statistically low at CAD patients than control patients (p=0.0004, p=0.0005, p=0.0107, p=0.0052 respectively). There was not any significant difference between triglyceride levels (p=0.0848). Waist circumferences were significantly high at CAD patients (p=0.0012). Allele frequencies were as e2 (7.25%), e3 (83.5%), e4 (9.25%) and genotype distributions were as E2/2 (0.5%), E2/3 (13%), E2/4 (0.5%), E3/3 (68.5%), E3/4 (16.5%), E4/4 (1%). The distribution of alleles and genotypes were not significantly different (p>0.05). ApoE levels were higher at e2 allele carriers than e3 and e4 allele carriers (p<0.05). However, there was no significant difference between e3 and e4 allele carriers. Conclusion: In conclusion, the distribution of apoE genotype and allele at our region is similar to the general of Turkey. The low apoE levels in CAD patients may show the influence of apoE on CAD by local and systemic mechanisms. PMID:27551170

  2. Impact of murine intestinal apolipoprotein A-IV expression on regional lipid absorption, gene expression, and growth

    PubMed Central

    Simon, Trang; Cook, Victoria R.; Rao, Anuradha; Weinberg, Richard B.

    2011-01-01

    Apolipoprotein A-IV (apoA-IV) is synthesized by intestinal enterocytes during lipid absorption and secreted into lymph on the surface of nascent chylomicrons. A compelling body of evidence supports a central role of apoA-IV in facilitating intestinal lipid absorption and in regulating satiety, yet a longstanding conundrum is that no abnormalities in fat absorption, feeding behavior, or weight gain were observed in chow-fed apoA-IV knockout (A4KO) mice. Herein we reevaluated the impact of apoA-IV expression in C57BL6 and A4KO mice fed a high-fat diet. Fat balance and lymph cannulation studies found no effect of intestinal apoA-IV gene expression on the efficiency of fatty acid absorption, but gut sac transport studies revealed that apoA-IV differentially modulates lipid transport and the number and size of secreted triglyceride-rich lipoproteins in different anatomic regions of the small bowel. ApoA-IV gene deletion increased expression of other genes involved in chylomicron assembly, impaired the ability of A4KO mice to gain weight and increase adipose tissue mass, and increased the distal gut hormone response to a high-fat diet. Together these findings suggest that apoA-IV may play a unique role in integrating feeding behavior, intestinal lipid absorption, and energy storage. PMID:21840868

  3. APOLIPOPROTEIN E GENE AND EARLY AGE-RELATED MACULOPATHY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE: To examine the association between the apolipoprotein E (APOE) gene and early age-related maculopathy (ARM) in middle-aged persons. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Participants from the Atherosclerosis Risk in Communities Study (n = 10139; age range, 49-73 ye...

  4. MR histology of advanced atherosclerotic lesions of ApoE- knockout mice

    NASA Astrophysics Data System (ADS)

    Naumova, A.; Yarnykh, V.; Ferguson, M.; Rosenfeld, M.; Yuan, C.

    2016-02-01

    The purposes of this study were to examine the feasibility of determining the composition of advanced atherosclerotic plaques in fixed ApoE-knockout mice and to develop a time-efficient microimaging protocol for MR histological imaging on mice. Five formalin-fixed transgenic ApoE-knockout mice were imaged at the 9.4T Bruker BioSpec MR scanner using 3D spoiled gradient-echo sequence with an isotropic field of view of 24 mm3; TR 20.8 ms; TE 2.6 ms; flip angle 20°, resulted voxel size 47 × 63 × 94 pm3. MRI examination has shown that advanced atherosclerotic lesions of aorta, innominate and carotid arteries in ApoE-knockout mice are characterized by high calcification and presence of the large fibrofatty nodules. MRI quantification of atherosclerotic lesion components corresponded to histological assessment of plaque composition with a correlation coefficient of 0.98.

  5. Gene Therapy

    PubMed Central

    Baum, Bruce J

    2014-01-01

    Applications of gene therapy have been evaluated in virtually every oral tissue, and many of these have proved successful at least in animal models. While gene therapy will not be used routinely in the next decade, practitioners of oral medicine should be aware of the potential of this novel type of treatment that doubtless will benefit many patients with oral diseases. PMID:24372817

  6. Trichoderma genes

    DOEpatents

    Foreman, Pamela; Goedegebuur, Frits; Van Solingen, Pieter; Ward, Michael

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  7. The Little Emperor: Chinese Parents&apos; Assessment of Their Own, Their Partner&apos;s and Their Only Child&apos;s Intelligence

    ERIC Educational Resources Information Center

    Furnham, Adrian; Wu, Chun

    2014-01-01

    This study set out to examine whether Chinese parents, more than people from other nations, over-estimate the intelligence of their son (little emperor) compared to their daughter. In this study, 155 pairs of married couples from mainland China estimated their own, their partner&apos;s and their only child&apos;s overall intelligence and 13…

  8. The Complexity of Thomas Jefferson. A Response to "&apos;The Diffusion of Light&apos;: Jefferson&apos;s Philosophy of Education"

    ERIC Educational Resources Information Center

    Carpenter, James

    2014-01-01

    This response argues that Jefferson&apos;s educational philosophy must be considered in a proper historical context. Holowchak accurately demonstrates both Jefferson&apos;s obsession with education and the political philosophy on which his educational beliefs are built. However, the effort to apply modern democratic and meritocratic attributes to…

  9. What&apos;s a Degree Got to Do with It? The Civic Engagement of Associate&apos;s and Bachelor&apos;s Degree Holders

    ERIC Educational Resources Information Center

    Newell, Mallory Angeli

    2014-01-01

    This study explored the civic engagement of adults holding an associate&apos;s degree compared to those holding a bachelor&apos;s degree. Most prior research has focused on individuals who hold 4-year degrees; the present study, however, sought to understand differences between holders of 2-year degrees and 4-year degrees. Descriptive statistics…

  10. Mothers&apos; Early Depressive Symptoms Predict Children&apos;s Low Social Competence in First Grade: Mediation by Children&apos;s Social Cognition

    ERIC Educational Resources Information Center

    Wang, Yiji; Dix, Theodore

    2015-01-01

    Background: This study examined whether social-cognitive processes in children mediate relations between mothers&apos; depressive symptoms across the first 3 years and children&apos;s first-grade social competence. Three maladaptive cognitions were examined: self-perceived social inadequacy, hostile attribution, and aggressive response generation.…

  11. How the Group Investigation Model and the Six-Mirror Model Changed Teachers&apos; Roles and Teachers&apos; and Students&apos; Attitudes towards Diversity

    ERIC Educational Resources Information Center

    Damini, Marialuisa

    2014-01-01

    This paper is based on research that demonstrates the positive effects of the cooperative learning model Group Investigation (GI) and the Six-Mirror model on teacher effectiveness in organizing and scaffolding CL activities, and changing students&apos; and teachers&apos; views of diversity. We explain how the connection between the two models…

  12. The Effect of Children&apos;s Rights Training on Primary School Students&apos; Utilisation and Knowledge Level about Children&apos;s Rights

    ERIC Educational Resources Information Center

    Ozmen, Suna Kaymak; Ocal, Tugba; Ozmen, Ahmet

    2014-01-01

    Recently, children&apos;s rights issue has taken attention. In this study, main purpose was to investigate the utilisation and knowledge level of 4th and 5th grade primary school students after children&apos;s rights training. The participants of this survey study were selected randomly from 10 schools. Results indicated that students had the…

  13. Readin&apos;, Writin&apos;, Ready for Testin&apos;? Adaptive Assessment in Elective and Standardized-Tested Social Studies Course Contexts

    ERIC Educational Resources Information Center

    Meuwissen, Kevin W.

    2013-01-01

    This is an instrumental case study of 1 novice and 1 experienced secondary social studies teachers&apos; concurrent assessment practices within tightly structured, standardized-tested curricula and flexible elective curricula. It is anchored by 2 questions: (1) How did the teachers&apos; assessment stances and practices manifest across the 2…

  14. Examining Educators&apos; and Employers&apos; Perceptions on Career and Technical Education Graduates&apos; Employability Skills for the Labor Market in Jordan

    ERIC Educational Resources Information Center

    Al-Alawneh, Muhammad Khaled

    2009-01-01

    Preparing skilled and knowledgeable workforce that fits the labor market requires continued collaboration between education and work. Studying educators&apos; and employers&apos; perspectives on technical and non-technical skills may result in improving the quality of the graduates to compete on the level of the local as well as the global labor…

  15. Pre-Service Teachers&apos; Views of Children&apos;s and Adults&apos; Play in Japan, Taiwan, and the USA

    ERIC Educational Resources Information Center

    Izumi-Taylor, Satomi; Ito, Yoko; Lin, Chia Hui; Lee, Yu-Yuan

    2014-01-01

    Teachers&apos; perspectives of play differ widely because of social and cultural influences that can be seen in their values and beliefs about play in different countries. In a global community, sharing educators&apos; knowledge of play and their perspectives of how to educate children through the use of play would be appropriate and complementary…

  16. A Quantitative Study of Head Start Children&apos;s Strengths, Families&apos; Perspectives, and Teachers&apos; Ratings in the Transition to Kindergarten

    ERIC Educational Resources Information Center

    Robinson, Chanele D.; Diamond, Karen E.

    2014-01-01

    This study examined the association between preschool children&apos;s social-interpersonal skills and their transition to school in the beginning months of kindergarten. One hundred and thirty-three preschool children participated in this study. During the spring of the pre-kindergarten year, children&apos;s social-interpersonal skills were…

  17. "I Mean, the Queen&apos;s Fierce and the King&apos;s Not": Gendered Embodiment in Children&apos;s Drawings

    ERIC Educational Resources Information Center

    Wright, Susan

    2014-01-01

    Gender differences in children&apos;s artwork have been the subject of study for over 100 years. The focus of early research was quite narrow, honing in on issues such as children&apos;s gendered subject preferences, or their ability to render spatial relationships or include detail in their artwork. This has led to some stereotypical conclusions…

  18. Convergent multi-miRNA Targeting of ApoE Drives LRP1/LRP8-Dependent Melanoma Metastasis and Angiogenesis

    PubMed Central

    Pencheva, Nora; Tran, Hien; Buss, Colin; Huh, Doowon; Drobnjak, Marija; Busam, Klaus; Tavazoie, Sohail F.

    2013-01-01

    SUMMARY Through in-vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target Apolipoprotein E (ApoE) and the heat-shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma-cell LRP1 and endothelial-cell LRP8 receptors, respectively–while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, while therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma. PMID:23142051

  19. Relationship between the diagnostic components of metabolic syndrome (MS) and cognition by ApoE genotype in the elderly.

    PubMed

    Lee, Kang Soo; Jang, Yangsoo; Chung, Young-Ki; Chung, Ji Hyung; Oh, Byoung Hoon; Hong, Chang Hyung

    2010-01-01

    The purpose of this study was to find out the effect of the ApoE genotype on the relationship between metabolic syndrome (MS) and its diagnostic components and cognitive impairment in the elderly. A total of 2944 subjects aged over 60 years were analyzed from the data of Gwangju Dementia and Mild Cognitive Impairment Study. We examined demographic characteristics, current and past illness history, drug history, Korean version-mini-mental state examination (K-MMSE). We also examined ApoE genotype and analyzed associated factors with MS. The MS was present in 53.8% of the subjects (36.8% of men and 61.1% of women). On multiple logistic regression analysis, MS was not associated with the cognitive impairment (K-MMSE score <18) adjusted for age, sex, and educational level. The interactive effect between systolic and diastolic blood pressure (SBP, and DBP, respectively) and ApoE on cognition was not significant (all p>0.3), but the interactive effect between triglyceride (TG), high-density-lipoprotein-cholesterol (HDLc) and ApoE on cognition was significant after adjustment for age, sex, and education (B=-0.285, Wald=4.194, p=0.041; B=0.372, Wald=4.134, p=0.042). These results suggest that blood TG and HDLc may affect cognitive function in the elderly in the presence of ApoE varepsilon4 allele. PMID:19243844

  20. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis.

    PubMed

    Pencheva, Nora; Tran, Hien; Buss, Colin; Huh, Doowon; Drobnjak, Marija; Busam, Klaus; Tavazoie, Sohail F

    2012-11-21

    Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma. PMID:23142051

  1. Uncleaved ApoM Signal Peptide Is Required for Formation of Large ApoM/Sphingosine 1-Phosphate (S1P)-enriched HDL Particles*

    PubMed Central

    Liu, Mingxia; Allegood, Jeremy; Zhu, Xuewei; Seo, Jeongmin; Gebre, Abraham K.; Boudyguina, Elena; Cheng, Dongmei; Chuang, Chia-Chi; Shelness, Gregory S.; Spiegel, Sarah; Parks, John S.

    2015-01-01

    Apolipoprotein M (apoM), a plasma sphingosine 1-phosphate (S1P) carrier, associates with plasma HDL via its uncleaved signal peptide. Hepatocyte-specific apoM overexpression in mice stimulates formation of both larger nascent HDL in hepatocytes and larger mature apoM/S1P-enriched HDL particles in plasma by enhancing hepatic S1P synthesis and secretion. Mutagenesis of apoM glutamine 22 to alanine (apoMQ22A) introduces a functional signal peptidase cleavage site. Expression of apoMQ22A in ABCA1-expressing HEK293 cells resulted in the formation of smaller nascent HDL particles compared with wild type apoM (apoMWT). When apoMQ22A was expressed in vivo, using recombinant adenoviruses, smaller plasma HDL particles and decreased plasma S1P and apoM were observed relative to expression of apoMWT. Hepatocytes isolated from both apoMWT- and apoMQ22A-expressing mice displayed an equivalent increase in cellular levels of S1P, relative to LacZ controls; however, relative to apoMWT, apoMQ22A hepatocytes displayed more rapid apoM and S1P secretion but minimal apoMQ22A bound to nascent lipoproteins. Pharmacologic inhibition of ceramide synthesis increased cellular sphingosine and S1P but not medium S1P in both apoMWT and apoMQ22A hepatocytes. We conclude that apoM secretion is rate-limiting for hepatocyte S1P secretion and that its uncleaved signal peptide delays apoM trafficking out of the cell, promoting formation of larger nascent apoM- and S1P-enriched HDL particles that are probably precursors of larger apoM/S1P-enriched plasma HDL. PMID:25627684

  2. APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage

    PubMed Central

    Phuah, Chia-Ling; Raffeld, Miriam R.; Ayres, Alison M.; Gurol, M. Edip; Viswanathan, Anand; Greenberg, Steven M.; Biffi, Alessandro; Rosand, Jonathan

    2016-01-01

    Objective: We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk. Methods: We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele–specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects. Results: A total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: −7.30 mg/dL/mo, p = 0.0035; LDL: −8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends. Conclusions: APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype–specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk. PMID:27433544

  3. 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

  4. 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

  5. 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

  6. Do Teachers&apos; Perceptions of Children&apos;s Math and Reading Related Ability and Effort Predict Children&apos;s Self-Concept of Ability in Math and Reading?

    ERIC Educational Resources Information Center

    Upadyaya, Katja; Eccles, Jacquelynne

    2015-01-01

    This study investigated to what extent primary school teachers&apos; perceptions of their students&apos; ability and effort predict developmental changes in children&apos;s self-concepts of ability in math and reading after controlling for students&apos; academic performance and general intelligence. Three cohorts (N?=?849) of elementary school…

  7. Mississippi Public High School Counselors&apos; and Principals&apos; Perceptions of the Subject Area Testing Program (SATP2) and Its Impact on Counselors&apos; Job Performance

    ERIC Educational Resources Information Center

    Edwards, Aretha Hargrove

    2012-01-01

    The purpose of this study was to examine Mississippi Delta area public high school counselors&apos; and principals&apos; perception of the impact of SATP2 testing on counselors&apos; services to students in order to determine whether or not testing responsibilities have an adverse effect on counselors&apos; delivery of services to students. This…

  8. Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis

    PubMed Central

    Forte, Trudy M.; Sharma, Vineeta; Ryan, Robert O.

    2016-01-01

    Abstract Apolipoprotein (apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol (TG) homeostasis. Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipo­protein lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of car­diovascular disease. Single nucleotide polymorphisms (SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction. Genetically engineered mouse mod­els and human population studies suggest that, in certain instances, supplementation with wild type (WT) apoA-V may have therapeutic benefit. It is hypothesized that individuals that manifest elevated plasma TG owing to deleter­ious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance. On the other hand, subjects with hypertriglyceridemia of independent origin (unrelated to apoA-V func­tion) may not respond to apoA-V augmentation in this manner. Improvement in the ability to identify individuals predicted to benefit, advances in gene transfer technology and the strong connection between HTG and heart disease, point to apoA-V supplementation as a viable disease prevention / therapeutic strategy. Candidates would include individuals that manifest chronic TG elevation, have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels. PMID:26679785

  9. Induction of Fatal Inflammation in LDL Receptor and ApoA-I Double-Knockout Mice Fed Dietary Fat and Cholesterol

    PubMed Central

    Zabalawi, Manal; Bhat, Shaila; Loughlin, Tara; Thomas, Michael J.; Alexander, Eric; Cline, Mark; Bullock, Bill; Willingham, Mark; Sorci-Thomas, Mary G.

    2003-01-01

    Atherogenic response to dietary fat and cholesterol challenge was evaluated in mice lacking both the LDL receptor (LDLr−/−) and apoA-I (apoA-I−/−) gene, LDLr−/−/apoA-I−/− or double-knockout mice. Gender- and age-matched LDLr−/−/apoA-I−/− mice were fed a diet consisting of 0.1% cholesterol and 10% palm oil for 16 weeks and compared to LDLr−/− mice or single-knockout mice. The LDLr−/− mice showed a 6- to 7-fold increase in total plasma cholesterol (TPC) compared to their chow-fed mice counterparts, while LDLr−/−/apoA-I−/− mice showed only a 2- to 3-fold increase in TPC compared to their chow-fed controls. This differential response to the atherogenic diet was unanticipated, since chow-fed LDLr−/− and LDLr−/−/apoA-I−/− mice began the study with similar LDL levels and differed primarily in their HDL concentration. The 6-fold diet-induced increase in TPC observed in the LDLr−/− mice occurred mainly in VLDL/LDL and not in HDL. Mid-study plasma samples taken after 8 weeks of diet feeding showed that LDLr−/− mice had TPC concentrations approximately 60% of their 16-week level, while the LDLr−/−/apoA-I−/− mice had reached 100% of their 16-week TPC concentration after only 8 weeks of diet. Male LDLr−/− mice showed similar aortic cholesterol levels to male LDLr−/−/apoA-I−/− mice despite a 4-fold higher VLDL/LDL concentration in the LDLr−/− mice. A direct comparison of the severity of aortic atherosclerosis between female LDLr−/− and LDLr−/−/apoA-I−/− mice was compromised due to the loss of female LDLr−/−/apoA-I−/− mice between 10 and 14 weeks into the study. Diet-fed female and, with time, male LDLr−/−/apoA-I−/− mice suffered from severe ulcerated cutaneous xanthomatosis. This condition, combined with a complete depletion of adrenal cholesterol, manifested in fatal wasting of the affected mice. In conclusion, LDLr−/− and LDLr−/−/apoA-I−/− mice showed

  10. Principals&apos; Perceptions of Novice School Counselors&apos; Induction: An Afterthought

    ERIC Educational Resources Information Center

    Bickmore, Dana L.; Curry, Jennifer R.

    2013-01-01

    Principals have a clear impact on the transition of teachers into their initial work setting (Allensworth, Ponisciak, Mazzeo, 2009; S. T. Bickmore & D. L. Bickmore, 2010; Scherff, 2008). School administrators&apos; influence on teacher induction is both organizational and relational as they develop structures and practices that support…

  11. Students&apos; Perceptions of Teachers: Implications for Classroom Practices for Supporting Students&apos; Success

    ERIC Educational Resources Information Center

    Guess, Pamela; Bowling, Sara

    2014-01-01

    Positive psychology represents a conceptual framework that emphasizes the need to capitalize on individuals&apos; strengths in order to facilitate optimal functioning. As applied to the educational setting, these concepts have primarily been investigated via teaching life skills to students that encourage overall wellness. School-based strategies…

  12. Master&apos;s-Level Students&apos; Integration of Faith and Professional Counselor Identity

    ERIC Educational Resources Information Center

    Brue, Jill Smith

    2013-01-01

    This study examined through qualitative methods how advanced master&apos;s-level counseling students conceptualized Christian professional counselor identity. This study also explored what experiences contributed to the understanding of integration of faith and practice. Participants from three different evangelical Christian counseling programs…

  13. Teacher Education Futures: Today&apos;s Trends, Tomorrow&apos;s Expectations

    ERIC Educational Resources Information Center

    Aubusson, Peter; Schuck, Sandy

    2013-01-01

    Education is facing significant political and contextual challenges that will impact its future. This study employs a Delphi methodology to investigate teacher educators&apos; views of current trends and their consequences for teacher education futures. Interviews were conducted with a sample of expert teacher educators drawn from eight countries.…

  14. Students&apos; Perception of Live Lectures&apos; Inherent Disadvantages

    ERIC Educational Resources Information Center

    Petrovic, Juraj; Pale, Predrag

    2015-01-01

    This paper aims to provide insight into various properties of live lectures from the perspective of sophomore engineering students. In an anonymous online survey conducted at the Faculty of Electrical Engineering and Computing, University of Zagreb, we investigated students&apos; opinions regarding lecture attendance, inherent disadvantages of…

  15. A Journey to Find What&apos;s Working in America&apos;s Schools

    ERIC Educational Resources Information Center

    Healy, Michelle

    2013-01-01

    This article provides a description of the birth of The Odyssey Initiative. As teachers, this group of three, all educators, knew that there was outrage about the state of education in America. Griping about our nation&apos;s schools has almost become a pastime, and with very good reason. However, they found the solutions being offered to save our…

  16. Understanding Teachers&apos; Perceptions of Student Support Systems in Relation to Teachers&apos; Stress

    ERIC Educational Resources Information Center

    Ball, Annahita; Anderson-Butcher, Dawn

    2014-01-01

    Expanded school mental health (ESMH) programs are critical for addressing children&apos;s social and emotional development in schools. As broad, multisystem approaches, ESMH programs rely on teachers for effective and sustainable primary, secondary, and tertiary school mental health service delivery. In light of the increasing mental health needs…

  17. Indian Mothers&apos; Perceptions of Their Roles in Their Daughters&apos; University Course Choices

    ERIC Educational Resources Information Center

    Khambhaita, Priya

    2014-01-01

    This paper presents new findings on the experiences of Indian mothers in the roles they play in their daughters&apos; higher education (HE) subject choices. Whilst there are existing studies on White British mothers and parents more generally in terms of parental involvement in education, and a growing number of papers presenting results on…

  18. Students&apos; and Teachers&apos; Perceptions of Using Video Games to Enhance Science Instruction

    ERIC Educational Resources Information Center

    Marino, Matthew T.; Israel, Maya; Beecher, Constance C.; Basham, James D.

    2013-01-01

    Science education video game research points toward promising, but inconclusive results in both student learning outcomes and attitudes. However, student-level variables other than gender have been largely absent from this research. This study examined how students&apos; reading ability level and disability status are related to their video…

  19. Exasperating or Exceptional? Parents&apos; Interpretations of Their Child&apos;s ADHD Behavior

    ERIC Educational Resources Information Center

    Lench, Heather C.; Levine, Linda J.; Whalen, Carol K.

    2013-01-01

    Objective: Attention Deficit/Hyperactivity Disorder (ADHD) is a commonly diagnosed childhood disorder associated with parent--child conflict and parental stress. This investigation explored whether parents&apos; interpretation of symptomatic behavior predicted negative interactions with and perceptions of their child. Method: We recruited parents…

  20. Administrators&apos; Views on Teacher Evaluation: Examining Ontario&apos;s Teacher Performance Appraisal

    ERIC Educational Resources Information Center

    Maharaj, Sachin

    2014-01-01

    This study examines the views of administrators (i.e., principals and vice-principals) in Ontario, Canada, with regard to the province&apos;s Teacher Performance Appraisal process. A total of 178 responses were collected from a survey that examined five areas: 1) preparation and training; 2) classroom observations; 3) preparing the formal…

  1. Researching Teachers&apos; and Parents&apos; Perceptions of Dialogue

    ERIC Educational Resources Information Center

    Tveit, Anne Dorthe

    2014-01-01

    While there has been a great deal of research done on parent involvement and the challenges of conducting effective dialogue in parent-teacher meetings, less attention has been paid to how teachers and parents themselves perceive dialogue. The purpose of the present article is to study whether deliberative principles are vital to teachers&apos;…

  2. Accuracy of Teachers&apos; Predictions of Language Minority and Majority Students&apos; Language Comprehension

    ERIC Educational Resources Information Center

    Wold, Astri Heen

    2013-01-01

    The classroom is an important context of second language learning for language minority children. Teachers are responsible for creating good learning opportunities by securing language use well adjusted to the children&apos;s level of comprehension. Thus, teachers should have realistic expectations of this. The purpose of the research is to…

  3. Time&apos;s Up: Applying Teacher Management Skills to Solving Philadelphia&apos;s Problems

    ERIC Educational Resources Information Center

    Lax, Zach

    2013-01-01

    Teachers are natural problem solvers, and they should be using this quality to their advantage when it comes to solving the systemic issues that plague Philadelphia&apos;s education system. Many of the articles in this issue have already gone into great detail about what is happening in Philadelphia. Torch Lytle has provided a summary of the…

  4. An Action Research Project&apos;s Impact on Teachers&apos; Leadership Attitudes and Perceptions

    ERIC Educational Resources Information Center

    Myers, Nancy; Dillard, Benita R.

    2013-01-01

    California Lutheran University is a regional site for the California Reading and Literature Project (CRLP). In 2010, CRLP began a two-year longitudinal study to examine the effects of participating in an institute called Reframing Teacher Leadership: Action Research Study Group had on PreK-12 teachers&apos; attitudes and perceptions. The…

  5. Exploring a National Book-Gifting Scheme: Parents&apos; and Children&apos;s Reactions

    ERIC Educational Resources Information Center

    Wray, David; Medwell, Jane

    2015-01-01

    Several early learning programmes have targeted children&apos;s reading, particularly their relationships with books. One, Bookstart, provided free books to babies attending their eighth-month health check at local clinics. Study of this programme suggested that it led to an improvement in language performance upon school entry. Booktime continues…

  6. Attracting the World: Institutional Initiatives&apos; Effects on International Students&apos; Decision to Enroll

    ERIC Educational Resources Information Center

    Bohman, Eric

    2014-01-01

    Community colleges have increased their efforts to attract international students, but little is known how these active efforts influence international students&apos; decisions to attend a community college. This longitudinal study focuses on international students at one community college that embarked on an active international student…

  7. Investigating Elementary Teachers&apos; Thinking about and Learning to Notice Students&apos; Science Ideas

    ERIC Educational Resources Information Center

    Luna, Melissa Jo

    2013-01-01

    Children naturally use observations and everyday thinking to construct explanations as to why phenomena happen in the world. Science instruction can benefit by starting with these ideas to help children build coherent scientific understandings of how the physical world works. To do so, science teaching must involve attending to students&apos;…

  8. But I&apos;m Married: Understanding Relationship Status and College Students&apos; Sexual Behaviors

    ERIC Educational Resources Information Center

    Oswalt, Sara B.; Wyatt, Tammy J.

    2014-01-01

    Sexual health programs on college campuses are often directed toward single individuals with a focus on sexual risk. Using a sample of college students, this study examines how relationship status relates to sexual behaviors and may be a factor for sexual risk. Based on the study&apos;s results, expansion of sexual health programming on college…

  9. Updating Understandings of "Teaching": Taking Account of Learners&apos; and Teachers&apos; Beliefs

    ERIC Educational Resources Information Center

    Maclellan, Effie

    2015-01-01

    The paper reviews recent psycho-educational literature to identify features of teacher thinking which enable learners to acquire meaningful knowledge. The review establishes that one powerful mechanism to improve teaching in higher education turns on exploiting adults&apos; epistemic beliefs: beliefs about the nature and the acquisition of…

  10. Preservice Elementary School Teachers&apos; Knowledge of Fractions: A Mirror of Students&apos; Knowledge?

    ERIC Educational Resources Information Center

    Van Steenbrugge, H.; Lesage, E.; Valcke, M.; Desoete, A.

    2014-01-01

    This research analyses preservice teachers&apos; knowledge of fractions. Fractions are notoriously difficult for students to learn and for teachers to teach. Previous studies suggest that student learning of fractions may be limited by teacher understanding of fractions. If so, teacher education has a key role in solving the problem. We first…

  11. Participants&apos; Experiences in Hellinger&apos;s Family Constellation Work: A Grounded Theory Study

    ERIC Educational Resources Information Center

    Georgiadou, Sofia

    2012-01-01

    As a recently introduced to the U.S. model of intergenerational systemic therapy from Germany, Bert Hellinger&apos;s Family Constellation Work (FCW) has very limited research support. Hellinger himself has authored a number of publications referencing hundreds of cases, where he implemented his method to approach a broad array of physical,…

  12. Using an APOS Framework to Understand Teachers&apos; Responses to Questions on the Normal Distribution

    ERIC Educational Resources Information Center

    Bansilal, Sarah

    2014-01-01

    This study is an exploration of teachers&apos; engagement with concepts embedded in the normal distribution. The participants were a group of 290 in-service teachers enrolled in a teacher development program. The research instrument was an assessment task that can be described as an "unknown percentage" problem, which required the…

  13. A School&apos;s Organizational Structure and Students&apos; Mathematics Achievements

    ERIC Educational Resources Information Center

    Teaching Children Mathematics, 2010

    2010-01-01

    How a school is organized--or, more specifically, the extent to which teachers work together and treat one another as professionals--can influence elementary school students&apos; mathematics achievement. So suggest the authors of a recent study on the impact of school organization on longitudinal student achievement (Moller, Stephanie, Roslyn A.…

  14. Vocational Education Approach: New TEL Settings--New Prospects for Teachers&apos; Instructional Activities?

    ERIC Educational Resources Information Center

    Hämäläinen, Raija; De Wever, Bram

    2013-01-01

    This study focuses on vocational education teachers&apos; instructional activities in a new technology-enhanced learning (TEL) setting. A content analysis is applied to investigate teachers&apos; and students&apos; interactions in a 3D game context. The findings illustrate that when teachers&apos; and students&apos; interactions are mediated by a…

  15. Teachers&apos; Spatial Anxiety Relates to 1st-and 2nd-Graders&apos; Spatial Learning

    ERIC Educational Resources Information Center

    Gunderson, Elizabeth A.; Ramirez, Gerardo; Beilock, Sian L.; Levine, Susan C.

    2013-01-01

    Teachers&apos; anxiety about an academic domain, such as math, can impact students&apos; learning in that domain. We asked whether this relation held in the domain of spatial skill, given the importance of spatial skill for success in math and science and its malleability at a young age. We measured 1st-and 2nd-grade teachers&apos; spatial anxiety…

  16. Teaching the Repeated Prisoner&apos;s Dilemma with a Non-Computerised Adaptation of Axelrod&apos;s Tournament

    ERIC Educational Resources Information Center

    Dennis, Catherine

    2015-01-01

    Darwin&apos;s theory of evolution is explicitly competitive, yet co-operation between individuals is a common phenomenon. The Prisoner&apos;s Dilemma model is central to the teaching of the evolution of co-operation. The best-known explorations of the Prisoner&apos;s Dilemma are the tournaments run by Robert Axelrod in the 1980s. Aimed at students…

  17. Cognitive changes preceding clinical symptom onset of mild cognitive impairment and relationship to ApoE genotype

    PubMed Central

    Albert, M; Soldan, A; Gottesman, R; McKhann, G; Sacktor, N; Farrington, L; Grega, M; Turner, RS; Lu, Y; Li, S; Wang, M-C; Selnes, O

    2014-01-01

    Background This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes. Methods Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/− 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined. Results Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p<0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/− 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers. Conclusions Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele. PMID:25212916

  18. [Language gene].

    PubMed

    Takahashi, Hiroshi

    2006-11-01

    The human capacity for acquiring speech and language must derive, at least in part, from the genome. Recent advance in the field of molecular genetics finally discovered 'Language Gene'. Disruption of FOXP2 gene, the firstly identified 'language gene' causes severe speech and language disorder. To elucidate the anatomical basis of language processing in the brain, we examined the expression pattern of FOXP2/Foxp2 genes in the monkey and rat brains through development. We found the preferential expression of FOXP2/Foxp2 in the striosomal compartment of the developing striatum. Thus, we suggest the striatum, particularly striosomal system may participate in neural information processing for language and speech. Our suggestion is consistent with the declarative/ procedural model of language proposed by Ullman (1997, 2001), which the procedural memory-dependent mental grammar is rooted in the basal ganglia and the frontal cortex, and the declarative memory-dependent mental lexicon is rooted in the temporal lobe. PMID:17432197

  19. Bisphenol A Increases Atherosclerosis in Pregnane X Receptor‐Humanized ApoE Deficient Mice

    PubMed Central

    Sui, Yipeng; Park, Se‐Hyung; Helsley, Robert N.; Sunkara, Manjula; Gonzalez, Frank J.; Morris, Andrew J.; Zhou, Changcheng

    2014-01-01

    Background Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) in multiple large‐scale human population studies, but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro‐atherogenic effects in animal models upon activation. Interestingly, BPA is a potent agonist of human PXR but does not activate mouse or rat PXR signaling, which confounds the use of rodent models to evaluate mechanisms of BPA‐mediated CVD risk. This study aimed to investigate the atherogenic mechanism of BPA using a PXR‐humanized mouse model. Methods and Results A PXR‐humanized ApoE deficient (huPXR•ApoE−/−) mouse line was generated that respond to human PXR ligands and feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. Exposure to BPA significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of huPXR•ApoE−/− mice by 104% (P<0.001) and 120% (P<0.05), respectively. By contrast, BPA did not affect atherosclerosis development in the control littermates without human PXR. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR•ApoE−/− mice. Conclusion These findings identify a molecular mechanism that could link BPA exposure to increased risk of CVD in exposed individuals. PXR is therefore a relevant target for future risk assessment of BPA and related environmental chemicals in humans. PMID:24755147

  20. Genes V.

    SciTech Connect

    Lewin, B.

    1994-12-31

    This fifth edition book encompasses a wide range of topics covering 1,272 pages. The book is arranged into nine parts with a total of 36 chapters. These nine parts include Introduction; DNA as a Store of Information; Translation; Constructing Cells; Control of Prokaryotypic Gene Expression; Perpetuation of DNA; Organization of the Eukaryotypic Genome; Eukaryotypic Transcription and RNA Processing; The Dynamic Genome; and Genes in Development.

  1. Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

    PubMed Central

    Li, Xinhui; Johnson, Kory R.; Bryant, Mark; Elkahloun, Abdel G.; Amar, Marcelo; Remaley, Alan T.; De Silva, Ranil; Hallenbeck, John M.; Quandt, Jacqueline A.

    2011-01-01

    Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke. PMID:21701687

  2. Association of the Trp316Ser variant (rs1801690) near the apolipoprotein H (β2-glycoprotein-I) gene and serum lipid levels

    PubMed Central

    Guo, Tao; Yin, Rui-Xing; Li, Hui; Wang, Yi-Ming; Wu, Jin-Zhen; Yang, De-Zhai

    2015-01-01

    The objective of the present study was to detect the association of the Trp316Ser variant (rs1801690) near the apolipoprotein H (β2-glycoprotein-I) gene and serum lipid levels in the Mulao and Han populations. A total of 879 subjects of Mulao and 844 subjects of Han Chinese were included. The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and ApoA1 in Mulao, and triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and the ratio of ApoA1/ApoB in Han were different among the three genotypes of the rs1801690 SNP (P < 0.05-0.01). Subgroup analyses showed that the levels of TC, TG, LDL-C, and ApoA1 in Mulao males; ApoA1 in Mulao females; TC, TG, HDL-C and ApoB and the ApoA1/ApoB ratio in Han males; and HDL-C, ApoA1 and the ApoA1/ApoB ratio in Han females were associated with the genotypes of rs1801690 (P < 0.05-0.001). Serum lipid parameters were also associated with several environmental factors (P < 0.05-0.001). The Trp316Ser variant (rs1801690) near the apolipoprotein H (β2-glycoprotein-I) gene was associated with some serum lipid parameters in the two ethnic groups, but the trends of association suggest that the Trp316Ser variant (rs1801690) near the apolipoprotein H (β2-glycoprotein-I) gene might have racial/ethnic-and/or gender-specificity. PMID:26261630

  3. 17-β-estradiol up-regulates apolipoprotein genes expression during osteoblast differentiation in vitro.

    PubMed

    Gui, Yuyan; Chu, Nan; Qiu, Xuemin; Tang, Wei; Gober, Hans-Jürgen; Li, Dajin; Wang, Ling

    2016-05-23

    Apolipoproteins are of great physiological importance and are associated with different diseases. Many independent studies of patterns of gene expression during osteoblast differentiation have been described, and some apolipoproteins have been induced during this process. 17-β-estradiol (E2) may enhance osteoblast physiological function. However, no studies have indicated whether E2 can modulate the expression of apolipoproteins during osteoblast differentiation in vitro. The aim of the current study was to observe the regulation of apolipoprotein mRNA expression by E2 during this process. Primary osteoblasts were collected from the calvaria of newborn mice and were subjected to osteoblast differentiation in vitro with serial concentrations of E2. RNA was isolated on days 0, 5, and 25 of differentiation. Real-time PCR was performed to analyze the levels of apolipoprotein mRNA. Results showed that during osteoblast differentiation all of the apolipoprotein genes were up-regulated by E2 in a dose-dependent manner. Moreover, only ApoE was strongly induced during the mineralization of cultured osteoblasts. This result suggests that ApoE might be involved in osteoblast differentiation. The hypothesis is that E2 promotes osteoblast differentiation by up-regulating ApoE gene expression, though further study is needed to confirm this hypothesis. PMID:27074899

  4. 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

  5. Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake.

    PubMed

    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

    2015-03-01

    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 and

  6. Maurice Gee&apos;s Brilliant Borrowings of Maurice Gee and Significant Others: Realism and Postmodernism in Gee&apos;s Books for Children and Adults

    ERIC Educational Resources Information Center

    van Rij, Vivien

    2013-01-01

    This paper examines the work of one of New Zealand&apos;s most acclaimed writers, Maurice Gee, and the use of his children&apos;s fiction as an experimental ground for postmodernist techniques further developed in his writing for adults. In particular, it considers Gee&apos;s borrowings of his own and others&apos; non-fictional and fictional…

  7. An Action Research Study of Mexican Teachers&apos; and Administrators&apos; Experiences in Developing and Implementing a Service Learning Program

    ERIC Educational Resources Information Center

    Acuna, Kym

    2013-01-01

    The purpose of this study was to examine the High Tec Middle School teachers&apos; and administrators&apos; knowledge of the service learning model upon which the school&apos;s service learning program has been based, their views regarding their role in student character formation through service learning, and the teachers&apos; feelings of…

  8. European-American and African-American Mothers&apos; Emotion Socialization Practices Relate Differently to Their Children&apos;s Academic and Social-Emotional Competence

    ERIC Educational Resources Information Center

    Nelson, Jackie A.; Leerkes, Esther M.; Perry, Nicole B.; O'Brien, Marion; Calkins, Susan D.; Marcovitch, Stuart

    2013-01-01

    The current study examines whether the relation between mothers&apos; responses to their children&apos;s negative emotions and teachers&apos; reports of children&apos;s academic performance and social-emotional competence are similar or different for European-American and African-American families. Two hundred mothers (137 European-American, 63…

  9. An Analysis of Information Technology Managers&apos; and Executives&apos; Security Concerns on Willingness to Adopt Cloud Computing Solutions

    ERIC Educational Resources Information Center

    Tanque, Marcus M.

    2012-01-01

    The research conducted in this study inquires about Information Technology (IT) managers&apos; and executives&apos; attitudes, beliefs, and knowledge on Cloud Computing (CC) security. The study evaluated how these factors affect IT managers&apos; and executives&apos; willingness to adopt CC solutions in their organizations. Confidentiality,…

  10. The Backpack Food Program&apos;s Effects on U.S. Elementary Students&apos; Hunger and On-Task Behavior

    ERIC Educational Resources Information Center

    Ecker, Meghan E.; Sifers, Sarah K.

    2013-01-01

    Purpose/Objectives: The purpose of this study was to evaluate the BackPack Food Program&apos;s effectiveness in combating students&apos; hunger over the weekends and school breaks, as well as analyze the program&apos;s effects on students&apos; on-task behavior in the classroom. Additionally, this study examined program satisfaction from students,…

  11. Apolipoprotein E Gene Polymorphisms in Saudi Patients with Systemic Lupus Erythematosus

    PubMed Central

    Al-Rayes, Hannan; Huraib, Ghaleb; Julkhuf, Saeed; Arfin, Misbahul; Tariq, Mohammad; Al-Asmari, Abdulrahman

    2016-01-01

    Apolipoprotein E (APOE) is a glycosylated protein with multiple biological properties. APOE gene polymorphism plays a central role in lipid metabolism and has recently been suggested to regulate inflammation. Our objective is to evaluate whether APOE polymorphism affects susceptibility to SLE. APOE genotyping was performed using ApoE StripAssay™ kit. Results indicated significantly higher frequencies of allele ε4 and genotype ε3/ε4 and lower frequencies of allele ε3 and genotype ε3/ε3 in SLE patients than controls. APOE ε2 allele was found in three patients, whereas it was absent in controls. The frequencies of allele ε4 and genotype ε3/ε4 were significantly higher in SLE patients with renal involvement and those of alleles ε2, ε4 and genotypes ε2/ε3, ε3/ε4 were higher in patients with neuropsychiatric symptoms. It is concluded that APOE allele ε4 is associated with susceptibility risk/clinical manifestations of SLE and ε2 may increase its severity while ε3 is protective for SLE in Saudis. PMID:27257397

  12. Student Teachers&apos; Conceptions of Teaching Biology

    ERIC Educational Resources Information Center

    Subramaniam, Karthigeyan

    2014-01-01

    The purpose of this qualitative study was to investigate prospective biology teachers&apos; conceptions of teaching biology and identify how these conceptions revealed their strategies for helping their future students&apos; learning of biology. The study utilized drawings, narratives and interviews to investigate the nature of the prospective…

  13. Teachers&apos; Work, Food Policies, and Gender in Argentina

    ERIC Educational Resources Information Center

    Robert, Sarah A.; McEntarfer, Heather Killelea

    2014-01-01

    Few studies explore teachers&apos; involvement in school feeding, questioning gendered implications within a feminine and feminized profession. Ethnographic data from one public high school in Metropolitan Buenos Aires suggest that teachers&apos; efforts to address student hunger added new work roles: food advocates/activists, food managers, and…

  14. Investigating Students&apos; Usage and Acceptance of Electronic Books

    ERIC Educational Resources Information Center

    Sieche, Susan; Krey, Birte; Bastiaens, Theo

    2013-01-01

    The purpose of this study is to investigate students&apos; usage and acceptance of electronic books. Factors correlating with students&apos; attitude towards e-books were examined using the Technology Acceptance Model (Davis, Bagozzi, & Warshaw 1989). A questionnaire was administered online for students at University of Hagen. Results indicate…

  15. A Study of Science Teachers&apos; Homework Practices

    ERIC Educational Resources Information Center

    Tas, Yasemin; Sungur-Vural, Semra; Öztekin, Ceren

    2014-01-01

    This study investigates Turkish middle school science teachers&apos; homework practices, the value teachers attach to homework and teachers&apos; communication with parents about homework. One hundred and sixty-eight teachers completed surveys. Teachers reported to assign homework frequently: 93.4 per cent of the teachers reported that they assign…

  16. College Students&apos; Beliefs about Supporting a Grieving Peer

    ERIC Educational Resources Information Center

    Tedrick Parikh, Sara J.; Servaty-Seib, Heather L.

    2013-01-01

    The present study used I. Ajzen&apos;s (1991) Theory of Planned Behavior (TBP) to explore college students&apos; beliefs about listening supportively to a grieving friend. Responses to open-ended questions suggested that students ("N" = 23) perceived both benefits and risks, connected with listening supportively, for the grieving friend…

  17. Children&apos;s Perception of Dialect Variation

    ERIC Educational Resources Information Center

    Wagner, Laura; Clopper, Cynthia G.; Pate, John K.

    2014-01-01

    A speaker&apos;s regional dialect is a rich source of information about that person. Two studies examined five- to six-year-old children&apos;s perception of regional dialect: Can they perceive differences among dialects? Have they made meaningful social connections to specific dialects? Experiment 1 asked children to categorize speakers into…

  18. Building Motherhood in the Young Mothers&apos; Group

    ERIC Educational Resources Information Center

    Simonic, Barbara; Poljanec, Andreja

    2014-01-01

    The primary relationship undermines how a newborn will develop. The first three years of a child&apos;s life in particular are fundamental for the development of the child&apos;s brain. This is when the "social brain" develops and grows in response to the spontaneous relationships experienced within the environment and when an…

  19. Examining the Factors Contributing to Students&apos; Life Satisfaction

    ERIC Educational Resources Information Center

    Dogan, Ugur; Celik, Eyup

    2014-01-01

    In this study, the authors examined the relationship between students&apos; life satisfaction, school engagement, and confidence in the classroom. An analysis was performed of how students&apos; life satisfaction differs according to their housing, school type, and classroom level. The multidimensional student satisfaction scale, confidence scale…

  20. Philosophical Remarks on Nelson Mandela&apos;s Education Legacy

    ERIC Educational Resources Information Center

    Waghid, Yusef

    2014-01-01

    In this article, I reflect on Nelson Mandela&apos;s (Madiba, the clan name of Mandela) education legacy. I argue that Madiba&apos;s education legacy is constituted by three interrelated aspects: firstly, an education for non-violence guided by deliberation, compassion and reconciliation; secondly, education as responsibility towards the Other; and…

  1. Should We Bother Improving Students&apos; Attendance at Seminars?

    ERIC Educational Resources Information Center

    Gbadamosi, Gbolahan

    2015-01-01

    This study uses action research intervention to improve students&apos; attendance at seminars. Specifically, the study asks the question: will students&apos; attendance improve if they drive their own learning by running their own seminars? Records of lecture and seminar attendance at a module and comparative ones were used. Focus group interviews…

  2. Enquiring into Primary Teachers&apos; Geographical Knowledge

    ERIC Educational Resources Information Center

    Catling, Simon; Morley, Emma

    2013-01-01

    Subject knowledge is an important component of primary teachers&apos; repertoire, though it has not been studied widely beyond their understandings of aspects of science and mathematics. Evaluations of the quality of teachers&apos; geographical knowledge for teaching primary geography indicate a disparity between high quality teachers and less…

  3. CTE&apos;s Role in Urban Education

    ERIC Educational Resources Information Center

    Hyslop, Alisha; Imperatore, Catherine

    2013-01-01

    Education in the United States is facing a crisis of completion and performance, both at the secondary and postsecondary levels, with high dropout rates and a significant number of students ill-prepared for further education and careers. These problems are even more acute in America&apos;s urban schools. Today&apos;s CTE is on the cutting edge of…

  4. Improving EFL Learners&apos; Reading Levels through Extensive Reading

    ERIC Educational Resources Information Center

    Mermelstein, Aaron David

    2014-01-01

    Today there is an increasing amount of research promoting the effectiveness of extensive reading (ER) towards increasing learners&apos; vocabulary, comprehension, reading speed, and motivation towards reading. However, little has been done to measure the effects of ER on learners&apos; reading levels. This quantitative study examined the effects…

  5. University Students&apos; Attitudes toward Physical Education Teaching

    ERIC Educational Resources Information Center

    Li, Fengjuan; Chen, Junjun; Baker, Miles

    2014-01-01

    While there have been many studies into students&apos; attitudes toward Physical Education at the school level, far fewer studies have been conducted at the university level, especially in China. This study explored 949 students&apos; attitudes toward their university Physical Education experiences in four Chinese universities. An intercorrelated…

  6. Meet AAPT&apos;s New President, Steve Iona

    ERIC Educational Resources Information Center

    Willis, Courtney

    2014-01-01

    I first met Steve Iona 40 years ago at a Denver Area Physics Teachers meeting. Steve had recently completed bachelor&apos;s and master&apos;s degrees in mathematics from the University of Chicago. Being a Colorado native, he was interested in returning to Colorado to teach. Steve had some rather high-powered recommendations, including one from a…

  7. Negative Integer Understanding: Characterizing First Graders&apos; Mental Models

    ERIC Educational Resources Information Center

    Bofferding, Laura

    2014-01-01

    This article presents results of a research study. Sixty-one first graders&apos; responses to interview questions about negative integer values and order and directed magnitudes were examined to characterize the students&apos; mental models. The models reveal that initially, students overrelied on various combinations of whole-number principles as…

  8. Analysis of Students&apos; Arguments on Evolutionary Theory

    ERIC Educational Resources Information Center

    Basel, Nicolai; Harms, Ute; Prechtl, Helmut

    2013-01-01

    A qualitative exploratory study was conducted to reveal students&apos; argumentation skills in the context of the topic of evolution. Transcripts from problem-centred interviews on secondary students&apos; beliefs about evolutionary processes of adaptation were analysed using a content analysis approach. For this purpose two categorical systems…

  9. Reliability of Ratings of Children&apos;s Expressive Reading

    ERIC Educational Resources Information Center

    Moser, Gary P.; Sudweeks, Richard R.; Morrison, Timothy G.; Wilcox, Brad

    2014-01-01

    This study examined ratings of fourth graders&apos; oral reading expression. Randomly assigned participants (n = 36) practiced repeated readings using narrative or informational passages for 7 weeks. After this period raters used the "Multidimensional Fluency Scale" (MFS) on two separate occasions to rate students&apos; expressive…

  10. Teachers&apos; Experiences of Science Curriculum Reform

    ERIC Educational Resources Information Center

    Ryder, Jim; Banner, Indira; Homer, Matt

    2014-01-01

    We report on a three-year study of teachers&apos; experiences of a major reform of the science National Curriculum for 14- to 16-year-olds in England. Teachers&apos; responses to this curriculum reform were guided by: "personal" aims and biography; "internal" features of their workplace such as departmental collegiality; and…

  11. Exploring Preschool Children&apos;s Science Content Knowledge

    ERIC Educational Resources Information Center

    Guo, Ying; Piasta, Shayne B.; Bowles, Ryan P.

    2015-01-01

    Research Findings: The purpose of this study was to describe children&apos;s science content knowledge and examine the early predictors of science content knowledge in a sample of 194 typically developing preschool children. Children&apos;s science content knowledge was assessed in the fall (Time 1) and spring (Time 2) of the preschool year.…

  12. Trends in Exiting Physics Master&apos;s. Focus On

    ERIC Educational Resources Information Center

    Mulvey, Patrick J.; Nicholson, Starr

    2014-01-01

    A physics master&apos;s degree provides the recipient with a variety of career options. Some master&apos;s recipients will continue their education at the graduate level in physics or another field, where others enter the workforce pursuing a wide range of employment opportunities. This "Focus On" provides an in-depth analysis of physics…

  13. An Exploration of Design Students&apos; Inspiration Process

    ERIC Educational Resources Information Center

    Dazkir, Sibel S.; Mower, Jennifer M.; Reddy-Best, Kelly L.; Pedersen, Elaine L.

    2013-01-01

    Our purpose was to explore how different sources of inspiration influenced two groups of students&apos; inspiration process and their attitudes toward their design projects. Assigned sources of inspiration and instructor&apos;s assistance in the search for inspiration varied for two groups of students completing a small culture inspired product…

  14. Educators&apos; Social and Emotional Skills Vital to Learning

    ERIC Educational Resources Information Center

    Jones, Stephanie M.; Bouffard, Suzanne M.; Weissbourd, Richard

    2013-01-01

    Teachers&apos; social and emotional competencies are very important to their overall effectiveness, but such skills are frequently overlooked. Social and emotional competencies like managing emotions and stress are needed more today than ever before. More practices and policies to support and foster educators&apos; social and emotional…

  15. Upper Secondary School Pupils&apos; Attitudes towards Natural Science

    ERIC Educational Resources Information Center

    Akarsu, Bayram; Kariper, Afsin

    2013-01-01

    Students&apos; attitudes towards natural science constitute an important area in science education as fewer students are interested in natural science and they do not choose corresponding science disciplines in postsecondary education. The current study reports preliminary results of a survey on high school students&apos; interests and attitudes…

  16. Labels Facilitate Infants&apos; Comparison of Action Goals

    ERIC Educational Resources Information Center

    Gerson, Sarah A.; Woodward, Amanda L.

    2014-01-01

    Understanding the actions of others depends on the insight that these actions are structured by intentional relations. In a number of conceptual domains, comparison with familiar instances has been shown to support children&apos;s and adults&apos; ability to discern the relational structure of novel instances. Recent evidence suggests that this…

  17. Guattari&apos;s Ecosophy and Implications for Pedagogy

    ERIC Educational Resources Information Center

    Greenhalgh-Spencer, Heather

    2014-01-01

    Guattari&apos;s ecosophy has implications for many types of pedagogy practiced in the school. While Guattari never explicitly advocated the educational use of ecosophy, I explore in this article how it can be used as a lens to "read" pedagogy in nuanced ways, highlighting oppressive premises and practices. I first discuss Guattari&apos;s…

  18. NOAA&apos;s Education Program: Review and Critique

    ERIC Educational Resources Information Center

    Farrington, John W., Ed.; Feder, Michael A., Ed.

    2010-01-01

    There is a national need to educate the public about the ocean, coastal resources, atmosphere and climate. The National Oceanic and Atmospheric Administration (NOAA), the agency responsible for understanding and predicting changes in the Earth&apos;s environment and conserving and managing coastal and marine resources to meet the nation&apos;s…

  19. Undergraduate Women&apos;s Persistence in the Sciences

    ERIC Educational Resources Information Center

    George-Jackson, Casey E.

    2014-01-01

    This study uses longitudinal data of undergraduate students from five public land-grant universities to better understand undergraduate students&apos; persistence in and switching of majors, with particular attention given to women&apos;s participation in science, technology, engineering, and mathematics (STEM) fields. Specifically, the study…

  20. Primary School Teacher Candidates&apos; Geometric Habits of Mind

    ERIC Educational Resources Information Center

    Köse, Nilu¨fer Y.; Tanisli, Dilek

    2014-01-01

    Geometric habits of mind are productive ways of thinking that support learning and using geometric concepts. Identifying primary school teacher candidates&apos; geometric habits of mind is important as they affect the development of their future students&apos; geometric thinking. Therefore, this study attempts to determine primary school…

  1. Pre-Reading Power: One Classroom&apos;s Experience

    ERIC Educational Resources Information Center

    Thomas, Angela Falter; Vannatta Reinhart, Rachel

    2014-01-01

    Because of the Common Core State Standards there is a renewed emphasis on the importance of visual literacies in today&apos;s classrooms. Students need prior knowledge before approaching these types of texts. This article describes the results of one 6th-grade language arts class&apos;s engagement in pre-reading prior to viewing a theatrical…

  2. Teachers&apos; Beliefs about Using a Professional Development Plan

    ERIC Educational Resources Information Center

    Janssen, Sandra; Kreijns, Karel; Bastiaens, Theo J.; Stijnen, Sjef; Vermeulen, Marjan

    2013-01-01

    Professional development plans (PDPs) have recently been introduced in Dutch schools to support teachers&apos; professional development. However, teachers&apos; beliefs regarding the use of PDPs have not been systematically researched, whereas research on the use of PDPs indicates that the implementation is not always successful and depends on how…

  3. Children&apos;s Eye Movements in Reading: A Commentary

    ERIC Educational Resources Information Center

    Rayner, Keith; Ardoin, Scott P.; Binder, Katherine S.

    2013-01-01

    are discussed. Specifically, the following topics are addressed: (1) basic methodological issues, (2) prior research findings on children&apos;s reading, (3) research that is missing in the literature regarding children&apos;s eye movements during reading, (4) applied…

  4. Main Factors of Teachers&apos; Professional Well-Being

    ERIC Educational Resources Information Center

    Yildirim, Kamil

    2014-01-01

    The purpose of the study was to reveal the main factors of teachers&apos; professional well being. Theoretically constructed model was tested on large scale data belong to 72.190 teachers working at lower secondary level. Theoretical model included teachers&apos; individual, professional and organizational characteristics. Professional well-being…

  5. Educators&apos; Perception of Administrative Leadership throughout School Restructuring

    ERIC Educational Resources Information Center

    Johnson, LeJuan

    2012-01-01

    Leaders in schools today have a crucial responsibility to employ school reform and restructure initiatives for the betterment of the student. This study sought educators&apos; perceptions of administrative leadership throughout school restructuring. The survey design assisted in connecting educators, levels of administrator&apos;s leadership, and…

  6. Stats Don&apos;t Tell the Whole Story

    ERIC Educational Resources Information Center

    Beitler, Alan; Bushong, Delores

    2013-01-01

    This article describes the Wakefield Cohort program at Wakefield High School, located in Arlington, Virginia, which has a thirteen-year history of success in supporting minority male students. While data show the program&apos;s effectiveness, former students&apos; stories are more powerful; therefore, this article presents the stories of two…

  7. Adolescent Boys&apos; Science Aspirations: Masculinity, Capital, and Power

    ERIC Educational Resources Information Center

    Archer, Louise; DeWitt, Jennifer; Willis, Beatrice

    2014-01-01

    There is widespread international concern about post-16 participation rates in science, with women&apos;s under-representation constituting a particular issue. This paper contributes to these debates through a novel, critical examination of the role of masculinity within boys&apos; negotiations of science aspirations. Drawing on a UK longitudinal…

  8. Infants&apos; Preferential Attention to Sung and Spoken Stimuli

    ERIC Educational Resources Information Center

    Costa-Giomi, Eugenia; Ilari, Beatriz

    2014-01-01

    Caregivers and early childhood teachers all over the world use singing and speech to elicit and maintain infants&apos; attention. Research comparing infants&apos; preferential attention to music and speech is inconclusive regarding their responses to these two types of auditory stimuli, with one study showing a music bias and another one…

  9. Students&apos; Stories of Studying Abroad: Reflections upon Return

    ERIC Educational Resources Information Center

    Costello, Jane

    2015-01-01

    Study abroad brings an enriching experience to students&apos; academic and personal lives. This narrative essay relays two students&apos; experiences with study abroad sojourns and touches upon their technology use during their study abroad as recounted in semi-structured interviews. Details of their cultural experiences and reflections thereof as…

  10. University Students&apos; Understanding of Electromagnetic Induction

    ERIC Educational Resources Information Center

    Guisasola, Jenaro; Almudi, Jose M.; Zuza, Kristina

    2013-01-01

    This study examined engineering and physical science students&apos; understanding of the electromagnetic induction (EMI) phenomena. It is assumed that significant knowledge of the EMI theory is a basic prerequisite when students have to think about electromagnetic phenomena. To analyse students&apos; conceptions, we have taken into account the…

  11. School Life and Adolescents&apos; Self-Esteem Trajectories

    ERIC Educational Resources Information Center

    Morin, Alexandre J. S.; Maïano, Christophe; Marsh, Herbert W.; Nagengast, Benjamin; Janosz, Michel

    2013-01-01

    This study investigates heterogeneity in adolescents&apos; trajectories of global self-esteem (GSE) and the relations between these trajectories and facets of the interpersonal, organizational, and instructional components of students&apos; school life. Methodologically, this study illustrates the use of growth mixture analyses, and how to obtain…

  12. Students&apos; Opinions on Facebook Supported Blended Learning Environment

    ERIC Educational Resources Information Center

    Erdem, Mukaddes; Kibar, Pinar Nuhoglu

    2014-01-01

    The first purpose of this study was to determine students&apos; opinions on blended learning and its implementation. The other purpose was to explore the students&apos; opinions on Facebook integration into blended learning environment. The participants of this study were 40 undergraduate students in their fourth semester of the program.…

  13. Describing Elementary Teachers&apos; Operative Systems: A Case Study

    ERIC Educational Resources Information Center

    Dotger, Sharon; McQuitty, Vicki

    2014-01-01

    This case study introduces the notion of an operative system to describe elementary teachers&apos; knowledge and practice. Drawing from complex systems theory, the operative system is defined as the network of knowledge and practices that constituted teachers&apos; work within a lesson study cycle. Data were gathered throughout a lesson study…

  14. School Leaders&apos; Guide to Elementary Mathematics

    ERIC Educational Resources Information Center

    Curtis-Bey, Linda

    2013-01-01

    High achievement in mathematics is a critical part of the portfolios of students seeking admission to the best high schools and colleges; it is essential to a school&apos;s success at district, state, and national levels and to America&apos;s future as a global competitor. Elementary school leaders need to provide their students with a balanced,…

  15. Tapping Technology&apos;s Potential to Motivate Readers

    ERIC Educational Resources Information Center

    Conradi, Kristin

    2014-01-01

    Technology isn&apos;t inherently motivational to students, but teachers can employ a variety of strategies that can harness technology to promote student engagement. In so doing, teachers can focus on students&apos; self-concept as well as their attitudes as particularly important levers of motivating students to engage in reading.

  16. Children&apos;s Creativity in Day Care

    ERIC Educational Resources Information Center

    Reunamo, Jyrki; Lee, Hui-Chun; Wang, Li-Chen; Ruokonen, Inkeri; Nikkola, Teemu; Malmstrom, Sanna

    2014-01-01

    In this research, children&apos;s creativity in pretend play and the conditions for creativity during high involvement are studied from four points of view: as a zone for proximal development, as a skill, as a personal orientation and as a culturally shared environment creation. The theoretical model is influenced by Vygotsky&apos;s ideas of…

  17. Symbolic Notations and Students&apos; Achievements in Algebra

    ERIC Educational Resources Information Center

    Peter, Ebiendele E.; Olaoye, Adetunji A.

    2013-01-01

    This study focuses on symbolic notations and its impact on students&apos; achievement in Algebra. The main reason for this study rests on the observation from personal and professional experiences on students&apos; increasing hatred for Algebra. One hundred and fifty (150) Senior Secondary School Students (SSS) from Ojo Local Education District,…

  18. Professional Learning Communities: Teachers&apos; Perceptions and Student Achievement

    ERIC Educational Resources Information Center

    Peters, Erica

    2013-01-01

    Professional Learning Communities (PLC&apos;s) are designed to help schools improve student achievement; all decisions are based on the needs of students. PLC&apos;s are an effective way to receive professional development (PD), allow for collaboration with fellow teachers, and offer timely intervention to all students. In a district known for PLC…

  19. Investigating Young Children&apos;s Learning of Mass Measurement

    ERIC Educational Resources Information Center

    Cheeseman, Jill; McDonough, Andrea; Ferguson, Sarah

    2014-01-01

    This paper reports results of a design experiment regarding young children&apos;s concepts of mass measurement. The research built on an earlier study in which a framework of "growth points" in early mathematics learning and a related, task-based, one-to-one interview to assess children&apos;s understanding of the measurement of mass…

  20. Adolescents&apos; Use of Academic Language in Historical Writing

    ERIC Educational Resources Information Center

    Shen, Ting

    2011-01-01

    Despite its importance of academic language, research on academic language is often limited to academic vocabulary and focused on the English language learners. Informed by systemic functional linguistics, this study examined adolescents&apos; use of academic language and the relationships between its use and students&apos; reading ability and…

  1. Online Games for Young Learners&apos; Foreign Language Learning

    ERIC Educational Resources Information Center

    Butler, Yuko Goto; Someya, Yuumi; Fukuhara, Eiji

    2014-01-01

    Young learners&apos; use of instructional games in foreign language learning is not yet well understood. Using games that were part of the learning tools for an online assessment, Jido-Eiken, a standardized English proficiency test for young learners in Japan, we examined young learners&apos; game-playing behaviours and the relationship of these…

  2. Eighth-Grade Students&apos; Perceptions of Teacher Effectiveness

    ERIC Educational Resources Information Center

    Sprague, Julie A.

    2013-01-01

    This quantitative study used a validated student survey instrument to collect 182 Midwestern eighth-grade students&apos; perceptions of effective teachers. Balch&apos;s (2011) survey was used. The original intent of this survey was to have students rate the effectiveness of one teacher. In this study, students were asked to rate teacher…

  3. Reflections on Jonathan Boston&apos;s Paper

    ERIC Educational Resources Information Center

    Devine, Nesta

    2014-01-01

    In this article, Nesta Devine responds to Jonathan Boston&apos;s article "Child Poverty in New Zealand: Why It Matters and How It Can Be Reduced" ("Educational Philosophy and Theory," v46 n9 p995-999, 2014). Devine wishes to consider Boston&apos;s position from two angles: one is to rehearse the point that these statistics are…

  4. Small Talk: Children&apos;s Everyday "Molecule" Ideas

    ERIC Educational Resources Information Center

    Jakab, Cheryl

    2013-01-01

    This paper reports on 6-11-year-old children&apos;s "sayings and doings" (Harré 2002) as they explore molecule artefacts in dialectical-interactive teaching interviews (Fleer, "Cultural Studies of Science Education" 3:781-786, 2008; Hedegaard et al. 2008). This sociocultural study was designed to explore children&apos;s…

  5. Supervisor&apos;s Interactive Model of Organizational Relationships

    ERIC Educational Resources Information Center

    O'Reilly, Frances L.; Matt, John; McCaw, William P.

    2014-01-01

    The Supervisor&apos;s Interactive Model of Organizational Relationships (SIMOR) integrates two models addressed in the leadership literature and then highlights the importance of relationships. The Supervisor&apos;s Interactive Model of Organizational Relationships combines the modified Hersey and Blanchard model of situational leadership, the…

  6. Storymakers: Hopa Mountain&apos;s Early Literacy Program

    ERIC Educational Resources Information Center

    Templin, Patricia A.

    2013-01-01

    Hopa Mountain&apos;s StoryMakers program is an innovative, research-based program for donating high quality young children&apos;s books to parents. Hopa Mountain is a nonprofit organization based in Bozeman, Montana. Hopa Mountain works with groups of rural and tribal citizen leaders who form StoryMakers Community Teams to talk one-on-one with…

  7. Responding to Students&apos; Learning Preferences in Chemistry

    ERIC Educational Resources Information Center

    Lewthwaite, Brian; Wiebe, Rick

    2014-01-01

    This paper reports on a teacher&apos;s and his students&apos; responsiveness to a new tetrahedral-oriented (Mahaffy in "J Chem Educ" 83(1):49-55, 2006) curriculum requiring more discursive classroom practices in the teaching of chemistry. In this instrumental case study, we identify the intentions of this learner-centered curriculum and…

  8. Turkish Primary Students&apos; Perceptions of Geography

    ERIC Educational Resources Information Center

    Senyurt, Secil

    2014-01-01

    This study provides an in-depth investigation of Turkish primary school students&apos; perceptions of geography. Gender differences in students&apos; perceptions of geography were investigated, including definitions of geography and its field of study. The findings showed that "landforms," "our geographical regions/Turkey,"…

  9. Finnish Secondary School Students&apos; Interreligious Sensitivity

    ERIC Educational Resources Information Center

    Holm, Kristiina; Nokelainen, Petri; Tirri, Kirsi

    2014-01-01

    The aim of this study was to assess the self-evaluations of Finnish secondary school students&apos; (N?=?549) interreligious sensitivity. The data were collected from 12-16-year-old young people with a 15-item Interreligious Sensitivity Scale Questionnaire (IRRSSQ). The IRRSSQ is based on Abu-Nimer&apos;s Developmental Model of Interreligious…

  10. Understanding Gauss&apos;s Law Using Spreadsheets

    ERIC Educational Resources Information Center

    Baird, William H.

    2013-01-01

    Some of the results from the electrostatics portion of introductory physics are particularly difficult for students to understand and/or believe. For students who have yet to take vector calculus, Gauss&apos;s law is far from obvious and may seem more difficult than Coulomb&apos;s. When these same students are told that the minimum potential…

  11. Coaching Discourse: Supporting Teachers&apos; Professional Learning

    ERIC Educational Resources Information Center

    Heineke, Sally F.

    2013-01-01

    Although coaching is used in many schools to facilitate teachers&apos; professional learning, few studies look closely at coaching discourse. Exploring how coaching facilitates teachers&apos; professional development, this study used tape-recorded coaching sessions and individual post-interviews to examine the one-on-one coaching interactions of 4…

  12. Students&apos; Conceptions as Dynamically Emergent Structures

    ERIC Educational Resources Information Center

    Brown, David E.

    2014-01-01

    There is wide consensus that learning in science must be considered a process of conceptual change rather than simply information accrual. There are three perspectives on students&apos; conceptions and conceptual change in science that have significant presence in the science education literature: students&apos; ideas as misconceptions, as…

  13. Deaf Students&apos; Metacognitive Awareness during Language Comprehension

    ERIC Educational Resources Information Center

    Morrison, Carolyn; Marschark, Marc; Sarchet, Thomastine; Convertino, Carol M.; Borgna, Georgianna; Dirmyer, Richard

    2013-01-01

    This study explored deaf and hearing university students&apos; metacognitive awareness with regard to comprehension difficulties during reading and classroom instruction. Utilising the Reading Awareness Inventory (Milholic, V. 1994. "An inventory to pique students&apos; metacognitive awareness of reading strategies." "Journal of…

  14. Vocational Education for China&apos;s Ethnic Minorities

    ERIC Educational Resources Information Center

    Qian, Minhui

    2013-01-01

    This article analyzes the current status and problems of vocational education for China&apos;s ethnic minorities. It concludes that these problems have both universal areas in common with China&apos;s overall education situation and individual characteristics; they also have both extrinsic and intrinsic qualities. The universal areas include the…

  15. Modality and Children&apos;s Scope Understanding

    ERIC Educational Resources Information Center

    Liu, Chin-Ting Jimbo; Lee, Hsiu-Fen Hélène

    2014-01-01

    This study intends to shed light on the inconclusive argument pertaining to children&apos;s acquisition of logical form (LF) operation. Specifically, we examined children&apos;s interpretations of sentences with the ambiguous modal verb "yinggai" "should," like "Xiaohua yinggai shangchuang shuijiao le", whose meanings…

  16. Exploring Preservice Teachers&apos; Emerging Understandings of Disciplinary Literacy

    ERIC Educational Resources Information Center

    Masuda, Avis M.

    2014-01-01

    This qualitative inquiry examined 14 secondary preservice teachers&apos; emerging understandings of disciplinary literacy. Data included preservice teachers&apos; written reflections and annotated lesson plans, which were analyzed for understanding of discipline-specific habits of thinking, texts, reading and writing demands of academic texts,…

  17. Modern Analogue of Ohm&apos;s Historical Experiment

    ERIC Educational Resources Information Center

    Mayer, V. V.; Varaksina, E. I.

    2014-01-01

    Students receive a more complete conception of scientific cognition methods if they reproduce fundamentally important historical investigations on their own. Ohm&apos;s investigation realized in 1826 is one of these. This paper presents a simple and accessible experimental unit, in which Ohm&apos;s ideas are implemented with the help of modern…

  18. Principals&apos; Leadership Styles and Student Achievement

    ERIC Educational Resources Information Center

    Harnish, David Alan

    2012-01-01

    Many schools struggle to meet No Child Left Behind&apos;s stringent adequate yearly progress standards, although the benchmark has stimulated national creativity and reform. The purpose of this study was to explore teacher perceptions of principals&apos; leadership styles, curriculum reform, and student achievement to ascertain possible factors to…

  19. Teachers&apos; Role in Curriculum Design in Portuguese Schools

    ERIC Educational Resources Information Center

    Mouraz, Ana; Leite, Carlinda; Fernandes, Preciosa

    2013-01-01

    Teachers&apos; role in curriculum design is a broad question that inspires political educational reforms among European countries, a trend that even extends to higher education politics. The perspective on teachers&apos; role in curriculum, both at the level of the policies and of the practices, shapes recent educational reforms in Portugal. These…

  20. Teachers&apos; Reported Utilization of Reading Disabilities Research

    ERIC Educational Resources Information Center

    Davidson, Katherine

    2013-01-01

    This study was conducted to explore elementary school teachers&apos; uses of reading disabilities research. A modified version of Knott and Wildavsky&apos;s (1980) knowledge utilization framework underpinned the investigation. Teachers completed a questionnaire and participated in focus groups which elicited their reported uses of reading…