WorldWideScience

Sample records for apolipoprotein-e forms dimers

  1. Apolipoprotein E genotype in schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Joober, R.; Lal, S.; Bloom, D.; Benkelfat, C. [McGill Research Centre for Schizophrenia, Douglas Hospital, Montreal (Canada)] [and others

    1996-04-09

    We investigated the association between schizophrenia and the allelic polymorphism in the apolipoprotein E (Apo E) gene in 51 schizophrenic patients and 35 controls. The Apo E4 allele was equally represented in the schizophrenic group (16%) and the control group (20%) suggesting no association between schizophrenia and the Apo E4 allele. The apolipoprotein E (Apo E) is a polymorphic (E2, E3, and E4) lipoprotein involved in the transmembrane transport of cholesterol and is thought to play an important role in neuronal growth and in the central nervous system response to injury, particularly in the hippocampal region. Recent findings strongly suggest that the Apo E4 allele is associated with cognitive deficits in normal and pathological aging, e.g., Alzheimer`s disease. 5 refs., 1 tab.

  2. Apolipoprotein E and familial longevity

    DEFF Research Database (Denmark)

    Schupf, Nicole; Barral, Sandra; Perls, Thomas;

    2013-01-01

    Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently. Offspring from long-lived families...... findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity....

  3. Role of apolipoprotein E in febrile convulsion.

    Science.gov (United States)

    Giray, Ozlem; Ulgenalp, Ayfer; Bora, Elçin; Uran, Nedret; Yilmaz, Ebru; Unalp, Aycan; Erçal, Derya

    2008-10-01

    Apolipoprotein E is consistently associated with the progression of some common human neurodegenerative diseases, e.g., epilepsy. We hypothesized that genetic variations in the apolipoprotein E gene have implications for susceptibility to, and prognoses in, febrile convulsion, which plays an apparent role in the development of epilepsy. We used the polymerase chain reaction and restriction enzyme digestion to characterize variations of the apolipoprotein E gene. Sixty-nine patients with febrile convulsion (simple/complex) and a corresponding cohort of healthy patients (n = 75) were used. There was no significant difference in genotypic distribution and allelic frequencies of the apolipoprotein E gene between the febrile convulsion and control groups. Comparing subpopulations of the febrile convulsion group (patients with simple and complex febrile convulsion), we noted that no patients with the epsilon3/epsilon4 genotype had complex febrile convulsions. The apolipoprotein E epsilon3/epsilon4 genotype was more frequently seen in the simple febrile than in the complicated febrile convulsion group (9 versus 0 patients, respectively). The data indicate an association with the epsilon3/epsilon4 genotype of the apolipoprotein E gene with a milder phenotype. Although apolipoprotein E4 is not a vulnerability factor regarding febrile convulsions, it seems effective in regard to prognoses. PMID:18805361

  4. Apolipoprotein E Polymorphism in Tuberculosis Patients

    Science.gov (United States)

    Naserpour Farivar, Taghi; Sharifi Moud, Batool; Sargazi, Mansur; Moeenrezakhanlou, Alireza

    In this study, we aimed to determine the significance of association between Tuberculosis and apolipoprotein E polymorphism. The apolipoprotein E genotypes were assayed in 250 tuberculosis patients by polymerase chain reaction followed by enzymatic digestion with Hha I. The results were compared with the results of the same experiments on 250 sex and age matched control peoples. Present results showed that in studied populations, prevalence of E4 genotype was lower in controls than in patients (8 v. 13.2%; OR = 1.75, pStatistically significant difference was found between patients and controls with respect to ɛ2 allele frequencies, while ɛ2 allele frequency was found to be much less prevalent in controls (6%) than in patients (35.8%; OR = 8.72, p<0.05). Also, our study revealed that there is an association between apolipoprotein E genotypes and amplitude to tuberculosis in studied populations. However, large population-based studies are needed to understand the exact role played by the locus in causing the condition.

  5. Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease.

    Science.gov (United States)

    Singhrao, Sim K; Harding, Alice; Chukkapalli, Sasanka; Olsen, Ingar; Kesavalu, Lakshmyya; Crean, StJohn

    2016-01-01

    The primary goal of advancement in clinical services is to provide a health care system that enhances an individual's quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual's lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer's disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia. PMID:26923007

  6. Apolipoprotein E mimetic peptide protects against diffuse brain injur y

    Institute of Scientific and Technical Information of China (English)

    Yaning Zhao; Jianmin Li; Qiqun Tang; Junling Gao; Changxiang Chen; Liwei Jing; Pan Zhang; Shuxing Li

    2014-01-01

    Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.

  7. Role of Apolipoprotein E in Anxiety

    Directory of Open Access Journals (Sweden)

    Jacob Raber

    2007-07-01

    Full Text Available Anxiety is most common among Alzheimer's disease (AD patients with an age at onset under age 65. Apolipoprotein E4 (apoE4 is a risk factor for developing AD at an earlier age and might contribute to this effect. In mice, apoE plays a role in the regulation of anxiety, which might involve histamine receptor-mediated signaling and steroidogenesis in the adrenal gland. In addition, human apoE isoforms have differential effects on anxiety in adult mice lacking apoE and probable AD patients. Compared to wild-type mice, mice lacking apoE and apoE4 mice showed pathological alterations in the central nucleus of the amygdala, which is involved in regulation of anxiety. ApoE4, but not mice lacking apoE, or apoE3 mice showed impaired dexamethasone suppression of plasma corticosterone. Understanding how apoE modulates measures of anxiety might help the developments of therapeutic targets to reduce or even prevent measures of anxiety in health and in dementing illnesses.

  8. Resolving the Relationship between Apolipoprotein E and Depression

    OpenAIRE

    Slifer, Michael A; Martin, Eden R.; Gilbert, John R.; Haines, Jonathan L.; Pericak-Vance, Margaret A.

    2009-01-01

    Several studies have reported an association between the ApolipoproteinE-ε4 (APOE4) allele and depression among elders. However others have failed to find an association. Since APOE4 is a well recognized risk factor for Alzheimer dementia, cognitive status may represent an important confounder between APOE4 and depression. In this investigation, we examined the relationship between the ApolipoproteinE-ε4 allele and depression among elders accounting for cognitive status.

  9. Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke

    DEFF Research Database (Denmark)

    Khan, Tauseef A; Shah, Tina; Prieto, David;

    2013-01-01

    At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less c...

  10. DMPD: Regulation of endogenous apolipoprotein E secretion by macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18388328 Regulation of endogenous apolipoprotein E secretion by macrophages. Kockx ...svg) (.html) (.csml) Show Regulation of endogenous apolipoprotein E secretion by macrophages. PubmedID 18388...328 Title Regulation of endogenous apolipoprotein E secretion by macrophages. Aut

  11. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    OpenAIRE

    Tuminello, Elizabeth R.; S Duke Han

    2011-01-01

    Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε 4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε 4 carriers has suggested that the APOE ε 4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an e...

  12. Antiatherogenic effects of oleanolic acid in apolipoprotein E knockout mice

    DEFF Research Database (Denmark)

    Buus, Niels Henrik; Hansson, Nicolaj Christopher; Rodriguez-Rodriguez, Rosalia;

    2011-01-01

    Oleanolic acid (OA) is a plant triterpenoid steroid with potentially antiatherogenic properties. We investigated whether OA affected atherosclerosis development and vascular function in apolipoprotein E knockout (ApoE(-/-)) mice. ApoE(-/-) mice were fed a high cholesterol Western-type diet in...... combination with OA (100 mg/kg/day), fluvastatin (5 mg/kg/day) or vehicle, with wild type (WT) mice serving as controls. After 8 weeks of treatment atherosclerotic plaque areas in the aortic arch and plasma lipid concentrations were determined. Vasoconstriction and relaxation of the proximal part of aorta...... were investigated in vitro. Inducible nitric oxide synthase (iNOS) was visualized using immunoblotting. As opposed to WT and fluvastatin- and vehicle-treated mice, OA-fed ApoE(-/-) mice gained no weight during the treatment period. Plasma concentrations of total-cholesterol and triglyceride were not...

  13. Cardiovascular effects of uremia in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Bro, Susanne

    2009-01-01

    of smooth muscle cell assigned genes indicates that besides intimal atherosclerosis, uremic vasculopathy in apoE-/- mice is characterized by a uremia-specific medial smooth muscle cell degeneration. Oxidative stress could also be important for the development of atherosclerotic lesions in uremia. In...... muscle cell degeneration. Furthermore, the studies suggested that vascular inflammation and systemic oxidative stress may explain some of the proatherogenic effects of uremia in mice. Interestingly, the accelerated atherosclerosis could be prevented by RAS inhibition, or markedly reduced by RAGE blockade......The purpose of this thesis work was to establish an experimental mouse model for studying the pathogenesis and therapy of accelerated atherosclerosis in uremia. Uremia was induced by surgical 5/6 nephrectomy in apolipoprotein E-deficient (apoE-/-) mice and led to development of severe aortic...

  14. Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Valérie Leduc

    2011-01-01

    Full Text Available Alzheimer's disease (AD—the most common type of dementia among the elderly—represents one of the most challenging and urgent medical mysteries affecting our aging population. Although dominant inherited mutation in genes involved in the amyloid metabolism can elicit familial AD, the overwhelming majority of AD cases, dubbed sporadic AD, do not display this Mendelian inheritance pattern. Apolipoprotein E (APOE, the main lipid carrier protein in the central nervous system, is the only gene that has been robustly and consistently associated with AD risk. The purpose of the current paper is thus to highlight the pleiotropic roles and the structure-function relationship of APOE to stimulate both the functional characterization and the identification of novel lipid homeostasis-related molecular targets involved in AD.

  15. Visfatin Destabilizes Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Bo Li

    Full Text Available Although there is evidence that visfatin is associated with atherogenesis, the effect of visfatin on plaque stability has not yet been explored.In vivo, vulnerable plaques were established by carotid collar placement in apolipoprotein E-deficient (ApoE-/- mice, and lentivirus expressing visfatin (lenti-visfatin was locally infused in the carotid artery. The lipid, macrophage, smooth muscle cell (SMC and collagen levels were evaluated, and the vulnerability index was calculated. In vitro, RAW264.7 cells were stimulated with visfatin, and the MMPs expressions were assessed by western blot and immunofluorescence. And the mechanism that involved in visfatin-induced MMP-8 production was investigated.Transfection with lenti-visfatin significantly promoted the expression of visfatin which mainly expressed in macrophages in the plaque. Lenti-visfatin transfection significantly promoted the accumulation of lipids and macrophages, modulated the phenotypes of smooth muscle cells and decreased the collagen levels in the plaques, which significantly decreased the plaque stability. Simultaneously, transfection with lenti-visfatin significantly up-regulated the expression of MMP-8 in vivo, as well as MMP-1, MMP-2 and MMP-9. Recombinant visfatin dose- and time-dependently up-regulated the in vitro expression of MMP-8 in macrophages. Visfatin promoted the translocation of NF-κB, and inhibition of NF-κB significantly reduced visfatin-induced MMP-8 production.Visfatin increased MMP-8 expression, promoted collagen degradation and increased the plaques vulnerability index.

  16. Characterization of dimeric forms of human pituitary growth hormone by bioassay, radioreceptor assay, and radioimmunoassay

    International Nuclear Information System (INIS)

    Seven highly purified dimeric forms of human pituitary growth hormone, composed of the monomeric forms 20 K hGH, 22K hGH and 24 k hBH linked together by noncovalent or covalent bounds, have been characterized by an in vitro bioassay (the Nb2 assay), a radioreceptor assay and a radioimmunoassay. Considerable differences in the ability to displace labelled recombinant hGH were observed in the radioreceptor assay. The seven dimeric forms varied over a range between 22 K hGH (most effective) and 20 K hGH. The three covalently-linked dimeric forms had nearly identical affinity constants. The mitogenic action of all but one of the hGH dimers in the Nb2 assay was in the same mutual order as the receptor binding activity in the radioreceptor assay. In the RIA, all dose-response curves were parallel except for those obtained with 20 K hGH and with the dimeric form (20 K-20 K)hGH. In this assay, dimeric variants of the constituents 22 K hGH and 24 K hGH were approximately twice as active as 22 K hGH on a molar basis, suggesting about the same affinity between the the antibodies and each of the monomeric forms. Determination of the amino acid compositions of the dimeric forms provided support for their content of monomeric constituents as established earlier by electrophoretic analysis. (author)

  17. Apolipoprotein E promotes lipid accumulation and differentiation in human adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lasrich, Dorothee; Bartelt, Alexander [Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Grewal, Thomas, E-mail: thomas.grewal@sydney.edu.au [Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW 2006 (Australia); Heeren, Joerg, E-mail: heeren@uke.de [Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany)

    2015-09-10

    Several studies in mice indicate a role for apolipoprotein E (APOE) in lipid accumulation and adipogenic differentiation in adipose tissue. However, little is yet known if APOE functions in a similar manner in human adipocytes. This prompted us to compare lipid loading and expression of adipocyte differentiation markers in APOE-deficient and control adipocytes using the differentiated human mesenchymal stem cell line hMSC-Tert as well as primary human and mouse adipocytes as model systems. Differentiated hMSC-Tert were stably transduced with or without siRNA targeting APOE while murine adipocytes were isolated from wild type and Apoe knockout mice. Human APOE knockdown hMSC-Tert adipocytes accumulated markedly less triglycerides compared to control cells. This correlated with strongly decreased gene expression levels of adipocyte markers such as adiponectin (ADIPOQ) and fatty acid binding protein 4 (FABP4) as well as the key transcription factor driving adipocyte differentiation, peroxisome proliferator activator receptor gamma (PPARG), in particular the PPARG2 isoform. Similarly, differentiation of murine Apoe-deficient adipocytes was characterized by reduced gene expression of Adipoq, Fabp4 and Pparg. Interestingly, incubation of APOE-deficient hMSC-Tert adipocytes with conditioned media from APOE3-overexpressing adipocytes or APOE-containing Very Low Density Lipoprotein (VLDL) partially restored triglyceride accumulation, but were unable to induce adipocyte differentiation, as judged by expression of adipocyte markers. Taken together, depletion of endogenous APOE in human adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation. - Highlights: • Immortalized human mesenchymal stem cells were used to study adipocyte development. • Knockdown of endogenous APOE lead to impaired lipid accumulation and adipogenesis. • APOE supplementation partially restored lipid accumulation but not differentiation.

  18. Apolipoprotein E promotes lipid accumulation and differentiation in human adipocytes

    International Nuclear Information System (INIS)

    Several studies in mice indicate a role for apolipoprotein E (APOE) in lipid accumulation and adipogenic differentiation in adipose tissue. However, little is yet known if APOE functions in a similar manner in human adipocytes. This prompted us to compare lipid loading and expression of adipocyte differentiation markers in APOE-deficient and control adipocytes using the differentiated human mesenchymal stem cell line hMSC-Tert as well as primary human and mouse adipocytes as model systems. Differentiated hMSC-Tert were stably transduced with or without siRNA targeting APOE while murine adipocytes were isolated from wild type and Apoe knockout mice. Human APOE knockdown hMSC-Tert adipocytes accumulated markedly less triglycerides compared to control cells. This correlated with strongly decreased gene expression levels of adipocyte markers such as adiponectin (ADIPOQ) and fatty acid binding protein 4 (FABP4) as well as the key transcription factor driving adipocyte differentiation, peroxisome proliferator activator receptor gamma (PPARG), in particular the PPARG2 isoform. Similarly, differentiation of murine Apoe-deficient adipocytes was characterized by reduced gene expression of Adipoq, Fabp4 and Pparg. Interestingly, incubation of APOE-deficient hMSC-Tert adipocytes with conditioned media from APOE3-overexpressing adipocytes or APOE-containing Very Low Density Lipoprotein (VLDL) partially restored triglyceride accumulation, but were unable to induce adipocyte differentiation, as judged by expression of adipocyte markers. Taken together, depletion of endogenous APOE in human adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation. - Highlights: • Immortalized human mesenchymal stem cells were used to study adipocyte development. • Knockdown of endogenous APOE lead to impaired lipid accumulation and adipogenesis. • APOE supplementation partially restored lipid accumulation but not differentiation.

  19. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing.

    Science.gov (United States)

    Bachmeier, Corbin; Shackleton, Ben; Ojo, Joseph; Paris, Daniel; Mullan, Michael; Crawford, Fiona

    2014-12-01

    Recent findings indicate an isoform-specific role for apolipoprotein E (apoE) in the elimination of beta-amyloid (Aβ) from the brain. ApoE is closely associated with various lipoprotein receptors, which contribute to Aβ brain removal via metabolic clearance or transit across the blood–brain barrier (BBB). These receptors are subject to ectodomain shedding at the cell surface, which alters endocytic transport and mitigates Aβ elimination. To further understand the manner in which apoE influences Aβ brain clearance, these studies investigated the effect of apoE on lipoprotein receptor shedding. Consistent with prior reports, we observed an increased shedding of the low-density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1) following Aβ exposure in human brain endothelial cells. When Aβ was co-treated with each apoE isoform, there was a reduction in Aβ-induced shedding with apoE2 and apoE3, while lipoprotein receptor shedding in the presence of apoE4 remained increased. Likewise, intracranial administration of Aβ to apoE-targeted replacement mice (expressing the human apoE isoforms) resulted in an isoform-dependent effect on lipoprotein receptor shedding in the brain (apoE4 > apoE3 > apoE2). Moreover, these results show a strong inverse correlation with our prior work in apoE transgenic mice in which apoE4 animals showed reduced Aβ clearance across the BBB compared to apoE3 animals. Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing Aβ from the brain. PMID:25015123

  20. Optimisation and evaluation of restriction fragment length polimorfism method for apolipoprotein E

    Directory of Open Access Journals (Sweden)

    Drljević Nevena

    2014-01-01

    Full Text Available Introduction. Apolipoprotein E gene polymorphism is characterized by the presence of three common alleles, e2, e3 and e4, which encode three isoforms of apolipoprotein E in plasma E2, E3 and E4. Genetic polymorphisms of apolipoprotein E gene are predictive markers for the development of numerous disorders of lipid metabolism, already proven in a large number of clinical trials. This study was aimed at assessing the success rate of restriction fragment length polymorphism method for the detections of genes coding for isoenzymes E2, E3 and E4. Material and Methods. Deoxyribonucleic acid, used in this study, was extracted from blood by standard procedure using chloroform and phenol. The polymerase chain reaction method was used to amplify the coding sequence of fourth exon of the apolipoprotein E gene. Amplification products were digested with HhaI. The fragments obtained were separated by electrophoresis and visualized with ultraviolet light. Results. Our results showed that the restriction fragment length polymorphism method is optimal for detection of apolipoprotein E polymorphisms. The restriction enzyme HhaI achieved the cleavage of the gene on the specific loci, directly depend of presence or absence of mutations at positions 112 and 158, of different alleles. Conclusion. This method enables simple, rapid and efficient analysis of restriction fragment length polymorphisms, directly determining the patient’s genotype.

  1. Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Svetlana Sarantseva

    Full Text Available BACKGROUND: Mutations of the amyloid precursor protein gene (APP are found in familial forms of Alzheimer's disease (AD and some lead to the elevated production of amyloid-beta-protein (Abeta. While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear. PRINCIPAL FINDINGS: In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies. CONCLUSIONS: The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE with neuroprotective activities.

  2. A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

    Directory of Open Access Journals (Sweden)

    Partha S Bhattacharjee

    Full Text Available Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp derived from the receptor binding region of human apolipoprotein E (apoE inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

  3. Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease.

    Science.gov (United States)

    Salameh, Therese S; Rhea, Elizabeth M; Banks, William A; Hanson, Angela J

    2016-09-01

    An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease. PMID:27470930

  4. Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells

    DEFF Research Database (Denmark)

    Merz, G S; Benedikz, Eirikur; Schwenk, V;

    1997-01-01

    To define the cellular processing of human cystatin C as well as to lay the groundwork for investigating its contribution to lcelandic Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA-I), we have characterized the trafficking, secretion, and extracellular fate of human cystatin C in...... the cystatin C dimer, formed during intracellular trafficking, is converted to monomer at or before secretion. Cells in which exit from the endoplasmic reticulum (ER) was blocked with brefeldin A contained the 33 kDa species, indicating that cystatin C dimerization occurs in the ER. After removal of......, presumably as a consequence of the low pH of late endosome/lysosomes. As a dimer, cystatin C would be prevented from inhibiting the lysosomal cysteine proteases. These results reveal a novel mechanism, transient dimerization, by which cystatin C is inactivated during the early part of its trafficking through...

  5. Structural and Vibrational Study on Monomer and Dimer Forms and Water Clusters of Acetazolamide

    Directory of Open Access Journals (Sweden)

    Aysen E. Ozel

    2013-01-01

    Full Text Available Experimental IR and Raman spectra of solid acetazolamide have been analysed by computing the molecular structures and vibrational spectra of monomer and dimer forms and water clusters of acetazolamide. The possible stable conformers of free acetazolamide molecule in the ground state were obtained by scanning the potential energy surface through the dihedral angles, D1 (1S-2C-6S-9N, D2 (4N-5C-12N-14C, and D3 (5C-12N-14C-16C. The final geometry parameters for the obtained stable conformers were determined by means of geometry optimization, carried out at DFT/B3LYP/6-31G++(d,p theory level. Afterwards the possible dimer forms of the molecule and acetazolamide-H2O clusters were formed and their energetically preferred conformations were investigated using the same method and the same level of theory. The effect of BSSE on the structure and energy of acetazolamide dimer has been investigated. The assignment of the vibrational modes was performed based on the potential energy distribution of the vibrational modes, calculated by using GAR2PED program. The experimental vibrational wavenumbers of solid acetazolamide are found to be in better agreement with the calculated wavenumbers of dimer form of acetazolamide than those of its monomeric form. NBO analysis has been performed on both monomer and dimer geometries.

  6. The Apolipoprotein E/CI/CII Gene Cluster and Late-Onset Alzheimer Disease

    OpenAIRE

    Yu, Chang-En; Payami, Haydeh; Olson, Jane M.; Boehnke, Michael; Wijsman, Ellen M; Orr, Harry T.; Kukull, Walter A.; Goddard, Katrina A B; Nemens, Ellen; White, June A.; Alonso, M. Elisa; Taylor, Todd D.; Ball, Melvyn J.; Kaye, Jeffrey; Morris, John

    1994-01-01

    The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset

  7. Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

    Czech Academy of Sciences Publication Activity Database

    Dolejší, Eva; Liraz, O.; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; Michaelson, D. M.

    Roč. 136, č. 3 ( 2016 ), s. 503-509. ISSN 0022-3042 R&D Projects: GA MŠk(CZ) LH13269 Institutional support: RVO:67985823 Keywords : acetylcholine release * Alzheimer's disease (AD) * apolipoprotein E4 (apoE4) * hippocampus Subject RIV: FH - Neurology Impact factor: 4.281, year: 2014

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

    Science.gov (United States)

    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 ...

  9. Overexpression and characterization of dimeric and tetrameric forms of recombinant serine hydroxymethyltransferase from Bacillus stearothermophilus

    Indian Academy of Sciences (India)

    Venkatakrishna R Jala; V Prakash; N Appaji Rao; H S Savithri

    2002-06-01

    Serine hydroxymethyltransferase (SHMT), a pyridoxal-5′-phosphate (PLP) dependent enzyme catalyzes the interconversion of L-Ser and Gly using tetrahydrofolate as a substrate. The gene encoding for SHMT was amplified by PCR from genomic DNA of Bacillus stearothermophilus and the PCR product was cloned and overexpressed in Escherichia coli. The purified recombinant enzyme was isolated as a mixture of dimer (90%) and tetramer (10%). This is the first report demonstrating the existence of SHMT as a dimer and tetramer in the same organism. The specific activities at 37°C of the dimeric and tetrameric forms were 6.7 U/mg and 4.1 U/mg, respectively. The purified dimer was extremely thermostable with a m of 85°C in the presence of PLP and L-Ser. The temperature optimum of the dimer was 80°C with a specific activity of 32.4 U/mg at this temperature. The enzyme catalyzed tetrahydrofolate-independent reactions at a slower rate compared to the tetrahydrofolate-dependent retro-aldol cleavage of L-Ser. The interaction with substrates and their analogues indicated that the orientation of PLP ring of B. stearothermophilus SHMT was probably different from sheep liver cytosolic recombinant SHMT (scSHMT).

  10. Endothelial surface layer degradation by chronic hyaluronidase infusion induces proteinuria in apolipoprotein e-deficient mice

    OpenAIRE

    Meuwese, Marijn C.; Broekhuizen, Lysette N.; Mayella Kuikhoven; Sylvia Heeneman; Esther Lutgens; Marion J J Gijbels; Max Nieuwdorp; Peutz, Carine J; Stroes, Erik S.G.; Hans Vink; van den Berg, Bernard M.

    2010-01-01

    OBJECTIVE: Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model. METHODS: Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 we...

  11. Expression analysis of apolipoprotein E and its associated genes in gastric cancer

    OpenAIRE

    Shi, Xiumin; Xu, Jianting; Wang, Jihan; CUI, MEIZI; Gao, Yushun; Niu, Haitao; Jin, Haofan

    2015-01-01

    Gastric cancer is a common type of cancer worldwide, and has a poor prognosis, in part due to the low rates of early diagnosis and the limited treatment methods available. Apolipoprotein E (ApoE) is involved in exogenous cholesterol transport and may be important in enabling tumor cells to fulfill their high cholesterol requirements. A number of reports have indicated that ApoE affects the development and prognosis of gastric cancer. Therefore, the aim of the present study was to investigate ...

  12. Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Lucotte, G.; David, F.; Berriche, S. [Regional Center of Neurogenetics, Reims (France)] [and others

    1994-09-15

    Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

  13. Apolipoprotein E Polymorphism and Colorectal Neoplasm: Results from a Meta-Analysis

    OpenAIRE

    Tian, Yun; Wang, Jirong; Ye, Ying; Sun, Liqun; Fan, Yingrui; Wang, Li; Juan LI; Wang, Zhaoxia; Wang, Keming

    2014-01-01

    To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 part...

  14. Enhanced Diabetes Susceptibility in Community Dwelling Han Elders Carrying the Apolipoprotein E 3/3 Genotype

    OpenAIRE

    Ban, Chun-Xia; Zhong, Li; Wang, Tao; Zhu, Min-jie; Wang, Jing-Hua; Zhang, Zhen-lian; Wang, Zhe; Su, Ning; Liu, Yuan-Yuan; Shi, Yan-chen; Xiao, Shi-fu; Xia LI

    2016-01-01

    Despite Apolipoprotein E (ApoE) being one of the main apolipoproteins in the blood, the association between its genotype and the high cholesterol or blood glucose levels commonly seen in clinical practice is inconclusive. Such research is also lacking in the Han population. The aim of this study was to investigate the association between APOE genotype, diabetes, and plasma glucose and lipid levels. We included 243 community-dwelling elderly residents in this study. Participant APOE genotypes ...

  15. The Apolipoprotein E Gene and Taq1A Polymorphisms in Childhood Obesity

    OpenAIRE

    Ergun, Mehmet Ali; Karaoguz, Meral Yirmibes; Koc, Altug; Camurdan, Orhun; Bideci, Aysun; Yazici, A. Canan; Cinaz, Peyami

    2010-01-01

    Obesity is a multifactorial disease that is influenced by genetic and environmental factors. The apolipoprotein E (Apo E) polymorphism has been reported to influence some lipid profile abnormalities associated with obesity in childhood. In this study, the relationship between the Apo E gene and Taq1A polymorphisms with childhood obesity has been studied. Regarding the Apo E genotypes, e3/4 was the most frequent in both the patient and control groups. Further, there was a significance between ...

  16. A detailed MSn study for the molecular identification of a dimer formed from oxidation of pinene

    Science.gov (United States)

    Beck, Martin; Hoffmann, Thorsten

    2016-04-01

    Dimeric products formed in the oxidation of α- and β-pinene have been frequently observed in laboratory and field studies of biogenic SOA formation. While their existence is undoubted, their exact chemical structures remain unclear. This study uses a combined two step approach aiming on the molecular identification of the most important of the various dimers that have been observed in biogenic secondary organic aerosol formation, a dimer with the molecular weight 358 g mol-1. The first step is the application of a functional group derivatization technique (esterification) to quantify the number of carboxylic acid groups in the target molecule. Based on the detailed interpretation of the MSn spectra (up to n = 7) of the derivatized product further information about the exact structure of the compound of interest is compiled. To increase the intensity of precursor ions for the MSn-studies and especially to facilitate successive fragmentation of the target molecule, which yields structurally informative product spectra, cationization reagents (Li+, NH4+) are introduced. The results clearly point to the formation of a dimer containing three carboxylic acid groups and a structure containing a terpenylic acid building block and a pinic acid building block, strongly supporting a structure suggestion by Claeys and coworkers (Yasmeen et al., 2010).

  17. Apolipoprotein E ε4 allele and malondialdehyde level are independent risk factors for Alzheimer’s disease

    OpenAIRE

    López-Riquelme, Natividad; Alom-Poveda, Jordi; Viciano-Morote, Nuria; Llinares-Ibor, Isabel; Tormo-Díaz, Consuelo

    2016-01-01

    Background: The ε4 allele of Apolipoprotein E is involved in lipid metabolism. Oxidative stress produces an increase in lipid peroxidation that has been implicated in the pathogenic cascade in Alzheimer’s disease. This study estimated the effect of the ε4 allele, malondialdehyde and lipid levels on the risk for Alzheimer’s disease. Methods: A total of 41 control subjects and 73 patients with Alzheimer’s disease were recruited. The Apolipoprotein E genotype was determined by amplification of e...

  18. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

    OpenAIRE

    Sumeet S Mitter; Oriá, Reinaldo B.; Kvalsund, Michelle P.; Paula Pamplona; Emanuella Silva Joventino; Rosa M. S. Mota; Davi C Gonçalves; Patrick, Peter D.; Guerrant, Richard L.; Lima, Aldo A. M.

    2012-01-01

    OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, thereby improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice we...

  19. Recombinant RXFP1-LDL-A module does not form dimers.

    Science.gov (United States)

    Petrie, Emma J; Periguini, Matthew A; Bathgate, Ross A D; Gooley, Paul R

    2013-01-01

    The Relaxin receptor, RXFP1, is a complex G-protein coupled receptor (GPCR). It has a rhodopsin-like 7 transmembrane helix region and a large ecto-domain containing Leucine-rich repeats and a Low Desnsity Lipoprotein Class-A module at the N-terminus. RXFP1 and the closely related receptor for INSL3, RXFP2 are the only mammalian GPCRs to contain an LDL-A module. The LDL-A module has been shown to be essential for receptor signal activation. RXFP1, like other GPCRs, has been shown to form dimers however the interface upon association is currently unknown. As LDL-A modules are commonly found as repeats we hypothesized that the LDL-A module may associate at the dimer interface and play a role in receptor activation. To this end we analyzed the ability for the LDL-A module to oligomerise via Analytical Ultracentrifugation (AUC). PMID:24640556

  20. Monomeric banana lectin at acidic pH overrules conformational stability of its native dimeric form.

    Directory of Open Access Journals (Sweden)

    Javed M Khan

    Full Text Available Banana lectin (BL is a homodimeric protein categorized among jacalin-related family of lectins. The effect of acidic pH was examined on conformational stability of BL by using circular dichroism, intrinsic fluorescence, 1-anilino-8-napthalene sulfonate (ANS binding, size exclusion chromatography (SEC and dynamic light scattering (DLS. During acid denaturation of BL, the monomerization of native dimeric protein was found at pH 2.0. The elution profile from SEC showed two different peaks (59.65 ml & 87.98 ml at pH 2.0 while single peak (61.45 ml at pH 7.4. The hydrodynamic radii (R h of native BL was 2.9 nm while at pH 2.0 two species were found with R h of 1.7 and 3.7 nm. Furthermore at, pH 2.0 the secondary structures of BL remained unaltered while tertiary structure was significantly disrupted with the exposure of hydrophobic clusters confirming the existence of molten globule like state. The unfolding of BL with different subunit status was further evaluated by urea and temperature mediated denaturation to check their stability. As inferred from high Cm and ΔG values, the monomeric form of BL offers more resistance towards chemical denaturation than the native dimeric form. Besides, dimeric BL exhibited a Tm of 77°C while no loss in secondary structures was observed in monomers even up to 95°C. To the best of our knowledge, this is the first report on monomeric subunit of lectins showing more stability against denaturants than its native dimeric state.

  1. Crystal structure of the dimeric unswapped form of bovine seminal ribonuclease.

    Science.gov (United States)

    Berisio, R; Sica, F; De Lorenzo, C; Di Fiore, A; Piccoli, R; Zagari, A; Mazzarella, L

    2003-11-01

    Bovine seminal ribonuclease is a unique case of protein dimorphism, since it exists in two dimeric forms, with different biological and kinetic behavior, which interconvert into one another through three-dimensional swapping. Here we report the crystal structure, at 2.2 A resolution, of the unswapped form of bovine seminal ribonuclease. Besides completing the structural definition of bovine seminal ribonuclease conformational dimorphism, this study provides the structural basis to explain the dependence of the enzyme cooperative effects on its swapping state. PMID:14596923

  2. Polymorphism of apolipoprotein E gene and post-stroke vascular dementia

    Institute of Scientific and Technical Information of China (English)

    Xinjing Lin; Changlin Hu; Yunlan Xie; Xin Zhang; Xiangping Liu; Ge Yan

    2006-01-01

    BACKGROUND: Studies have indicated that the more certain etiological factors of vascular dementia are the sites, size and number of cerebrovascular lesions, but there are arguments all the time in the relationship of genetic factors, especially apolipoprotein E gene, with the occurrence and development of vascular dementia. OBJECTIVE: To analyze the relationship between the polymorphism of apolipoprotein E gene and vascular dementia in stroke patients. DESIGN: A non-randomized grouped comparative observation at the same time. SETTING: The Laboratory of Neurology, the Second Affiliated Hospital of Chongqing University of Medical Sciences.PARTICIPANTS: Totally 121 inpatients with stroke were selected from the Department of Neurology, the Second Affiliated Hospital of Chongqing University of Medical Sciences from January 2000 to December 2001. All the patients were accorded with the diagnostic standards for cerebrovascular diseases set by the Second National Academic Meeting for Cerebrovascular Disease, and confirmed by cranial CT or MRI. According to with vascular dementia or not, they were divided into vascular dementia group (n =58) and non-vascular dementia group (n =63). In the vascular dementia group, there were 37 males and 21 females, the average age was (59±8) years. They were all in accordance with the standard of the third edition of Diagnostic and Statistical Manual of Mental Disorders (DMS-Ⅲ), without conscious disturbance and language disorder; hospitalized within 3 days after the attack of cerebrovascular disease. In the non-vascular dementia group, there were 37 males and 26 females, the average age was (59±9.5) years. They all had no intellectual disturbance within 3 months after the attack of cerebrovascular disease. All the subjects agreed to supply blood samples for the experiment. METHODS: ①Fasting venous blood (2 mL) was drawn from each patient in the morning to extract DNA. The frequencies of apolipoprotein E genotypes and alleles were

  3. Immunolocalization of an Amino-Terminal Fragment of Apolipoprotein E in the Pick's Disease Brain

    OpenAIRE

    Rohn, Troy T.; Day, Ryan J; Catlin, Lindsey W; Brown, Raquel J.; Rajic, Alexander J.; Poon, Wayne W.

    2013-01-01

    Although the risk factor for apolipoprotein E (apoE) polymorphism in Alzheimer's disease (AD) has been well described, the role that apoE plays in other neurodegenerative diseases, including Pick's disease, is not well established. To examine a possible role of apoE in Pick's disease, an immunohistochemical analysis was performed utilizing a novel site-directed antibody that is specific for an amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE cleava...

  4. Angiotensin II-Induced Hypertension in Apolipoprotein E-Deficient Rats

    OpenAIRE

    Gorman, Sydney N; Goergen, Craig J.; Blaize, A Nicole

    2015-01-01

    Abdominal aortic aneurysms (AAAs) are characterized by a weakened vessel wall and a diameter 50% greater than normal. AAA are usually asymptomatic until they are near rupturing, which can be fatal if not treated immediately. Apolipoprotein E-deficient (ApoE) mice are commonly used as a model to study aneurysm growth. Our lab has created a similar model using rats, which are more similar to humans. This study focuses on the analysis of blood pressures collected from ApoE rats for comparison wi...

  5. Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice[S

    OpenAIRE

    Slätis, Katharina; Gåfvels, Mats; Kannisto, Kristina; Ovchinnikova, Olga; Paulsson-Berne, Gabrielle; Parini, Paolo; Jiang, Zhao-Yan; Eggertsen, Gösta

    2010-01-01

    To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice. This effect was associated with reduced inte...

  6. Apolipoprotein E4 Domain Interaction Induces Endoplasmic Reticulum Stress and Impairs Astrocyte Function*

    OpenAIRE

    Zhong, Ning; Ramaswamy, Gayathri; Weisgraber, Karl H.

    2009-01-01

    Domain interaction, a structural property of apolipoprotein E4 (apoE4), is predicted to contribute to the association of apoE4 with Alzheimer disease. Arg-61 apoE mice, a gene-targeted mouse model specific for domain interaction, have lower brain apoE levels and synaptic, functional, and cognitive deficits. We hypothesized that domain interaction elicits an endoplasmic reticulum (ER) stress in astrocytes and an unfolded protein response that targets Arg-61 apoE for degradation. Primary Arg-61...

  7. Apolipoprotein E4 and a change in episodic memory functioning among normal aging Norwegian adults

    OpenAIRE

    2009-01-01

    The e4 allele of the apolipoprotein E (APOE) gene is a known risk factor for Alzheimer’s disease and may also affect cognitive performance in normal aging. The data presented in the current study represent the first two time points of an ongoing longitudinal study examining cognitive changes in genetically at-risk individuals with much emphasis on test of episodic recall as measured by the California Verbal Learning Test. A total of 110 of 139 people who participated in the first phase of the...

  8. Apolipoprotein E gene and age-related macular degeneration in a Chinese population

    OpenAIRE

    Sun, Erdan; Lim, Apiradee; Liu, Xipu; Snellingen, Torkel; Wang, Ningli; Liu, Ningpu

    2011-01-01

    Purpose To examine the association between apolipoprotein E (APOE) polymorphisms and age-related macular degeneration (AMD) in a Chinese population. Methods The study consisted of 712 subjects, including 201 controls, 363 cases with early AMD, and 148 cases with exudative AMD. Genomic DNA was extracted from venous blood leukocytes. Common allelic variants of APOE (ε2, ε3, and ε4) were analyzed by PCR and direct sequencing. Results APOE ε3ε3 was the most frequent genotype, with a frequency of ...

  9. Apolipoprotein E genotypes do not influence the age of onset in Huntington's disease

    OpenAIRE

    Saft, C.; Andrich, J; Brune, N; Gencik, M; Kraus, P; Przuntek, H; Epplen, J

    2004-01-01

    Objective: The ε4 allele of the apolipoprotein E (ApoE) gene has been defined as a critical factor for early onset neurodegeneration in Pick's, Parkinson's, and Alzheimer's disease. Unexpectedly, the ε4 allele appeared to delay the age of onset in Huntington's disease (HD) patients. Furthermore, sex specific effects were reported on earlier age of onset due to the ApoE ε2ε3 genotype in males with HD. The age of onset of HD is known to be negatively correlated with increasing lengths of pathog...

  10. Apolipoprotein E allele-dependent pathogenesis: A model for age-related retinal degeneration

    OpenAIRE

    Malek, G; Johnson, L V; Mace, B E; Saloupis, P.; Schmechel, D E; Rickman, D. W.; Toth, C. A.; Sullivan, P. M.; Rickman, C. Bowes

    2005-01-01

    Age-related macular degeneration (AMD) is a late-onset, multifactorial, neurodegenerative disease of the retina and the leading cause of irreversible vision loss in the elderly in the Western world. We describe here a murine model that combines three known AMD risk factors: advanced age, high fat cholesterol-rich (HF-C) diet, and apolipoprotein E (apoE) genotype. Eyes of aged, targeted replacement mice expressing human apoE2, apoE3, or apoE4 and maintained on a HF-C diet show apoE isoform-dep...

  11. The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer's disease

    OpenAIRE

    Lambert, J; Coyle, N; Lendon, C

    2004-01-01

    Background: The ε4 allele of the apolipoprotein E (APOE) gene is a major genetic risk factor for Alzheimer's disease but appears to be associated with greater risk in women than in men. Some studies suggest that the level of APOE may of its own modulate the risk for Alzheimer's disease. Sex differences and an apparent benefit of oestrogen therapy suggest a role for oestrogen. APOE expression is influenced by oestrogen and oestrogen therapy may not benefit women bearing an APOE ε4 allele. Thes...

  12. Association of apolipoprotein E polymorphism in late-onset Alzheimer's disease and vascular dementia in Brazilians

    Directory of Open Access Journals (Sweden)

    D.R.S. Souza

    2003-07-01

    Full Text Available The genetic basis for dementias is complex. A common polymorphism in the apolipoprotein E (APOE gene is considered to be the major risk factor in families with sporadic and late-onset Alzheimer's disease as well as in the general population. The distribution of alleles and genotypes of the APOE gene in late-onset Alzheimer's disease (N = 68, other late-life dementias (N = 39, and in cognitively normal controls (N = 58 was determined, as also was the risk for Alzheimer's disease associated with the epsilon4 allele. Peripheral blood samples were obtained from a total of 165 individuals living in Brazil aged 65-82 years. Genomic DNA was amplified by the polymerase chain reaction and the products were digested with HhaI restriction enzyme. APOE epsilon2 frequency was considerably lower in the Alzheimer's disease group (1%, and the epsilon3 allele and epsilon3/epsilon3 genotype frequencies were higher in the controls (84 and 72%, respectively as were the epsilon4 allele and epsilon3/epsilon4 genotype frequencies in Alzheimer's disease (25 and 41%, respectively. The higher frequency of the epsilon4 allele in Alzheimer's disease confirmed its role as a risk factor, while epsilon2 provided a weak protection against development of the disease. However, in view of the unexpectedly low frequency of the epsilon4 allele, additional analyses in a more varied Brazilian sample are needed to clarify the real contribution of apolipoprotein E to the development of Alzheimer's disease in this population.

  13. Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer’s Disease Therapy from Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Hung-Jin Huang

    2014-01-01

    Full Text Available Apolipoprotein E4 (Apo E4 is the major genetic risk factor in the causation of Alzheimer’s disease (AD. In this study we utilize virtual screening of the world’s largest traditional Chinese medicine (TCM database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

  14. Supramolecular hydrogels formed from poly(viologen cross-linked with cyclodextrin dimers and their physical properties

    Directory of Open Access Journals (Sweden)

    Yoshinori Takashima

    2012-09-01

    Full Text Available Supramolecular materials with noncovalent bonds have attracted much attention due to their exclusive properties differentiating them from materials formed solely by covalent bonds. Especially interesting are rotor molecules of topological complexes that shuttle along a polymer chain. The shuttling of these molecules should greatly improve the tension strength. Our research employs cyclodextrin (CD as a host molecule, because CD effectively forms polyrotaxanes with polymers. Herein we report the formation of supramolecular hydrogels with an α-CD dimer (α,α-CD dimer as a topological linker molecule, and a viologen polymer (VP as the polymer chain. The supramolecular hydrogel of α,α-CD dimer/VP forms a self-standing gel, which does not relax (G' > G'' in the frequency range 0.01–10 rad·s−1. On the other hand, the supramolecular hydrogel decomposes upon addition of bispyridyl decamethylene (PyC10Py as a competitive guest. Moreover, the β-CD dimer (β,β-CD dimer with VP does not form a supramolecular hydrogel, indicating that complexation between the C10 unit of VP and the α-CD unit of the α,α-CD dimer plays an important role in the formation of supramolecular hydrogels.

  15. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

    Directory of Open Access Journals (Sweden)

    Sumeet S Mitter

    2012-01-01

    Full Text Available OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ received 200,000 IU of retinol (every four months, zinc (40 mg twice weekly, or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-forheight z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6 later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+, with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+ children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+ children and improved delta lactulose/mannitol. Apolipoprotein E4(- children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may

  16. Overcoming the signaling defect of Lyn-sequestering, signal-curtailing FcepsilonRI dimers: aggregated dimers can dissociate from Lyn and form signaling complexes with Syk.

    Science.gov (United States)

    Lara, M; Ortega, E; Pecht, I; Pfeiffer, J R; Martinez, A M; Lee, R J; Surviladze, Z; Wilson, B S; Oliver, J M

    2001-10-15

    Clustering the tetrameric (alphabetagamma(2)) IgE receptor, FcepsilonRI, on basophils and mast cells activates the Src-family tyrosine kinase, Lyn, which phosphorylates FcepsilonRI beta and gamma subunit tyrosines, creating binding sites for the recruitment and activation of Syk. We reported previously that FcepsilonRI dimers formed by a particular anti-FcepsilonRI alpha mAb (H10) initiate signaling through Lyn activation and FcepsilonRI subunit phosphorylation, but cause only modest activation of Syk and little Ca(2+) mobilization and secretion. Curtailed signaling was linked to the formation of unusual, detergent-resistant complexes between Lyn and phosphorylated receptor subunits. Here, we show that H10-FcepsilonRI multimers, induced by adding F(ab')(2) of goat anti-mouse IgG to H10-treated cells, support strong Ca(2+) mobilization and secretion. Accompanying the recovery of signaling, H10-FcepsilonRI multimers do not form stable complexes with Lyn and do support the phosphorylation of Syk and phospholipase Cgamma2. Immunogold electron microscopy showed that H10-FcepsilonRI dimers colocalize preferentially with Lyn and are rarely within the osmiophilic "signaling domains" that accumulate FcepsilonRI and Syk in Ag-treated cells. In contrast, H10-FcepsilonRI multimers frequently colocalize with Syk within osmiophilic patches. In sucrose gradient centrifugation analyses of detergent-extracted cells, H10-treated cells show a more complete redistribution of FcepsilonRI beta from heavy (detergent-soluble) to light (Lyn-enriched, detergent-resistant) fractions than cells activated with FcepsilonRI multimers. We hypothesize that restraints imposed by the particular orientation of H10-FcepsilonRI dimers traps them in signal-initiating Lyn microdomains, and that converting the dimers to multimers permits receptors to dissociate from Lyn and redistribute to separate membrane domains that support Syk-dependent signal propagation. PMID:11591756

  17. Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin.

    Science.gov (United States)

    Hjorth, Christian Fogt; Norrman, Mathias; Wahlund, Per-Olof; Benie, Andrew J; Petersen, Bent O; Jessen, Christian M; Pedersen, Thomas Å; Vestergaard, Kirsten; Steensgaard, Dorte B; Pedersen, Jan Skov; Naver, Helle; Hubálek, František; Poulsen, Christian; Otzen, Daniel

    2016-04-01

    A specific covalently linked dimeric species of insulin high molecular weight products (HMWPs), formed during prolonged incubation of a neutral pharmaceutical formulation of human insulin, were characterized in terms of tertiary structure, self-association, biological activity, and fibrillation properties. The dimer was formed by a covalent link between A21Asn and B29Lys. It was analyzed using static and dynamic light scattering and small-angle X-ray scattering to evaluate its self-association behavior. The tertiary structure was obtained using nuclear magnetic resonance and X-ray crystallography. The biological activity of HMWP was determined using 2 in vitro assays, and its influence on fibrillation was investigated using Thioflavin T assays. The dimer's tertiary structure was nearly identical to that of the noncovalent insulin dimer, and it was able to form hexamers in the presence of zinc. The dimer exhibited reduced propensity for self-association in the absence of zinc but significantly postponed the onset of fibrillation in insulin formulations. Consistent with its dimeric state, the tested species of HMWP showed little to no biological activity in the used assays. This study is the first detailed characterization of a specific type of human insulin HMWP formed during storage of a marketed pharmaceutical formulation. These results indicate that this specific type of HMWP is unlikely to antagonize the physical stability of the formulation, as HMWP retained a tertiary structure similar to the noncovalent dimer and participated in hexamer assembly in the presence of zinc. In addition, increasing amounts of HMWP reduce the rate of insulin fibrillation. PMID:26921119

  18. Study on relationship of apolipoprotein E gene polymorphism and genetic susceptibility of stress urinary incontinence

    Institute of Scientific and Technical Information of China (English)

    Tong Jia-li; Lang Jing-he; Zhu lan

    2010-01-01

    Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility of stress urinary incontinence (SUI).Methods: ApoE genotypes were examined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) technique in 99 patients with SUI and 101 asymptomatic controls. Results: The frequency of allele e3 of ApoE was slightly lower in patients with anatomic SUI than that in controls (79.44% vs. 81.68%), while the frequency of allele e4 of ApoE was slightly higher in patients with anatomic SUI than that in controls (10.00% vs. 9.90%). No significant difference was found in frequency of allele e3 or e4 between SUI patients and controls (χ2=0.523, P=0.770).Conclusion: The gene polymorphism of ApoE is not independently involved in the development of SUI.

  19. Sex, but not Apolipoprotein E Polymorphism, Differences in Spatial Performance in Young Adults.

    Science.gov (United States)

    Yasen, Alia L; Raber, Jacob; Miller, Jeremy K; Piper, Brian J

    2015-11-01

    The purpose of this study was to examine how sex and apolipoprotein E (APOE) genotype contribute to individual differences in spatial learning and memory. The associations of APOE genotype with neurocognitive function have been well studied among the elderly but less is known at earlier ages. Young adults (n = 169, 88 females) completed three neurocognitive tasks: mental rotation, spatial span, and Memory Island, a spatial navigation test. Males outperformed females on all three tasks: finding the hidden targets more quickly on Memory Island (Cohen's d = 0.62) and obtaining higher scores on mental rotation (d = 0.54) and spatial span (d = 0.37). In contrast, no significant effects of APOE were observed. The identified sex differences elaborate upon past literature documenting sexually dimorphic performance on specific neurobehavioral tasks. PMID:25750133

  20. Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention

    NARCIS (Netherlands)

    Matualatupauw, J.C.; Radonjic, M.; Nieuwerth-van de Rest, O.; Groot, de C.P.G.M.; Geleijnse, J.M.; Müller, M.R.; Afman, L.A.

    2016-01-01

    Scope
    People who carry the apolipoprotein E4 (APOE4) single nucleotide polymorphism have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though interindividual differences in the response to n-3 PUFAs have been observed. We aimed to

  1. The apolipoprotein E epsilon4-allele and antihypertensive treatment are associated with increased risk of cerebral MRI white matter hyperintensities

    DEFF Research Database (Denmark)

    Høgh, P; Garde, Ellen; Mortensen, Erik Lykke;

    2007-01-01

    OBJECTIVE: Apolipoprotein E-epsilon4 (APOE-epsilon4) is a potential risk factor for cerebral vascular disease. The aim of the present study was to examine the relative importance of APOE-epsilon4 and other relevant risk factors for the extent of cerebral white matter hyperintensity (WMH) in a...

  2. Recombinant Neural Protein PrP Can Bind with Both Recombinant and Native Apolipoprotein E In Vitro

    Institute of Scientific and Technical Information of China (English)

    Chen GAO; Wei ZHOU; Xiao-Ping DONG; Yan-Jun LEI; Jun HAN; Qi SHI; Lan CHEN; Yan GUO; Yong-Jun GAO; Jian-Ming CHEN; Hui-Ying JIANG

    2006-01-01

    The most essential and crucial step during the pathogenesis of transmissible spongiform encephalopathy is the conformational change of cellular prion protein (PrPC) to pathologic isoform (prpSc). A lot of data revealed that caveolae-like domains (CLDs) in the cell surface were the probable place where the conversion of PrP proteins happened. Apolipoprotein E (ApoE) is an apolipoprotein which is considered to play an important role in the development of Alzheimer's disease and other neurodegenerative diseases by forming protein complex through binding to the receptor located in the clathrin-coated pits of the cell surface.In this study, a 914-bp cDNA sequence encoding human ApoE3 was amplified from neuroblastoma cell line SH-SY5Y. Three human ApoE isomers were expressed and purified from Escherichia coli. ApoE-specific antiserum was prepared by immunizing rabbits with the purified ApoE3. GST/His pull-down assay,immunoprecipitation and ELISA revealed that three full-length ApoE isomers interact with the recombinant full-length PrP protein in vitro. The regions corresponding to protein binding were mapped in the N-terminal segment of ApoE (amino acid 1-194) and the N-terminal of PrP (amino acid 23-90). Moreover, the recombinant PrP showed the ability to form a complex with the native ApoE from liver tissues. Our data provided direct evidence of molecular interaction between ApoE and PrP. It also supplied scientific clues for assessing the significance of CLDs on the surface of cellular membrane in the process of conformational conversion from PrPC to PrPSc and probing into the pathogenesis of transmissible spongiform encephalopathy.

  3. Tor forms a dimer through an N-terminal helical solenoid with a complex topology

    Science.gov (United States)

    Baretić, Domagoj; Berndt, Alex; Ohashi, Yohei; Johnson, Christopher M.; Williams, Roger L.

    2016-04-01

    The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates a range of anabolic and catabolic processes. Tor is present in two complexes, TORC1 and TORC2, in which the Tor-Lst8 heterodimer forms a common sub-complex. We have determined the cryo-electron microscopy (EM) structure of Tor bound to Lst8. Two Tor-Lst8 heterodimers assemble further into a dyad-symmetry dimer mediated by Tor-Tor interactions. The first 1,300 residues of Tor form a HEAT repeat-containing α-solenoid with four distinct segments: a highly curved 800-residue N-terminal 'spiral', followed by a 400-residue low-curvature 'bridge' and an extended `railing' running along the bridge leading to the 'cap' that links to FAT region. This complex topology was verified by domain insertions and offers a new interpretation of the mTORC1 structure. The spiral of one TOR interacts with the bridge of another, which together form a joint platform for the Regulatory Associated Protein of TOR (RAPTOR) regulatory subunit.

  4. Tor forms a dimer through an N-terminal helical solenoid with a complex topology.

    Science.gov (United States)

    Baretić, Domagoj; Berndt, Alex; Ohashi, Yohei; Johnson, Christopher M; Williams, Roger L

    2016-01-01

    The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates a range of anabolic and catabolic processes. Tor is present in two complexes, TORC1 and TORC2, in which the Tor-Lst8 heterodimer forms a common sub-complex. We have determined the cryo-electron microscopy (EM) structure of Tor bound to Lst8. Two Tor-Lst8 heterodimers assemble further into a dyad-symmetry dimer mediated by Tor-Tor interactions. The first 1,300 residues of Tor form a HEAT repeat-containing α-solenoid with four distinct segments: a highly curved 800-residue N-terminal 'spiral', followed by a 400-residue low-curvature 'bridge' and an extended 'railing' running along the bridge leading to the 'cap' that links to FAT region. This complex topology was verified by domain insertions and offers a new interpretation of the mTORC1 structure. The spiral of one TOR interacts with the bridge of another, which together form a joint platform for the Regulatory Associated Protein of TOR (RAPTOR) regulatory subunit. PMID:27072897

  5. Expression of the human apolipoprotein E gene suppresses steroidogenesis in mouse Y1 adrenal cells

    International Nuclear Information System (INIS)

    The lipid transport protein, apolipoprotein E (apoE), is expressed in many peripheral tissues in vivo including the adrenal gland and testes. To investigate the role of apoE in adrenal cholesterol homeostasis, the authors have expressed a human apoE genomic clone in the Y1 mouse adrenocortical cell line. Y1 cells do not express endogenous apoE mRNA or protein. Expression of apoE in Y1 cells resulted in a dramatic decrease in basal steroidogenesis; secretion of fluorogenic steroid was reduced 7- to >100-fold relative to Y1 parent cells. Addition of 5-cholesten-3β,25-idol failed to overcome the suppression of steroidogenesis in these cells. Cholesterol esterification under basal conditions, as measured by the production of cholesteryl [14C]oleate, was similar in the Y1 parent and the apoE-transfected cell lines. Upon incubation with adrenocorticotropin or dibutyryl cAMP, production of cholesteryl [14C]oleate decreased 5-fold in the Y1 parent cells but was unchanged in the apoE-transfected cell lines. These results suggest that apoE may be an important modulator of cholesterol utilization and steroidogenesis in adrenal cells

  6. Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's disease in a Southern Brazilian population

    Directory of Open Access Journals (Sweden)

    de-Andrade F.M.

    2000-01-01

    Full Text Available Apolipoprotein E (protein: apo E; gene: APOE plays an important role in the multifactorial etiology of both Alzheimer's disease (AD and lipid level concentrations. The polymerase chain reaction (PCR was used to investigate the APOE gene polymorphism in 446 unrelated Caucasians, among them 23 AD patients, and 100 Afro-Brazilians living in Porto Alegre, Brazil. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.075, 0.810 and 0.115 in Caucasians and 0.075, 0.700 and 0.225 in Afro-Brazilians, respectively (c2 = 8.72, P = 0.013. A highly significant association was observed between the APOE*4 allele and AD in this population-based sample. The APOE*4 frequency in AD patients (39% was about four times higher than in the general Caucasian population (11.5%. The influence of each of the three common APOE alleles on lipid traits was evaluated by the use of the average excess statistic. The E*2 allele is associated with lower levels of triglycerides and of total and non-HDL cholesterol in both men and women. Conversely, the E*4 allele is associated with higher levels of these traits in women only. The effect of APOE alleles was of greater magnitude in women.

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

    Science.gov (United States)

    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

  8. Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain.

    Science.gov (United States)

    Teter, Bruce; LaDu, Mary Jo; Sullivan, Patrick M; Frautschy, Sally A; Cole, Greg M

    2016-08-01

    The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling is modulated by ApoE and observed in AD, ApoE isotype-specific effects remain poorly understood. Therefore, we examined the effect of the ApoE isotype on the brain levels of major regulators of TLR signaling including miR146a, a microRNA enriched in the brain. We used 6-month-old ApoE3 or ApoE4 targeted replacement mice with and without mutant familial AD transgenes. ApoE4 reduced the levels of miR146a compared with ApoE3, both in the brain (29%; Pimmune stimuli (including Aβ) in ApoE4 carriers. Thus, ApoE4 causes early dysregulation of a central controller of the innate immune system both centrally and systemically. This defect persists with familial AD pathology and may be relevant to ApoE4 AD risk. PMID:27281274

  9. Longitudinal Trajectories of Cholesterol from Midlife through Late Life according to Apolipoprotein E Allele Status

    Directory of Open Access Journals (Sweden)

    Brian Downer

    2014-10-01

    Full Text Available Background: Previous research indicates that total cholesterol levels increase with age during young adulthood and middle age and decline with age later in life. This is attributed to changes in diet, body composition, medication use, physical activity, and hormone levels. In the current study we utilized data from the Framingham Heart Study Original Cohort to determine if variations in apolipoprotein E (APOE, a gene involved in regulating cholesterol homeostasis, influence trajectories of total cholesterol, HDL cholesterol, and total: HDL cholesterol ratio from midlife through late life. Methods: Cholesterol trajectories from midlife through late life were modeled using generalized additive mixed models and mixed-effects regression models. Results: APOE e2+ subjects had lower total cholesterol levels, higher HDL cholesterol levels, and lower total: HDL cholesterol ratios from midlife to late life compared to APOE e3 and APOE e4+ subjects. Statistically significant differences in life span cholesterol trajectories according to gender and use of cholesterol-lowering medications were also detected. Conclusion: The findings from this research provide evidence that variations in APOE modify trajectories of serum cholesterol from midlife to late life. In order to efficiently modify cholesterol through the life span, it is important to take into account APOE allele status.

  10. Guanosine effect on cholesterol efflux and apolipoprotein E expression in astrocytes.

    Science.gov (United States)

    Ballerini, Patrizia; Ciccarelli, Renata; Di Iorio, Patrizia; Buccella, Silvana; D'Alimonte, Iolanda; Giuliani, Patricia; Masciulli, Arianna; Nargi, Eleonora; Beraudi, Alina; Rathbone, Michel P; Caciagli, Francesco

    2006-11-01

    The main source of cholesterol in the central nervous system (CNS) is represented by glial cells, mainly astrocytes, which also synthesise and secrete apolipoproteins, in particular apolipoprotein E (ApoE), the major apolipoprotein in the brain, thus generating cholesterol-rich high density lipoproteins (HDLs). This cholesterol trafficking, even though still poorly known, is considered to play a key role in different aspects of neuronal plasticity and in the stabilisation of synaptic transmission. Moreover, cell cholesterol depletion has recently been linked to a reduction in amyloid beta formation. Here we demonstrate that guanosine, which we previously reported to exert several neuroprotective effects, was able to increase cholesterol efflux from astrocytes and C6 rat glioma cells in the absence of exogenously added acceptors. In this effect the phosphoinositide 3 kinase/extracellular signal-regulated kinase 1/2 (PI3K/ERK1/2) pathway seems to play a pivotal role. Guanosine was also able to increase the expression of ApoE in astrocytes, whereas it did not modify the levels of ATP-binding cassette protein A1 (ABCA1), considered the main cholesterol transporter in the CNS. Given the emerging role of cholesterol balance in neuronal repair, these effects provide evidence for a role of guanosine as a potential pharmacological tool in the modulation of cholesterol homeostasis in the brain. PMID:18404467

  11. Influences of apolipoprotein E on soluble and heparin-immobilized hepatic lipase

    Energy Technology Data Exchange (ETDEWEB)

    Landis, B.A.; Rotolo, F.S.; Meyers, W.C.; Clark, A.B.; Quarfordt, S.H.

    1987-06-01

    The effect of human apolipoprotein E (apoE), either alone or in combination with apoC, on the lipolysis of a radiolabeled triglyceride emulsion was studied with hepatic lipase in solution and immobilized on heparin-Sepharose. The soluble hepatic lipase was inhibited, whereas the heparin-immobilized lipase was stimulated by apoE. This stimulation was attenuated by combining apoE with either apoC-II or C-III. The heparin-immobilized lipase demonstrated much less lipolysis of the zwitterionic phosphatidylcholine-stabilized triglyceride emulsion than did the soluble enzyme. This difference was less when the emulsion was stabilized by a nonionic detergent. apoE inhibited lipase activity when assayed under conditions (0.4 M NaCl) of bound enzyme and unbound substrate. Increasing the emulsion apoE content beyond optimum inhibited lipolysis by the immobilized enzyme. Kinetic analysis of phosphatidylcholine-stabilized triglyceride emulsions revealed a significant decrease in immobilized enzyme K/sub m/ and an increase in V/sub max/ when the emulsion was supplemented with apoE. Distributing the immobilized lipase in clustered aggregates produced more lipolysis than when the same enzyme content was uniformly bound.

  12. Apolipoprotein E in the genetics and epidemiology of Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, J. [Univ. of South Florida, Tampa, FL (United States)

    1995-10-09

    The role of apolipoprotein E (ApoE) alleles and isoforms in the etiology and pathogenesis of Alzheimer`s disease is discussed. The possibility that ApoE itself is not involved in the disease pathogenesis but is merely in genetic disequilibrium with the real locus is discussed and dismissed. The data showing that the {epsilon}4 allele is associated with an increased risk of developing the disease and with an earlier onset age are reviewed. The data showing that, at least in some circumstances, the {epsilon}2 allele is associated with a decrease in the risk of developing the disease, and with a later onset age are also reviewed. Data from the genetic analysis of other disorders are reviewed and presented, and it is suggested that the genetic data support the notion that the role of ApoE in the etiology of the disease directly relates to {beta}-amyloid deposition and plaque formation. This suggestion is in concordance with the most likely mechanism for the role of P-amyloid precursor protein gene mutations as other risk factors for the disease. 68 refs.

  13. Plasma levels of apolipoprotein E and risk of dementia in the general population

    DEFF Research Database (Denmark)

    Rasmussen, Katrine L; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G; Frikke-Schmidt, Ruth

    2015-01-01

    OBJECTIVE: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis. METHODS: Using 75,708 participants from the general population, we tested...... whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype. RESULTS: Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia...... increased from the highest to the lowest apoE tertile (p for trends < 1 × 10(-6) ). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval [CI] = 2.04-3.52) and 1.80 (95% CI = 1.52-2.13) for Alzheimer disease and all dementia, respectively. After further...

  14. Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

    LENUS (Irish Health Repository)

    Trompet, Stella

    2009-12-01

    Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

  15. Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Liu, Zhiping; Wang, Jiaojiao; Huang, Xiaoyang; Li, Zhuoming; Liu, Peiqing

    2016-06-01

    Sirtuin 6 (SIRT6) is a chromatin-associated deacetylase that plays a leading role in genomic stability and aging. However, the precise role of SIRT6 in atherosclerosis, an aging-associated cardiovascular disease, remains elusive. This study aims at defining the role of SIRT6 in atherosclerotic lesion development. SIRT6 messenger RNA and protein expression are markedly decreased in atherosclerotic aortas of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-cholesterol diet. SIRT6 was knocked down in ApoE(-/-) mice using small hairpin RNAs (shRNAs) lentivirus injection. SIRT6-shRNA-treated ApoE(-/-) mice showed impaired endothelium-dependent vasodilation, increased plaque size (in aortic sinus, aortic root and en face aorta), and augmented plaque vulnerability (evidenced by increased necrotic core areas and macrophage accumulation and reduced collagen content). At the cellular level, SIRT6 depletion by RNA interference in human umbilical vein endothelial cells significantly increased monocyte adhesion to endothelial cells by inducing the expression of intracellular adhesion molecule-1. Consistently, intracellular adhesion molecule-1 expression was significantly upregulated in aortic endothelium of SIRT6-shRNA-treated ApoE(-/-) mice compared with controls. In sum, the aforementioned findings suggest that SIRT6 is a primary negative regulation factor in endothelial dysfunction and atherosclerosis development. As a result, SIRT6 is a promising therapeutic target for treating atherosclerosis and its cardiovascular complications. PMID:26924042

  16. Effects of Simvastatin on adiponectin and endothelial function in apolipoprotein E-deficient mice

    Institute of Scientific and Technical Information of China (English)

    Meng Liu; Donghua Yin; Ming Gui; Kejiang Cao

    2009-01-01

    0bjective:To investigate the effects of simvastatin,a 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor,on adiponectin and markers of endothelial function in apolipoprotein E-deficient mice at an early stage of atherosclerosis.Methods:Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups:control group(normal saline) and treatment group[simvastatin(5 mg/(kg·d)].Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 4 weeks.Total cholesterol(TC),superoxide dismutase(SOD),malondialdehyde (MDA),and nitric oxide(NO) were measured by biochemical analysis,and adiponectin was measured by an ABC-ELISA method.Results:There was no significant difference in serum TC between control and treatment groups.Compared with the control animals,simvastafin-treated animals exhibited a significant increase in serurn levels of adponectin,SOD and NO,and decrease in serum MDA(P <0.01).Conclusion:Simvastatin protects endothelial function by increasing serum adiponectin,which may increase serum SOD and NO,and decrease serum MDA.This study suggests that sirnvastatin has therapeutic advantages,unrelated to its cholesterol-lowering effect,that are mediated by adiponectin.

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

    Science.gov (United States)

    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

  18. Apolipoprotein E ε4 allele modulates the immediate impact of acute exercise on prefrontal function.

    Science.gov (United States)

    De Marco, Matteo; Clough, Peter J; Dyer, Charlotte E; Vince, Rebecca V; Waby, Jennifer S; Midgley, Adrian W; Venneri, Annalena

    2015-01-01

    The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity. PMID:25218559

  19. Apolipoprotein E Genotype Linked to Spatial Gait Characteristics: Predictors of Cognitive Dual Task Gait Change

    Science.gov (United States)

    MacAulay, Rebecca K.; Allaire, Ted; Brouillette, Robert; Foil, Heather; Bruce-Keller, Annadora J.; Keller, Jeffrey N.

    2016-01-01

    Background Developing measures to detect preclinical Alzheimer’s Disease is vital, as prodromal stage interventions may prove more efficacious in altering the disease’s trajectory. Gait changes may serve as a useful clinical heuristic that precedes cognitive decline. This study provides the first systematic investigation of gait characteristics relationship with relevant demographic, physical, genetic (Apolipoprotein E genotype), and health risk factors in non-demented older adults during a cognitive-load dual task walking condition. Methods The GAITRite system provided objective measurement of gait characteristics in APOE-e4 “carriers” (n = 75) and “non-carriers” (n = 224). Analyses examined stride length and step time gait characteristics during simple and dual-task (spelling five-letter words backwards) conditions in relation to demographic, physical, genetic, and health risk factors. Results Slower step time and shorter stride length associated with older age, greater health risk, and worse physical performance (ps attention decrements and structural brain changes in older adults. Our results indicate that stride length is a useful behavioral marker of cognitive change that is associated with genetic risk for AD. Sex disparities in motor decline may be a function of health risk factors. PMID:27486898

  20. Influences of apolipoprotein E on soluble and heparin-immobilized hepatic lipase

    International Nuclear Information System (INIS)

    The effect of human apolipoprotein E (apoE), either alone or in combination with apoC, on the lipolysis of a radiolabeled triglyceride emulsion was studied with hepatic lipase in solution and immobilized on heparin-Sepharose. The soluble hepatic lipase was inhibited, whereas the heparin-immobilized lipase was stimulated by apoE. This stimulation was attenuated by combining apoE with either apoC-II or C-III. The heparin-immobilized lipase demonstrated much less lipolysis of the zwitterionic phosphatidylcholine-stabilized triglyceride emulsion than did the soluble enzyme. This difference was less when the emulsion was stabilized by a nonionic detergent. apoE inhibited lipase activity when assayed under conditions (0.4 M NaCl) of bound enzyme and unbound substrate. Increasing the emulsion apoE content beyond optimum inhibited lipolysis by the immobilized enzyme. Kinetic analysis of phosphatidylcholine-stabilized triglyceride emulsions revealed a significant decrease in immobilized enzyme K/sub m/ and an increase in V/sub max/ when the emulsion was supplemented with apoE. Distributing the immobilized lipase in clustered aggregates produced more lipolysis than when the same enzyme content was uniformly bound

  1. Intracellular trafficking of recycling apolipoprotein E in Chinese hamster ovary cells.

    Science.gov (United States)

    Braun, Nicole A; Mohler, Peter J; Weisgraber, Karl H; Hasty, Alyssa H; Linton, MacRae F; Yancey, Patricia G; Su, Yan Ru; Fazio, Sergio; Swift, Larry L

    2006-06-01

    We have investigated apolipoprotein E (apoE) recycling in Chinese hamster ovary (CHO) cells, a peripheral cell that does not produce lipoproteins or express apoE. Using a pulse-chase protocol in which cells were pulsed with 125I-apoE-VLDL and chased for different periods, approximately 30% of the apoE internalized during the pulse was resecreted within a 4 h chase in a relatively lipid-free state. The addition of lysosomotropic agents or brefeldin A had no effect on apoE recycling. Unlike previous results with hepatocytes and macrophages, neither apoA-I nor upregulation of ABCA1 stimulated apoE recycling. However, cyclodextrin, which extracts cholesterol from plasma membrane lipid rafts, increased recycling. Confocal studies revealed that apoE, internalized during a 1 h pulse, colocalizes with early endosomal antigen-1, Rab5, Rab11a, and lysobisphosphatidic acid but not with lysosomal-associated membrane protein-1. Colocalization of apoE and Rab11a persisted even after cells had been chased for 1 h, suggesting a pool of apoE within the endosomal recycling compartment (ERC). Our data suggest that apoE recycling in CHO cells is linked to cellular cholesterol removal via the ERC and phospholipid-containing acceptors in a pathway alternative to the ABCA1-apoA-I axis. PMID:16534141

  2. Relationship Between Plasma Insulin Level and Apolipoprotein E Gene Polymorphysm in Alzheimer′s Disease

    Institute of Scientific and Technical Information of China (English)

    Luo Zhuming; Yuan Qiang

    2000-01-01

    Objective: To study relationship between plasma insulin level and apolipoprotein E Gene polymorphysm in Alzheimcr′s Disease. Background: Recent researches have shown that there was a close relationship between ApoE- ε 4 allele and AD. Because of the discovery of hyperinsulineamia in AD patients, the study of insulin on the pathogenesis of AD become a hot point of AD reseearch. Methods: We apply PCR-RFLP to the ApoE genotype study of 45 AD paticnts and 32 normal controls. At the same time, plasma insulin and glucose level was measured in the abovc objects. Results and Discussion: The frequency of ApoE- ε 4 in AD (32.2%) is much higher than in controls (10.9%). On the contrary, the frequency of ApeE- ε 4 is relatively lower in AD than in thc controls. The resistence of hyperinsulineamia in AD. Insulin sensitivity decreased in AD. Conclusion: When gene dose of ApoE- ε 4 increases, the prcvalance of AD increase, while the on-set ages of AD decrease (P<0.05). These findings indicatc that AD patients may have insulin resistance anbd insulin probably play a role in AD pathogenesis. In addition, the s 4 homozygote AD patients seem to have loweer plasma insulin level that the non- ε 4 homozygote AD patients (P<0.05). But this situation need to be replicated in studies of larger sample.

  3. Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Chong Wang

    Full Text Available BACKGROUND: Peripheral blood Apolipoprotein E (ApoE levels have been proposed as biomarkers of Alzheimer's disease (AD, but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker. METHODS: We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD and 95% confidence interval (CI were used to estimate the association between ApoE levels and AD risk. RESULTS: Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was -5.59 mg/l (95% CI: [-8.12, -3.06]. The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type. CONCLUSIONS: Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.

  4. Endothelial Dysfunction in the Apolipoprotein E-deficient Mouse: insights into the influence of diet, gender and aging

    OpenAIRE

    Meyrelles Silvana S; Peotta Veronica A; Pereira Thiago MC; Vasquez Elisardo C

    2011-01-01

    Abstract Since the early 1990s, several strains of genetically modified mice have been developed as models for experimental atherosclerosis. Among the available models, the apolipoprotein E-deficient (apoE-/-) mouse is of particular relevance because of its propensity to spontaneously develop hypercholesterolemia and atherosclerotic lesions that are similar to those found in humans, even when the mice are fed a chow diet. The main purpose of this review is to highlight the key achievements th...

  5. The influence of parental history of Alzheimer's disease and apolipoprotein E ε4 on the BOLD signal during recognition memory

    OpenAIRE

    Xu, Guofan; McLaren, Donald G.; Ries, Michele L.; Fitzgerald, Michele E.; Barbara B. Bendlin; Howard A. Rowley; Sager, Mark A.; Atwood, Craig; Asthana, Sanjay; Johnson, Sterling C.

    2008-01-01

    First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E ε4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal indi...

  6. Vitamin D Deficiency and Exogenous Vitamin D Excess Similarly Increase Diffuse Atherosclerotic Calcification in Apolipoprotein E Knockout Mice

    OpenAIRE

    Ellam, Timothy; Hameed, Abdul; ul Haque, Risat; Muthana, Munitta; Wilkie, Martin; Francis, Sheila E.; Chico, Timothy J. A.

    2014-01-01

    Background Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. Methods Mice were fed athe...

  7. Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

    OpenAIRE

    Oriá, Reinaldo B.; Patrick, Peter D.; Blackman, James A.; Lima, Aldo A.M.; Guerrant, Richard L.

    2006-01-01

    Our group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive ...

  8. Apolipoprotein E4 Genotype and Depressive Symptoms as Risk Factors for Dementia in an Older Korean Population

    OpenAIRE

    Kim, Jae-Min; Kim, Seon-Young; Bae, Kyung-Yeol; Kim, Sung-Wan; Shin, Il-Seon; Yang, Su-Jin; Song, Young-Heon; Yoon, Jin-Sang

    2010-01-01

    Objective Growing evidence suggests the separate associations of apolipoprotein E e4 allele (apo E4) and depression with incident dementia. This study investigated the separate and combined effects of apo E4 and depression on the incidence of dementia in both men and women. Methods Of 625 elderly without dementia at baseline, 518 (83%) were followed over a 2.4-year period and were assessed clinically for incident dementia. The apo E polymorphism was ascertained, and depression was identified ...

  9. Solid lipid nanoparticles as a vehicle for brain-targeted drug delivery: two new strategies of functionalization with apolipoprotein E

    Science.gov (United States)

    Rute Neves, Ana; Fontes Queiroz, Joana; Weksler, Babette; Romero, Ignacio A.; Couraud, Pierre-Olivier; Reis, Salette

    2015-12-01

    Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between -10 mV and -15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC/D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml-1 over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC/D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier.

  10. Impact of psychological stress on the associations between apolipoprotein E variants and metabolic traits: findings in an American sample of caregivers and controls

    DEFF Research Database (Denmark)

    Kring, Sofia Iqbal; Brummett, Beverly H; Barefoot, John;

    2010-01-01

    To examine the association between apolipoprotein E (APOE) gene variants and waist circumference, fasting plasma glucose, serum insulin, serum high-density lipoprotein cholesterol, and serum triglycerides, all metabolic traits known as cardiovascular disease (CVD) endophenotypes, in a population ...

  11. Rapid and safe determination of human apolipoprotein E genotypes by miniaturised SDS-PAGE in non-insulin dependent diabetes mellitus.

    OpenAIRE

    C Clavel; Durlach, A.; Durlach, V; Birembaut, P

    1995-01-01

    AIMS--To present a non-isotopic procedure for the analysis of the different apolipoprotein E genotypes in normal subjects and patients with non-insulin dependent diabetes mellitus. METHODS--Apolipoprotein E genotypes were detected following polymerase chain reaction and miniaturised sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) (PhastSystem Pharmacia). RESULTS--The time taken from extraction of DNA from 6 microliters whole blood to the final result was eight hours. The...

  12. Relevance of apolipoprotein E4 for the lipid profile of Brazilian patients with coronary artery disease

    Directory of Open Access Journals (Sweden)

    D.R.S. Souza

    2007-02-01

    Full Text Available Apolipoprotein E (apoE - e2, e3, e4 alleles plays a role in the regulation of lipid metabolism, with the e4 considered to be a risk factor for coronary artery disease (CAD. We aimed to evaluate the apoE polymorphisms in Brazilians with CAD and their influence on the lipid profile and other risk factors (hypertension, diabetes mellitus, smoking. Two hundred individuals were examined: 100 patients with atherosclerosis confirmed by coronary angiography and 100 controls. Blood samples were drawn to determine apoE polymorphisms and lipid profile. As expected, the e3 allele was prevalent in the CAD (0.87 and non-CAD groups (0.81; P = 0.099, followed by the e4 allele (0.09 and 0.14, respectively; P = 0.158. The e3/3 (76 and 78% and e3/4 (16 and 23% were the most common genotypes for patients and controls, respectively. The lipid profile was altered in patients compared to controls (P < 0.05, independently of the e4 allele. However, in the controls this allele was prevalent in individuals with elevated LDL-cholesterol levels only (odds ratio = 2.531; 95% CI = 1.028-6.232. The frequency of risk factors was higher in the CAD group (P < 0.05, but their association with the lipid profile was not demonstrable in e4 carriers. In conclusion, the e4 allele is not associated with CAD or lipid profile in patients with atherosclerosis. However, its frequency in the non-CAD group is associated with increased levels of LDL-cholesterol, suggesting an independent effect of the e4 allele on lipid profile when the low frequency of other risk factors in this group is taken into account.

  13. Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Hong-Bo, E-mail: xhbzhb@yahoo.com [College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128 (China); Lu, Xiang-Yang; Sun, Zhi-Liang [Hunan Agricultural University, Changsha 410128 (China); Zhang, Heng-Bo [Furong District Red Cross Hospital, Changsha 410126 (China)

    2011-12-15

    Recent studies show that osteopontin (OPN) and its receptor cluster of differentiation 44 (CD44) are two pro-inflammatory cytokines contributing to the development of atherosclerosis. The objective of this study was to explore the inhibitory effect of kaempferol, a naturally occurring flavonoid compound, on atherogenesis and the mechanisms involved. The experiments were performed in aorta and plasma from C57BL/6J control and apolipoprotein E-deficient (ApoE{sup -/-}) mice treated or not with kaempferol (50 or 100 mg/kg, intragastrically) for 4 weeks. Kaempferol treatment decreased atherosclerotic lesion area, improved endothelium-dependent vasorelaxation, and increased the maximal relaxation value concomitantly with decrease in the half-maximum effective concentration, plasma OPN level, aortic OPN expression, and aortic CD44 expression in ApoE{sup -/-} mice. In addition, treatment with kaempferol also significantly decreased reactive oxygen species production in mice aorta. The present results suggest that kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. -- Graphical abstract: Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. Highlights: Black-Right-Pointing-Pointer OPN-CD44 pathway plays a critical role in the development of atherosclerosis. Black-Right-Pointing-Pointer We examine lesion area, OPN and CD44 changes after kaempferol treatment. Black-Right-Pointing-Pointer Kaempferol treatment decreased atherosclerotic lesion area in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol treatment decreased aortic OPN and CD44 expressions in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis.

  14. Blue-Green Algae Inhibit the Development of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice.

    Science.gov (United States)

    Ku, Chai Siah; Kim, Bohkyung; Pham, Tho X; Yang, Yue; Wegner, Casey J; Park, Young-Ki; Balunas, Marcy; Lee, Ji-Young

    2015-12-01

    Hyperlipidemia and inflammation contribute to the development of atherosclerotic lesions. Our objective was to determine antiatherogenic effect of edible blue-green algae (BGA) species, that is, Nostoc commune var. sphaeroides Kützing (NO) and Spirulina platensis (SP), in apolipoprotein E knockout (ApoE(-/-)) mice, a well-established mouse model of atherosclerosis. Male ApoE(-/-) mice were fed a high-fat/high-cholesterol (HF/HC, 15% fat and 0.2% cholesterol by wt) control diet or a HF/HC diet supplemented with 5% (w/w) of NO or SP powder for 12 weeks. Plasma total cholesterol (TC) and triglycerides (TG) were measured, and livers were analyzed for histology and gene expression. Morphometric analysis for lesions and immunohistochemical analysis for CD68 were conducted in the aorta and the aortic root. NO supplementation significantly decreased plasma TC and TG, and liver TC, compared to control and SP groups. In the livers of NO-fed mice, less lipid droplets were present with a concomitant decrease in fatty acid synthase protein levels than the other groups. There was a significant increase in hepatic low-density lipoprotein receptor protein levels in SP-supplemented mice than in control and NO groups. Quantification of aortic lesions by en face analysis demonstrated that both NO and SP decreased aortic lesion development to a similar degree compared with control. While lesions in the aortic root were not significantly different between groups, the CD68-stained area in the aortic root was significantly lowered in BGA-fed mice than controls. In conclusion, both NO and SP supplementation decreased the development of atherosclerotic lesions, suggesting that they may be used as a natural product for atheroprotection. PMID:26566121

  15. Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

    International Nuclear Information System (INIS)

    Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2 Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. Rotarod test: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. Open field test: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. Morris water maze: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the central nervous system (CNS). ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process. (author)

  16. Enhanced Diabetes Susceptibility in Community Dwelling Han Elders Carrying the Apolipoprotein E 3/3 Genotype.

    Science.gov (United States)

    Ban, Chun-Xia; Zhong, Li; Wang, Tao; Zhu, Min-Jie; Wang, Jing-Hua; Zhang, Zhen-Lian; Wang, Zhe; Su, Ning; Liu, Yuan-Yuan; Shi, Yan-Chen; Xiao, Shi-Fu; Li, Xia

    2016-01-01

    Despite Apolipoprotein E (ApoE) being one of the main apolipoproteins in the blood, the association between its genotype and the high cholesterol or blood glucose levels commonly seen in clinical practice is inconclusive. Such research is also lacking in the Han population. The aim of this study was to investigate the association between APOE genotype, diabetes, and plasma glucose and lipid levels. We included 243 community-dwelling elderly residents in this study. Participant APOE genotypes were assessed and were simultaneously tested for weight, height, blood glucose, triglycerides, cholesterol, and high- and low-density lipoprotein. In addition, gender, age, years of education, cognitive function, and medical history was recorded. Subjects were divided into 3 groups based on APOE genotype: APOE ε2 group (ε2/ε2 and ε2/ε3), APOE ε3 group (ε3/ε3), and APOE ε4 group (ε2/ε4, ε3/ε4 and ε4/ε4). Comparisons between groups were conducted for the incidence of diabetes, high blood pressure, and dementia, as well as for differences in body-mass index, fasting plasma glucose, and blood lipids. The APOE ε3/ε3 genotype exhibited the highest frequency (70.4%) among the subjects. Participants in the APOE ε3 group demonstrated significantly higher levels of fasting plasma glucose than those in the APOE ε2 and APOE ε4 groups (Pfasting plasma glucose values than did the APOE ε2 group (P = 0.065). Furthermore, the APOE3 genotype was significantly correlated with both fasting plasma glucose level and glucose abnormality (P< 0.05) and trended toward statistically significant correlation with diabetes (P = 0.082). The correlation between APOE2 and low low-density lipoprotein levels also approached statistical significance (P = 0.052). Thus, elderly community dwelling residents of Han ethnicity carrying the APOE ε3/ε3 genotype might have higher plasma glucose levels and a higher occurrence of diabetes. PMID:26998902

  17. Effects of simvastatin on early oxidative stress and endothelial function in apolipoprotein E-deficient mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective:To investigate the mechanisms that Simvastatin,a 3-ydroxy-3-methylglutaryl coenzyme A(HMG-CoA)reductase inhibitor,plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E-deficient mice in the early stage of atherosclerosis.Methods:Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups:control group(normal saline)and treatment group[simvastatin(5 mg/(kg·d))].Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 2 or 4 weeks.Total cholesterol(TC),super-oxide dismutase(SOD),malondialdehyde(MDA)and serum nitric oxide(NO)were measured by biochemical analysis.Results:There was no significant difference in serum TC between control and treatment groups.Compared with the control's,the effects of simvastatin were more signiticant in decreasing serum MDA level(P<0.01 vs control's at 2-week;P<0.006 vs control's at 4-week),increasing serum SOD level(P<0.03 vs control's at 2-week;P<0.003 vs control's at 4-week)and NO level (P<0.01 control's at 2-week;P<0.001 vs control's at 4-week)either at 2 or 4 weeks.Conclusion:Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of decreasing serum MDA level,increasing serum SOD level and NO level,which were inconsistent with its cholesterol-lowering effect.It may play an important role in primary(if not all)prevention of atherosclerosis and might be independent of lipid-regulation mechanism.

  18. Functional network endophenotypes unravel the effects of apolipoprotein E epsilon 4 in middle-aged adults.

    Directory of Open Access Journals (Sweden)

    Joseph S Goveas

    Full Text Available Apolipoprotein E-ε4 (APOE-ε4 accentuates memory decline, structural volume loss and cerebral amyloid deposition in cognitively healthy adults. We investigated whether APOE-ε4 carriers will show disruptions in the intrinsic cognitive networks, including the default mode (DMN, executive control (ECN and salience (SN networks, relative to noncarriers in middle-aged healthy adults; and the extent to which episodic-memory performance is related to the altered functional connectivity (Fc in these networks. Resting-state functional connectivity MRI (R-fMRI was used to measure the differences in the DMN, ECN and SN Fc between 20 APOE-ε4 carriers and 26 noncarriers. Multiple linear regression analyses were performed to determine the relationship between episodic-memory performance and Fc differences in the three resting-state networks across all subjects. There were no significant differences in the demographic and neuropsychological characteristics and the gray-matter volumes in the carriers and noncarriers. While mostly diminished DMN and ECN functional connectivities were seen, enhanced connections to the DMN structures were found in the SN in ε4 carriers. Altered DMN and ECN were associated with episodic memory performance. Significant Fc differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD, in the absence of cognitive decline and gray-matter atrophy. Prospective studies are essential to elucidate the potential of R-fMRI technique as a biomarker for predicting conversion from normal to early AD in healthy APOE-ε4 carriers.

  19. Radiative-SPR platform for the detection of apolipoprotein E for use in medical diagnostics

    Science.gov (United States)

    Sciacca, Beniamino; Francois, Alexandre; Penno, Megan A. S.; Brazzatti, Julie A.; Klingler-Hoffmann, Manuela; Hoffmann, Peter; Monro, Tanya M.

    2012-03-01

    Surface Plasmon Resonance (SPR) based sensors enable the rapid, label-free and highly sensitive detection of a large range of biomolecules. We have previously shown that, using silver coated optical fibres with an high surface roughness, a re-scattering of the surface plasmons is possible, turning SPR into a radiative process. This approach overcomes limitations associated with current SPR technologies such as the tight tolerance on the metallic coating thickness, and results in a more compact, versatile, robust and cost-effective approach. However, the specific detection of small molecules is a challenge in SPR systems, regardless of the SPR architecture that is used. This new sensing platform, which has proved effective for the detection of large molecules such as viruses, is now demonstrated to be able to detect small proteins thanks to an improved surface functionalization procedure, a key point for reliable and robust immunosensors. Avidin, a tetrameric biotin-binding protein, was used to link biotinylated antibodies to the biotinylated surface, with a given orientation, to enable efficient sensing of the analyte. This approach may offer significant advantages compared to protein A surface functionalization strategies such as a limited cross reactivity with free IgG antibodies in clinical samples. We demonstrate that by bringing together this novel emission-based fibre SPR platform, with an improved surface functionalization process, is possible to rapidly and specifically detect human apolipoprotein E, a low molecular weight protein (~39kDa) known to be involved in cardiovascular diseases, in Alzheimer's disease and in gastric cancer. The results obtained clearly show that this new sensing platform has the potential to serve as a tool for point-of-decision medical diagnostics.

  20. Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.

    Science.gov (United States)

    Zhang, Xilin; Hu, Jin; Zhong, Li; Wang, Na; Yang, Longyu; Liu, Chia-Chen; Li, Huifang; Wang, Xin; Zhou, Ying; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun; Zhuang, Jiangxing

    2016-09-01

    Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also associated with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degradation in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insoluble Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy. PMID:27114256

  1. The Ras G Domain Lacks the Intrinsic Propensity to Form Dimers.

    Science.gov (United States)

    Kovrigina, Elizaveta A; Galiakhmetov, Azamat R; Kovrigin, Evgenii L

    2015-09-01

    Ras GTPase is a molecular switch controlling a number of cellular pathways including growth, proliferation, differentiation, and apoptosis. Recent reports indicated that Ras undergoes dimerization at the membrane surface through protein-protein interactions. If firmly established this property of Ras would require profound reassessment of a large amount of published data and modification of the Ras signaling paradigm. One proposed mechanism of dimerization involves formation of salt bridges between the two GTPase domains (G domains) leading to formation of a compact dimer as observed in Ras crystal structures. In this work, we interrogated the intrinsic ability of Ras to self-associate in solution by creating conditions of high local concentration through irreversibly tethering the two G domains together at their unstructured C-terminal tails. We evaluated possible self-association in this inverted tandem conjugate via analysis of the time-domain fluorescence anisotropy and NMR chemical shift perturbations. We did not observe the increased rotational correlation time expected for the G domain dimer. Variation of the ionic strength (to modulate stability of the salt bridges) did not affect the rotational correlation time in the tandem further supporting independent rotational diffusion of two G domains. In a parallel line of experiments to detect and map weak self-association of the G domains, we analyzed NMR chemical shifts perturbations at a number of sites near the crystallographic dimer interface. The nearly complete lack of chemical shift perturbations in the tandem construct supported a simple model with the independent G domains repelled from each other by their overall negative charge. These results lead us to the conclusion that self-association of the G domains cannot be responsible for homodimerization of Ras reported in the literature. PMID:26331257

  2. Electrochemical, spectral, and computational studies of metalloporphyrin dimers formed by cation complexation of crown ether cavities.

    Science.gov (United States)

    Chitta, Raghu; Rogers, Lisa M; Wanklyn, Amber; Karr, Paul A; Kahol, Pawan K; Zandler, Melvin E; D'Souza, Francis

    2004-11-01

    The effect on the electrochemical oxidation and reduction potentials of 5,10,15,20-tetrakis(benzo-15-crown-5)porphyrin (TCP) and its metal derivatives (MTCP; M = Mg(II), VO(IV), Co(II), Ni(II), Cu(II), Zn(II), Pd(II), Ag(II)) upon potassium ion induced dimerization of the porphyrins was systematically performed in benzonitrile containing 0.1 M (TBA)ClO(4) by differential pulse voltammetry technique. The HOMO--LUMO energy level diagram constructed from the electrochemical data revealed destabilization of the HOMO level and stabilization of the LUMO level upon dimer formation while such a perturbation was larger for the HOMO level than the LUMO level. The geometry and electronic structure of a representative ZnTCP and its dimer, K(4)(ZnTCP)(2), were evaluated by the ab initio B3LYP method utilizing a mixed basis set of 3-21G(*) for Zn, K, O, and N and STO-3G for C and H. The inter-porphyrin ring distance of the dimer calculated from the optimized geometry agreed with the spectroscopically determined one, and the calculated HOMO and LUMO frontier orbitals revealed delocalization on both of the porphyrins rings. The metal-metal distances calculated from the triplet ESR spectra of the K(+) induced porphyrin dimers bearing paramagnetic metal ions in the cavity followed the trend Cu--Cu < VO--VO < Ag--Ag. However, the spectral shifts resulting from the exciton coupling of the interacting porphyrin pi-systems revealed no specific trend with respect to the metal ion in the porphyrin cavity. Additionally, linear trends in the electrochemically measured HOMO--LUMO gap and the energy corresponding to the most intense visible band of both MTCP and K(4)(MTCP)(2) were observed. A reduced HOMO--LUMO gap predicted for the dimer by B3LYP/(3-21G(), STO-3G) calculations was confirmed by the results of optical absorption and electrochemical studies. PMID:15500335

  3. Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin

    DEFF Research Database (Denmark)

    Hjorth, Christian Fogt; Norrman, Mathias; Wahlund, Per-Olof; Benie, Andrew J.; Petersen, Bent O.; Jessen, Christian M; Pedersen, Thomas Å.; Vestergaard, Kirsten; Steensgaard, Dorte B; Pedersen, Jan Skov; Naver, Helle; Hubálek, František; Poulsen, Christian; Otzen, Daniel

    2016-01-01

    first detailed characterization of a specific type of human insulin HMWP formed during storage of a marketed pharmaceutical formulation. These results indicate that this specific type of HMWP is unlikely to antagonize the physical stability of the formulation, as HMWP retained a tertiary structure......A specific covalently linked dimeric species of insulin high molecular weight products (HMWPs), formed during prolonged incubation of a neutral pharmaceutical formulation of human insulin, were characterized in terms of tertiary structure, self-association, biological activity, and fibrillation...

  4. Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia.

    Directory of Open Access Journals (Sweden)

    Dimitra Georgiadou

    Full Text Available BACKGROUND: Apolipoprotein E (apoE is a major protein of the lipoprotein transport system that plays important roles in lipid homeostasis and protection from atherosclerosis. ApoE is characterized by structural plasticity and thermodynamic instability and can undergo significant structural rearrangements as part of its biological function. Mutations in the 136-150 region of the N-terminal domain of apoE, reduce its low density lipoprotein (LDL receptor binding capacity and have been linked with lipoprotein disorders, such as type III hyperlipoproteinemia (HLP in humans. However, the LDL-receptor binding defects for these apoE variants do not correlate well with the severity of dyslipidemia, indicating that these variants may carry additional properties that contribute to their pathogenic potential. METHODOLOGY/PRINCIPAL FINDINGS: In this study we examined whether three type III HLP predisposing apoE3 variants, namely R136S, R145C and K146E affect the biophysical properties of the protein. Circular dichroism (CD spectroscopy revealed that these mutations do not significantly alter the secondary structure of the protein. Thermal and chemical unfolding analysis revealed small thermodynamic alterations in each variant compared to wild-type apoE3, as well as effects in the reversibility of the unfolding transition. All variants were able to remodel multillamelar 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC vesicles, but R136S and R145C had reduced kinetics. Dynamic light scattering analysis indicated that the variant R136S exists in a higher-order oligomerization state in solution. Finally, 1-anilinonaphthalene-8-sulfonic acid (ANS binding suggested that the variant R145C exposes a larger amount of hydrophobic surface to the solvent. CONCLUSIONS/SIGNIFICANCE: Overall, our findings suggest that single amino acid changes in the functionally important region 136-150 of apoE3 can affect the molecule's stability and conformation in solution and may

  5. Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity

    Directory of Open Access Journals (Sweden)

    Maezawa Izumi

    2006-08-01

    Full Text Available Abstract Background Innate immune activation, including a role for cluster of differentiation 14/toll-like receptor 4 co-receptors (CD14/TLR-4 co-receptors, has been implicated in paracrine damage to neurons in several neurodegenerative diseases that also display stratification of risk or clinical outcome with the common alleles of the apolipoprotein E gene (APOE: APOE2, APOE3, and APOE4. Previously, we have shown that specific stimulation of CD14/TLR-4 with lipopolysaccharide (LPS leads to greatest innate immune response by primary microglial cultures from targeted replacement (TR APOE4 mice and greatest p38MAPK-dependent paracrine damage to neurons in mixed primary cultures and hippocampal slice cultures derived from TR APOE4 mice. In contrast, TR APOE2 astrocytes had the highest NF-kappaB activity and no neurotoxicity. Here we tested the hypothesis that direct activation of CD14/TLR-4 in vivo would yield different amounts of paracrine damage to hippocampal sector CA1 pyramidal neurons in TR APOE mice. Methods We measured in vivo changes in dendrite length in hippocampal CA1 neurons using Golgi staining and determined hippocampal apoE levels by Western blot. Neurite outgrowth of cultured primary neurons in response to astrocyte conditioned medium was assessed by measuring neuron length and branch number. Results Our results showed that TR APOE4 mice had slightly but significantly shorter dendrites at 6 weeks of age. Following exposure to intracerebroventricular LPS, there was comparable loss of dendrite length at 24 hr among the three TR APOE mice. Recovery of dendrite length over the next 48 hr was greater in TR APOE2 than TR APOE3 mice, while TR APOE4 mice had failure of dendrite regeneration. Cell culture experiments indicated that the enhanced neurotrophic effect of TR APOE2 was LDL related protein-dependent. Conclusion The data indicate that the environment within TR APOE2 mouse hippocampus was most supportive of dendrite regeneration

  6. Plasma level and genetic variation of apolipoprotein E in patients with lipoprotein glomerulopathy

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bo; LIU Zhi-hong; ZENG Cai-hong; ZHENG Jing-min; CHEN Hui-ping; ZHOU Hong; LI Lei-shi

    2005-01-01

    Background Lipoprotein glomerulopathy (LPG) is a renal disease characterized by thrombus-like lipoproteins in the glomerular capillaries and its abnormal lipoprotein profiles with marked elevation of apolipoprotein E (apoE). In this study, 15 Chinese patients with LPG were involed in exploring the association of the genetic variation and its plasma level in the pathogenesis of LPG.Methods A retrospective analysis of the clinical and pathological features was made in 15 patients with LPG. Plasma concentrations of apoE were measured with radial immunodiffusion assay. Genetic variations of apoE gene were detected using polymerase chain reaction and restriction fragment length polymorphism. Glomerular deposition of apoA, apoB and apoE in these patients were detected by immunofluorescence staining using monoclonal antibodies. Results Biochemical profiles of lipids and lipoproteins revealed markedly elevated levels of triglyceride, apoB and apoE, but approximately normal levels of total cholesterol, apoA1 and lipoprotein(a) [Lp(a)], which resembled familial hypertriglyceridemia. Genetic analysis demonstrated that the genotype distribution of apoE were 7 cases with ε3/ε 4, 4 cases with ε3/ε 3 and 2 cases with ε2/ε 3. The other 2 cases (a mother and her son) showed a same distinct band. The band pattern of later 2 cases was quite similar to the apoE variant of Tokyo type. The calculated allele frequency of ε 4 was relatively high in cases with LPG in comparison with that in the normal controls. We further divided the 13 patients into three groups according to their genotypes of apoE. Patients with the genotype of apoE ε2/ε3 showed a lower level of plasma apoE as compared to those with apoE ε3/ε4 (P<0.05). The serum level of high-density lipoprotein (HDL) was the lowest in patients with the genotype of apoE ε3/ε4. No difference was found among the patients with different apoE genotype in the other clinical and pathological characteristics. Conclusions The

  7. Apolipoprotein E COG 133 mimetic peptide improves 5-fluorouracil-induced intestinal mucositis

    Directory of Open Access Journals (Sweden)

    Azevedo Orleâncio Gomes R

    2012-07-01

    Full Text Available Abstract Background Intestinal mucositis is one of the major troublesome side effects of anticancer chemotherapy leading to poor patient compliance. In this study we addressed the role of the novel apolipoprotein E (ApoE COG 133 mimetic peptide in 5-fluorouracil (5-FU-challenged Swiss mice and IEC-6 cell monolayers. Experiments were also conducted in C57BL6J ApoE knock-out mice to assess the effects of apoE peptide treatment. Methods Experimental groups were as follows: unchallenged controls, 5-FU-challenged mice (450 mg/kg, i.p with or without the ApoE peptide (0.3, 1, and 3 μM, given twice daily i.p. for 4 days. Mice were sacrificed 3 days after 5-FU challenge. Proximal small intestinal samples were harvested for molecular biology and histological processing. We conducted ELISA assays and RT-PCR to target IL-1β, TNF-α, IL-10, iNOS, and myeloperoxidase (MPO to assess intestinal inflammation. Cell death and NF-κB assays were also conducted in apoE knock-out mice. In our in vitro models, IEC-6 cells were exposed to 1 mM of 5-FU in glutamine free media with or without the ApoE peptide (0.02, 0.2, 2, 5, 10, and 20 μM. We investigated IEC-6 cell proliferation and migration, 24 h after the 5-FU challenge. Additionally, apoptotic IEC-6 cells were measured by Tunel and flow cytometry. Equimolar doses of the ApoA-I (D4-F peptide were also used in some experiments for comparative studies. Results Villus blunting and heavy inflammatory infiltrates were seen in the 5-FU-challenged group, findings that were partially ameliorated by the ApoE peptide. We found increased intestinal MPO and pro-inflammatory IL-1β and TNF-α levels, and TNF-α and iNOS transcripts, and reduction of IL-10 following 5-FU treatment, each of which were partially abrogated by the peptide. Improvements were also found in IEC-6 cell apoptosis and migration following ApoE and D-4F treatment. Conclusion Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide

  8. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Araújo, C.V. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Lazzarotto, C.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Aquino, C.C.; Figueiredo, I.L.; Costa, T.B.; Oliveira Alves, L.A. de [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Ribeiro, R.A. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Bertolini, L.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Lima, A.A.M. [Laboratório de Doenças Infecciosas, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Brito, G.A.C. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Oriá, R.B. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil)

    2015-04-28

    Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE{sup -/-}) and wild-type (APOE{sup +/+}) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE{sup -/-} mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE{sup +/+} mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE{sup -/-}-challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU

  9. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

    Directory of Open Access Journals (Sweden)

    C.V. Araújo

    2015-06-01

    Full Text Available Apolipoprotein E (APOE=gene, apoE=protein is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/- and wild-type (APOE+/+ C57BL6J male and female mice (N=86 were given either Ala-Gln (100 mM or phosphate buffered saline (PBS by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU challenge (450 mg/kg, via intraperitoneal injection. Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1 and B-cell lymphoma 2 (Bcl-2 intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001 in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05 were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

  10. Apolipoprotein E gene polymorphism and total serum cholesterol level in Iranian population

    Directory of Open Access Journals (Sweden)

    Bazzaz J

    2010-01-01

    Full Text Available Background: Apolipoprotein E (APOE is known as a major regulator of blood lipid levels in humans. A number of APOE gene allelic variants have been reported including E2, E3 and E4. Recent studies suggested a role for APOE in obesity and increased Body Mass Index (BMI and plasma lipid levels in obese children. Aim: The aim of this study was to examine the association between APOE genetic variants and the BMI and lipid profile in an Iranian cohort. Setting and Design: Samples were obtained from subjects who participated in a study based on the WHO-designed MONICA (multinational monitoring of trends and determinants in cardiovascular disease study for coronary artery disease risk assessment in Zone 17 of Tehran. The study was approved by the local ethical committee. Informed consent was obtained from all subjects included in this study. Materials and Methods: Subjects (n=320 were recruited. The level of triglyceride (TG and total serum cholesterol was tested for all subjects in this study. Genotyping for APOE was carried using polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLPtechnique. Statistical Analysis: Levels of significance were determined using contingency tables by either Chi-square or Fisher exact analysis using the STATA (v8 software. The analysis of regression and significance of differences for level of cholesterol and TG was established by one-way analysis of variance followed by Dunnett post hoc multiple comparison tests using SPSS software Version 11.5. Results: The frequency of allele E2 was significantly higher in patients with total serum cholesterol level <200 mg/dl (P 0.01 OR 2.1 95% CI 1.1-4.2. Conclusion: The association found in this study between allele E2 and lower total cholesterol level had been reported in previous studies. We have also observed that the frequency of genotype E2/E3 and E2/E4 was significantly higher in patients with normal total serum cholesterol level compared to patients with

  11. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

    International Nuclear Information System (INIS)

    Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge

  12. Enhanced Diabetes Susceptibility in Community Dwelling Han Elders Carrying the Apolipoprotein E 3/3 Genotype.

    Directory of Open Access Journals (Sweden)

    Chun-Xia Ban

    Full Text Available Despite Apolipoprotein E (ApoE being one of the main apolipoproteins in the blood, the association between its genotype and the high cholesterol or blood glucose levels commonly seen in clinical practice is inconclusive. Such research is also lacking in the Han population. The aim of this study was to investigate the association between APOE genotype, diabetes, and plasma glucose and lipid levels. We included 243 community-dwelling elderly residents in this study. Participant APOE genotypes were assessed and were simultaneously tested for weight, height, blood glucose, triglycerides, cholesterol, and high- and low-density lipoprotein. In addition, gender, age, years of education, cognitive function, and medical history was recorded. Subjects were divided into 3 groups based on APOE genotype: APOE ε2 group (ε2/ε2 and ε2/ε3, APOE ε3 group (ε3/ε3, and APOE ε4 group (ε2/ε4, ε3/ε4 and ε4/ε4. Comparisons between groups were conducted for the incidence of diabetes, high blood pressure, and dementia, as well as for differences in body-mass index, fasting plasma glucose, and blood lipids. The APOE ε3/ε3 genotype exhibited the highest frequency (70.4% among the subjects. Participants in the APOE ε3 group demonstrated significantly higher levels of fasting plasma glucose than those in the APOE ε2 and APOE ε4 groups (P<0.05. The APOE ε3 group had slightly higher abnormal fasting plasma glucose values than did the APOE ε2 group (P = 0.065. Furthermore, the APOE3 genotype was significantly correlated with both fasting plasma glucose level and glucose abnormality (P< 0.05 and trended toward statistically significant correlation with diabetes (P = 0.082. The correlation between APOE2 and low low-density lipoprotein levels also approached statistical significance (P = 0.052. Thus, elderly community dwelling residents of Han ethnicity carrying the APOE ε3/ε3 genotype might have higher plasma glucose levels and a higher occurrence of

  13. Apolipoprotein E gene polymorphisms are associated with primary hyperuricemia in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jie Wu

    Full Text Available OBJECTIVE: Primary hyperuricemia, an excess of uric acid in the blood, is a major public health problem. In addition to the morbidity that is attributable to gout, hyperuricemia is also associated with metabolic syndrome, hypertension, and cardiovascular disease. This study aims to assess the genetic associations between Apolipoprotein E (APOE polymorphisms and hyperuricemia in a Chinese population. METHODS: A total of 770 subjects (356 hyperuricemic cases and 414 normouricemic controls were recruited from the Ningxia Hui Autonomous Region, China. A physical examination was performed and fasting blood was collected for biochemical tests, including determination of the levels of serum lipid, creatinine, and uric acid. Multi-ARMS PCR was applied to determine the APOE genotypes, followed by an investigation of the distribution of APOE genotypes and alleles frequencies in the controls and cases. RESULTS: The frequencies of the APOE-ε2ε3 genotype (17.70% vs. 10.39%, P = 0.003 and the APOE-ε2 allele (10.53% vs. 5.80%, P = 0.001 were significantly higher in the hyperuricemic group than in the normouricemic group. Furthermore, male cases were more likely to have the APOE-ε2ε3 genotype and APOE-ε2 allele, compared with male controls. In both Han and Hui subjects, cases were more likely to have the APOE-ε2ε3 genotype and the APOE-ε2 allele compared with controls. Furthermore, multivariate logistic regression showed that carriers of the APOE-ε2ε3 genotype (P = 0.001, OR = 2.194 and the ε2 allele (P = 0.001, OR = 2.099 were significantly more likely to experience hyperuricemia than carriers of the ε3/ε3 genotype and the ε3 allele after adjustment for sex, body mass index (BMI, diastolic blood pressure (DBP, triglyceride (TG, low density lipoprotein cholesterol (LDL-C, creatinine (Cr and fasting blood glucose (FBG. CONCLUSIONS: The APOE-ε2ε3 genotype and the APOE-ε2 allele are associated with serum uric acid levels

  14. Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice

    Institute of Scientific and Technical Information of China (English)

    Xiao-xing WANG; Xiao-xi LV; Jia-ping WANG; Hui-min YAN; Zi-yan WANG; Han-zhi LIU; Xiao-ming FU

    2013-01-01

    Aim:Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis.The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis.Methods:Forty-week old apolipoprotein E-deficient (ApoE-/-) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks.Double-knockout ApoE-/-Tlr2-/-mice were taken as a positive control.At the end of the treatments,the plasma lipid levels were measured,and the plaque morphology,pro-inflammatory cytokines expression and apoptosis in arteries were analyzed.In the second part of this study,6-week old ApoE-/-and ApoE-/-Tlr2-/-mice fed on a high-cholesterol diet for 12 to 24 weeks,the expression levels of TLR2 and apoptotic markers in arteries were examined.Results:Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE-/-mice.However,the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis,and increased plaque stability in the brachiocephalic arteries.The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-KB and Stat3.In addition,blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries,which could promote the resolution of necrotic cores in advanced atherosclerosis.Moreover,high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE-/-mice than in ApoE-/-Tlr2-/-mice.Conclusion:The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE-/-mice.Thus,targeting TLR2 signaling may be a promising therapeutic strategy against

  15. Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations.

    Science.gov (United States)

    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

    2014-01-15

    Apolipoprotein E, a protein component of blood lipid particles, plays an important role in lipid transport. Different mutations in the apolipoprotein E 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. On the basis of this observation, we hypothesized that the R145C polymorphism might be common in African-derived populations. The prevalence of the R145C variant was assessed worldwide in the "1000 Genomes Project" and in 1,012 whites and 1,226 African-Americans in New York, New York. The 1000 Genomes Project data demonstrated that the R145C polymorphism is rare in non-African-derived populations but present in 5% to 12% of Sub-Saharan African-derived populations. The R145C polymorphism was also rare in New York whites (1 of 1,012, 0.1%); however, strikingly, 53 of the 1,226 New York African-Americans (4.3%) were R145C heterozygotes. The lipid profiles of the Qatari and New York R145C heterozygotes were compared with those of controls. The Qatari R145C subjects had higher triglyceride levels than the Qatari controls (p worldwide derived from Sub-Saharan Africans are apolipoprotein E R145C. In conclusion, although 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

  16. Apolipoprotein E Variation at the Sequence Haplotype Level: Implications for the Origin and Maintenance of a Major Human Polymorphism

    OpenAIRE

    Fullerton, Stephanie M.; Clark, Andrew G.; Weiss, Kenneth M.; Nickerson, Deborah A.; Taylor, Scott L.; Stengård, Jari H.; Salomaa, Veikko; Vartiainen, Erkki; Perola, Markus; Boerwinkle, Eric; Sing, Charles F.

    2000-01-01

    Three common protein isoforms of apolipoprotein E (apoE), encoded by the ε2, ε3, and ε4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n=4...

  17. Depression and Plasma Amyloid β Peptides in the Elderly with and without the Apolipoprotein E4 Allele

    OpenAIRE

    Sun, Xiaoyan; Chiu, Chi Chia; Liebson, Elizabeth; Crivello, Natalia A.; Wang, Lixia; Caunch, Joshua; Folstein, Marshal; Rosenberg, Irwin; Mwamburi, D. Mkaya; Peter, Inga; Qiu, Wei Qiao

    2009-01-01

    Depression associated with low plasma Amyloid-β peptide 42 (Aβ42) leading to a high ratio of Aβ40/Aβ42, a biomarker of Alzheimer’s disease (AD), may represent a unique depression subtype. The relationship between low plasma Aβ42 in depression and the major risk factor of AD, Apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Aβ40 and Aβ42 wer...

  18. Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

    OpenAIRE

    Huang, Ying; WANG, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili

    2014-01-01

    The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old ApoE−/− mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE−/− mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption cau...

  19. Crystal Structure of the Mycoplasma arthritidis-Derived Mitogen in Apo Form Reveals a 3D Domain-Swapped Dimer

    Energy Technology Data Exchange (ETDEWEB)

    Liu, L.; Li, Z; Guo, Y; VanVranken, S; Mourad, W; Li, H

    2010-01-01

    Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing particular V{beta} elements of T cell receptor. Here, we report the crystal structure of a MAM mutant K201A in apo form (unliganded) at 2.8-{angstrom} resolutions. We also partially refined the crystal structures of the MAM wild type and another MAM mutant L50A in apo forms at low resolutions. Unexpectedly, the structures of these apo MAM molecules display a three-dimensional domain-swapped dimer. The entire C-terminal domains of these MAM molecules are involved in the domain swapping. Functional analyses demonstrated that the K201A and L50A mutants do not show altered ability to bind to their host receptors and that they stimulate the activation of T cells as efficiently as does the wild type. Structural comparisons indicated that the 'reconstituted' MAM monomer from the domain-swapped dimer displays large differences at the hinge regions from the MAM{sub wt} molecule in the receptor-bound form. Further comparison indicated that MAM has a flexible N-terminal loop, implying that conformational changes could occur upon receptor binding.

  20. Hydrogen sulfide regulates vascular endoplasmic reticulum stress in apolipoprotein E knockout mice

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhi-fang; ZHAO Bin; TANG Xiu-ying; LI Wei; ZHU Lu-lu; TANG Chao-shu; DU Jun-bao; JIN Hong-fang

    2011-01-01

    Background Atherosclerosis is an important cardiovascular disease,becoming a major and increasing health problem in developed countries.However,the possible underlying mechanisms were not completely clear.In 2009,our research group first discovered that hydrogen sulfide (H2S) as a novel gastrotransmitter played an important anti-atherosclerotic role.The study was designed to examine the regulatory effect of hydrogen sulfide (H2S) on endoplasmic reticulum stress (ERS) in apolipoprotein E knockout (apoE(-/-)) mice fed a Western type diet.Methods C57BL/6 mice and homozygous apoE(-/-) mice were fed a Western type diet.C57BL/6 mice were injected intraperitoneally with normal saline (5 ml/kg per day) as control group.The apoE+ mice were treated with the same dose of normal saline as the apoE(-/-) group,injected intraperitoneally with sodium hydrosulfide (NaHS,an H2S donor,56μmol/kg per day) as the apoE(-/-)+NaHS group and injected intraperitoneally with DL-propargylglycine (PPG,a cystathionine-y-lyase inhibitor,50 mg/kg,per day) as the apoE/ +PPG group.After 10 weeks,the mice were sacrificed and the plasma lipids were detected.Sections of aortic root from these animals were examined for atherosclerotic lesions by HE and oil red O staining.The aortic ultrastructure and microstructure were analyzed with the help of light and electronic microscope.Glucose-regulated protein 78 (GRP78),caspase-12,copper-andzinc-containing superoxide dismutase (Cu/ZnSOD) and Mn-containing superoxide dismutase (MnSOD) protein expression in aortic tissues were detected with immunohistochemistry.The level of intracellular reactive oxygen species (ROS) were measured by using a commercial assay kit.Results Compared with control mice,apoE(-/-) mice showed increased plasma levels of total cholesterol (TC),triglyceride (TG) and low density lipoprotein (LDL),decreased high density lipoprotein (HDL),increased aortic plaque size,destroyed ultra-structure of aortic tissue,and increased expression of GRP

  1. The activation domain of the bovine papillomavirus E2 protein mediates association of DNA-bound dimers to form DNA loops

    OpenAIRE

    Knight, J. D.; Li, R; Botchan, M

    1991-01-01

    The E2 transactivator protein of bovine papillomavirus binds its specific DNA target sequence as a dimer. We have found that E2 dimers, preformed in solution independent of DNA, exhibit substantial cooperativity of DNA binding as detected by both nitrocellulose filter retention and footprint analysis techniques. If the binding sites are widely spaced, E2 forms stable DNA loops visible by electron microscopy. When three widely separated binding sites reside on the DNA, E2 condenses the molecul...

  2. P-selectin glycoprotein ligand-1 forms dimeric interactions with E-selectin but monomeric interactions with L-selectin on cell surfaces.

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    Full Text Available Interactions of selectins with cell surface glycoconjugates mediate the first step of the adhesion and signaling cascade that recruits circulating leukocytes to sites of infection or injury. P-selectin dimerizes on the surface of endothelial cells and forms dimeric bonds with P-selectin glycoprotein ligand-1 (PSGL-1, a homodimeric sialomucin on leukocytes. It is not known whether leukocyte L-selectin or endothelial cell E-selectin are monomeric or oligomeric. Here we used the micropipette technique to analyze two-dimensional binding of monomeric or dimeric L- and E-selectin with monomeric or dimeric PSGL-1. Adhesion frequency analysis demonstrated that E-selectin on human aortic endothelial cells supported dimeric interactions with dimeric PSGL-1 and monomeric interactions with monomeric PSGL-1. In contrast, L-selectin on human neutrophils supported monomeric interactions with dimeric or monomeric PSGL-1. Our work provides a new method to analyze oligomeric cross-junctional molecular binding at the interface of two interacting cells.

  3. Repair of dipyrimidine dimers formed during the UVC irradiation of sugar beet

    International Nuclear Information System (INIS)

    Most of the mutations induced in living organisms by both mid- and short wave UV irradiation are located at dipyrimidine sites. The two major classes of photoproducts induced by UVC are cyclobutane pyrimidine dimers (CPD) and the pyrimidine pyramidones (6,4 photoproducts), constituting the two major mutagenic lesions. This paper reports investigations into the repair efficiency of the two classes of photoproducts induced by UVC and the relative importance of photoreactivation (light repair) and excision repair (dark repair) in sugar beet plants. The overall objective of the study is to determine whether differences in tolerance to UV-induced stress occur in sugar beet varieties. The results from yeast and mammalian systems indicate that 6-4 photoproducts are repaired much more rapidly than cyclobutane dimers. The present work investigates CPD and 6-4 photoproducts independently, as well as total lesions, in sugar beet hypocotyls and cotyledons irradiated with UVC at 20-200 J.m-2. The amount of damage to DNA and the speed of both light and dark repair has been determined in experiments over periods from 30 min to 3 hours. The technique applied involves dot blot immunoassay using a polyclonal antiserum raised against UVC-irradiated DNA. Detection of the individual lesions was based on their differential sensitivities to hot alkali and photoreactivating enzyme. It has been shown that hypocotyls and cotyledons were affected by UV irradiation at all the doses used. The dot blot immunoassay has allowed determination of total lesions and each type of lesion independently in sugar beet tissues. At all UVC doses the damage was repaired in the light (photoreactivation) in 2-3 hours. In hypocotyls some 'dark repair' occurred at the lower doses (20 and 50 Jm-2) but not at the higher doses (100 and 200 Jm-2). Although it can be concluded that sugar beet plants are able to repair damage caused by UVC irradiation, work is continuing to determine which of the two mechanisms is

  4. Structure of 1,5-Anhydro-D-Fructose: X-ray Analysis of Crystalline Acetylated Dimeric Forms

    DEFF Research Database (Denmark)

    Lundt, Inge; Andersen, Søren Møller; Marcussen, Jan; Søtofte, Inger; Yu, Shukun

    1998-01-01

    Acetylation of 1,5-anhydro-D-fructose under acidic conditions gave two crystalline acetylated dimeric forms, which by X-ray analysis were shown to be diastereomeric spiroketals formed between C-2 and C-2´/C-3´. The structures of the compounds differed only at the configuration at C-2. Acetylation...... or benzoylation of 1,5-anhydro-D-fructose in pyridine yielded 3,6-di-O-acetyl-1,5-anhydro-4-deoxy-D-glycero-hex-3-enos-2-ulopyra -nose or crystalline 1,5-anhydro-3,6-di-O-benzoyl-4-deoxy-D-glycero-hex-3-enos-2-ulo-py ranose....

  5. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J; Bie, Peter; Skøtt, Ole; Gan, Li-ming; Bergström, Göran

    2009-01-01

    atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We......OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible to...... used urinary isoprostane as a marker for oxidative stress. RESULTS: Although high-salt diet per se did not affect plaque extension, high salt combined with Ang II increased plaque area significantly in both the aorta and the innominate artery as compared with Ang II or salt alone (P < 0.05 and P < 0...

  6. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  7. Cloning and Expression of Apolipoprotein E3 and Its Variant apoE2 and apoE4

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In order to obtain three isoforms of apolipoprotein E (apoE), the cDNA encoding apoE3 was obtained by RT-PCR from normal human liver tissue. Site-directed mutagenesis was used to obtain the cDNAs encoding apoE2 and apoE4 isoforms. The 3 cDNAs were subcloned into vector pGEM-3Z and verified by DNA sequencing. The expression recombinant which can express the target protein as a (His) 6-tagged fusion was constructed by subcloning apoE cDNA into vector pT7-PL. The purified proteins were gained by Ni-NTA column. The SDS-PAGE results revealed the 6 His fusion proteins (apoE2, apoE3 and apoE4) were correctly expressed and purified successfully.

  8. Enhanced synthesis and secretion of apolipoprotein E from sciatic nerves of streptozotocin-induced diabetic rats after injury

    International Nuclear Information System (INIS)

    To elucidate the pathogenesis of diabetic neuropathy, synthesis and secretion of apolipoprotein E (apo E) from sciatic nerves after injury was studied in normal and streptozotocin-induced diabetic rats. Seven, 14, 28, 45 and 59 days after making crush injury on sciatic nerves with concomitant administration of streptozotocin (50 mg/kg body weight), the nerves were taken out and incubated with [35S]methionine. The [35S]labeled apo E was precipitated with specific antiserum. The amounts of apo E secreted into medium by nerves of diabetic rats were 7 times greater than those of non-diabetic rats 7 days after injury. This enhanced secretion of apo E was relatively selective for this protein, since the ratio of the immunoprecipitable apo E to the TCA preciptitable protein in the medium increased in diabetic rats. Intriguing possibility deduced from these results is that the secretion of apo E is involved in the development of diabetic neuropathy

  9. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice

    DEFF Research Database (Denmark)

    Bentzon, Jacob F; Sondergaard, Claus S; Kassem, Mustafa;

    2007-01-01

    circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. METHODS AND RESULTS: To determine the origin of SMCs after spontaneous plaque disruption......GFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical...... originating from outside the local arterial segment were detected in healed plaques. CONCLUSIONS: Healing SMCs after atherosclerotic plaque disruption are derived entirely from the local arterial wall and not circulating progenitor cells in apoE-/- mice. Udgivelsesdato: 2007-Oct-30...

  10. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J;

    2009-01-01

    < 0.001 vs. Ang II alone). Ang II increases macrophage content in lesions (P < 0.05), whereas salt likely increases collagen content. CONCLUSION: High-salt diet per se does not influence BP in ApoE-/- mice and is only moderately atherogenic. Possibly mediated via increased oxidative stress, a high...... atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...... used urinary isoprostane as a marker for oxidative stress. RESULTS: Although high-salt diet per se did not affect plaque extension, high salt combined with Ang II increased plaque area significantly in both the aorta and the innominate artery as compared with Ang II or salt alone (P < 0.05 and P < 0...

  11. Proteomic Profile of Unstable Atheroma Plaque: Increased Neutrophil Defensin 1, Clusterin, and Apolipoprotein E Levels in Carotid Secretome.

    Science.gov (United States)

    Aragonès, Gemma; Auguet, Teresa; Guiu-Jurado, Esther; Berlanga, Alba; Curriu, Marta; Martinez, Salomé; Alibalic, Ajla; Aguilar, Carmen; Hernández, Esteban; Camara, María-Luisa; Canela, Núria; Herrero, Pol; Ruyra, Xavier; Martín-Paredero, Vicente; Richart, Cristóbal

    2016-03-01

    Because of the clinical significance of carotid atherosclerosis, the search for novel biomarkers has become a priority. The aim of the present study was to compare the protein secretion profile of the carotid atherosclerotic plaque (CAP, n = 12) and nonatherosclerotic mammary artery (MA, n = 10) secretomes. We used a nontargeted proteomic approach that incorporated tandem immunoaffinity depletion, iTRAQ labeling, and nanoflow liquid chromatography coupled to high-resolution mass spectrometry. In total, 162 proteins were quantified, of which 25 showed statistically significant differences in secretome levels between carotid atherosclerotic plaque and nondiseased mammary artery. We found increased levels of neutrophil defensin 1, apolipoprotein E, clusterin, and zinc-alpha-2-glycoprotein in CAP secretomes. Results were validated by ELISA assays. Also, differentially secreted proteins are involved in pathways such as focal adhesion and leukocyte transendothelial migration. In conclusion, this study provides a subset of identified proteins that are differently expressed in secretomes of clinical significance. PMID:26795031

  12. The Immune-Modulatory Role of Apolipoprotein E with Emphasis on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Hong-Liang Zhang

    2010-01-01

    Full Text Available Apolipoprotein E (apoE is a 34.2 kDa glycoprotein characterized by its wide tissue distribution and multiple functions. The nonlipid-related properties of apoE include modulating inflammation and oxidation, suppressing T cell proliferation, regulating macrophage functions, and facilitating lipid antigen presentation by CD1 molecules to natural killer T (NKT cells, and so forth. Increasing studies have revealed that APOE ε allele might be associated with multiple sclerosis (MS, although evidence is still not sufficient enough. In this review, we summarized the current progress of the immunomodulatory functions of apoE, with special focus on the association of APOE ε allele with the clinical features of MS and of its animal model experimental autoimmune encephalomyelitis (EAE.

  13. Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Christie, R.H.; Chung, Haeyong; Rebeck, G.W.; Hyman, B.T. [Massachusetts General Hospital, Boston, MA (United States)] [and others

    1996-04-01

    The very low density lipoprotein receptor (VLDL-r) is a cell-surface molecule specialized for the internalization of multiple diverse ligands, including apolipoprotein E (apoE)-containing lipoprotein particles, via clathrin-coated pits. Its structure is similar to the low-density lipoprotein receptor (LDL-r), although the two have substantially different systemic distributions and regulatory pathways. The present work examines the distribution of VLDL-r in the central nervous system (CNS) and in relation to senile plaques in Alzheimer disease (AD). VLDL-r is present on resting and activated microglia, particularly those associated with senile plaques (SPs). VLDL-r immunoreactivity is also found in cortical neurons. Two exons of VLDL-r mRNA are differentially spliced in the mature receptor mRNA. One set of splice forms gives rise to receptors containing (or lacking) an extracellular O-linked glycosylation domain near the transmembrane portion of the molecule. The other set of splice forms appears to be brain-specific, and is responsible for the presence or absence of one of the cysteine-rich repeat regions in the binding region of the molecule. Ratios of the receptor variants generated from these splice forms do not differ substantially across different cortical areas or in AD. We hypothesize that VLDL-r might contribute to metabolism of apoE and apoE/A{beta} complexes in the brain. Further characterization of apoE receptors in Alzheimer brain may help lay the groundwork for understanding the role of apoE in the CNS and in the pathophysiology of AD. 43 refs., 5 figs.

  14. Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis.

    Directory of Open Access Journals (Sweden)

    Benjamin A Neely

    Full Text Available Domoic acid toxicosis (DAT in California sea lions (Zalophus californianus is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05. Interestingly, 11 apolipoprotein E (ApoE charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value and high specificity (92.3% with 85.7% positive predictive value. These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers.

  15. Proteomic and meatbolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice

    NARCIS (Netherlands)

    Mayr, M; Zampetaki, A.; Sidibe, A.; Mayr, U.; Yin, X.; Souza, A.I. de; Chung, Y.L.; Madhu, B.; Quax, P.H.; Hu, Y.; Griffiths, J.R.; Xu, Q.

    2008-01-01

    We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic app

  16. Apolipoprotein A-II Influences Apolipoprotein E-Linked Cardiovascular Disease Risk in Women with High Levels of HDL Cholesterol and C-Reactive Protein

    NARCIS (Netherlands)

    Corsetti, James P.; Bakker, Stephan J. L.; Sparks, Charles E.; Dullaart, Robin P. F.

    2012-01-01

    Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as

  17. The Influence of the Epsilon4 Allele of the Apolipoprotein E Gene on Childhood IQ, Nonverbal Reasoning in Old Age, and Lifetime Cognitive Change.

    Science.gov (United States)

    Deary, Ian J.; Whalley, Lawrence J.; St. Clair, David; Breen, Gerome; Leaper, Steve; Lemmon, Helen; Hayward, Caroline; Starr, John M.

    2003-01-01

    Examines the influence of apolipoprotein E gene states on three cognitive outcomes in 173 people at age 11 and in the same people at age 77 and examined the change in IQ between these ages. There was no significant main effect of gene status on IQ in youth or old age, nor in cognitive change across the lifespan. (SLD)

  18. The Activation Domain of the Bovine Papillomavirus E2 Protein Mediates Association of DNA-Bound Dimers to form DNA Loops

    Science.gov (United States)

    Knight, Jonathan D.; Li, Rong; Botchan, Michael

    1991-04-01

    The E2 transactivator protein of bovine papillomavirus binds its specific DNA target sequence as a dimer. We have found that E2 dimers, performed in solution independent of DNA, exhibit substantial cooperativity of DNA binding as detected by both nitrocellulose filter retention and footprint analysis techniques. If the binding sites are widely spaced, E2 forms stable DNA loops visible by electron microscopy. When three widely separated binding sites reside on te DNA, E2 condenses the molecule into a bow-tie structure. This implies that each E2 dimer has at least two independent surfaces for multimerization. Two naturally occurring shorter forms of the protein, E2C and D8/E2, which function in vivo as repressors of transcription, do not form such loops. Thus, the looping function of E2 maps to the 161-amino acid activation domain. These results support the looping model of transcription activation by enhancers.

  19. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuehai [Cardiovascular Department, Liaocheng People’s Hospital of Shandong University, Liaocheng, Shandong 252000 (China); Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Huang, Ziyang, E-mail: huangziyang666@126.com [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Huili [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lei, Zhenmin [Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Chen, Xiaoqing [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Gao, Fei; Dong, Mei [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Li, Rongda [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Ling, E-mail: qzlinl@163.com [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China)

    2014-07-18

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

  20. Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB

    International Nuclear Information System (INIS)

    Apolipoprotein E (ApoE) plays a major role in the transport and metabolism of lipid. Other functions of ApoE include modulation of innate and adaptive immune responses. The expression of ApoE in osteoblasts and its relevance with bone formation have also been reported. However, the effect of ApoE on osteoclasts has not yet been examined. Here, we investigated the role of ApoE in osteoclast differentiation using bone marrow-derived macrophages (BMMs) and RAW264.7 cells. We found a down-regulation of ApoE gene expression during osteoclastic differentiation of those cells. Overexpression of ApoE in BMMs and RAW264.7 cells significantly blocked the induction of c-Fos and nuclear factor of activated T cell c1 (NFATc1), transcription factors critical for expression of osteoclast marker genes, by receptor activator of nuclear factor κB ligand (RANKL), the osteoclast differentiation factor. ApoE inhibited osteoclast differentiation, as measured by decreased number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNCs). In addition, ApoE reduced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d2 (ATP6v0d2), genes involved in cell–cell fusion during osteoclastogenesis. Knock-down of ApoE using a specific siRNA promoted the RANKL-mediated induction of osteoclast differentiation. While ApoE did not affect the activation of ERK, JNK, and p38 MAPK signaling pathways by RANKL, the phosphorylation of p65 trans-activation domain on serine 536 and transcription activity of NF-κB were reduced by ApoE overexpression. These findings suggest that ApoE plays an inhibitory role in osteoclast differentiation via the suppression of RANKL-dependent activation of NF-κB and induction of c-Fos and NFATc1. - Highlights: ► Apolipoprotein E (ApoE) significantly inhibited osteoclast differentiation and activation of NF-κB. ► ApoE decreased the induction of osteoclast marker genes

  1. Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Woo-Shin; Kim, Hyung Joon; Lee, Zang Hee [Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749 (Korea, Republic of); Lee, Youngkyun [Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Kim, Hong-Hee, E-mail: hhbkim@snu.ac.kr [Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749 (Korea, Republic of)

    2013-02-15

    Apolipoprotein E (ApoE) plays a major role in the transport and metabolism of lipid. Other functions of ApoE include modulation of innate and adaptive immune responses. The expression of ApoE in osteoblasts and its relevance with bone formation have also been reported. However, the effect of ApoE on osteoclasts has not yet been examined. Here, we investigated the role of ApoE in osteoclast differentiation using bone marrow-derived macrophages (BMMs) and RAW264.7 cells. We found a down-regulation of ApoE gene expression during osteoclastic differentiation of those cells. Overexpression of ApoE in BMMs and RAW264.7 cells significantly blocked the induction of c-Fos and nuclear factor of activated T cell c1 (NFATc1), transcription factors critical for expression of osteoclast marker genes, by receptor activator of nuclear factor κB ligand (RANKL), the osteoclast differentiation factor. ApoE inhibited osteoclast differentiation, as measured by decreased number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNCs). In addition, ApoE reduced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase, H{sup +} transporting, lysosomal 38 kDa, V0 subunit d2 (ATP6v0d2), genes involved in cell–cell fusion during osteoclastogenesis. Knock-down of ApoE using a specific siRNA promoted the RANKL-mediated induction of osteoclast differentiation. While ApoE did not affect the activation of ERK, JNK, and p38 MAPK signaling pathways by RANKL, the phosphorylation of p65 trans-activation domain on serine 536 and transcription activity of NF-κB were reduced by ApoE overexpression. These findings suggest that ApoE plays an inhibitory role in osteoclast differentiation via the suppression of RANKL-dependent activation of NF-κB and induction of c-Fos and NFATc1. - Highlights: ► Apolipoprotein E (ApoE) significantly inhibited osteoclast differentiation and activation of NF-κB. ► ApoE decreased the induction of osteoclast marker

  2. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    International Nuclear Information System (INIS)

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE−/− and Fas−/− mice. • The spleen weights and glomerular areas were similar in ApoE−/− and Fas−/− mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE−/− and Fas−/− mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE−/− mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE−/−) mice is a classic model of atherosclerosis. We have found that ApoE−/− mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE−/− mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE−/−, Fas−/− and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas−/− mice, a model of systemic lupus erythematosus (SLE), ApoE−/− mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE−/− mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE−/− mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

  3. Primary Genetic Investigation of a Hyperlipidemia Model: Molecular Characteristics and Variants of the Apolipoprotein E Gene in Mongolian Gerbil

    Directory of Open Access Journals (Sweden)

    Yuehuan Liu

    2014-01-01

    Full Text Available The objective of this work was to establish a novel Mongolian gerbil (Meriones unguiculatus hyperlipidemia model and to investigate its susceptibility genetic basis. Two rodent (gerbil and rat hyperlipidemia models were induced by feeding a high fat/high-cholesterol (HF/HC diet. There were significant increases of serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C, and high-density lipoprotein cholesterol (HDL-C in gerbils within a 4-week modeling period. About 10–30% of >8-month-old individuals developed hyperlipidemia spontaneously. The apolipoprotein E (ApoE gene was cloned by merging a sequence of rapid amplification of cDNA ends (RACE and nested polymerase chain reaction products. The results revealed an open reading frame of 948 bp, encoding a protein of 298 amino acids. The gene without a 5′-UTR region in the first intron was highly homologous to human Apo-A-I and rat Apo-A-IV. The distribution of expression of the ApoE gene in liver, brain, heart, lung, kidney, and adrenal gland was detected by an ABC immunohistochemical procedure. Three single nucleotide polymorphisms (SNPs; C97T, G781T, and A1774T were first found using PCR-single-strand conformation polymorphism (PCR-SSCP in a closed population containing 444 animals. Correlation analysis confirmed that new SNPs , age, and gender were associated significantly (P<0.05 with hyperlipidemia.

  4. Apolipoprotein E polymorphism and acute ischemic stroke: a diffusion- and perfusion-weighted magnetic resonance imaging study.

    Science.gov (United States)

    Liu, Yawu; Laakso, Mikko P; Karonen, Jari O; Vanninen, Ritva L; Nuutinen, Juho; Soimakallio, Seppo; Aronen, Hannu J

    2002-11-01

    Diffusion- and perfusion-weighted magnetic resonance imaging (MRI) was used to study the putative effects of apolipoprotein E (ApoE) polymorphism in stroke. Thirty-one patients with acute stroke, comparative for age and gender were scanned, nine of whom were ApoE allele epsilon 4 carriers. Initially, less than 24 hours from the onset of stroke, the epsilon 4 carriers had significantly smaller volumes of hypoperfusion on relative cerebral blood volume map (P = 0.001), and smaller infarct volumes (P = 0.008) compared with the noncarriers. By day 8, this difference in the infarct volumes had disappeared, suggesting relatively enhanced infarct growth. On average, the total infarct volume increased 145% of the initial infarct volume in the epsilon 4 carriers, and 84% in the noncarriers. There were strong correlations between the imaging findings and clinical status initially and with the outcome 3 months after the stroke in the epsilon 4 noncarriers, but, with a single exception at acute phase, a lack thereof in the epsilon 4 carriers. These patterns were virtually similar in a subgroup of patients with middle cerebral artery stroke. These data support the hypothesis of increased general vulnerability of the brain in the epsilon 4 carriers. Thus, the effects of ApoE polymorphism should be accounted for when interpreting diffusion- and perfusion-weighted MRI studies, particularly if predicting lesion growth. PMID:12439291

  5. Apolipoprotein E gene polymorphism and its effect on anthropometric measures in normoglycemic subjects and type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Tabatabaei-Malazy Ozra

    2012-10-01

    Full Text Available Abstract Background Apolipoprotein E (apo E plays a major role in lipid metabolism, obesity and accordingly in development of diabetes and coronary heart disease (CHD. Our main objective was to evaluate the association between apo E gene polymorphism with anthropometric measures. Methods Participants were selected from zone 17 Tehran/Iran. We assessed height, weight, body mass index (BMI, waist circumference (WC, blood pressure, serum fasting blood sugar, total cholesterol and triglycerides. Genotyping for apo E gene polymorphism was carried out using PCR-RFLP technique. Results Among total study population (n=311, 156 subjects were diabetic. The apo E3/E3 was the most common genotype in our population while E2 and E4 alleles had lower frequencies, respectively. After adjustment for diabetes, the apo E2 and E4 alleles were significantly associated with hypercholesterolemia and WC, respectively (p= 0.009, 0.034. This association was also related to sex and age. The probability of having abdominal obesity in E4 allele carriers was increased from 0.22 to 8.12 in women and to 3.08 in age ≥ 50 years. Conclusions Apo E polymorphism had significant influences on WC and total cholesterol level in patients with type 2 diabetes. This study highlights the importance of lifestyle modifications which may be more beneficial in hypercholesterolemic women carriers of E2 and E4 alleles concomitant central obesity.

  6. Structural and functional characterization of human apolipoprotein E 72-166 peptides in both aqueous and lipid environments

    Directory of Open Access Journals (Sweden)

    Chou Chi-Yuan

    2011-01-01

    Full Text Available Abstract Backgrounds There are three apolipoprotein E (apoE isoforms involved in human lipid homeostasis. In the present study, truncated apoE2-, apoE3- and apoE4-(72-166 peptides that are tailored to lack domain interactions are expressed and elucidated the structural and functional consequences. Methods & Results Circular dichroism analyses indicated that their secondary structure is still well organized. Analytical ultracentrifugation analyses demonstrated that apoE-(72-166 produces more complicated species in PBS. All three isoforms were significantly dissociated in the presence of dihexanoylphosphatidylcholine. Dimyristoylphosphatidylcholine turbidity clearance assay showed that apoE4-(72-166 maintains the highest lipid-binding capacity. Finally, only apoE4-(72-166 still maintained significant LDL receptor binding ability. Conclusions Overall, apoE4-(72-166 peptides displayed a higher lipid-binding and comparable receptor-binding ability as to full-length apoE. These findings provide the explanation of diverged functionality of truncated apoE isoforms.

  7. Demographic and Lifestyle Characteristics, but Not Apolipoprotein E Genotype, Are Associated with Intelligence among Young Chinese College Students.

    Directory of Open Access Journals (Sweden)

    Xiao-Fen Chen

    Full Text Available Intelligence is an important human feature that strongly affects many life outcomes, including health, life-span, income, educational and occupational attainments. People at all ages differ in their intelligence but the origins of these differences are much debated. A variety of environmental and genetic factors have been reported to be associated with individual intelligence, yet their nature and contribution to intelligence differences have been controversial.To investigate the contribution of apolipoprotein E (APOE genotype, which is associated with the risk for Alzheimer's disease, as well as demographic and lifestyle characteristics, to the variation in intelligence.A total of 607 Chinese college students aged 18 to 25 years old were included in this prospective observational study. The Chinese revision of Wechsler Adult Intelligence Scale (the fourth edition, short version was used to determine the intelligence level of participants. Demographic and lifestyle characteristics data were obtained from self-administered questionnaires.No significant association was found between APOE polymorphic alleles and different intelligence quotient (IQ measures. Interestingly, a portion of demographic and lifestyle characteristics, including age, smoking and sleep quality were significantly associated with different IQ measures.Our findings indicate that demographic features and lifestyle characteristics, but not APOE genotype, are associated with intelligence measures among young Chinese college students. Thus, although APOE ε4 allele is a strong genetic risk factor for Alzheimer's disease, it does not seem to impact intelligence at young ages.

  8. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: No cosegregation with severe hyperlipidemia

    Energy Technology Data Exchange (ETDEWEB)

    Maagdenberg, A.M.J.M. van den; Bruijn, I.H. de; Hofker, M.H.; Frants, R.R. (Leiden Univ. (Netherlands)); Knijff, P. de; Smelt, A.H.M.; Leuven, J.A.G.; van' t Hooft, F.; Assmann, G.; Havekes, L.M. (Univ. Hospital, Leiden (Netherlands)); Weng, Wei; Funke, H. (Westfalische Wilhelms-Universitaet, Muester (Germany))

    1993-05-01

    Assessment of the apolipoprotein E (apoE) phenotype by isoelectric focusing of both hyperlipidemic and normolipidemic individuals identified five new variants. All mutations were confined to the downstream part of the APOE gene by using denaturing gradient gel electrophoresis (DGGE). Sequence analysis revealed five new mutations causing unique amino acid substitutions in the carboxyl-terminal part of the protein containing the putative lipid-binding domain. Three hyperlipoproteinemic probands were carriers of the APOE*2(Va1236[r arrow]Glu) allele, the APOE*3(Cys112-Arg; Arg251[r arrow]Gly) allele, or the APOE*1(Arg158[r arrow]Cys; Leu252[r arrow]Glu) allele. DGGE of the region encoding the receptor-binding domain was useful for haplotyping the mutations at codons 112 and 158. Family studies failed to demonstrate cosegregation between the new mutations and severe hyperlipoproteinemia, although a number of carriers for the APOE*3(Cys112[r arrow]Arg; Arg251[r arrow]Gly) allele and the APOE*1(Arg158-Cys; Leu252[r arrow]Glu) allele expressed hypertriglyceridemia and/ or hypercholesterolemia. Two other mutant alleles, APOE*4[sup [minus

  9. Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease.

    Science.gov (United States)

    Nieminen, Tuomo; Kähönen, Mika; Viiri, Leena E; Grönroos, Paula; Lehtimäki, Terho

    2008-10-01

    A non-optimal plasma concentration of lipids is among the major modifiable risk factors of atherosclerosis. Therefore, the prevention of cardiovascular disease by means of lipid-lowering therapy with statins and other agents is of great importance for patient groups where a lifestyle change, for example, diet modification, does not lead to adequately reduced lipid levels. The response of low-density-lipoprotein cholesterol (LDL-C) levels to statin therapy is highly variable. This is partly attributed to hereditary variation in genes involved in pharmacokinetics, pharmacodynamics and lipid metabolism. The pharmacogenetics of lipid-lowering therapy have been investigated for more than 40 different genes. The gene for apolipoprotein E (APOE) has been the most frequently studied, particularly regarding the epsilon2/epsilon3/epsilon4 polymorphism. Those with the epsilon4 allele seem to have the poorest and those with the epsilon2 allele the strongest response to statins with regards to LDL-C levels. In addition, the epsilon2 carriers may reach the LDL-C treatment goals more frequently than epsilon4 carriers. Few studies have investigated the interaction of the APOE epsilon2/epsilon3/epsilon4 polymorphism and lipid-lowering therapy in relation to the course of coronary heart disease; the results are contradictory and so far inconclusive. This review summarizes the pharmacogenetic findings related to the influence of APOE gene variation on lipid responses and the prevention of coronary heart disease during lipid-lowering therapy. PMID:18855536

  10. Data from a cross-sectional study on Apolipoprotein E (APOE-ε4 and snoring/sleep apnea in non-demented older adults

    Directory of Open Access Journals (Sweden)

    Angeliki Tsapanou

    2015-12-01

    Full Text Available In the present data, we provide the details of the cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP that examined the association between Apolipoprotein E (APOE-ε4 and snoring/sleep apnea. A total of 1944 non-demented older adults constituted our sample. Sleep dysfunction was measured using sleep categories derived from the Medical Outcomes Study Sleep Scale. Stratified analyses were conducted in order to examine the association between APOE-ε4 and sleep variables by ethnic group. For further analyses and enhanced discussion, see “Examining the association between Apolipoprotein E (APOE and self-reported sleep disturbances in non-demented older adults” by Tsapanou et al. (2015 [1].

  11. Involvement of toll-like receptor 2 and 4 in association between dyslipidemia and osteoclast differentiation in apolipoprotein E deficient rat periodontium

    OpenAIRE

    Tomofuji, Takaaki; Ekuni, Daisuke; Azuma, Tetsuji; Irie, Koichiro; Endo, Yasumasa; Kasuyama, Kenta; Yoneda, Toshiki; Morita, Manabu

    2013-01-01

    Background Dyslipidemia increases circulating levels of oxidized low-density lipoprotein (OxLDL) and this may induce alveolar bone loss through toll-like receptor (TLR) 2 and 4. The purpose of this study was to investigate the effects of dyslipidemia on osteoclast differentiation associated with TLR2 and TLR4 in periodontal tissues using a rat dyslipidemia (apolipoprotein E deficient) model. Methods Levels of plasma OxLDL, and the cholesterol and phospholipid profiles in plasma lipoproteins w...

  12. Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse

    OpenAIRE

    Braun, Anne; Zhang, Songwen; Miettinen, Helena E.; Ebrahim, Shamsah; Holm, Teresa M.; Vasile, Eliza; Mark J Post; Yoerger, Danita M.; Picard, Michael H.; Joshua L. Krieger; Andrews, Nancy C.; Simons, Michael; Krieger, Monty

    2003-01-01

    Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean a...

  13. ATR–FTIR, a new tool to analyze the oligomeric content of Aβ samples in the presence of apolipoprotein E isoforms

    OpenAIRE

    Cerf, Emilie; Ruysschaert, Jean-Marie; Goormaghtigh, Erik; Raussens, Vincent

    2010-01-01

    Alzheimer̕s disease (AD) is a neurodegenerative disorder caused by the aggregation of the amyloid-beta peptide (Aβ), leading to amyloid plaques deposition in the brain. Although Aβ aggregation pathway still remains unclear, recent studies point out the enhanced toxicity of oligomers compared to fibrils. The E4 isoform of apolipoprotein E (ApoE) is the major risk factor in AD as people carrying one ɛ4 allele have significantly higher chances to develop the disease. Nevertheless, this phenomeno...

  14. A Phytophthora sojae effector PsCRN63 forms homo-/hetero-dimers to suppress plant immunity via an inverted association manner.

    Science.gov (United States)

    Li, Qi; Zhang, Meixiang; Shen, Danyu; Liu, Tingli; Chen, Yanyu; Zhou, Jian-Min; Dou, Daolong

    2016-01-01

    Oomycete pathogens produce a large number of effectors to promote infection. Their mode of action are largely unknown. Here we show that a Phytophthora sojae effector, PsCRN63, suppresses flg22-induced expression of FRK1 gene, a molecular marker in pathogen-associated molecular patterns (PAMP)-triggered immunity (PTI). However, PsCRN63 does not suppress upstream signaling events including flg22-induced MAPK activation and BIK1 phosphorylation, indicating that it acts downstream of MAPK cascades. The PsCRN63-transgenic Arabidopsis plants showed increased susceptibility to bacterial pathogen Pseudomonas syringae pathovar tomato (Pst) DC3000 and oomycete pathogen Phytophthora capsici. The callose deposition were suppressed in PsCRN63-transgenic plants compared with the wild-type control plants. Genes involved in PTI were also down-regulated in PsCRN63-transgenic plants. Interestingly, we found that PsCRN63 forms an dimer that is mediated by inter-molecular interactions between N-terminal and C-terminal domains in an inverted association manner. Furthermore, the N-terminal and C-terminal domains required for the dimerization are widely conserved among CRN effectors, suggesting that homo-/hetero-dimerization of Phytophthora CRN effectors is required to exert biological functions. Indeed, the dimerization was required for PTI suppression and cell death-induction activities of PsCRN63. PMID:27243217

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

    International Nuclear Information System (INIS)

    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

  16. Apolipoprotein E Variation at the Sequence Haplotype Level: Implications for the Origin and Maintenance of a Major Human Polymorphism

    Science.gov (United States)

    Fullerton, Stephanie M.; Clark, Andrew G.; Weiss, Kenneth M.; Nickerson, Deborah A.; Taylor, Scott L.; Stengård, Jari H.; Salomaa, Veikko; Vartiainen, Erkki; Perola, Markus; Boerwinkle, Eric; Sing, Charles F.

    2000-01-01

    Three common protein isoforms of apolipoprotein E (apoE), encoded by the ε2, ε3, and ε4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n=48 chromosomes), Mayans from Campeche, Mexico (n=48), Finns from North Karelia, Finland (n=48), and non-Hispanic whites from Rochester, MN (n=48). In the region sequenced, 23 sites varied (21 single nucleotide polymorphisms, or SNPs, 1 diallelic indel, and 1 multiallelic indel). The 22 diallelic sites defined 31 distinct haplotypes in the sample. The estimate of nucleotide diversity (site-specific heterozygosity) for the locus was 0.0005±0.0003. Sequence analysis of the chimpanzee APOE gene showed that it was most closely related to human ε4-type haplotypes, differing from the human consensus sequence at 67 synonymous (54 substitutions and 13 indels) and 9 nonsynonymous fixed positions. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. This analysis suggests that haplotypes defining the ε3 and ε2 alleles are derived from the ancestral ε4s and that the ε3 group of haplotypes have increased in frequency, relative to ε4s, in the past 200,000 years. Substantial heterogeneity exists within all three classes of sequence haplotypes, and there are important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms. PMID:10986041

  17. Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain

    International Nuclear Information System (INIS)

    Purpose: In humans, apolipoprotein E (apoE) is encoded by three major alleles (ε2, ε3, and ε4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials: We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results: In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions: The short-term effects of 56Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

  18. Long-Term Effects of 56Fe Irradiation on Spatial Memory of Mice: Role of Sex and Apolipoprotein E Isoform

    International Nuclear Information System (INIS)

    Purpose: To assess whether the effects of cranial 56Fe irradiation on the spatial memory of mice in the water maze are sex and apolipoprotein E (apoE) isoform dependent and whether radiation-induced changes in spatial memory are associated with changes in the dendritic marker microtubule-associated protein 2 (MAP-2) and the presynaptic marker synaptophysin. Methods and Materials: Two-month-old male and female mice expressing human apoE3 or apoE4 received either a 3-Gy dose of cranial 56Fe irradiation (600 MeV/amu) or sham irradiation. Mice were tested in a water maze task 13 months later to assess effects of irradiation on spatial memory retention. After behavioral testing, the brain tissues of these mice were analyzed for synaptophysin and MAP-2 immunoreactivity. Results: After irradiation, spatial memory retention of apoE3 female, but not male, mice was impaired. A general genotype deficit in spatial memory was observed in sham-irradiated apoE4 mice. Strikingly, irradiation prevented this genotype deficit in apoE4 male mice. A similar but nonsignificant trend was observed in apoE4 female mice. Although there was no change in MAP-2 immunoreactivity after irradiation, synaptophysin immunoreactivity was increased in irradiated female mice, independent of genotype. Conclusions: The effects of 56Fe irradiation on the spatial memory retention of mice are critically influenced by sex, and the direction of these effects is influenced by apoE isoform. Although in female mice synaptophysin immunoreactivity provides a sensitive marker for effects of irradiation, it cannot explain the apoE genotype-dependent effects of irradiation on the spatial memory retention of the mice.

  19. Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of {sup 56}Fe Irradiation on the Brain

    Energy Technology Data Exchange (ETDEWEB)

    Haley, Gwendolen E. [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR (United States); Villasana, Laura; Dayger, Catherine; Davis, Matthew J. [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Raber, Jacob, E-mail: raberj@ohsu.edu [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR (United States); Department of Neurology, Oregon Health and Science University, Portland, OR (United States)

    2012-11-01

    Purpose: In humans, apolipoprotein E (apoE) is encoded by three major alleles ({epsilon}2, {epsilon}3, and {epsilon}4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of {sup 56}Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials: We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after {sup 56}Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results: In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions: The short-term effects of {sup 56}Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

  20. Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.

    Science.gov (United States)

    Caselli, R J; Osborne, D; Reiman, E M; Hentz, J G; Barbieri, C J; Saunders, A M; Hardy, J; Graff-Radford, N R; Hall, G R; Alexander, G E

    2001-08-15

    In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9+/-5.9 years), gender (60% women), and education (15.9+/-2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup. PMID:11535238

  1. Effects of radiation and apolipoprotein E on lipid profile among workers of nuclear power plants in Korea

    International Nuclear Information System (INIS)

    Complete text of publication follows. Several studies reported that the radiation was positively related to fatty liver, low HDL cholesterol, and hypertriglyceridemia. Genetic polymorphism affect prevalence of chronic disease by molecular epidemiology studies. Apolipoprotein E is an important genetic determinant of cardiovascular disease (CVD), namely through its influence on lipid metabolism. Thus, we investigated whether radiation and apo E polymorphism, and environmental factors contribute to the lipid profile in workers of nuclear power plants in Korea. DNA was extracted from the whole blood of 6896 study subjects (6357 males and 359 females), and apo E polymorphism was investigated using PCR. Plasma lipid profiles were measured by standardized enzymatic procedures and radiation dose was measured by the thermoluminescence dosemeter (TLD). Environmental factors such as exercise, smoking were measured from health management database of KHNP. Total of 6802 subjects (aged 20-58) were investigated and radiation exposure dose was 168.51±463.94 mSv in the recent 1-year dose and 248.24±559.21 mSv in the total accumulative dose. In addition, Apo E polymorphism was associated with significant differences in total cholesterol, HDL cholesterol, radiation dose, AI but others no significant. The multiple regression model showed that total cholesterol was positively correlated with age, SBP, BMI, AI, fasting glucose. HDL cholesterol was negatively correlated with AI. LDL cholesterol was positively correlated with age, BMI, fasting glucose. And triglyceride was significantly correlated in the BMI, AI, somking dose, vegetables but others no significant. Metabolic syndrome did not show any relation to the others; only age, SBP, DBP, BMI, fasting glucose, HOMA-IR influenced. However, there was no significant association between radiation dose and lipid profile. In conclusion, Apo E and well-known variables such as SBP, BMI were significantly associated with lipid profile level

  2. Apolipoprotein E mRNA expression in mononuclear cells from normolipidemic and hypercholesterolemic individuals treated with atorvastatin

    Directory of Open Access Journals (Sweden)

    Cerda Alvaro

    2011-11-01

    Full Text Available Abstract Background Apolipoprotein E (apoE is a key component of the lipid metabolism. Polymorphisms at the apoE gene (APOE have been associated with cardiovascular disease, lipid levels and lipid-lowering response to statins. We evaluated the effects on APOE expression of hypercholesterolemia, APOE ε2/ε3/ε4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population. Methods APOE ε2/ε3/ε4 and plasma lipids were evaluated in 181 normolipidemic (NL and 181 hypercholesterolemic (HC subjects. HC individuals with indication for lowering-cholesterol treatment (n = 141 were treated with atorvastatin (10 mg/day/4-weeks. APOE genotypes and APOE mRNA in peripheral blood mononuclear cells (PBMC were analyzed by TaqMan real time PCR. Results HC had lower APOE expression than NL group (p APOE expression showed higher plasma total and LDL cholesterol and apoB, as well as higher apoAI (p APOE genotypes did not affect APOE expression and atorvastatin response. Atorvastatin treatment do not modify APOE expression, however those individuals without LDL cholesterol goal achievement after atorvastatin treatment according to the IV Brazilian Guidelines for Dyslipidemia and Atherosclerosis Prevention had lower APOE expression than patients with desirable response after the treatment (p Conclusions APOE expression in PBMC is modulated by hypercholesterolemia and the APOE mRNA level regulates the plasma lipid profile. Moreover the expression profile is not modulated neither by atorvastatin nor APOE genotypes. In our population, APOE ε2 allele confers protection against hypercholesterolemia and a less atherogenic lipid profile. Moreover, low APOE expression after treatment of patients with poor response suggests a possible role of APOE level in atorvastatin response.

  3. A case–control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

    Directory of Open Access Journals (Sweden)

    De Feo Emma

    2012-10-01

    Full Text Available Abstract Background Apolipoprotein E (ApoE is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2 has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. Methods One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles. The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs and their 95% confidence intervals (CIs from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model. Results Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84 compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium. Conclusions Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings.

  4. Apolipoprotein E polymorphism and outcome after mild to moderate traumatic brain injury: A study of patient population in India

    Directory of Open Access Journals (Sweden)

    Pruthi Nupur

    2010-01-01

    Full Text Available Background: The nature and extent of recovery after traumatic brain injury (TBI is heterogeneous. Apolipoprotein E (APOE plays a major role in repair of cell membrane and growth of neurites following injury to cells. Studies done on the western population have shown that the APOE e4 genotype is associated with poor survival following neurotrauma. Aim: To explore the association of APOE polymorphism and outcome following TBI in a patient population from a tertiary care hospital exclusive for neurological diseases in south India. Patients and Methods: Ninety eight patients who sustained mild to moderate TBI (computed tomography (CT scan brain showing traumatic parenchymal contusions were the subjects of the study and the study period was from November 2003 to December 2008. APOE polymorphism status was determined by PCR technique using venous blood. Patients were assessed on follow-up with a battery of four neuropsychological tests as well as Glasgow outcome scale. Results: Of the 98 patients, 20 (20% patients had at least one APOE e4 allele. A follow-up of minimum six months was available for 73 patients. None of the12 patients who had at least one APOE e4 allele had a poor outcome at six-month follow-up whereas 11(18% patients without an APOE e4 allele had a poor outcome (Fisher′s Exact test, P=0.192. On the neuropsychological tests, performance of patients with APOE e4 allele did not differ significantly from those without these alleles. Conclusion: This study does not support the current contention that the presence of APOE e4 allele should have a significant negative effect on the outcome after TBI.

  5. Nuclear microprobe investigation into the trace elemental contents of carotid artery walls of apolipoprotein E deficient mice

    International Nuclear Information System (INIS)

    Atherosclerosis is a progressive disease that causes lesions in large and medium-sized arteries. There is increasing evidence that the function of vascular endothelial cells is impaired by oxidation reactions, and that metal ions may participate in these processes. The nuclear microscopy facility in NUS, which has the ability to focus a 2 MeV proton beam down to sub micron spot sizes, was used to investigate the trace elemental changes (e.g. Zn and Fe) in atherosclerotic lesions in the common carotid artery of apolipoprotein E deficient mice fed a high fat diet. In this preliminary study, which is part of a larger study to investigate the effects of probucol on carotid artery atherosclerosis, two sets of mice were used; a test set fed a high fat diet +1% probucol, and a control set which was fed a high fat diet only. The results show that the Zn/Fe ratio was significantly higher in the media of arteries of probucol treated animals without overlying lesion (4.3) compared to the media with overlying lesion (1.3) (p = 0.004) for test mice. For the control mice, the arterial Zn/Fe ratio was 1.8 for media without overlying lesion, compared with 1.0 for media with overlying lesion (p = 0.1). Thus, for media without overlying lesion, the Zn/Fe ratio was significantly higher (p = 0.009) in probucol-treated (4.3) than control mice (1.8), whereas there was little difference in the ratios between the two groups in media with overlying lesion (1.3 compared with 1.0). These preliminary results are consistent with the idea that the levels of iron and zinc concentrations within the artery wall may influence the formation of atherosclerotic plaque in the carotid artery

  6. Influence of environmental enrichment and depleted uranium on behaviour, cholesterol and acetylcholine in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Lestaevel, P; Airault, F; Racine, R; Bensoussan, H; Dhieux, B; Delissen, O; Manens, L; Aigueperse, J; Voisin, P; Souidi, M

    2014-07-01

    Alzheimer's disease is associated with genetic risk factors, of which the apolipoprotein E (ApoE) is the most prevalent, and is affected by environmental factors that include education early in life and exposure to metals. The industrial and military use of depleted uranium (DU) resulted in an increase of its deposition in some areas and led to a possible environmental factor. The present study aims to ascertain the effects on the behaviour and the metabolism of cholesterol and acetylcholine of ApoE-/- mice exposed to enriched environment (EE) and exposed to DU (20 mg/L) for 14 weeks. Here we show that ApoE-/- mice were unaffected by the EE and their learning and memory were similar to those of the non-enriched ApoE-/- mice. ApoE-/- mice showed a significant decrease in total (-16 %) and free (-16 %) cholesterol in the entorhinal cortex in comparison to control wild-type mice. Whatever the housing conditions, the exposure to DU of ApoE-/- mice impaired working memory, but had no effect on anxiety-like behaviour, in comparison to control ApoE-/- mice. The exposure of ApoE-/- mice to DU also induced a trend toward higher total cholesterol content in the cerebral cortex (+15 %) compared to control ApoE-/- mice. In conclusion, these results demonstrate that enriched environment does not ameliorate neurobehaviour in ApoE-/- mice and that ApoE mutation induced specific effects on the brain cholesterol. These findings also suggested that DU exposure could modify the pathology in this ApoE model, with no influence of housing conditions. PMID:23749703

  7. Vitamin D deficiency and exogenous vitamin D excess similarly increase diffuse atherosclerotic calcification in apolipoprotein E knockout mice.

    Directory of Open Access Journals (Sweden)

    Timothy Ellam

    Full Text Available BACKGROUND: Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol administration in apolipoprotein E knockout mice. METHODS: Mice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. RESULTS: Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001, trabecular bone volume (p<0.01 and bone mineral density (p<0.005. These changes were accompanied by an increase in calcification density (number of calcifications per mm(2 of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01. Paricalcitol administration suppressed parathyroid hormone (p<0.001, elevated plasma calcium phosphate product (p<0.005 and induced an increase in calcification density (472 versus 200, p<0.005 similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. CONCLUSION: Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal

  8. Analysis of the Association Between Apolipoprotein E Polymorphism and Cardiovascular Risk Factors in an Elderly Population with Longevity

    Directory of Open Access Journals (Sweden)

    Schwanke Carla Helena Augustin

    2002-01-01

    Full Text Available OBJECTIVE: To establish the allelic and genotypic frequencies related to apolipoprotein E (ApoE polymorphism and association of the genotypes with risk factors and cardiovascular morbidity in an elderly population with longevity. METHODS: We analyzed 70 elderly patients aged 80 years or more who were part of the Projeto Veranópolis. We used the gene amplification technique through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and cleavage with the restriction enzyme Hha I to identify the ApoE genotypes. The most frequent genotypes were compared considering biological variables and cardiovascular risks and morbidity. RESULTS: The frequencies of the E2, E3, and E4 alleles were 0.05, 0.84, and 0.11, respectively, and of the genotypes were as follows: E3E3 (0.70, E3E4 (0.22, E2E3 (0.06, and E2E2 (0.02. Individuals with the E3E4 had a mean age greater than those with the E3E3. No association was observed between the genotypes and the variables analyzed, except for obesity, which was associated with the E3E3 genotype. Individuals with the E3E4 genotype had high levels of LDL-cholesterol and fibrinogen as compared with those with the E3E3 genotype. CONCLUSION: The results suggest that the E4E4 genotype may be associated with early mortality. A balance between the protective or neutral factors and the cardiovascular risk factors may occur among the individuals with different genotypes, attenuating the negative effects of the E4 allele.

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

    Energy Technology Data Exchange (ETDEWEB)

    Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya; Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro

    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.

  10. A case–control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

    International Nuclear Information System (INIS)

    Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model. Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium. Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings

  11. Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5' proximal promoter region

    International Nuclear Information System (INIS)

    While other plasma lipoproteins are exclusively expressed in liver and intestine, apoliprotein E (apoE) is ubiquitously synthesized in many tissues. To understand the molecular mechanism of non-tissue-specific apoE expression, we tested the testicular orphan receptor 4 (TR4) effect on apoE expression in different cell lines, such as HepG2, COS-1, and H1299 cells. Gel shift assay and 5' promoter activity analyses identified one distinct hormone response element (TR4RE-DR0-apoE at -303 to -292 bp) that binds to TR4 and results in full induction of apoE gene transcription. TR4 also forms a complex with Sp1 to synergistically induce apoE expression via a region containing the TR4RE-DR0-apoE and the Sp1 binding site (-169 to -140 bp). Induction of apoE expression by TR4 was also confirmed at the mRNA and protein levels in H1299 cells. Together, our data demonstrate that TR4 can enhance apoE gene expression via binding to TR4RE-DR0 in apoE 5' promoter and this TR4 binding is essential for synergistic interaction with another transcription factor, Sp1

  12. The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Steinmetz, Martin, E-mail: martin.steinmetz@ukb.uni-bonn.de [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Internal Medicine II, University Hospital Bonn, 53105 Bonn (Germany); Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Mallat, Ziad [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke' s Hospital, Cambridge, CB2 2QQ (United Kingdom)

    2015-08-14

    Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

  13. The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

    International Nuclear Information System (INIS)

    Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 107 OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen-coupled splenocytes

  14. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease

    Directory of Open Access Journals (Sweden)

    Chaudhary Rajesh

    2012-04-01

    Full Text Available Abstract Background The most common apolipoprotein E (apoE gene polymorphism has been found to influence plasma lipid concentration and its correlation with coronary artery disease (CAD has been extensively investigated in the last decade. It is, however, unclear whether apoE gene polymorphism is also associated with increased risk of type 2 diabetes mellitus (T2DM. The knowledge of this study may provide the primary prevention for T2DM and CAD development before its initiation and progression. Therefore, this study was carried out to determine the association between apoE gene polymorphism and T2DM with and without CAD and its role in lipid metabolism. Methods The case-control study was carried out on a total of 451 samples including 149 normal control subjects, 155 subjects with T2DM, and 147 subjects with T2DM complicated with CAD. The apoE gene polymorphism was tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP. Univariable and multivariable logistic regression analyses were used to identify the possible risks of T2DM and CAD. Results A significantly increased frequency of E3/E4 genotype was observed only in T2DM with CAD group (p = 0.0004, whereas the ε4 allele was significantly higher in both T2DM (p = 0.047 and T2DM with CAD (p = 0.009 as compared with controls. E3/E4 genotype was also the independent risk in developing CAD after adjusting with established risk factors with adjusted odds ratio (OR 2.52 (95%CI 1.28-4.97, p = 0.008. The independent predictor of individuals carrying ε4 allele still remained significantly associated with both CAD (adjusted OR 2.32, 95%CI 1.17-4.61, p = 0.016 and T2DM (adjusted OR 2.04, 95%CI 1.07-3.86, p = 0.029. After simultaneously examining the joint association of E3/E4 genotype combined with either obesity or smoking the risk increased to approximately 5-fold in T2DM (adjusted OR 4.93, 95%CI 1.74-13.98, p = 0.003 and 10-fold in CAD (adjusted OR 10.48, 95%CI 3

  15. Meta-analysis for the Association of Apolipoprotein E ε2/ε3/ε4 Polymorphism with Coronary Heart Disease

    Institute of Scientific and Technical Information of China (English)

    Yong Zhang; Hai-Qin Tang; Wen-Jia Peng; Bing-Bing Zhang; Ming Liu

    2015-01-01

    Background:Coronary heart disease (CHD) is a multifactorial disease and is thought to have a polygenic basis.Apolipoprotein E (APOE) gene is one such candidate with its common ε2/ε3/ε4 polymorphism in CHD.In recent years,numerous case-control studies have investigated the relationship ofAPOE polymorphism with CHD risk.However,the results are confusing.Methods:To clarify this point,we undertook a meta-analysis based on 14 published studies including 5746 CHD cases and 19,120 controls.Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for association using a random-effects or fixed-effects model using STATA version 10 (StataCorp LP,College Station,TX,USA).Results:Overall,the analysis showed that carriers of APOE ε2 allele decreased risk for CHD (ε2 allele vs.ε3 allele:OR =0.82,95% CI:0.75-0.90,P < 0.001;ε2 carriers vs.ε3 carriers:OR =0.81,95% CI:0.73-0.89,P < 0.001),compared with those carrying ε3 allele,especially in Caucasian population.However,those with ε4 allele had a significant increased risk for CHD (ε4 allele vs.ε3 allele:OR =1.34,95% CI:1.15-1.57,P < 0.001),especially in Mongoloid population.Potential publication bias was observed in the genetic model of ε4 versus ε3,but the results might not be affected deeply by the publication bias.When we accounted for publication bias using the trim and fill method,the results were not materially alerted,suggesting the stability of our results.Conclusions:Taken together,our meta-analysis supported a genetic association between APOE gene and CHD.ε4 increased the risk of CHD,whereas ε2 decreased the risk of CHD.

  16. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    International Nuclear Information System (INIS)

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) −/− mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE−/− mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 ± 6 vs 137 ± 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 ± 0.4 vs 0.9 ± 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: ► Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. ► PCB77 augments AngII-induced atherosclerosis. ► PCB77 promotes Ang

  17. Association of apolipoprotein E gene polymorphism with small-vessel lesions and stroke type in moyamoya disease: a preliminary study.

    Science.gov (United States)

    Jang, Dong-Kyu; Huh, Pil Woo; Lee, Kwan-Sung

    2016-06-01

    OBJECT The present study was conducted to investigate whether microbleeds or microinfarcts are associated with apolipoprotein E (APOE) gene polymorphisms in patients with moyamoya disease (MMD), and if so, whetherAPOE gene polymorphisms are also associated with stroke type in patients with MMD. METHODS This cross-sectional, multicenter study included 86 consecutive patients with MMD who underwent T2*-weighted gradient echo or susceptibility-weighted MR imaging and 83 healthy control volunteers. Baseline clinical and radiological characteristics were recorded at diagnosis, and inter- and intragroup differences in the APOE genotypes were assessed. Multivariate binary logistic regression models were used to determine the association factors for small-vessel lesions (SVLs) and hemorrhagic presentation in patients with MMD. RESULTS There was no difference in APOE gene polymorphism and the incidence of SVLs between patients with MMD and healthy controls (p > 0.05). In the MMD group, 7 (8.1%) patients had microbleeds and 32 (37.2%) patients had microinfarcts. Microbleeds were more frequently identified in patients with hemorrhagic-type than in nonhemorrhagictype MMD (p = 0.003). APOE genotypes differed according to the presence of microbleeds (p = 0.024). APOE ε2 or ε4 carriers also experienced microbleeds more frequently than APOE ε3/ε3 carriers (p = 0.013). In the multivariate regression analysis in patients with MMD, microbleeds were significantly related to APOE ε2 or ε4 carrier status (OR 7.86; 95% CI1.20-51.62; p = 0.032) and cerebral aneurysm (OR 17.31; 95% CI 2.09-143.57; p = 0.008). Microinfarcts were independently associated with hypertension (OR 3.01; 95% CI 1.05-7.86; p = 0.007). Hemorrhagic presentation was markedly associated with microbleeds (OR 10.63; 95% CI 1.11-102.0; p = 0.041). CONCLUSIONS These preliminary results did not show a difference in APOE gene polymorphisms between patients with MMD and healthy persons. However, they imply that APOE

  18. Receptor-selective IL-4 mutein modulates inflammatory vascular cell phenotypes and attenuates atherogenesis in apolipoprotein E-knockout mice.

    Science.gov (United States)

    Lin, Yanhui; Chen, Zhiheng; Kato, Seiya

    2015-08-01

    The therapeutic potential of interleukin-4-mediated immunomodulation has not been proven in atherogenesis. Type I IL-4 receptor consists of IL-4Rα and a common γ chain, whereas type II IL-4R is a heterodimer of IL-4Rα and IL-13Rα1. Reportedly, the human IL-4 mutein IL-4/R121E is able to act as an IL-4RI-specific agonist. Here, we investigated the effect of receptor-specific IL-4 mutein on vascular cell phenotypes and atherogenesis. Initially, a plasmid expressing murine IL-4/Q116E, analogous to human IL-4/R121E, was transfected to vascular lineage cells in-vitro. IL-4/Q116E induced the activation of STAT6 in b.End3 endothelial cells, Mm1 macrophages, and splenocytes isolated from C57BL6/J (B6) mice, but it failed to activate STAT6 in SMC and J774.1 macrophages. IL-4/Q116E induced the expression of vascular cell adhesion protein-1 in b.End3 cells but not in SMC. IL-4/Q116E did not exhibit pro-inflammatory actions in either macrophage cell line. Splenocytes were also infected with an adenovirus vector expressing IL-4/Q116E (AdIL-4/Q116E). Enzyme-linked immunosorbent assay for interferon-γ, IL-10 and IL-13 revealed that AdIL-4/Q116E-infected splenocytes showed Th2 deviation. Th2 deviation and M2 marker up-regulation were further revealed in ex-vivo assays using the splenocytes isolated from AdIL-4/Q116E-infected apolipoprotein-E knockout (ApoEKO) mice. Finally, adenoviral induction of IL-4/Q116E, but not wild type IL-4, double mutein IL-4/Q116D/Y119D or control β-galactosidase, significantly attenuated in-vivo atherogenesis of ApoEKO mice. Our data suggest that IL-4 signaling plays a pivotal role in the regulation of vascular cell phenotypes, and atherogenesis. The IL-4RI-selective mutein IL-4/Q116E may have therapeutic potential in vascular diseases. PMID:26093164

  19. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Arsenescu, Violeta [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Arsenescu, Razvan [Digestive Diseases and Nutrition, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Parulkar, Madhura; Karounos, Michael [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Zhang, Xuan [Graduate Center for Toxicology, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Baker, Nicki [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Cassis, Lisa A., E-mail: lcassis@uky.edu [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States)

    2011-11-15

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) -/- mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE-/- mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 {+-} 6 vs 137 {+-} 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 {+-} 0.4 vs 0.9 {+-} 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: Black-Right-Pointing-Pointer Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. Black-Right-Pointing-Pointer PCB77 augments Ang

  20. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuehai [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Huang, Ziyang, E-mail: huangziyang666@126.com [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Lin, Huili; Wang, Zhenhua [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Chen, Xiaoqing [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Ouyang, Qiufang [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Hao, Panpan [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Ni, Jingqin [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Xu, Dongming [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Zhang, Mingxiang; Zhang, Qunye [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Lin, Ling [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); and others

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Titers of ANA and anti-dsDNA antibodies were higher in ApoE{sup -/-} than C57B6/L mice. Black-Right-Pointing-Pointer Spleen was greater and splenocyte apoptosis lower in ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer Level of TLR4 was lower in spleen tissue of ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. Black-Right-Pointing-Pointer The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE{sup -/-}) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE{sup -/-} mice. The spleens of all ApoE{sup -/-} and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE{sup -/-} mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE{sup -/-} mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE{sup -/-} than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE{sup -/-} spleen tissue. The

  1. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    International Nuclear Information System (INIS)

    Highlights: ► Titers of ANA and anti-dsDNA antibodies were higher in ApoE−/− than C57B6/L mice. ► Spleen was greater and splenocyte apoptosis lower in ApoE−/− than B6 mice. ► Level of TLR4 was lower in spleen tissue of ApoE−/− than B6 mice. ► The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. ► The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE−/−) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE−/− mice. The spleens of all ApoE−/− and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE−/− mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE−/− mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE−/− than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE−/− spleen tissue. The down-regulation of TLR4 signal molecules induced by LPS led to decreased expression of Bax and increased serum titers of ANA and anti

  2. Apolipoprotein E4 (1–272 fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells

    Directory of Open Access Journals (Sweden)

    Michikawa Makoto

    2009-08-01

    Full Text Available Abstract Background Apolipoprotein E allele ε4 (apoE4 is a strong risk factor for developing Alzheimer's disease (AD. Secreted apoE has a critical function in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis. In addition, previous reports have shown that apoE4 is cleaved by a protease in neurons to generate apoE4(1–272 fragment, which is associated with neurofibrillary tanglelike structures and mitochondria, causing mitochondrial dysfunction. However, it still remains unclear how the apoE fragment associates with mitochondria and induces mitochondrial dysfunction. Results To clarify the molecular mechanism, we carried out experiments to identify intracellular apoE-binding molecules and their functions in modulating mitochondria function. Here, we found that apoE4 binds to ubiquinol cytochrome c reductase core protein 2 (UQCRC2 and cytochrome C1, both of which are components of mitochondrial respiratory complex III, and cytochrome c oxidase subunit 4 isoform 1 (COX IV 1, which is a component of complex IV, in Neuro-2a cells. Interestingly, these proteins associated with apoE4(1–272 more strongly than intact apoE4(1–299. Further analysis showed that in Neuro-2a cells expressing apoE4(1–272, the enzymatic activities of mitochondrial respiratory complexes III and IV were significantly lower than those in Neuro-2a cells expressing apoE4(1–299. Conclusion ApoE4(1–272 fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1–272 fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration.

  3. Apolipoprotein E Regulates the Integrity of Tight Junctions in an Isoform-dependent Manner in an in Vitro Blood-Brain Barrier Model*

    OpenAIRE

    Nishitsuji, Kazuchika; Hosono, Takashi; Nakamura, Toshiyuki; Bu, Guojun; Michikawa, Makoto

    2011-01-01

    Apolipoprotein E (apoE) is a major apolipoprotein in the brain. The ϵ4 allele of apoE is a major risk factor for Alzheimer disease, and apoE deficiency in mice leads to blood-brain barrier (BBB) leakage. However, the effect of apoE isoforms on BBB properties are as yet unknown. Here, using an in vitro BBB model consisting of brain endothelial cells and pericytes prepared from wild-type (WT) mice, and primary astrocytes prepared from human apoE3- and apoE4-knock-in mice, we show that the barri...

  4. Utilization of cognitive support in episodic free recall as a function of apolipoprotein E and vitamin B12 or folate among adults aged 75 years and older

    OpenAIRE

    Bunce, D; Kivipelto, M.; Wahlin, A

    2004-01-01

    Apolipoprotein E (APOE), vitamin B12, and folate were examined in relation to free recall among 167 community-based older adults. Cognitive support at encoding and retrieval was also taken into account. Participants were classified as APOE e4 or non-e4 allele carriers and as either low or normal vitamin B12 or folate status. A significant association was identified between low vitamin B12 and the e4 genotype in respect to free recall, but only in circumstances of low cognitive support. This r...

  5. Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke

    DEFF Research Database (Denmark)

    Ruscher, Karsten; Johannesson, Emelie; Brugiere, Elena;

    2009-01-01

    Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions that...... differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100beta...

  6. Effects of Chronic Mild Stress on the Development of Atherosclerosis and Expression of Toll-Like Receptor 4 Signaling Pathway in Adolescent Apolipoprotein E Knockout Mice

    Directory of Open Access Journals (Sweden)

    Hongfeng Gu

    2009-01-01

    Full Text Available Here, we investigated the effect of chronic mild stress (CMS on the development of atherosclerosis as well as the expression of Toll-like receptors (TLRs signaling pathway in adolescent apolipoprotein E knockout (apoE-/- mice. Mice were subjected to daily CMS for 0, 4, and 12 weeks, respectively. To identify the expression of Toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice subjected to CMS, we compared gene expression in aortas of stressed and unstressed mice using TLRs signaling pathway real-time PCR microarrays consisting of 87 genes. We found that atherosclerosis lesions both in aortic tress and sinuses of CMS mice were significantly increased linearly in response to duration of CMS exposure. Among 87 genes analyzed, 15 genes were upregulated in stressed mice, especially TLR4, myeloid differentiation factor 88 (MyD88, and IL-1β, and 28 genes were downregulated compared with nonstressed mice. CMS mice demonstrated markedly increased aortic atherosclerosis that were associated with significant increases in levels of expression of TLR4, MyD88, nuclear factor κB (NF-κB, MCP-1, IL-1β, TNF-α, and sICAM-1. Taken together, our results suggest an important role for TLR4 signaling pathway in atherosclerosis in a CMS mouse model.

  7. Association between apolipoprotein E promoter-219G/T polymorphism and total cholesterol level in patients with Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Fang Liu; Xiao Sun; Jing Wang; Yan Kong; Li Cui; Xiangdang Shi

    2006-01-01

    BACKGROUND: Many researches have suggested that apolipoprotein E (APOE) and total cholesterol metabolism are closely related with dementia. In the supposed theory, 219 site of APOE promoter region is near gene coding region, so its polymorphism may result in the abnormality of APOE gene and protein expression,and finally lead to dementia.OBJECTIVE: To observe the association between APOE promoter-219G/T polymorphisms with serum total cholesterol in patients with Alzheimer disease, and compare it with non-dementia people.DESIGN: Case-control, comparative observation.SETTING: Department of Neurology, Fengtian Hospital of Shenyang Medical College.PARTICIPANTS: Fifty-five dementia patients including 27 males and 28 females aged (66±3) years and treated in the Department of Neurology, Fengtian Hospital were selected from January 2002 to December 2005 as the Alzheimer disease group. They all diagnosed according to the DSM- Ⅳ diagnostic criteria of Alzheimer disease instituted by American Psychiatry Association in 1994. Meanwhile, 44 none-dementia patients including 21 males and 23 females aged (66±3) years were selected from other clinical departments of Fengtian Hospital as control group. All the participants were informed the detection and agreed.METHODS: Genomic DNA was extracted from the peripheral blood of all subjects, then "NEST"PCR, DNA sequence and enzyme digestion were adopted to detect the expression of APOE promoter-219 polymorphism,following by biomedical statistics analysis based on the clinical total cholesterol level.MAIN OUTCOME MEASURES: Polymorphism of APOEpromoter-219 G/T and total cholesterol level.RESULTS: All 55 dementia patients and 44 non-dementia ones were involved in the result analysis. ①Allele and genotype frequency: The T allele frequency of the Alzheimer disease group was significantly higher than that in the control group [88.2% (97/110), 54.5% (48/88)], while G allele frequency was remarkably lower than that in the control group [11

  8. Unusual bonding modes of perfluorobenzene in its polymeric (dimeric, trimeric and tetrameric) forms: entirely negative fluorine interacting cooperatively with entirely negative fluorine.

    Science.gov (United States)

    Varadwaj, Pradeep R; Varadwaj, Arpita; Jin, Bih-Yaw

    2015-12-21

    The F(δ-)···F(δ-) intermolecular synthon was recently observed to be useful for generating a two-dimensional layered supramolecular architecture on the Ag(111) surface (Kawai, et al., ACS Nano, 2015). This was formed when the entirely negative covalently bonded fluorine atoms in phenyleneethynylene(bis(2,3,5,6-tetrafluoro-4-(2,3,4,5,6-pentafluorophenylethynyl)phenyl)-ethyne (BPEPE-F18)) were in close proximity to the same atoms in another BPEPE-F18 molecule. With a view to provide rigorous insights into the physical chemistry of such an intermolecular synthon, we have selected perfluorobenzene (C6F6) as a model compound, and have performed extensive DFT-M06-2X/6-311++G(d,p) investigations on a number of its homomolecular dimers, trimers, and tetramers. Of the twelve (C6F6)2 dimers investigated, a displaced-parallel arrangement with an uncorrected binding energy (ΔE) of -7.4 kcal mol(-1) was found to be the most stable, and an incorporation of the basis set superposition error (BSSE) has significantly reduced its ΔE to -4.7 kcal mol(-1). Besides, the ΔE for a minimum-energy least stable conformation of the same dimer, which involves a single σhole(-)···σhole(-) type F(δ-)···F(δ-) intermolecular bonding interaction, amounts to -0.62 and -0.24 kcal mol(-1) without and with BSSE, respectively. The geometry of another conformation of the dimer, which accompanies a set of three F(δ-)···F(δ-) intermolecular interactions somehow similarly to those observed in the layered supramolecular structure formed by the BPEPE-F18 molecules, lies at a relative energy of 6.5 kcal mol(-1) above the most stable conformation. Passing from the latter dimer to an analogous (C6F6)3 trimer, as well as from the trimer to an analogous (C6F6)4 tetramer, the latter two clusters comprising windmill-type F(δ-)···F(δ-) intermolecular topologies, we have marked a preferential increase in the value of ΔE from -0.94 (dimer) to -2.76 (trimer) to -4.49 kcal mol(-1) (tetramer

  9. Mast cell degranulator compound 48-80 promotes atherosclerotic plaque in apolipoprotein E knockout mice with perivascular common carotid collar placement

    Institute of Scientific and Technical Information of China (English)

    TANG Ya-ling; YANG Yong-zong; WANG Shuang; HUANG Tao; TANG Chao-ke; XU Zeng-xiang; SUN Yu-hui

    2009-01-01

    Background Study of the relationship between mast cells and atherosclerosis is mostly dependent on pathological observation and cytology experiments. To investigate the effects of mast cells degranulation on plaque and their possible mechanisms we used apolipoprotein E knockout mice which had been placed perivascular common carotid collar with mast cells degranulator compound 48-80.Methods Forty apolipoprotein E knockout mice were fed a western-type diet and operated on with placement of perivascular right common carotid collar. Four weeks after surgery, the mice were intraperitoneally injected with compound 48-80 (0.5 mg/kg) or D-Hanks every other day for 4 times. The serum lipids and activity of tryptase were measured. Tissue sections were stained with hematoxylin and eosin. Corresponding sections were stained with toluidine blue and immunohistochemically with antibodies against macrophage-specific antigen, α-smooth muscle actin, interleukin-1β and van Willebrand factor. Simultaneously, basic fibroblast growth factor was detected by in situ hybridization and immunofluorescence.Results No pathological change was observed in common carotid non-collar placement but atherogenesis in common carotid collar placement of both groups. There was a significant increase in plaque area ((5.85±0.75)×104 vs (0.86±0.28)×104 μm2, P<0.05), the degree of lumen stenosis ((81±15)% vs (41±12)%, P <0.05), the activity of tryptase in serum ((0.57±0.13) U/L vs (0.36±0.10) U/L, P <0.05), and the percentage of degranulated mast cells ((80.6±17.8)% vs (13.5±4.1)%, P <0.05). The expressions of macrophage-specific antigen, α-smooth muscle actin, interleukin-1β, basic fibroblast growth factor and the density of neovessel in plaque were more in the compound 48-80 group than in the control group.Conclusions Perivascular common carotid collar placement can promote atherosclerotic plaque formation in apolipoprotein E knockout mice. Compound 48-80 increases plaque area and the degree

  10. Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

    DEFF Research Database (Denmark)

    Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina;

    2014-01-01

    Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring...... cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The...... analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3...

  11. The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants

    Energy Technology Data Exchange (ETDEWEB)

    Reilly, S.L.; Sing, C.F. (Univ. of Michigan, Ann Arbor (United States)); Ferrell, R.E. (Univ. of Pittsburgh, PA (United States)); Kottke, B.A. (Mayo Clinic, Rochester, MN (United States))

    1992-12-01

    The influence of the apolipoprotein E (Apo E) polymorphism and gender on the regression relationships between each of nine plasma lipid and apolipoprotein traits (total cholesterol; ln triglycerides; high-density-lipoprotein chloesterol; apolipoproteins AI, AII, B, and CII; ln CIII; and ln E) and four concomitants (age, weight, waist-to-hip ratio, and smoking) was studied in 507 unrelated individuals representative of the adult population of Rochester, MN. Analyses are presented separately for females and males. Each lipid and apolipoprotein trait exhibited at least one Apo E genotype-specific regression relationship with the concomitants investigated in this study. In most cases the heterogeneity of regression was associated with differences between the [var epsilon]32 and [var epsilon]33 genotype. This study documents that the influence of Apo E genotype on average levels of plasma lipids and apolipoproteins varies among subdivisions of the population defined by age, body size, and smoking status. 61 refs., 1 fig., 5 tabs.

  12. Modest vasomotor dysfunction induced by low doses of C60 fullerenes in apolipoprotein E knockout mice with different degree of atherosclerosis

    DEFF Research Database (Denmark)

    Vesterdal, Lise K; Folkmann, Janne K; Jacobsen, Nicklas R;

    2009-01-01

    ABSTRACT: BACKGROUND: Exposure to small size particulate matter in urban air is regarded as a risk factor for cardiovascular effects, whereas there is little information about the impact on the cardiovascular system by exposure to pure carbonaceous materials in the nano-size range. C60 fullerenes...... are nano-sized particles that are expected to have a widespread use, including cosmetics and medicines. METHODS: We investigated the association between intraperitoneal injection of pristine C60 fullerenes and vasomotor dysfunction in the aorta of 11-13 and 40-42 weeks old apolipoprotein E knockout...... intraperitoneal injection of 0.05 or 0.5 mg/kg of C60 fullerenes, the young apoE-/- mice had slightly reduced maximal endothelium-dependent vasorelaxation. A similar tendency was observed in the old apoE-/- mice. Hampered endothelium-independent vasorelaxation was also observed as slightly increased EC50 of...

  13. Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system

    Directory of Open Access Journals (Sweden)

    Waksman Gabriel

    2011-01-01

    Full Text Available Abstract Background Type IV secretion (T4S systems are involved in secretion of virulence factors such as toxins or transforming molecules, or bacterial conjugation. T4S systems are composed of 12 proteins named VirB1-B11 and VirD4. Among them, three ATPases are involved in the assembly of the T4S system and/or provide energy for substrate transfer, VirB4, VirB11 and VirD4. The X-ray crystal structures of VirB11 and VirD4 have already been solved but VirB4 has proven to be reluctant to any structural investigation so far. Results Here, we have used small-angle X-ray scattering to obtain the first structural models for the membrane-extracted, dimeric form of the TraB protein, the VirB4 homolog encoded by the E. coli pKM101 plasmid, and for the monomeric soluble form of the LvhB4 protein, the VirB4 homolog of the T4S system encoded by the Legionella pneumophila lvh operon. We have obtained the low resolution structures of the full-length TraB and of its N- and C-terminal halves. From these SAXS models, we derive the internal organisation of TraB. We also show that the two TraB N- and C-terminal domains are independently involved in the dimerisation of the full-length protein. Conclusions These models provide the first structural insights into the architecture of VirB4 proteins. In particular, our results highlight the modular arrangement and functional relevance of the dimeric-membrane-bound form of TraB.

  14. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

    Science.gov (United States)

    Zhao, Lingzhi; Gottesdiener, Andrew J; Parmar, Mayur; Li, Mingjie; Kaminsky, Stephen M; Chiuchiolo, Maria J; Sondhi, Dolan; Sullivan, Patrick M; Holtzman, David M; Crystal, Ronald G; Paul, Steven M

    2016-08-01

    The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease. PMID:27318144

  15. Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

    Science.gov (United States)

    Ackers, Gary K.; Dalessio, Paula M.; Lew, George H.; Daugherty, Margaret A.; Holt, Jo M.

    2002-07-01

    The mechanism of cooperativity in the human hemoglobin tetramer (a dimer of dimers) has historically been modeled as a simple two-state system in which a low-affinity structural form (T) switches, on ligation, to a high-affinity form (R), yielding a net loss of hydrogen bonds and salt bridges in the dimer-dimer interface. Modifications that weaken these cross-dimer contacts destabilize the quaternary T tetramer, leading to decreased cooperativity and enhanced ligand affinity, as demonstrated in many studies on symmetric double modifications, i.e., a residue site modified in both - or both -subunits. In this work, hybrid tetramers have been prepared with only one modified residue, yielding molecules composed of a wild-type dimer and a modified dimer. It is observed that the cooperative free energy of ligation to the modified dimer is perturbed to the same extent whether in the hybrid tetramer or in the doubly modified tetramer. The cooperative free energy of ligation to the wild-type dimer is unperturbed, even in the hybrid tetramer, and despite the overall destabilization of the T tetramer by the modification. This asymmetric response by the two dimers within the same tetramer shows that loss of dimer-dimer contacts is not communicated across the dimer-dimer interface, but is transmitted through the dimer that bears the modified residue. These observations are interpreted in terms of a previously proposed dimer-based model of cooperativity with an additional quaternary (T/R) component.

  16. Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke : Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals

    NARCIS (Netherlands)

    Khan, Tauseef A.; Shah, Tina; Prieto, David; Zhang, Weili; Price, Jackie; Fowkes, Gerald R.; Cooper, Jackie; Talmud, Philippa J.; Humphries, Steve E.; Sundstrom, Johan; Hubacek, Jaroslav A.; Ebrahim, Shah; Lawlor, Debbie A.; Ben-Shlomo, Yoav; Abdollahi, Mohammad R.; Slooter, Arjen J. C.; Szolnoki, Zoltan; Sandhu, Manjinder; Wareham, Nicholas; Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne; Fillenbaum, Gerda; Heijmans, Bastiaan T.; Katsuya, Tomohiro; Gromadzka, Grazyna; Singleton, Andrew; Ferrucci, Luigi; Hardy, John; Worrall, Bradford; Rich, Stephen S.; Matarin, Mar; Whittaker, John; Gaunt, Tom R.; Whincup, Peter; Morris, Richard; Deanfield, John; Donald, Ann; Smith, George Davey; Kivimaki, Mika; Kumari, Meena; Smeeth, Liam; Khaw, Kay-Tee; Nalls, Michael; Meschia, James; Sun, Kai; Hui, Rutai; Day, Ian; Hingorani, Aroon D.; Casas, Juan P.

    2013-01-01

    Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk

  17. The C-terminal region of the transcriptional regulator THAP11 forms a parallel coiled-coil domain involved in protein dimerization.

    Science.gov (United States)

    Cukier, Cyprian D; Maveyraud, Laurent; Saurel, Olivier; Guillet, Valérie; Milon, Alain; Gervais, Virginie

    2016-06-01

    Thanatos associated protein 11 (THAP11) is a cell cycle and cell growth regulator differentially expressed in cancer cells. THAP11 belongs to a distinct family of transcription factors recognizing specific DNA sequences via an atypical zinc finger motif and regulating diverse cellular processes. Outside the extensively characterized DNA-binding domain, THAP proteins vary in size and predicted domains, for which structural data are still lacking. We report here the crystal structure of the C-terminal region of human THAP11 protein, providing the first 3D structure of a coiled-coil motif from a THAP family member. We further investigate the stability, dynamics and oligomeric properties of the determined structure combining molecular dynamics simulations and biophysical experiments. Our results show that the C-ter region of THAP11 forms a left-handed parallel homo-dimeric coiled-coil structure possessing several unusual features. PMID:26975212

  18. Leukemogenic membrane glycoprotein encoded by Friend spleen focus-forming virus: Transport to cell surfaces and shedding are controlled by disulfide-bonded dimerization and by cleavage of a hydrophobic membrane anchor

    International Nuclear Information System (INIS)

    The leukemogenic glycoprotein (gp55) encoded by Friend spleen focus-forming virus is predominantly retained in the rough endoplasmic reticulum (RER). However, a small proportion (ca. 5%) is processed to form a derivative that occurs on plasma membranes and causes mitosis of infected erythroblasts. The authors have now found that gp55 folds heterogeneously in the RER to form components with different disulfide bonds and that this difference may determine their processing fates. RER gp55 consists predominantly of monomers with intrachain disulfide bonds. In contrast, the processed molecules are disulfide-bonded dimers. These dimers are extensively modified in transit to cell surfaces by conversion of four N-linked high-mannose oligosaccharides to complex derivatives and by attachment of a sialylated O-linked oligosaccharide. The plasma membrane dimers are then slowly shed into the medium by a mechanism that involves proteolytic cleavage of approximately 25 membrane-anchoring hydrophobic amino acids from the carboxyl termini of the glycoproteins. Consequently, shed molecules have shorter polypeptide chains than cell-associated gp55. They conclude that gp55 folds into different disulfide-bonded components that do not substantially isomerize, and that only one specific dimer is competent for export from the RER. Mitogenic activity of gp55 could be caused by the cell surface dimers, by the shed derivative, or by the carboxyl-terminal hydrophobic anchors that remain in the membranes after the shedding reaction

  19. Cloning of a cDNA encoding a putative human very low density lipoprotein/Apolipoprotein E receptor and assignment of the gene to chromosome 9pter-p23[sup 6

    Energy Technology Data Exchange (ETDEWEB)

    Gafvels, M.E.; Strauss, J.F. III (Univ. of Pennyslvania, Philadelphia, PA (United States)); Caird, M.; Patterson, D. (Eleanor Roosevelt Institute, Denver, CO (United States)); Britt, D.; Jackson, C.L. (Brown Univ., Providence, RI (United States))

    1993-11-01

    The authors report the cloning of a 3656-bp cDNA encoding a putative human very low density lipoprotein (VLDL)/apolipoprotein E (ApoE) receptor. The gene encoding this protein was mapped to chromosome 9pter-p23. Northern analysis of human RNA identified cognate mRNAs of 6.0 and 3.8 kb with most abundant expression in heart and skeletal muscle, followed by kidney, placenta, pancreas, and brain. The pattern of expression generally paralleled that of lipoprotein lipase mRNA but differed from that of the low density lipoprotein (LDL) receptor and the low density lipoprotein receptor-related protein/[alpha][sub 2]-macroglobulin receptor (LRP), which are members of the same gene family. VLDL/ApoE receptor message was not detected in liver, whereas mRNAs for both LDL receptor and LRP were found in hepatic tissue. In mouse 3T3-L1 cells, VLDL/ApoE receptor mRNA was induced during the transformation of the cells into adipocytes. Expression was also detected in human choriocarcinoma cells, suggesting that at least part of the expression observed in placenta may be in trophoblasts, cells which would be exposed to maternal blood. Expression in brain may be related to high levels of ApoE expression in that organ, an observation of potential relevance to the recently hypothesized role for ApoE in late onset Alzheimer disease. The results suggest that the putative VLDL/ApoE receptor could play a role in the uptake of triglyceride-rich lipoprotein particles by specific organs including striated and cardiac muscle and adipose tissue and in the transport of maternal lipids across the placenta. The findings presented here, together with recent observations from other laboratories, bring up the possibility that a single gene, the VLDL/ApoE receptor, may play a role in the pathogenesis of certain forms of atherosclerosis, Alzheimer disease, and obesity.

  20. Crystal Structure of a Novel Dimeric Form of NS5A Domain I Protein from Hepatitis C Virus

    Energy Technology Data Exchange (ETDEWEB)

    Love, Robert A.; Brodsky, Oleg; Hickey, Michael J.; Wells, Peter A.; Cronin, Ciarán N.; Pfizer

    2009-07-10

    A new protein expression vector design utilizing an N-terminal six-histidine tag and tobacco etch virus protease cleavage site upstream of the hepatitis C virus NS5A sequence has resulted in a more straightforward purification method and improved yields of purified NS5A domain I protein. High-resolution diffracting crystals of NS5A domain I (amino acids 33 to 202) [NS5A(33-202)] were obtained by using detergent additive crystallization screens, leading to the structure of a homodimer which is organized differently from that published previously (T. L. Tellinghuisen, J. Marcotrigiano, and C. M. Rice, Nature 435:374-379, 2005) yet is consistent with a membrane association model for NS5A. The monomer-monomer interface of NS5A(33-202) features an extensive buried surface area involving the most-highly conserved face of each monomer. The two alternate structural forms of domain I now available may be indicative of the multiple roles emerging for NS5A in viral RNA replication and viral particle assembly.

  1. Protonated nanostructured aluminosilicate (NSAS reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet

    Directory of Open Access Journals (Sweden)

    Constantinides Panayiotis P

    2009-07-01

    Full Text Available Abstract The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w, untreated control and 2% (w/w stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w and stigmastanol at 2% (w/w treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w NSAS and 2% (w/w stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model.

  2. 17β-estradiol potentiates endothelium-dependent nitric oxide- and hyperpolarization-mediated relaxations in blood vessels of male but not female apolipoprotein-E deficient mice.

    Science.gov (United States)

    Kong, Billy W C; Vanhoutte, Paul M; Man, Ricky Y K; Leung, Susan W S

    2015-08-01

    The present study investigated the influence of gender on the changes underlying endothelial dysfunction in hyperlipidemia during aging. Isometric tension in rings (with endothelium) of the aortae and superior mesenteric arteries from apolipoprotein-E deficient mice was determined in wire myographs. Nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations were smaller in the aortae and mesenteric arteries of 32weeks old males than eight weeks old males. In females, NO- and EDH-mediated relaxations were impaired only at 84weeks of age. The levels of reactive oxygen species were elevated in the blood vessels of 32weeks old males, but not females. Acute in vitro treatment with 17β-estradiol and apocynin improved NO- and EDH-mediated relaxations in 32weeks old males but not in 84weeks old males. Relaxations to SKA-31, activator of intermediate (IKCa) and small (SKCa) conductance calcium-activated potassium channels, were attenuated in the mesenteric arteries of 32weeks old males. Such impairment was restored by acute treatment with apocynin. These findings suggest that male hyperlipidemic mice develop endothelial dysfunction at an earlier age than females. This endothelial dysfunction is associated with impaired NO bioavailability and reduced IKCa and SKCa activity. Apocynin and 17β-estradiol restore the endothelial function only in younger male animals but not in older male or female animals. PMID:25869512

  3. Fucoidan alleviates high-fat diet-induced dyslipidemia and atherosclerosis in ApoE(shl) mice deficient in apolipoprotein E expression.

    Science.gov (United States)

    Yokota, Takashi; Nomura, Koichi; Nagashima, Mikio; Kamimura, Naomi

    2016-06-01

    Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, possesses many biological activities including anti-inflammatory and antioxidant activities. We aimed to investigate the protective effects of fucoidan on dyslipidemia and atherosclerosis in apolipoprotein E-deficient mice (ApoE(shl) mice) and to elucidate its molecular targets in the liver by using a transcriptomic approach. For 12weeks, ApoE(shl) mice were fed a high-fat diet (HFD) supplemented with either 1% or 5% fucoidan. Fucoidan supplementation significantly reduced tissue weight (liver and white adipose tissue), blood lipid, total cholesterol (TC), triglyceride (TG), non-high-density lipoprotein cholesterol (non-HDL-C) and glucose levels in HFD-fed ApoE(shl) mice but increased plasma lipoprotein lipase (LPL) activity and HDL-C levels. Fucoidan also reduced hepatic steatosis levels (liver size, TC and TG levels, and lipid peroxidation) and increased white adipose tissue LPL activity. DNA microarray analysis and quantitative reverse transcription-polymerase chain reaction demonstrated differential expression of genes encoding proteins involved in lipid metabolism, energy homeostasis and insulin sensitivity, by activating Ppara and inactivating Srebf1. Fucoidan supplementation markedly reduced the thickness of the lipid-rich plaque, lipid peroxidation and foaming macrophage accumulation in the aorta in HFD-fed ApoE(shl) mice. Thus, fucoidan supplementation appears to have anti-dyslipidemic and anti-atherosclerotic effects by inducing LPL activity and inhibiting the effects of inflammation and oxidative stress in HFD-fed ApoE(shl) mice. PMID:27142736

  4. Influences of a-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet

    Directory of Open Access Journals (Sweden)

    Peluzio M.C.G.

    2001-01-01

    Full Text Available Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60% in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids.

  5. Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause

    Science.gov (United States)

    Rył, Aleksandra; Jasiewicz, Andrzej; Grzywacz, Anna; Adler, Grażyna; Skonieczna-Żydecka, Karolina; Rotter, Iwona; Sipak-Szmigiel, Olimpia; Rumianowski, Bogdan; Karakiewicz, Beata; Jurczak, Anna; Parczewski, Miłosz; Urbańska, Anna; Grabowska, Marta; Laszczyńska, Maria

    2016-01-01

    Background: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman’s body after menopause and different genetic variants are still being sought. Methods: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE) and lepitn (LEP) genotypes were determined by real-time PCR and polymerase chain reaction–restriction fragment length polymorphism, respectively. Results: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. Conclusions: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels. PMID:27240396

  6. Apolipoprotein E (APOE) genotype and the pesticide chlorpyrifos modulate attention, motivation and impulsivity in female mice in the 5-choice serial reaction time task.

    Science.gov (United States)

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

    2016-06-01

    Organophosphate pesticides - and chlorpyrifos (CPF) in particular - contribute to a wide range of neurobehavioural disorders. Most experimental research focuses on learning and memory processes, while other behaviours remain understudied. The isoforms of the human apolipoprotein E (apoE) confer different cognitive skills on their carriers, but data on this topic are still limited. The current study was performed to assess whether the APOE genotypic variability differently modulates the effects of CPF on attentional performance, inhibitory control and motivation. Human apoE targeted replacement adult female mice (apoE2, apoE3 and apoE4) were trained to stably perform the 5-choice serial reaction time task (5-CSRTT). Animals were then subjected to daily dietary CPF (3.75 mg/kg body weight) for 4 weeks. After CPF exposure, we established a 4-week CPF-free period to assess recovery. All individuals acquired the task, apoE2 mice showed enhanced learning, while apoE4 mice displayed increased premature and perseverative responding. This genotype-dependent lack of inhibitory control was reversed by CPF. Overall, the pesticide induced protracted impairments in sustained attention and motivation, and it reduced anticipatory responding. ApoE3 mice exhibited delayed attentional disruptions throughout the wash-out period. Taken together, these findings provide notable evidence on the emergence of CPF-related attentional and motivational deficits. PMID:27106138

  7. New potential role of serum apolipoprotein E mediated by its binding to clumping factor A during Staphylococcus aureus invasive infections to humans.

    Science.gov (United States)

    Elkhatib, Walid F; Hair, Pamela S; Nyalwidhe, Julius O; Cunnion, Kenji M

    2015-04-01

    Staphylococcus aureus is a crucial human pathogen expressing various immune-evasion proteins that interact with the host-cell molecules. Clumping factor A (ClfA) is a microbial surface protein that promotes S. aureus binding to fibrinogen, and is associated with septic arthritis and infective endocarditis. In order to identify the major human serum proteins that bind the ClfA, we utilized recombinant ClfA region A in a plate-based assay. SDS-PAGE analysis of the bound proteins yielded five prominent bands, which were analysed by MS yielding apolipoprotein E (ApoE) as the predominant protein. ClfA-sufficient S. aureus bound purified ApoE by more than one log greater than an isogenic ClfA-deficient mutant. An immunodot-blot assay yielded a linearity model for ClfA binding to human ApoE with a stoichiometric-binding ratio of 1.702 at maximal Pearson's correlation coefficient (0.927). These data suggest that ApoE could be a major and novel binding target for the S. aureus virulence factor ClfA. Thus, ClfA recruitment of serum ApoE to the S. aureus surface may sequester ApoE and blunt its host defence function against S. aureus-invasive infections to humans. In this context, compounds that can block or suppress ClfA binding to ApoE might be utilized as prophylactic or therapeutic agents. PMID:25878259

  8. Crystallization and preliminary x-ray crystallography data of the dimer of tetramer s (abcd)2 of extracellular hemoglobin from Glossoscolex paulistus in cyano met form

    International Nuclear Information System (INIS)

    Full text. The extracellular hemoglobin from Glossoscolex paulistus has a molecular weight near to 3.1 x 106 Da and a structure organized in a double-layered hexagonal oligomer. The tertiary complex of dimer of tetramers (abcd)2 was obtained by chromography in Sephadex G-200, in pH 9.0, as a result of alkaline dissociation. Aiming to obtain a better understanding of the oligomeric structure and specially for the inter subunit interactions the extracellular hemoglobins, we have obtained crystals of dimer of tetramers (abcd)2 of hemoglobin from Glossoscolex and we are studying the in behavior in different conditions of precipitants and pH's. Our goal is to solve the crystal structure in order to characterize, at atomic level, the subunits contacts, heme environment and differences in residues involved in oxygenation in order to understand in this hemoglobin. The crystallization experiments the protein concentration in the cyanomet form was about 10 mg/ml and the experiments were carried out at 180C. The optimal crystallization condition achieved from factorial assays was 10% (w/v). Polyethylene glycol (PEG) 8,000 and 8%(v/v) ethylene glycol in 100 mM HEPES pH 7.5. The optimization of this condition was carried out with the variation of PEG concentrations from 6% up to 10% (by 1% step) and pH between 7.0 and 8.0. A quite critical p-H-dependence has been observed on crystal nucleation, decreasing from pH 7.0, in which the number of microcrystals in higher, up to pH 8.0, in which crystals did not appear even at higher PEG 8,000 (10% w/v). As several structures of hemoglobin from different sources (vertebrate and invertebrates) are available, we hope to solve their structure of hemoglobin from Glossoscolex paulistus by Molecular Replacement, even though the tetramer organization may be different in the earthworm as compared related to other known tetrameric hemoglobin structures. (author)

  9. Tumor Necrosis Factor-α-Mediated Suppression of Adipocyte Apolipoprotein E Gene Transcription: Primary Role for the Nuclear Factor (NF)-κB Pathway and NFκB p50

    OpenAIRE

    Yue, Lili; Christman, John W.; Mazzone, Theodore

    2008-01-01

    The adipose tissue inflammation accompanying obesity has important consequences for adipocyte lipid metabolism, and increased adipose tissue TNFα plays an important role for mediating the effect of inflammation on adipocyte function. Recent studies have shown that apolipoprotein E (apoE) is highly expressed in adipose tissue where it plays an important role in modulating adipocyte triglyceride metabolism, triglyceride mass, and adipocyte size. We have previously reported that TNFα reduces adi...

  10. Mechanism of FGF receptor dimerization and activation

    Science.gov (United States)

    Sarabipour, Sarvenaz; Hristova, Kalina

    2016-01-01

    Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation. The pathogenic A391E mutation in FGFR3 TM domain emulates the action of fgf2, trapping the FGFR3 dimer in its most active state. This study establishes the existence of multiple active ligand-bound states, and uncovers a novel molecular mechanism through which FGFR-linked pathologies can arise.

  11. Development of a Melting Curve-Based Allele-Specific PCR of Apolipoprotein E (APOE) Genotyping Method for Genomic DNA, Guthrie Blood Spot, and Whole Blood

    Science.gov (United States)

    Chen, Chia-Hsiang

    2016-01-01

    Genetic polymorphisms of apolipoprotein E (APOE) are associated with various health conditions and diseases, such as Alzheimer’s disease, cardiovascular diseases, type 2 diabetes, etc. Hence, genotyping of APOE has broad applications in biomedical research and clinical settings, particularly in the era of precision medicine. The study aimed to develop a convenient and accurate method with flexible throughput to genotype the APOE polymorphisms. A melting curve-based allele-specific PCR method was developed to genotype two single nucleotide polymorphisms (SNPs) of APOE, i.e. rs429358 at codon 112 and rs7412 at codon 158. These two SNPs determine the genotype of APOE2, E3, and E4. PCR-based Sanger sequencing was used as the reference method for APOE genotyping. A 100% concordance rate was obtained in 300 subjects between the melting curve-based allele-specific PCR method and the Sanger sequencing method. This method was applied to a genetic association analysis of APOE and schizophrenia consisting of 711 patients with schizophrenia and 665 control subjects from Taiwan. However, no significant differences in the allele and genotype frequencies were detected between these two groups. Further experiments showed that DNA dissolved from blood collected on Guthrie filter paper and total blood cell lysate without DNA extraction can be used in the melting curve-based allele-specific PCR method. Thus, we suggest that this is a fast, accurate and robust APOE genotyping method with a flexible throughput and suitable for DNA template from different preparations. This convenient method shall meet the different needs of various research and clinical laboratories. PMID:27078154

  12. Plasma Lipidomic Profiling in a Military Population of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder with Apolipoprotein E ɛ4-Dependent Effect.

    Science.gov (United States)

    Emmerich, Tanja; Abdullah, Laila; Crynen, Gogce; Dretsch, Michael; Evans, James; Ait-Ghezala, Ghania; Reed, Jon; Montague, Hannah; Chaytow, Helena; Mathura, Venkatarajan; Martin, Justin; Pelot, Robert; Ferguson, Scott; Bishop, Alex; Phillips, John; Mullan, Michael; Crawford, Fiona

    2016-07-15

    In the military population, there is high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) due to the inherent risk of psychological trauma associated with combat. These disorders present with long-term neurological dysfunction and remain difficult to diagnose due to their comorbidity and overlapping clinical presentation. Therefore, we performed cross-sectional analysis of blood samples from demographically matched soldiers (total, n = 120) with mTBI, PTSD, and mTBI+PTSD and those who were considered cognitively and psychologically normal. Soldiers were genotyped for apolipoprotein E (APOE) ɛ4, and phospholipids (PL) were examined using liquid chromatography/mass spectrometry analysis. We observed significantly lower levels of several major PL classes in TBI, PTSD, and TBI+PTSD, compared with controls. PTSD severity analysis revealed that significant PL decreases were primarily restricted to the moderate-to-severe PTSD group. An examination of the degree of unsaturation showed that monounsaturated fatty acid-containing phosphatidylcholine (PC) and phosphatidylinositol (PI) species were lower in the TBI and TBI+PTSD groups. However, these PLs were unaltered among PTSD subjects, compared with controls. Similarly, ether PC (ePC) levels were lower in PTSD and TBI+PTSD subjects, relative to controls. Ratios of arachidonic acid (AA) to docosahexaenoic acid (DHA)-containing species were significantly decreased within PC and phosphatidylethanolamine (PE) classes. APOE ɛ4 (+) subjects exhibited higher PL levels than their APOE ɛ4 (-) counterparts within the same diagnostic groups. These findings suggest that PL profiles, together with APOE genotyping, could potentially aid to differentiate diagnosis of mTBI and PTSD and warrant further validation. In conclusion, PL profiling may facilitate clinical diagnosis of mTBI and PTSD currently hindered by comorbid pathology and overlapping symptomology of these two conditions

  13. COG1410, an apolipoprotein E-based peptide, improves cognitive performance and reduces cortical loss following moderate fluid percussion injury in the rat.

    Science.gov (United States)

    Kaufman, Nicholas A; Beare, Jason E; Tan, Arlene A; Vitek, Michael P; McKenna, Suzanne E; Hoane, Michael R

    2010-12-25

    COG1410, a small, novel ApoE-mimetic peptide derived from the receptor binding region of apolipoprotein E (ApoE), has been classified as anti-inflammatory in nature and improves motor, sensorimotor, and cognitive dysfunction following cortical contusion injury (CCI). In order to further examine COG1410's preclinical efficacy on cognitive recovery, the present study evaluated COG1410 following moderate fluid percussion injury (FPI). Animals were prepared with a moderate, unilateral FPI over the hippocampus. Following FPI, animals received a regimen of five doses of COG1410 or vehicle at 2 and 4h (1.0mg/kg, i.v.) followed by additional doses administered 24, 48, and 72 h (1.0mg/kg, i.p.). Prior to injury, animals were trained for 4 days (4 trials/day) in the Morris water maze (MWM) and then tested for retrograde amnesia on post-FPI day 11 and then on a working memory task on day 18. Testing for motor dysfunction on the tapered balanced beam began on day 2 post-FPI. Administration of this regimen of COG1410 significantly improved retention of memory in the retrograde amnesia test compared to vehicle post-FPI. However, COG1410 did not significantly improve acquisition of working memory in the MWM. Motor dysfunction on the tapered beam post-FPI was improved in the COG1410-treated group compared to vehicle treatment. Cortical lesion analysis revealed that the COG1410-treated animals demonstrated significantly less tissue loss compared to vehicle-treated animals. The results of this study suggest that COG1410 significantly limited the behavioral dysfunction and tissue loss associated with FPI and demonstrated continued preclinical efficacy for TBI. PMID:20600347

  14. Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy

    Directory of Open Access Journals (Sweden)

    Monteiro Pedro

    2011-03-01

    Full Text Available Abstract Background The risk of coronary heart disease (CHD is related to environmental factors and genetic variants. Apolipoprotein E (apoE polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol, with some authors suggesting an association between the ε4 allele and CHD. We investigated the relationship between apoE genotype and age at referral to a specialized lipid clinic by the primary care physician and whether the benefits of treatment with statin differed between genotypes. Methods We assessed individual apoE genotypes and lipid blood profile in a total of 463 patients followed at a specialized lipid clinic due to dyslipidemia, with a 3-year median follow-up time. The primary care physician at the time of the referral had no access to the apoE genotyping results. Carriers of apoE ε4/ε2 genotype were excluded. Results The frequencies of ε2, ε3 and ε4 alleles were 7.8, 78.9 and 13.3%, respectively. There were no significant differences between genders. Although with similar lipid profiles and antidyslipidemic drug usage at baseline, ε4-carriers were referred to the clinic at a younger age (44.2 ± 14.7 years compared with non-ε4 carriers (50.6 ± 13.8 years (p Conclusion Our findings support the concept that there is a reduced response to anti-dyslipidemic treatment in ε4 carriers; this can be a contributing factor for the earlier referral of these patients to our specialized lipid clinic and reinforces the usefulness of apoE genotyping in predicting patients response to lipid lowering therapies.

  15. A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E ε4 allele

    Directory of Open Access Journals (Sweden)

    Gleason Carey E

    2008-04-01

    Full Text Available Abstract Genetic and biochemical studies support the apolipoprotein E (APOE ε4 allele as a major risk factor for late-onset Alzheimer's disease (AD, though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB and its receptor (LHCGR have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2 and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE ε4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR = 3.08(95%confidence interval: 1.37, 6.91], ε4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38; p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE ε4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.

  16. Identification of aortic arch-specific quantitative trait loci for atherosclerosis by an intercross of DBA/2J and 129S6 apolipoprotein E-deficient mice.

    Directory of Open Access Journals (Sweden)

    Yukako Kayashima

    Full Text Available The genetic background of apolipoprotein E (apoE deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL, Aath1-Aath3, that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE and 129S6 apoEKO mice (129-apoE. To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE. The extent of atherosclerosis in the aortic arch was very similar in the two parental strains. Nevertheless, a genome-wide scan identified two significant QTL for plaque size in the aortic arch: Aath4 on Chromosome (Chr 2 at 137 Mb and Aath5 on Chr 10 at 51 Mb. The DBA alleles of Aath4 and Aath5 respectively confer susceptibility and resistance to aortic arch atherosclerosis over 129 alleles. Both QTL are also independent of those affecting plaque size at the aortic root. Genome analysis suggests that athero-susceptibility of Aath4 in DBA may be contributed by multiple genes, including Mertk and Cd93, that play roles in phagocytosis of apoptotic cells and modulate inflammation. A candidate gene for Aath5 is Stab2, the DBA allele of which is associated with 10 times higher plasma hyaluronan than the 129 allele. Overall, our identification of two new QTL that affect atherosclerosis in an aortic arch-specific manner further supports the involvement of distinct pathological processes at different vascular locations.

  17. Modest vasomotor dysfunction induced by low doses of C60 fullerenes in apolipoprotein E knockout mice with different degree of atherosclerosis

    Directory of Open Access Journals (Sweden)

    Loft Steffen

    2009-02-01

    Full Text Available Abstract Background Exposure to small size particulate matter in urban air is regarded as a risk factor for cardiovascular effects, whereas there is little information about the impact on the cardiovascular system by exposure to pure carbonaceous materials in the nano-size range. C60 fullerenes are nano-sized particles that are expected to have a widespread use, including cosmetics and medicines. Methods We investigated the association between intraperitoneal injection of pristine C60 fullerenes and vasomotor dysfunction in the aorta of 11–13 and 40–42 weeks old apolipoprotein E knockout mice (apoE-/- with different degree of atherosclerosis. Results The aged apoE-/-mice had lower endothelium-dependent vasorelaxation elicited by acetylcholine in aorta segments mounted in myographs and the phenylephrine-dependent vasoconstriction response was increased. One hour after an intraperitoneal injection of 0.05 or 0.5 mg/kg of C60 fullerenes, the young apoE-/- mice had slightly reduced maximal endothelium-dependent vasorelaxation. A similar tendency was observed in the old apoE-/- mice. Hampered endothelium-independent vasorelaxation was also observed as slightly increased EC50 of sodium nitroprusside-induced vasorelaxation response in young apoE-/- mice. Conclusion Treatment with C60 fullerenes affected mainly the response to vasorelaxation in young apoE-/- mice, whereas the vasomotor dysfunction in old apoE-/- mice with more advanced atherosclerosis was less affected by acute C60 fullerene treatment. These findings represent an important step in the hazard characterization of C60 fullerenes by showing that intraperitoneal administration is associated with a moderate decrease in the vascular function of mice with atherosclerosis.

  18. Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding.

    Science.gov (United States)

    Oriá, Reinaldo B; Vieira, Carlos Meton G; Pinkerton, Relana C; de Castro Costa, Carlos M; Lopes, Maria Beatriz; Hussaini, Isa; Shi, Weibin; Brito, Gerly A C; Lima, Aldo A M; Guerrant, Richard L

    2006-08-01

    Apolipoprotein E (apoE) is synthesized mainly in the liver and in the brain and is critical for cholesterol metabolism and recovery from brain injury. However, although apoE mRNA increases at birth, during suckling, and after fasting in rat liver, little is known about its role in early postnatal development. Using an established postnatal malnutrition model and apoE knock-out (ko) mice, we examined the role of apoE in intestinal adaptation responses to early postnatal malnutrition. Wild-type and apoE-ko mice were separated from their lactating dams for defined periods each day (4 hours on day 1, 8 hours on day 2, and 12 hours thereafter). We found significant growth deficits, as measured by weight gain or tail length, in the apoE-ko mice submitted to a malnutrition challenge, as compared with malnourished wild type, especially during the second week of postnatal development (P animals failed to show growth catch-up after refeeding, compared with wild-type malnourished controls. Furthermore, we found shorter crypts and reduced villus height and area in the apoE-ko malnourished mice, compared with controls, after refeeding. Insulinlike growth factor 1 expression was also blunted in the ileum in apoE-ko mice after refeeding, compared with wild-type controls, which exhibited full insulinlike growth factor 1 expression along the intestinal crypts, villi, and in the muscular layer. Taken together, these findings suggest the importance of apoE in coping with a malnutrition challenge and during the intestinal adaptation after refeeding. PMID:25210213

  19. Synthetic liver X receptor agonist T0901317 inhibits semicarbazide-sensitive amine oxidase gene expression and activity in apolipoprotein E knockout mice

    Institute of Scientific and Technical Information of China (English)

    Xiaoyan Dai; Xiang Ou; Xinrui Hao; Dongli Cao; Yaling Tang; Yanwei Hu; Xiaoxu Li; Chaoke Tang

    2008-01-01

    Semicarbazide-sensitive amine oxidase(SSAO)catalyzes oxidative deamination of primary aromatic and aliphatic amines.Increased SSAO activity has been found in atherosclerosis and diabetes mellitus.We hypothesize that the anti-atherogenic effect of liver X receptors(LXRs)might be related to the inhibition of SSAD gene expression and its activity.In this study,we investigated the effect of LXR agonist T0901317 on SSAO gene expression and its activity in apolipoprotein E knockout(apoE-/-)mice.Male apoE-/-mice(8 weeks old) were randomly divided into four groups:basal control group;vehicle group;prevention group;and treatment group.SSAO gene expression was analyzed by real-time quantitative polymerase chain reaction and its activity was determined.The activity of superoxide dismutase and content of malondialdehy de in the aorta and liver were also determined.In T0901317-treated mice,SSAO gene expression was significantly decreased in the aorta,liver,small intestine,and brain.SSAO activities in serum and in these tissues were also inhibited.The amount of superoxide dismutase in the aorta and liver of the prevention group and treatment group was significantly higher compared with the vehicle group(P<0.05).Malondialdehyde in the tissues of these two groups was significantly lower compared with the vehicle group(P<0.05).Our results showed that T0901317 inhibits SSAO gene expression and its activity in atherogenic apoE-/-mice.The atheroprotective effect of LXR agonist T0901317 is related to the inhibition of SSAO gene expression and its activity.

  20. Development of a Melting Curve-Based Allele-Specific PCR of Apolipoprotein E (APOE) Genotyping Method for Genomic DNA, Guthrie Blood Spot, and Whole Blood.

    Science.gov (United States)

    Chen, Chia-Hsiang

    2016-01-01

    Genetic polymorphisms of apolipoprotein E (APOE) are associated with various health conditions and diseases, such as Alzheimer's disease, cardiovascular diseases, type 2 diabetes, etc. Hence, genotyping of APOE has broad applications in biomedical research and clinical settings, particularly in the era of precision medicine. The study aimed to develop a convenient and accurate method with flexible throughput to genotype the APOE polymorphisms. A melting curve-based allele-specific PCR method was developed to genotype two single nucleotide polymorphisms (SNPs) of APOE, i.e. rs429358 at codon 112 and rs7412 at codon 158. These two SNPs determine the genotype of APOE2, E3, and E4. PCR-based Sanger sequencing was used as the reference method for APOE genotyping. A 100% concordance rate was obtained in 300 subjects between the melting curve-based allele-specific PCR method and the Sanger sequencing method. This method was applied to a genetic association analysis of APOE and schizophrenia consisting of 711 patients with schizophrenia and 665 control subjects from Taiwan. However, no significant differences in the allele and genotype frequencies were detected between these two groups. Further experiments showed that DNA dissolved from blood collected on Guthrie filter paper and total blood cell lysate without DNA extraction can be used in the melting curve-based allele-specific PCR method. Thus, we suggest that this is a fast, accurate and robust APOE genotyping method with a flexible throughput and suitable for DNA template from different preparations. This convenient method shall meet the different needs of various research and clinical laboratories. PMID:27078154

  1. The relationship of sterol regulatory element-binding protein cleavage-activation protein and apolipoprotein E gene polymorphisms with metabolic changes during weight reduction.

    Science.gov (United States)

    Nieminen, Tuomo; Matinheikki, Jussi; Nenonen, Arja; Kukkonen-Harjula, Katriina; Lindi, Virpi; Hämelahti, Päivi; Laaksonen, Reijo; Fan, Yue-Mei; Kähönen, Mika; Fogelholm, Mikael; Lehtimäki, Terho

    2007-07-01

    Sterol regulatory element-binding protein cleavage-activating protein (SCAP) and apolipoprotein E (apo E) regulate cellular and plasma lipid metabolism. Therefore, variations in the corresponding genes might influence weight reduction and obesity-associated metabolic changes. We investigated the relationships of SCAP (Ile796Val) and apo E polymorphisms on metabolic changes during weight reduction by using a 12-week very low-energy diet. Body composition, serum lipids, plasma glucose, and insulin were assessed in 78 healthy premenopausal women (initial body mass index, 34 +/- 4 kg/m(2); age, 40 +/- 4 years) before and after the intervention. The SCAP genotype groups did not differ in the responses of any parameters measured during weight reduction. Apo E did not differentiate the weight loss, but the changes in total and low-density lipoprotein cholesterol for the genotype groups apo E epsilon2/3, epsilon3/3, as well as epsilon3/4 and epsilon4/4 combined were -0.94 +/- 0.56 and -0.59 +/- 0.32, -0.71 +/- 0.49 and -0.49 +/- 0.45, and -0.55 +/- 0.47 and -0.37 +/- 0.39 mmol/L, respectively (P < .05 for both). In conclusion, neither the SCAP Ile796Val nor the apo E polymorphism was associated with weight loss in obese premenopausal women. However, the apo E-but not SCAP genotype-seems to be one of the modifying factors for serum cholesterol concentrations during very low-energy diet in obese premenopausal women. PMID:17570245

  2. Localization and regulation of the human very low density lipoprotein/apolipoprotein-E receptor: trophoblast expression predicts a role for the receptor in placental lipid transport.

    Science.gov (United States)

    Wittmaack, F M; Gåfvels, M E; Bronner, M; Matsuo, H; McCrae, K R; Tomaszewski, J E; Robinson, S L; Strickland, D K; Strauss, J F

    1995-01-01

    The very low density lipoprotein/apolipoprotein-E receptor (VLDLR) is the newest member of the low density lipoprotein receptor (LDLR) family. Very little is known about VLDLR localization and regulation. Immunohistochemical analysis of human placenta with a specific polyclonal antibody detected VLDLR in syncytiotrophoblast and intermediate trophoblast cells. VLDLR transcripts were also localized in these cells by in situ hybridization histochemistry. In addition, VLDLR messenger RNA (mRNA) was detected in villous core endothelial cells and cells appearing to be Hofbauer cells. Northern blot analysis of placenta revealed a 2.6-fold increase in VLDLR mRNA at term compared to that in the first trimester. The regulation of VLDLR expression was studied in JEG-3 and BeWo choriocarcinoma cells, two trophoblast-derived cell lines. Treatment of these cells with 8-bromo-cAMP caused a profound suppression of VLDLR message, whereas LDLR transcripts were increased. Incubation of JEG-3 cells with 25-hydroxycholesterol did not lead to sterol negative feedback on VLDLR gene expression, unlike LDLR mRNA, which declined markedly. Insulin (200 mg/L) up-regulated VLDLR message in JEG-3 cells 2-fold, as did the fibrate hypolipidemic drug, clofibric acid. We conclude that 1) VLDLR is expressed in human placental trophoblast cells in a pattern consistent with a role in placental lipid transport; 2) VLDLR expression is high at term relative to that in the first trimester; and 3) the trophoblast VLDLR is subject to down-regulation by cAMP and up-regulation by insulin and fibrate hypolipidemic drugs. PMID:7828550

  3. Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

    Energy Technology Data Exchange (ETDEWEB)

    Zubenko, G.S.; Stiffler, S.; Kopp, U. [Univ. of Pittsburgh School of Medicine, PA (United States)] [and others

    1994-09-15

    Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.

  4. Electronic spectroscopy of transition metal dimer

    OpenAIRE

    Qian, Yue; 钱玥

    2013-01-01

    This thesis reports laser spectroscopic studies of gas-phase transition metal dimers using laser ablation/reaction with free jet expansion and laser-induced fluorescence (LIF) spectroscopy technique. Themolecules studied in this work are palladium dimer (Pd2) and vanadium dimer (V2). Many compounds formed from these transition metals are important and functional catalysts in chemical reactions. Therefore, it is of great significance to start from the fundamental level to understand the prope...

  5. Apolipoprotein E polymorphism in India

    DEFF Research Database (Denmark)

    Singh, P; Singh, M; Gerdes, Lars Ulrik;

    2001-01-01

    , India. Three alleles APOE*E2, APOE*E3 and APOE*E4 were observed in Ramgarhia and Ramdasia with the frequencies of 0.031, 0.913, 0.056 and 0.043, 0.886 and 0.071, respectively. Higher heterozygosity (20.8%) in Ramdasia reflects greater variation at the APOE locus. The APOE*E3 allele is found to be the...

  6. RecFOR is not required for pneumococcal transformation but together with XerS for resolution of chromosome dimers frequently formed in the process.

    Directory of Open Access Journals (Sweden)

    Calum Johnston

    2015-01-01

    Full Text Available Homologous recombination (HR is required for both genome maintenance and generation of diversity in eukaryotes and prokaryotes. This process initiates from single-stranded (ss DNA and is driven by a universal recombinase, which promotes strand exchange between homologous sequences. The bacterial recombinase, RecA, is loaded onto ssDNA by recombinase loaders, RecBCD and RecFOR for genome maintenance. DprA was recently proposed as a third loader dedicated to genetic transformation. Here we assessed the role of RecFOR in transformation of the human pathogen Streptococcus pneumoniae. We firstly established that RecFOR proteins are not required for plasmid transformation, strongly suggesting that DprA ensures annealing of plasmid single-strands internalized in the process. We then observed no reduction in chromosomal transformation using a PCR fragment as donor, contrasting with the 10,000-fold drop in dprA- cells and demonstrating that RecFOR play no role in transformation. However, a ∼1.45-fold drop in transformation was observed with total chromosomal DNA in recFOR mutants. To account for this limited deficit, we hypothesized that transformation with chromosomal DNA stimulated unexpectedly high frequency (>30% of cells formation of chromosome dimers as an intermediate in the generation of tandem duplications, and that RecFOR were crucial for dimer resolution. We validated this hypothesis, showing that the site-specific recombinase XerS was also crucial for dimer resolution. An even higher frequency of dimer formation (>80% of cells was promoted by interspecies transformation with Streptococcus mitis chromosomal DNA, which contains numerous inversions compared to pneumococcal chromosome, each potentially promoting dimerization. In the absence of RecFOR and XerS, dimers persist, as confirmed by DAPI staining, and can limit the efficiency of transformation, since resulting in loss of transformant chromosome. These findings strengthen the view that

  7. Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein.

    Directory of Open Access Journals (Sweden)

    James P Corsetti

    Full Text Available BACKGROUND: In a previous report by our group, high levels of apolipoprotein E (apoE were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP in the setting of both low (designated as HR1 subjects and high (designated as HR2 subjects levels of high-density lipoprotein cholesterol (HDL-C. To assess whether apolipoprotein A-II (apoA-II plays a role in apoE-associated risk in the two female groups. METHODOLOGY/PRINCIPAL: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I without apoA-II (LpA-I and HDL particles with both apoA-I and apoA-II (LpA-I:A-II. Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036. Furthermore, high LpA-I:A-II levels interacted with high apoE levels in establishing subgroup risk. CONCLUSIONS/SIGNIFICANCE: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

  8. ApolipoproteinE ε4 allelic variant, cognitive decline and psychosis in Alzheimer disease: a review of the literature and suggestions for upcoming studies

    Directory of Open Access Journals (Sweden)

    Ilaria Spoletini

    2006-06-01

    Full Text Available Apolipoprotein E (ApoE ε4 allele represents a well known vascular risk factor for developing Alzheimer disease (AD and differences in ApoE genotypes may explain a part of the variability in AD phenotypes. In fact, ApoE ε4 allele possession seems to be associated with a more precocious age of onset, greater episodic memory impairment, and psychotic symptoms. The first question we discuss regards the role of ApoE ε4 on cognitive progression of AD. In fact, while a general agreement exists about the role played by ApoE ε4 on the precocious onset of AD, cognitive decline has been differently associated with ApoE ε4 allele possession in AD patients in a continuum of faster decline, no effect, and slower decline. An attemptable interpretation is that the biological processes leading to the onset of AD are different from those involved in determining its clinical course. The second question regards the possible relationship between the presence of the degenerative pathological hallmarks of the disease in specific cerebral areas and different cognitive or behavioural symptoms. In fact, there is evidence that degenerative pathology in hippocampal formation and frontal cortex reflects the progression of cognitive deficits in brain aging and AD and that hypometabolism in right frontal lobe and greater frontal neuropsychological deficits occur in AD patients with psychosis in comparison to those without. The third question regards, specifically, the relationship between ApoE ε4 variant and behavioural symptoms. In fact, there is evidence supporting the link between being carriers of ApoE ε4 allele and severity of delusions, mostly at the early stage of the illness. In an interpretative challenge, we suggest that the link between being carriers of ApoE ε4 allele and suffering from delusions in AD may be explained by frontal lobe dysfunctions. Finally, we hypothesize that the most precocious onset of AD illness, described in carriers of ApoE ε4

  9. MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice

    Science.gov (United States)

    Cheng, Hai-Peng; Gong, Duo; Lv, Yun-Cheng; Yao, Feng; He, Ping-Ping; Ouyang, Xin-Ping; Lan, Gang; Liu, Dan; Zhao, Zhen-Wang; Tan, Yu-Lin; Zheng, Xi-Long; Yin, Wei-Dong; Tang, Chao-Ke

    2016-01-01

    Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid

  10. Functional Significance of Serotonin Receptor Dimerization

    Science.gov (United States)

    Herrick-Davis, Katharine

    2013-01-01

    The original model of G protein activation by a single G-protein-coupled receptor (GPCR) is giving way to a new model wherein two protomers of a GPCR dimer interact with a single G protein. This article will review the evidence suggesting that 5-HT receptors form dimers/oligomers and will compare the findings with results obtained from studies with other biogenic amine receptors. Topics to be covered include the origin or biogenesis of dimer formation, potential dimer interface(s), and oligomer size (dimer versus tetramer or higher order). The functional significance will be discussed in terms of G-protein activation following ligand binding to one or two protomers in a dimeric structure, the formation of heterodimers and the development of bivalent ligands. PMID:23811735

  11. Synthetic covalently linked dimeric form of H2 relaxin retains native RXFP1 activity and has improved in vitro serum stability.

    Science.gov (United States)

    Nair, Vinojini B; Bathgate, Ross A D; Separovic, Frances; Samuel, Chrishan S; Hossain, Mohammed Akhter; Wade, John D

    2015-01-01

    Human (H2) relaxin is a two-chain peptide member of the insulin superfamily and possesses potent pleiotropic roles including regulation of connective tissue remodeling and systemic and renal vasodilation. These effects are mediated through interaction with its cognate G-protein-coupled receptor, RXFP1. H2 relaxin recently passed Phase III clinical trials for the treatment of congestive heart failure. However, its in vivo half-life is short due to its susceptibility to proteolytic degradation and renal clearance. To increase its residence time, a covalent dimer of H2 relaxin was designed and assembled through solid phase synthesis of the two chains, including a judiciously monoalkyne sited B-chain, followed by their combination through regioselective disulfide bond formation. Use of a bisazido PEG7 linker and "click" chemistry afforded a dimeric H2 relaxin with its active site structurally unhindered. The resulting peptide possessed a similar secondary structure to the native monomeric H2 relaxin and bound to and activated RXFP1 equally well. It had fewer propensities to activate RXFP2, the receptor for the related insulin-like peptide 3. In human serum, the dimer had a modestly increased half-life compared to the monomeric H2 relaxin suggesting that additional oligomerization may be a viable strategy for producing longer acting variants of H2 relaxin. PMID:25685807

  12. Synthetic Covalently Linked Dimeric Form of H2 Relaxin Retains Native RXFP1 Activity and Has Improved In Vitro Serum Stability

    Directory of Open Access Journals (Sweden)

    Vinojini B. Nair

    2015-01-01

    Full Text Available Human (H2 relaxin is a two-chain peptide member of the insulin superfamily and possesses potent pleiotropic roles including regulation of connective tissue remodeling and systemic and renal vasodilation. These effects are mediated through interaction with its cognate G-protein-coupled receptor, RXFP1. H2 relaxin recently passed Phase III clinical trials for the treatment of congestive heart failure. However, its in vivo half-life is short due to its susceptibility to proteolytic degradation and renal clearance. To increase its residence time, a covalent dimer of H2 relaxin was designed and assembled through solid phase synthesis of the two chains, including a judiciously monoalkyne sited B-chain, followed by their combination through regioselective disulfide bond formation. Use of a bisazido PEG7 linker and “click” chemistry afforded a dimeric H2 relaxin with its active site structurally unhindered. The resulting peptide possessed a similar secondary structure to the native monomeric H2 relaxin and bound to and activated RXFP1 equally well. It had fewer propensities to activate RXFP2, the receptor for the related insulin-like peptide 3. In human serum, the dimer had a modestly increased half-life compared to the monomeric H2 relaxin suggesting that additional oligomerization may be a viable strategy for producing longer acting variants of H2 relaxin.

  13. E2 polypeptides encoded by bovine papillomavirus type 1 form dimers through the common carboxyl-terminal domain: transactivation is mediated by the conserved amino-terminal domain.

    Science.gov (United States)

    McBride, A A; Byrne, J C; Howley, P M

    1989-01-01

    The E2 open reading frame (ORF) of bovine papillomavirus type 1 (BPV-1) encodes positive- and negative-acting factors that regulate viral gene expression. The full-length ORF encodes a transactivator, and two transcriptional repressors are expressed from the 3' half of the ORF. Previous analysis has shown that a conserved C-terminal region of 101 amino acids, which is shared by E2 transactivator and repressor proteins, contains the specific DNA binding activity. Further analysis of the E2 transactivator shows that a conserved N-terminal domain of approximately 220 amino acids is crucial for the transcriptional activation function, whereas the variable internal region is not required. The E2 proteins bind to a sequence, ACCGN4CGGT, several copies of which are sufficient to constitute an E2-dependent enhancer. By using a gel retardation assay and proteins derived by in vitro transcription and translation, we were able to show that the E2 polypeptides bind as dimers to a single DNA binding site. The dimeric E2 proteins are stable in the absence of DNA and dimerization is mediated through the DNA binding domain. This may reveal an additional mechanism of repression that could potentially result from the formation of inactive heterodimers between transactivator and repressor species. PMID:2536165

  14. Association between polymorphisms of apolipoprotein E, bone mineral density of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in postmenopausal women with hip or lower forearm fracture

    DEFF Research Database (Denmark)

    Sennels, Henriette Pia; Sand, J C; Madsen, B; Lauritzen, J B; Fenger, Mogens; Jørgensen, H L

    2003-01-01

    A genetic contribution to the development of osteoporosis is well documented. Although the association between the common allelic variation of apolipoprotein E (APOE), fracture risk, bone loss and bone mineral density (BMD) has been examined in several studies, the results of these investigations...... fragment length polymorphism (PCR-RFLP) was used to detect the APOE genotypes. Quantitative ultrasound was measured at the calcaneus. Bone mineral density (BMD) of the lower forearm was measured with dual-energy X-ray absorptiometry. The distributions of genotype frequencies in this study were: E2/E2: 0...

  15. Neutron scattering in dimers

    DEFF Research Database (Denmark)

    Gudel, H. U.; Furrer, A.; Kjems, Jørgen

    1986-01-01

    Insulating compounds containing dimers of transition metal and rare earth ions have been studied by inelastic neutron scattering (INS). Energy splittings can be directly determined, and the corresponding parameters are easily extracted from the experimental data. The intensities of dimer...

  16. Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

    OpenAIRE

    Ackers, Gary K.; Dalessio, Paula M.; Lew, George H.; Daugherty, Margaret A.; Holt, Jo M.

    2002-01-01

    The mechanism of cooperativity in the human hemoglobin tetramer (a dimer of αβ dimers) has historically been modeled as a simple two-state system in which a low-affinity structural form (T) switches, on ligation, to a high-affinity form (R), yielding a net loss of hydrogen bonds and salt bridges in the dimer–dimer interface. Modifications that weaken these cross-dimer contacts destabilize the quaternary T tetramer, leading to decreased cooperativity and enhanced ligand affinity, as demonstrat...

  17. Neutron scattering in dimers

    DEFF Research Database (Denmark)

    Gudel, H. U.; Furrer, A.; Kjems, Jørgen

    Insulating compounds containing dimers of transition metal and rare earth ions have been studied by inelastic neutron scattering (INS). Energy splittings can be directly determined, and the corresponding parameters are easily extracted from the experimental data. The intensities of dimer excitati......Insulating compounds containing dimers of transition metal and rare earth ions have been studied by inelastic neutron scattering (INS). Energy splittings can be directly determined, and the corresponding parameters are easily extracted from the experimental data. The intensities of dimer...

  18. A Nove Asymmetric ent—Kauranoid Dimer from Isodon enanderianus

    Institute of Scientific and Technical Information of China (English)

    纳智; 黎胜红; 等

    2002-01-01

    Further investigation on the aerial parts of Isodon enanderianus afforded a novel asymmetric ent-kauranoid dimer,enanderi-nanin J(1).The structure of the dimer was elucidated by means of spectroscopic methods (including 2D NMR tecniques ),Enanderinanin J was a dimer of xerophilusin A and probably formed by [4+2] cycloaddition.

  19. A Novel Asymmetric ent-Kauranoid Dimer from Isodon enanderianus

    Institute of Scientific and Technical Information of China (English)

    NA,Zhi(纳智); LI,Sheng-Hong(黎胜红); XIANG,Wei(项伟); ZHAO,Ai-Hua(赵爱华); LI,Chao-Ming(李朝明); SUN,Han-Dong(孙汉董)

    2002-01-01

    Further investigation on the aerial parts of Isodon enanderianus afforded a novel asymmetric ent-kauranoid dimer, enanuderinaninJ (1). The structure of the dimer was elucidated by means of spectroscopic methods (including 2D NMR techniques ). Enanderinanin J was a dimer of xerophilusin A and probably formed by [ 4 + 2] cycloaddition.

  20. Peptides interfering 3A protein dimerization decrease FMDV multiplication

    OpenAIRE

    Mónica González-Magaldi; Ángela Vázquez-Calvo; de la Torre, Beatriz G; Javier Valle; David Andreu; Francisco Sobrino

    2015-01-01

    Nonstructural protein 3A is involved in relevant functions in foot-and-mouth disease virus (FMDV) replication. FMDV 3A can form homodimers and preservation of the two hydrophobic ??-helices (??1 and ??2) that stabilize the dimer interface is essential for virus replication. In this work, small peptides mimicking residues involved in the dimer interface were used to interfere with dimerization and thus gain insight on its biological function. The dimer interface peptides ??1, ??2 and that span...

  1. Double-dimer pairings and skew Young diagrams

    OpenAIRE

    Kenyon, Richard W.; Wilson, David B.

    2010-01-01

    We study the number of tilings of skew Young diagrams by ribbon tiles shaped like Dyck paths, in which the tiles are "vertically decreasing". We use these quantities to compute pairing probabilities in the double-dimer model: Given a planar bipartite graph $G$ with special vertices, called nodes, on the outer face, the double-dimer model is formed by the superposition of a uniformly random dimer configuration (perfect matching) of $G$ together with a random dimer configuration of the graph fo...

  2. Polymorphisms in the genes of citohrom oxidase P450 2D6 (CYP2D6, paraoxonase 1 (PON1 and apolipoproteine E (APOE as risk factors for Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Đurić Gordana

    2007-01-01

    Full Text Available Background/Aim. The presence of Parkinson's disease (PD among the members of a family is a clear indication of the significance of genetics in its development. In spite of that, the majority of patients with PD shows a sporadic form of the disease induced as a result of interaction of both environmental and genetic factors. The aim of this study was to examine the effects of polymorphisms in the genes of cytohrome P450 2D6(CYP2D6, paraoxonase 1 (PON 1 and apolipoprotein E (APOE, as risk factors for PD. Methods. We examined 106 patients with PD (65 men and 41 women and 75 ethnically matched control subjects. The mean age at onset of PD in the patients was 46.9±9.4 years (ranging from 30 to 70 years. Genotyping was performed using standard PCR amplification and restriction endonuclease digestion protocols described for known polymorphism in the candidate genes under study. Results. The genotype A/A polymorphisms 2D6* gene of CYP2D6 and genotype M/M polymorphisms L54M gene of PON1 were significantly more frequent in the patients with PD than in the control group. The patients with genotypes A/A and M/M had 3.4 and 3.2 higher risk of PD, respectively than the control group (p = 0.01. The relation between genotypes A/A gene of CYP2D6 and M/M gene of PON1 was modified by the age at onset. The genotypes were associated with early onset of PD (p = 0.001, p = 0.004. The carriers of the A and M alleles in homozygote had 2.4 and 4.2 years respectively earlier onset of PD than carriers of other genotypes with these polymorphisms. The frequency allele ε4 gene of APOE was higher in the PD patients with early onset (20% than in PD with later onset (7.4%, while the genotype ε3/ε3 was associated with PD late onset (p = 0.024. Combined genotype I (carriers of the two risk allels in homozygote and one alleles risk in heterozygote and combined genotype II (carriers of the three alleles risk in homozygote caused early PD. Combined genotype II was detected in 12

  3. Small angle x-ray studies reveal that Aspergillus niger glucoamylase has a defined extended conformation and can form dimers in solution

    DEFF Research Database (Denmark)

    Jørgensen, Anders Dysted; Nøhr, Jane; Kastrup, Jette Sandholm;

    2008-01-01

    The industrially important glucoamylase 1 is an exo-acting glycosidase with substrate preference for alpha-1,4 and alpha-1,6 linkages at non-reducing ends of starch. It consists of a starch binding and a catalytic domain interspersed by a highly glycosylated polypeptide linker. The linker function......, which lacks a starch binding domain, and an engineered low-glycosylated variant of glucoamylase 1 with a short linker. Low resolution solution structures show that the linker adopts a compact structure rendering a well defined extended overall conformation to glucoamylase. We demonstrate that binding of...... a short heterobidentate inhibitor simultaneously directed toward the catalytic and starch binding domains causes dimerization of glucoamylase and not, as suggested previously, an intramolecular conformational rearrangement mediated by linker flexibility. Our results suggest that glucoamylase...

  4. Dimerized Mott insulators in hexagonal optical lattices

    International Nuclear Information System (INIS)

    We study bosonic atoms in optical honeycomb lattices with anisotropic tunneling and find dimerized Mott insulator (MI) phases with fractional filling. These incompressible insulating phases are characterized by an interaction-driven localization of particles in respect to the individual dimers and large local particle-number fluctuations within the dimers. We calculate the ground-state phase diagrams and the excitation spectra using an accurate cluster mean-field method. The cluster treatment enables us to probe the fundamental excitations of the dimerized MI where the excitation gap is dominated by the intra-dimer tunneling amplitude. This allows the distinction from normal Mott insulating phases gapped by the on-site interaction. In addition, we present analytical results for the phase diagram derived by a higher-order strong-coupling perturbative expansion approach. By computing finite lattices with large diameters the influence of a harmonic confinement is discussed in detail. It is shown that a large fraction of atoms forms the dimerized MI under experimental conditions. The necessary anisotropic tunneling can be realized either by periodic driving of the optical lattice or by engineering directly a dimerized lattice potential. The dimers can be mapped to their antisymmetric states creating a lattice with coupled p-orbitals. (paper)

  5. 血管性痴呆患者与载脂蛋白E基因多态性关系的配对分组实验%Relationship between vascular dementia and apolipoprotein E gene polymorphism: a case-control study

    Institute of Scientific and Technical Information of China (English)

    苏净; 刘风军; 常高峰

    2005-01-01

    important plasma apolipoproteins with polymorphism and involved in lipid metabolism and cholesterol balance modulation, playing also a role in the normal growth and repair of the nervous system.OBJECTIVE: To analyze apolipoprotein E gene polymorphism in patients with vascular dementia (VaD) in comparison with patients with cerebral infarction (CI) patients and healthy controls, so as to elicit the relationship between apolipoprotein E gene polymorphism and VaD.DESIGN: Case-control study.SETTING: Department of Neurology, General Hospital of Jinan Military Area Command of Chinese PLA.PARTICIPANTS: The participants were recruited from the inpatients and outpatients with cerebrovascular diseases and healthy subjects for routine physical examination in the General Hospital of Jinan Military Area Command of Chinese PLA between August 2001 and October 2003, including 35 cases of VaD, 36 CI cases and 40 healthy controls.METHODS: Four milliliters of venous blood was collected from the elbow vein form all participants after fasting for 12 hours for detection of apolipoprotein E genotype using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Blood lipids and apolipoprotein contents were also examined.of triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDL-C), as well as apolipoprotein A and aoplipoprotein B.RESULTS: Data of 35 VaD 36 CI patients and 40 healthy controls were all VaD group and CI group had higher ε4 allele frequency were higher (22.86% and 22.22% vs 7.5%, respectively, P < 0.05) but lower ε3 allele frequency (70% and 69.45% vs 86.25%, respectively, P < 0.05); the frequencies of all alleles were basically comparable between VaD and CI groups er in E ε4 allele carriers [(5.85±L03), (4.73±0.29), (4.96±0.87) mmol/L, respectively] than in E ε2 [(3.91±0.87), (3.12±0.65), (3.06±0.33) mmol/L] and ε3 [(1.34±0.21), (1.00±0.28), (0.94±0.32) g/L] allele carriers in Va

  6. Association between polymorphisms of apolipoprotein E, bone mineral density of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in postmenopausal women with hip or lower forearm fracture

    DEFF Research Database (Denmark)

    Sennels, Henriette Pia; Sand, J C; Madsen, B; Lauritzen, J B; Fenger, Mogens; Jørgensen, H L

    2003-01-01

    fragment length polymorphism (PCR-RFLP) was used to detect the APOE genotypes. Quantitative ultrasound was measured at the calcaneus. Bone mineral density (BMD) of the lower forearm was measured with dual-energy X-ray absorptiometry. The distributions of genotype frequencies in this study were: E2/E2: 0......A genetic contribution to the development of osteoporosis is well documented. Although the association between the common allelic variation of apolipoprotein E (APOE), fracture risk, bone loss and bone mineral density (BMD) has been examined in several studies, the results of these investigations...... are contradictory. The aim of this study was to examine the association between polymorphisms of APOE, BMD of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in a population of postmenopausal women with hip or lower forearm fractures admitted to a department of...

  7. Influence of socio-demographic features and apolipoprotein E epsilon 4 expression on the prevalence of dementia and cognitive impairment in a population of 70-74-year olds: the InveCe.Ab study.

    Science.gov (United States)

    Guaita, Antonio; Vaccaro, Roberta; Davin, Annalisa; Colombo, Mauro; Vitali, Silvia Francesca; Polito, Letizia; Abbondanza, Simona; Valle, Eleonora; Forloni, Gianluigi; Ferretti, Virginia Valeria; Villani, Simona

    2015-01-01

    The age-specific prevalence rates of dementia vary widely. Studies focusing on specific age groups are needed to provide reliable estimates for healthcare providers and policy makers. We estimated the prevalence of dementia, dementia subtypes and cognitive impairment in "InveCe.Ab" (ClinicalTrials.gov, NCT01345110), a single-step multidimensional population-based study of 70-74-year olds living in Abbiategrasso (Milan, Italy). We also looked for associations with socio-demographic factors and the presence of the apolipoprotein E-ɛ4 allele. The overall dementia prevalence was 3% (95%CI: 2.1-4.1%) [Alzheimer's disease (AD): 1.2% (95%CI 0.6-1.9%); vascular dementia (VD): 1.4% (95%CI: 0.8-2.2%)]. Being single was found to be a risk factor for vascular dementia; subjects born in southern Italy were shown to be at greater risk both of overall dementia and of vascular dementia. The prevalence of cognitive impairment, with or without subjective cognitive complaints (cognitive impairment, no dementia, CIND) was 7.8% (95%CI: 6.4-9.4%). As regards the CIND subgroups, the prevalence of subjects with subjective cognitive complaints (mild cognitive impairment, MCI) was 5.0% (95%CI 3.9-6.3%), while the prevalence of those without MCI (CIND-other) was 2.8% (95%CI: 1.9-3.8). The males had a higher risk of MCI and CIND-other; the older subjects were more likely to have MCI, and those born in north-eastern Italy to have CIND-other. The prevalence of AD was higher among the apolipoprotein E-ɛ4 carriers. Our data highlight the importance of dementia and cognitive impairment in the transitional period from adulthood to old age, and reveal the presence of different associations with socio-demographic and genetic factors. PMID:25466513

  8. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration

    Science.gov (United States)

    Burk, Raymond F.; Hill, Kristina E.; Motley, Amy K.; Winfrey, Virginia P.; Kurokawa, Suguru; Mitchell, Stuart L.; Zhang, Wanqi

    2014-01-01

    Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1−/− or apoER2−/− mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.—Burk, R. F., Hill, K. E., Motley, A. K., Winfrey, V. P., Kurokawa, S., Mitchell, S. L., Zhang, W. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. PMID:24760755

  9. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

    Energy Technology Data Exchange (ETDEWEB)

    Du, Fengxia [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Zhang, Minjie [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Li, Xiaohua; Yang, Caiyun [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Meng, Hao; Wang, Dong; Chang, Shuang [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Xu, Ye [Department of Radiation Oncology, Division of Genomic Stability, Dana Farber Cancer Institute, Harvard Medical School, MA 02134 (United States); Price, Brendan, E-mail: Brendan_Price@dfci.harvard.edu [Department of Radiation Oncology, Division of Genomic Stability, Dana Farber Cancer Institute, Harvard Medical School, MA 02134 (United States); Sun, Yingli, E-mail: sunyl@big.ac.cn [Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China)

    2014-10-03

    Highlights: • ATM phosphorylates the opposite strand of the dimer in response to DNA damage. • The PETPVFRLT box of ATM plays a key role in its dimer dissociation in DNA repair. • The dephosphorylation of ATM is critical for dimer re-formation after DNA repair. - Abstract: The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair.

  10. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

    International Nuclear Information System (INIS)

    Highlights: • ATM phosphorylates the opposite strand of the dimer in response to DNA damage. • The PETPVFRLT box of ATM plays a key role in its dimer dissociation in DNA repair. • The dephosphorylation of ATM is critical for dimer re-formation after DNA repair. - Abstract: The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair

  11. RING domain dimerization is essential for RNF4 function.

    Science.gov (United States)

    Liew, Chu Wai; Sun, Huaiyu; Hunter, Tony; Day, Catherine L

    2010-10-01

    RNF4 [RING (really interesting new gene) finger protein 4] family ubiquitin ligases are RING E3 ligases that regulate the homoeostasis of SUMOylated proteins by promoting their ubiquitylation. In the present paper we report that the RING domain of RNF4 forms a stable dimer, and that dimerization is required for ubiquitin transfer. Our results suggest that the stability of the E2~ubiquitin thioester bond is regulated by RING domain dimerization. PMID:20681948

  12. Peptides Interfering 3A Protein Dimerization Decrease FMDV Multiplication.

    Directory of Open Access Journals (Sweden)

    Mónica González-Magaldi

    Full Text Available Nonstructural protein 3A is involved in relevant functions in foot-and-mouth disease virus (FMDV replication. FMDV 3A can form homodimers and preservation of the two hydrophobic α-helices (α1 and α2 that stabilize the dimer interface is essential for virus replication. In this work, small peptides mimicking residues involved in the dimer interface were used to interfere with dimerization and thus gain insight on its biological function. The dimer interface peptides α1, α2 and that spanning the two hydrophobic α-helices, α12, impaired in vitro dimer formation of a peptide containing the two α-helices, this effect being higher with peptide α12. To assess the effect of dimer inhibition in cultured cells, the interfering peptides were N-terminally fused to a heptaarginine (R7 sequence to favor their intracellular translocation. Thus, when fused to R7, interference peptides (100 μM were able to inhibit dimerization of transiently expressed 3A, the higher inhibitions being found with peptides α1 and α12. The 3A dimerization impairment exerted by the peptides correlated with significant, specific reductions in the viral yield recovered from peptide-treated FMDV infected cells. In this case, α2 was the only peptide producing significant reductions at concentrations lower than 100 μM. Thus, dimer interface peptides constitute a tool to understand the structure-function relationship of this viral protein and point to 3A dimerization as a potential antiviral target.

  13. Antiparallel coiled-coil–mediated dimerization of myosin X

    OpenAIRE

    Lu, Qing; Ye, Fei; Wei, Zhiyi; Wen, Zilong; Zhang, Mingjie

    2012-01-01

    Processive movements of unconventional myosins on actin filaments generally require motor dimerization. A commonly accepted myosin dimerization mechanism is via formation of a parallel coiled-coil dimer by a stretch of amino acid residues immediately carboxyl-terminal to the motor’s lever-arm domain. Here, we discover that the predicted coiled-coil region of myosin X forms a highly stable, antiparallel coiled-coil dimer (anti-CC). Disruption of the anti-CC either by single-point mutations or ...

  14. Photoionization of helium dimers

    International Nuclear Information System (INIS)

    The helium dimer is one of the most weakly bound systems in the universe. This makes it an interesting quantum mechanical object for investigation. These Van der Waals Clusters can be produced in an expansion of a cryogenic gas jet through a small nozzle into vacuum. In the present experiment we examine the interaction of He dimers with synchrotron radiation at an energy range from 64 to 78 eV. We observed different pathways leading to single ionization of both He atoms of the dimer compound. This two close standing ions begin now to dissociate in cause of their coulomb potential. All charged fragments were detected in coincidence with a COLTRIMS system. Especially Interatomic Coulombic Decay (ICD) and the two step process (TS1) were clearly identified. Furthermore a distribution of the internuclear distance was obtained from the measured Kinetic Energy Release (KER). (orig.)

  15. Linkage of the cholesterol 7α-hydroxylase gene and low-density lipoprotein cholesterol conditional on apolipoprotein E association: the National Heart, Lung, and Blood Institute Family Heart Study

    Institute of Scientific and Technical Information of China (English)

    Jing-Ping Lin; Richard H. Myers; Laura Almasy; Hilary H. Coon; Donna K. Arnett; Yuling Hong; Steven C. Hunt

    2005-01-01

    Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7α-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. Methods Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. Results The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly.Conclusion Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.

  16. Tetraphenylporphyrin dimers. An optical and magnetic resonance study

    NARCIS (Netherlands)

    Benthem, L.

    1984-01-01

    Tetraphenylporphyrin (TPP) molecules have been linked together to form dimers, using two positions of the phenyl groups at which the linking chain, which consisted mostly of 5 atoms, is attached (ortho or para position). The resulting dimers have different relative orientations of the porphyrin macr

  17. Alkane dimers interaction

    DEFF Research Database (Denmark)

    Ferrighi, Lara; Madsen, Georg Kent Hellerup; Hammer, Bjørk

    The interaction energies of a series of n-alkane dimers, from methane to decane, have been investigated with Density Functional Theory (DFT), using the MGGA-M06-L density functional. The results are compared both to the available wavefunction-based values as well as to dispersion corrected DFT...

  18. Double-dimer pairings and skew Young diagrams

    CERN Document Server

    Kenyon, Richard W

    2010-01-01

    We study the number of tilings of skew Young diagrams by ribbon tiles shaped like Dyck paths, in which the tiles are "vertically decreasing". We use these quantities to compute pairing probabilities in the double-dimer model: Given a planar bipartite graph $G$ with special vertices, called nodes, on the outer face, the double-dimer model is formed by the superposition of a uniformly random dimer configuration (perfect matching) of $G$ together with a random dimer configuration of the graph formed from $G$ by deleting the nodes. The double-dimer configuration consists of loops, doubled edges, and chains that start and end at the boundary nodes. We are interested in how the chains connect the nodes. An interesting special case is when the graph is $\\varepsilon(\\Z\\times\\N)$ and the nodes are at evenly spaced locations on the boundary $\\R$ as the grid spacing $\\varepsilon\\to 0$.

  19. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

    DEFF Research Database (Denmark)

    Presman, Diego M; Ogara, M Florencia; Stortz, Martín;

    2014-01-01

    , reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state...

  20. Dimerization of Protegrin-1 in Different Environments

    Directory of Open Access Journals (Sweden)

    Yiannis N. Kaznessis

    2010-09-01

    Full Text Available The dimerization of the cationic β-hairpin antimicrobial peptide protegrin-1 (PG1 is investigated in three different environments: water, the surface of a lipid bilayer membrane, and the core of the membrane. PG1 is known to kill bacteria by forming oligomeric membrane pores, which permeabilize the cells. PG1 dimers are found in two distinct, parallel and antiparallel, conformations, known as important intermediate structural units of the active pore oligomers. What is not clear is the sequence of events from PG1 monomers in solution to pores inside membranes. The step we focus on in this work is the dimerization of PG1. In particular, we are interested in determining where PG1 dimerization is most favorable. We use extensive molecular dynamics simulations to determine the potential of mean force as a function of distance between two PG1 monomers in the aqueous subphase, the surface of model lipid bilayers and the interior of these bilayers. We investigate the two known distinct modes of dimerization that result in either a parallel or an antiparallel β-sheet orientation. The model bilayer membranes are composed of anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG and palmitoyl-oleoyl-phosphatidylethanolamine (POPE in a 1:3 ratio (POPG:POPE. We find the parallel PG1 dimer association to be more favorable than the antiparallel one in water and inside the membrane. However, we observe that the antiparallel PG1 β-sheet dimer conformation is somewhat more stable than the parallel dimer association at the surface of the membrane. We explore the role of hydrogen bonds and ionic bridges in peptide dimerization in the three environments. Detailed knowledge of how networks of ionic bridges and hydrogen bonds contribute to peptide stability is essential for the purpose of understanding the mechanism of action for membrane-active peptides as well as for designing peptides which can modulate membrane properties. The findings are suggestive of the

  1. Dimerization of the thyrotropin-releasing hormone receptor potentiates hormone-dependent receptor phosphorylation

    OpenAIRE

    Song, Gyun Jee; Jones, Brian W.; Hinkle, Patricia M.

    2007-01-01

    The G protein-coupled thyrotropin (TSH)-releasing hormone (TRH) receptor forms homodimers. Regulated receptor dimerization increases TRH-induced receptor endocytosis. These studies test whether dimerization increases receptor phosphorylation, which could potentiate internalization. Phosphorylation at residues 355–365, which is critical for internalization, was measured with a highly selective phospho-site-specific antibody. Two strategies were used to drive receptor dimerization. Dimerization...

  2. Bis(triethanolamine)bis(μ2-trimesato)dicobalt(II): a Co(II) dimer with an unreported two-dimensional supramolecular topology formed from triethanolamine and trimesic acid ligands.

    Science.gov (United States)

    Xie, Min; Xu, Guo-Hai

    2016-02-01

    Supramolecular networks are an important subset in the field of coordination polymer (CP) frameworks and are widely encountered in crystal engineering research. The search for novel topologies continues to be a significant goal in CP chemistry. The dimeric compound bis(μ-5-carboxybenzene-1,3-dicarboxylato-κ(2)O(1):O(3))bis[(triethanolamine-κ(4)N,O,O',O'')cobalt(II)], [Co2(C9H4O6)2(C6H15NO3)2], formed from the coligands 5-carboxybenzene-1,3-dicarboxylate (tmaH(2-)) and triethanolamine (teaH3), namely [Co(μ2-tmaH)(teaH3)]2, was synthesized and characterized by single-crystal and powder X-ray diffraction analyses, IR spectroscopy, thermogravimetric analysis (TGA) and magnetic measurements. The crystal structure features a zero-dimensional molecular structure consisting of centrosymmetric macrocyclic dinuclear complexes. Four classical hydrogen bonds between carboxylate groups and hydroxyethyl arms stabilize and extend the molecules into a two-dimensional supramolecular network. The topological analysis indicates that an unreported (3,5)-binodal supramolecular topology with a short Schläfli symbol of (4.5.6)(4.5(5).6(3).7) can be achieved by means of intermolecular hydrogen bonds. The crystal structure accounts for the potential to obtain unique topological types from two excellent hydrogen-bonding candidates, i.e. tmaH3 and teaH3. A variable-temperature magnetic study shows the existence of antiferromagnetic behaviour in the complex. PMID:26846500

  3. Bacteriochlorophyll dimers in photosynthesis

    International Nuclear Information System (INIS)

    The X-ray crysallagraphic study of reaction center (RC) single crystals of the photosynthetic bacteria Rps.Viridis and Rb. sphaeroides confirms the existence of bacteriochlorophyll (BChl) dimers which were postulated earlier from EPR and ENDOR studies at low temperature to be the primary electron donors P960 and P870. Apart from the spatial structure of these dimers a knowlegde of the electron density distribution in various electronic stated in indispensable for an understanding of their functional properties. For P870+ and P960+ under physiological ocnditions the electron spin density distrubutions were obtained by ENDOR-in-solution via the hyperifne couplings. The comparison between the EPR/ENDOR data of P870+ and P960+ in RC's and of onomeric BChl a. and BChl b. shows that the primary donors are pie conjugated supermolecules with more or less asymmetric spin dnesity distrubutions over the dimer halves. Theoretical spian and charge densities were calculated by an all-valence electron SCF MO method, RHF-INDO/SP, using coordinates from refined X-ray data. These calculations yield asymmetry ratios similar to those observed.Consequences of the asymmetries in the charge distribution with respect to the observed unidirectionality of the electron transfer are discussed. (author). 29 refs.; 4 figs

  4. Molecular mechanisms of asymmetric RAF dimer activation.

    Science.gov (United States)

    Jambrina, Pablo G; Bohuszewicz, Olga; Buchete, Nicolae-Viorel; Kolch, Walter; Rosta, Edina

    2014-08-01

    Protein phosphorylation is one of the most common post-translational modifications in cell regulatory mechanisms. Dimerization plays also a crucial role in the kinase activity of many kinases, including RAF, CDK2 (cyclin-dependent kinase 2) and EGFR (epidermal growth factor receptor), with heterodimers often being the most active forms. However, the structural and mechanistic details of how phosphorylation affects the activity of homo- and hetero-dimers are largely unknown. Experimentally, synthesizing protein samples with fully specified and homogeneous phosphorylation states remains a challenge for structural biology and biochemical studies. Typically, multiple changes in phosphorylation lead to activation of the same protein, which makes structural determination methods particularly difficult. It is also not well understood how the occurrence of phosphorylation and dimerization processes synergize to affect kinase activities. In the present article, we review available structural data and discuss how MD simulations can be used to model conformational transitions of RAF kinase dimers, in both their phosphorylated and unphosphorylated forms. PMID:25109958

  5. Antiparallel coiled-coil-mediated dimerization of myosin X.

    Science.gov (United States)

    Lu, Qing; Ye, Fei; Wei, Zhiyi; Wen, Zilong; Zhang, Mingjie

    2012-10-23

    Processive movements of unconventional myosins on actin filaments generally require motor dimerization. A commonly accepted myosin dimerization mechanism is via formation of a parallel coiled-coil dimer by a stretch of amino acid residues immediately carboxyl-terminal to the motor's lever-arm domain. Here, we discover that the predicted coiled-coil region of myosin X forms a highly stable, antiparallel coiled-coil dimer (anti-CC). Disruption of the anti-CC either by single-point mutations or by replacement of the anti-CC with a parallel coiled coil with a similar length compromised the filopodial induction activity of myosin X. We further show that the anti-CC and the single α-helical domain of myosin X are connected by a semirigid helical linker. The anti-CC-mediated dimerization may enable myosin X to walk on both single and bundled actin filaments. PMID:23012428

  6. A variant form of the human deleted in malignant brain tumor 1 (DMBT1 gene shows increased expression in inflammatory bowel diseases and interacts with dimeric trefoil factor 3 (TFF3.

    Directory of Open Access Journals (Sweden)

    Jens Madsen

    Full Text Available The protein deleted in malignant brain tumors (DMBT1 and the trefoil factor (TFF proteins have all been proposed to have roles in epithelial cell growth and cell differentiation and shown to be up regulated in inflammatory bowel diseases. A panel of monoclonal antibodies was raised against human DMBT1(gp340. Analysis of lung washings and colon tissue extracts by Western blotting in the unreduced state, two antibodies (Hyb213-1 and Hyb213-6 reacted with a double band of 290 kDa in lung lavage. Hyb213-6, in addition, reacted against a double band of 270 kDa in colon extract while Hyb213-1 showed no reaction. Hyb213-6 showed strong cytoplasmic staining in epithelial cells of both the small and large intestine whereas no staining was seen with Hyb213-1. The number of DMBT1(gp340 positive epithelial cells, stained with Hyb213-6, was significantly up regulated in inflammatory colon tissue sections from patients with ulcerative colitis (p<0.0001 and Crohn's disease (p = 0.006 compared to normal colon tissue. Immunohistochemical analysis of trefoil factor TFF1, 2 and 3 showed that TFF1 and 3 localized to goblet cells in both normal colon tissue and in tissue from patients with ulcerative colitis or Crohn's disease. No staining for TFF2 was seen in goblet cells in normal colon tissue whereas the majority of tissue sections in ulcerative colitis and Crohn's disease showed sparse and scattered TFF2 positive goblet cells. DMBT1 and TFF proteins did therefore not co-localize in the same cells but localized in adjacent cells in the colon. The interaction between DMBT1(gp340 and trefoil TFFs proteins was investigated using an ELISA assay. DMBT1(gp340 bound to solid-phase bound recombinant dimeric TFF3 in a calcium dependent manner (p<0.0001 but did not bind to recombinant forms of monomeric TFF3, TFF2 or glycosylated TFF2. This implies a role for DMBT1 and TFF3 together in inflammatory bowel disease.

  7. Stereoselective self-sorting in the self-assembly of a Phe-Phe extended guanidiniocarbonyl pyrrole carboxylate zwitterion: formation of two diastereomeric dimers with significantly different stabilities.

    Science.gov (United States)

    Rodler, Fabian; Sicking, Wilhelm; Schmuck, Carsten

    2011-07-28

    The 'dipeptide extended' guanidiniocarbonyl pyrrole carboxylate zwitterion GCP-Phe-Phe 1 forms stable dimers in DMSO. However, dimerization is highly stereoselective. Only homochiral dimers are formed and the (L,L)·(L,L) dimer (K(dim) > 10(5) M(-1)) is significantly more stable by a factor of 10(3) than the diastereomeric (D,L)·(D,L) dimer (K(dim) = 120 M(-1)). PMID:21670799

  8. Dimerization and oligomerization of the chaperone calreticulin

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte S; Ryder, L Rebekka; Steinø, Anne; Højrup, Peter; Hansen, Jesper; Beyer, N Helena; Heegaard, Niels H H; Houen, Gunnar

    2003-01-01

    The chaperone calreticulin is a highly conserved eukaryotic protein mainly located in the endoplasmic reticulum. It contains a free cysteine SH group but does not form disulfide-bridged dimers under physiological conditions, indicating that the SH group may not be fully accessible in the native...... calreticulin was oligomerized. Thus, calreticulin shares the ability to self-oligomerize with other important chaperones such as GRP94 and HSP90, a property possibly associated with their chaperone activity....

  9. Dimer model for Tau proteins bound in microtubule bundles

    Science.gov (United States)

    Hall, Natalie; Kluber, Alexander; Hayre, N. Robert; Singh, Rajiv; Cox, Daniel

    2013-03-01

    The microtubule associated protein tau is important in nucleating and maintaining microtubule spacing and structure in neuronal axons. Modification of tau is implicated as a later stage process in Alzheimer's disease, but little is known about the structure of tau in microtubule bundles. We present preliminary work on a proposed model for tau dimers in microtubule bundles (dimers are the minimal units since there is one microtubule binding domain per tau). First, a model of tau monomer was created and its characteristics explored using implicit solvent molecular dynamics simulation. Multiple simulations yield a partially collapsed form with separate positively/negatively charged clumps, but which are a factor of two smaller than required by observed microtubule spacing. We argue that this will elongate in dimer form to lower electrostatic energy at a cost of entropic ``spring'' energy. We will present preliminary results on steered molecular dynamics runs on tau dimers to estimate the actual force constant. Supported by US NSF Grant DMR 1207624.

  10. Tetraphenylporphyrin dimers. An optical and magnetic resonance study

    OpenAIRE

    Benthem, L.

    1984-01-01

    Tetraphenylporphyrin (TPP) molecules have been linked together to form dimers, using two positions of the phenyl groups at which the linking chain, which consisted mostly of 5 atoms, is attached (ortho or para position). The resulting dimers have different relative orientations of the porphyrin macrocycles w.r.t. each other and different centre-to-centre distances. Using standard procedures, metal ions have been inserted into the porphyrin ring; depending on the type of experiment different m...

  11. Versatile SPR aptasensor for detection of lysozyme dimer in oligomeric and aggregated mixtures.

    Science.gov (United States)

    Vasilescu, Alina; Purcarea, Cristina; Popa, Elena; Zamfir, Medana; Mihai, Iuliana; Litescu, Simona; David, Sorin; Gaspar, Szilveszter; Gheorghiu, Mihaela; Jean-Louis Marty

    2016-09-15

    A Surface Plasmon Resonance (SPR) sensor for the quantitation of lysozyme dimer in monomer-dimer mixtures, reaching a detection limit of 1.4nM dimer, has been developed. The sensor is based on an aptamer which, although developed for the monomeric form, binds also the dimeric form but with a strikingly different kinetics. The aptasensor was calibrated using a dimer obtained by cross-linking. Sensorgrams acquired with the aptasensor in monomer-dimer mixtures were analysed using Principal Components Analysis and Multiple Regression to establish correlations with the dimer content in the mixtures. The method allows the detection of 0.1-1% dimer in monomer solutions without any separation. As an application, the aptasensor was used to qualitatively observe the initial stages of aggregation of lysozyme solutions at 60°C and pH 2, through the variations in lysozyme dimer amounts. Several other methods were used to characterize the lysozyme dimer obtained by cross-linking and confirm the SPR results. This work highlights the versatility of the aptasensor, which can be used, by simply tuning the experimental conditions, for the sensitive detection of either the monomer or the dimer and for the observation of the aggregation process of lysozyme. PMID:27135941

  12. Human Erythropoietin Dimers with Markedly Enhanced in vivo Activity

    Science.gov (United States)

    Sytkowski, Arthur J.; Dotimas Lunn, Elizabeth; Davis, Kerry Lynn; Feldman, Laurie; Siekman, Suvia

    1998-02-01

    Human erythropoietin, a widely used and important therapeutic glycoprotein, has a relatively short plasma half-life due to clearance by glomerular filtration as well as by other mechanisms. We hypothesized that an erythropoietin species with a larger molecular size would exhibit an increased plasma half-life and, potentially, an enhanced biological activity. We now report the production of biologically active erythropoietin dimers and trimers by chemical crosslinking of the conventional monomeric form. We imparted free sulfhydryl residues to a pool of erythropoietin monomer by chemical modification. A second pool was reacted with another modifying reagent to yield monomer with male-imido groups. Upon mixing these two pools, covalently linked dimers and trimers were formed that were biologically active in vitro. The plasma half-life of erythropoietin dimers in rabbits was >24 h compared with 4 h for the monomers. Importantly, erythropoietin dimers were biologically active in vivo as shown by their ability to increase the hematocrits of mice when injected subcutaneously. In addition, the dimers exhibited >26-fold higher activity in vivo than did the monomers and were very effective after only one dose. Dimeric and other oligomeric forms of Epo may have an important role in therapy.

  13. Biosynthesis of intestinal microvillar proteins. Dimerization of aminopeptidase N and lactase-phlorizin hydrolase

    DEFF Research Database (Denmark)

    Danielsen, E M

    1990-01-01

    explants. For aminopeptidase N, dimerization did not begin until 5-10 min after synthesis, and maximal dimerization by cross-linking of the transient form of the enzyme required 1 h, whereas the mature form of aminopeptidase N cross-linked with unchanged efficiency from 45 min to 3 h of labeling. Formation...... of dimers of this enzyme therefore occurs prior to the Golgi-associated processing, and the slow rate of dimerization may be the rate-limiting step in the transport from the endoplasmic reticulum to the Golgi complex. For lactase-phlorizin hydrolase, the posttranslational processing includes a...... proteolytic cleavage of its high molecular weight precursor. Since only the mature form and not the precursor of this enzyme could be cross-linked, formation of tightly associated dimers only takes place after transport out of the endoplasmic reticulum. Dimerization of the two brush border enzymes therefore...

  14. Apolipoprotein E genotyping by multiplex amplification refractory mutation system PCR with optimized conditions%优化的多重扩增阻滞突变系统-PCR对载脂蛋白E基因的简易分型

    Institute of Scientific and Technical Information of China (English)

    刘静; 刘建伟; 叶玲

    2011-01-01

    Objective To set up a simple method for apolipoprotein E (ApoE) genotyping by modifying the conditions of multiplex amplification refractory mutation system PCR (multi-ARMS-PCR). Methods Based on the principle of multi-ARMS-PCR and considering the faults existed in some published papers, new primers were designed to improve PCR conditions. DNA genome of peripheral white blood cells was used as the template. Four allele-specific oligonucleotide upstream primers, one common downstream primer and a pair of internal positive control primers were constructed. Multi-ARMS-PCR were performed with combination of different primers in 2 reaction tubes synchronously. Amplified multiplex products were electrophoresed on agarose gels containing ethidium bromide. Six ApoE genotypes were distinguished by the band sizes. Results Using the new primers,amplification efficiency and specificity were significantly increased and the misclassification was diminished due to removing the interference of non-specific bands. Conclusion The optimized multi-ARMS-PCR is an easy, time-saving, efficient and economical method for determination of ApoE genotypes applied in a minimally equipped laboratory.%目的 通过改进和优化多重扩增阻滞突变系统-PCR(multi-ARMS-PCR)条件,建立载脂蛋白E(ApoE)基因的简易分型方法.方法 基于multi-ARMS-PCR的原理和特点,针对文献报道方法中存在的缺陷和错误,重新设计或改进引物.以外周血白细胞基因组DNA为模板,应用4个等位基因特异性寡核酸上游引物、1个通用下游引物和一对内参引物,分A,B两个管同步进行多重PCR反应.PCR扩增产物经过琼脂糖凝胶电泳分离-EB染色,根据电泳带型的差异,实现对ApoE 6种基因型的判定.结果 新引物显著提高了扩增效率和反应特异性,排除了非特异条带的干扰,减少了ApoE基因分型的错判.结论 采用优化后的multi-ARMS-PCR方法对ApoE基因型进行鉴定,具有操作简便、时间短

  15. The arthritis-associated HLA-B*27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B*27:09

    OpenAIRE

    Cauli, A; Shaw, J; Giles, J.; Hatano, H; Rysnik, O; Payeli, S.; McHugh, K; Dessole, G; G. Porru; Desogus, E; Fiedler, S.; Hölper, S; CARETTE A.; Blanco-Gelaz, MA; Vacca, A.

    2013-01-01

    OBJECTIVES: HLA-B*27:05 is associated with AS whereas HLA-B*27:09 is not associated. We hypothesized that different interactions with KIR immune receptors could contribute to the difference in disease association between HLA-B*27:05 and HLAB*27:09. Thus, the objective of this study was to compare the formation of β2m-free heavy chain (FHC) including B27 dimers (B272) by HLA-B*27:05 and HLA-B*27:09 and their binding to KIR immunoreceptors. METHODS: We studied the formation of HLA-B*27:05 and H...

  16. The arthritis-associated HLA-B*27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B*27:09.

    OpenAIRE

    Cauli, A; Shaw, J; Giles, J.; Hatano, H; Rysnik, O; Payeli, S.; McHugh, K; Dessole, G; G. Porru; Desogus, E; Fiedler, S.; Hölper, S; CARETTE A.; Blanco-Gelaz, MA; Vacca, A.

    2013-01-01

    OBJECTIVES: HLA-B*27:05 is associated with AS whereas HLA-B*27:09 is not associated. We hypothesized that different interactions with KIR immune receptors could contribute to the difference in disease association between HLA-B*27:05 and HLAB*27:09. Thus, the objective of this study was to compare the formation of β2m-free heavy chain (FHC) including B27 dimers (B272) by HLA-B*27:05 and HLA-B*27:09 and their binding to KIR immunoreceptors. METHODS: We studied the formation of HLA-B*27:05 and H...

  17. MspA nanopores from subunit dimers.

    Directory of Open Access Journals (Sweden)

    Mikhail Pavlenok

    Full Text Available Mycobacterium smegmatis porin A (MspA forms an octameric channel and represents the founding member of a new family of pore proteins. Control of subunit stoichiometry is important to tailor MspA for nanotechnological applications. In this study, two MspA monomers were connected by linkers ranging from 17 to 62 amino acids in length. The oligomeric pore proteins were purified from M. smegmatis and were shown to form functional channels in lipid bilayer experiments. These results indicated that the peptide linkers did not prohibit correct folding and localization of MspA. However, expression levels were reduced by 10-fold compared to wild-type MspA. MspA is ideal for nanopore sequencing due to its unique pore geometry and its robustness. To assess the usefulness of MspA made from dimeric subunits for DNA sequencing, we linked two M1-MspA monomers, whose constriction zones were modified to enable DNA translocation. Lipid bilayer experiments demonstrated that this construct also formed functional channels. Voltage gating of MspA pores made from M1 monomers and M1-M1 dimers was identical indicating similar structural and dynamic channel properties. Glucose uptake in M. smegmatis cells lacking porins was restored by expressing the dimeric mspA M1 gene indicating correct folding and localization of M1-M1 pores in their native membrane. Single-stranded DNA hairpins produced identical ionic current blockades in pores made from monomers and subunit dimers demonstrating that M1-M1 pores are suitable for DNA sequencing. This study provides the proof of principle that production of single-chain MspA pores in M. smegmatis is feasible and paves the way for generating MspA pores with altered stoichiometries. Subunit dimers enable better control of the chemical and physical properties of the constriction zone of MspA. This approach will be valuable both in understanding transport across the outer membrane in mycobacteria and in tailoring MspA for nanopore

  18. MspA nanopores from subunit dimers.

    Science.gov (United States)

    Pavlenok, Mikhail; Derrington, Ian M; Gundlach, Jens H; Niederweis, Michael

    2012-01-01

    Mycobacterium smegmatis porin A (MspA) forms an octameric channel and represents the founding member of a new family of pore proteins. Control of subunit stoichiometry is important to tailor MspA for nanotechnological applications. In this study, two MspA monomers were connected by linkers ranging from 17 to 62 amino acids in length. The oligomeric pore proteins were purified from M. smegmatis and were shown to form functional channels in lipid bilayer experiments. These results indicated that the peptide linkers did not prohibit correct folding and localization of MspA. However, expression levels were reduced by 10-fold compared to wild-type MspA. MspA is ideal for nanopore sequencing due to its unique pore geometry and its robustness. To assess the usefulness of MspA made from dimeric subunits for DNA sequencing, we linked two M1-MspA monomers, whose constriction zones were modified to enable DNA translocation. Lipid bilayer experiments demonstrated that this construct also formed functional channels. Voltage gating of MspA pores made from M1 monomers and M1-M1 dimers was identical indicating similar structural and dynamic channel properties. Glucose uptake in M. smegmatis cells lacking porins was restored by expressing the dimeric mspA M1 gene indicating correct folding and localization of M1-M1 pores in their native membrane. Single-stranded DNA hairpins produced identical ionic current blockades in pores made from monomers and subunit dimers demonstrating that M1-M1 pores are suitable for DNA sequencing. This study provides the proof of principle that production of single-chain MspA pores in M. smegmatis is feasible and paves the way for generating MspA pores with altered stoichiometries. Subunit dimers enable better control of the chemical and physical properties of the constriction zone of MspA. This approach will be valuable both in understanding transport across the outer membrane in mycobacteria and in tailoring MspA for nanopore sequencing of DNA. PMID

  19. Dimer-dimer interaction of the bacterial selenocysteine synthase SelA promotes functional active-site formation and catalytic specificity.

    Science.gov (United States)

    Itoh, Yuzuru; Bröcker, Markus J; Sekine, Shun-ichi; Söll, Dieter; Yokoyama, Shigeyuki

    2014-04-17

    The 21st amino acid, selenocysteine (Sec), is incorporated translationally into proteins and is synthesized on its specific tRNA (tRNA(Sec)). In Bacteria, the selenocysteine synthase SelA converts Ser-tRNA(Sec), formed by seryl-tRNA synthetase, to Sec-tRNA(Sec). SelA, a member of the fold-type-I pyridoxal 5'-phosphate-dependent enzyme superfamily, has an exceptional homodecameric quaternary structure with a molecular mass of about 500kDa. Our previously determined crystal structures of Aquifex aeolicus SelA complexed with tRNA(Sec) revealed that the ring-shaped decamer is composed of pentamerized SelA dimers, with two SelA dimers arranged to collaboratively interact with one Ser-tRNA(Sec). The SelA catalytic site is close to the dimer-dimer interface, but the significance of the dimer pentamerization in the catalytic site formation remained elusive. In the present study, we examined the quaternary interactions and demonstrated their importance for SelA activity by systematic mutagenesis. Furthermore, we determined the crystal structures of "depentamerized" SelA variants with mutations at the dimer-dimer interface that prevent pentamerization. These dimeric SelA variants formed a distorted and inactivated catalytic site and confirmed that the pentamer interactions are essential for productive catalytic site formation. Intriguingly, the conformation of the non-functional active site of dimeric SelA shares structural features with other fold-type-I pyridoxal 5'-phosphate-dependent enzymes with native dimer or tetramer (dimer-of-dimers) quaternary structures. PMID:24456689

  20. Rotational spectra of propargyl alcohol dimer: A dimer bound with three different types of hydrogen bonds

    International Nuclear Information System (INIS)

    Pure rotational spectra of the propargyl alcohol dimer and its three deuterium isotopologues have been observed in the 4 to 13 GHz range using a pulsed-nozzle Fourier transform microwave spectrometer. For the parent dimer, a total of 51 transitions could be observed and fitted within experimental uncertainty. For two mono-substituted and one bi-substituted deuterium isotopologues, a total of 14, 17, and 19 transitions were observed, respectively. The observed rotational constants for the parent dimer [A = 2321.8335(4) MHz, B = 1150.4774(2) MHz, and C = 1124.8898(2) MHz] are close to those of the most stable structure predicted by ab initio calculations. Spectra of the three deuterated isotopologues and Kraitchman analysis positively confirm this structure. Geometrical parameters and “Atoms in Molecules” analysis on the observed structure reveal that the two propargyl alcohol units in the dimer are bound by three different types of hydrogen bonds: O–H⋯O, O–H⋯π, and C–H⋯π. To the best of our knowledge, propargyl alcohol seems to be the smallest molecule forming a homodimer with three different points of contact

  1. UV-sensitivity of hemoglobin dimers in free state and in valency hybrids modification by serotonin

    International Nuclear Information System (INIS)

    Changes of oxygen-binding activity of hemoglobin dimers modified by the therapeutical doses of UV-light and serotonin in free state and in valency hybrids are analysed. The prior role of photodissociation to dimers at the UV-radiation action on heme-protein molecules has been shown. It has been observed that the complex between hemoglobin serotonin is formed in fields of αβ-dimers contacts

  2. Covalently dimerized SecA is functional in protein translocation.

    Science.gov (United States)

    de Keyzer, Jeanine; van der Sluis, Eli O; Spelbrink, Robin E J; Nijstad, Niels; de Kruijff, Ben; Nouwen, Nico; van der Does, Chris; Driessen, Arnold J M

    2005-10-21

    The ATPase SecA provides the driving force for the transport of secretory proteins across the cytoplasmic membrane of Escherichia coli. SecA exists as a dimer in solution, but the exact oligomeric state of SecA during membrane binding and preprotein translocation is a topic of debate. To study the requirements of oligomeric changes in SecA during protein translocation, a non-dissociable SecA dimer was formed by oxidation of the carboxyl-terminal cysteines. The cross-linked SecA dimer interacts with the SecYEG complex with a similar stoichiometry as non-cross-linked SecA. Cross-linking reversibly disrupts the SecB binding site on SecA. However, in the absence of SecB, the activity of the disulfide-bonded SecA dimer is indistinguishable from wild-type SecA. Moreover, SecYEG binding stabilizes a cold sodium dodecylsulfate-resistant dimeric state of SecA. The results demonstrate that dissociation of the SecA dimer is not an essential feature of the protein translocation reaction. PMID:16115882

  3. Kit receptor dimerization is driven by bivalent binding of stem cell factor.

    Science.gov (United States)

    Lemmon, M A; Pinchasi, D; Zhou, M; Lax, I; Schlessinger, J

    1997-03-01

    Most growth factors and cytokines activate their receptors by inducing dimerization upon binding. We have studied binding of the dimeric cytokine stem cell factor (SCF) to the extracellular domain of its receptor Kit, which is a receptor tyrosine kinase similar to the receptors for platelet-derived growth factor and colony-stimulating factor-1. Calorimetric studies show that one SCF dimer binds simultaneously to two molecules of the Kit extracellular domain. Gel filtration and other methods show that this results in Kit dimerization. It has been proposed that SCF-induced Kit dimerization proceeds via a conformational change that exposes a key receptor dimerization site in the fourth of the five immunoglobulin (Ig)-like domains in Kit. We show that a form of Kit containing just the first three Ig domains (Kit-123) binds to SCF with precisely the same thermodynamic parameters as does Kit-12345. Analytical ultracentrifugation, light scattering, and gel filtration show that Kit-123 dimerizes upon SCF binding in a manner indistinguishable from that seen with Kit-12345. These data argue that the fourth Ig-like domain of Kit is not required for SCF-induced receptor dimerization and provide additional support for a model in which bivalent binding of the SCF dimer provides the driving force for Kit dimerization. PMID:9045650

  4. 血清载脂蛋白E在儿童感染性疾病中的变化%The changes of serum apolipoprotein E in pediatric infectious diseases

    Institute of Scientific and Technical Information of China (English)

    付盼; 王传清; 王爱敏; 谢文华; 冯志敏

    2012-01-01

    目的 探讨血清载脂蛋白E(ApoE)在儿童感染性疾病中的变化.方法 279例感染性疾病患儿中,脓毒症65例,化脓性脑膜炎47例,细菌性肺炎67例,无菌性脑膜炎47例,支原体肺炎53例.采用透射免疫比浊法(IA)检测感染性疾病患儿的血清ApoE水平.构建B组鼠伤寒沙门菌诱导的脓毒症小鼠模型,采用IA检测小鼠血清ApoE水平,实时荧光定量PCR和Western印迹法检测小鼠肝脏ApoE mRNA和蛋白的表达.两组间均数比较采用独立样本t检验.结果 血清ApoE在细菌性感染性疾病患儿中明显升高,在脓毒症患儿中高达(59.8±23.5) mg/L(t=-5.118,P<0.01),在无菌性脑膜炎和支原体肺炎患儿中无明显变化.脓毒症小鼠模型血清ApoE水平明显升高,但肝脏ApoE mRNA和蛋白的表达下降,mRNA的相对值在造模后3h下降了71%(t=5.022,P<0.01),在造模后24 h下降了73%(t=4.181,P<0.01).结论 血清ApoE水平在细菌性感染性疾病中显著升高,而肝脏中ApoE表达下降,说明ApoE血清升高机制与肝脏表达不相关.%Objective To investigate the changes of serum apolipoprotein E (ApoE) in children with infectious diseases.Methods A total of 279 pediatric patients with infectious diseases were enrolled in this study,including 65 patients with sepsis,47 patients with bacterial meningitis,67 patients with bacterial pneumonia, 47 patients with aseptic meningitis and 53 patients with mycoplasma pneumonia. The serum ApoE collected from all patients was detected by immunoturbidimetric assay (IA).The septic mouse model was established by intraperitoneal injection of group B Salmonella typhimurium.Mouse serum ApoE levels were detected by IA,and the hepatic ApoE mRNA and protein expressions of mice were detected by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot,respectively.Data in two groups were compared by independent-sample t test.Results Serum ApoE levels in patients with bacterial

  5. The influence of apolipoprotein E gene polymorphism on brain volume in healthy young adults%载脂蛋白E基因多态性对健康青年人群大脑容积的影响

    Institute of Scientific and Technical Information of China (English)

    刘百薇; 柏琦; 陶霖; 佡剑非; 郑东明

    2015-01-01

    Objective To explore the effect of apolipoprotein E (ApoE) gene polymorphism on brain volume in healthy young adults.Methods One hundred and ninety-three healthy young volunteers (age:20-40 years) were recruited in Shengjing Hospital of China Medical University between August 2013 and May 2014.Two milliliters of peripheral blood were collected for the determination of ApoE genotype using direct sequencing of polymerase chain reaction (PCR) products.Brain MRI scans were performed using three-dimensional T1-weighted turbo field echo imaging sequence.The diffcrences of brain morphometry between the ε4 carriers group (ε3/ε4 and ε4/ε4 genotype) and the ε4 non-carriers group (ε3/ε3 genotype) were analyzed using voxel based morphometry (VBM).Results The ε4 carriers accounted for 14.51% (28/193) of the total population.Twenty of ε4 carriers and 45 of ε4 non-carriers were included in the final images analysis.VBM analysis showed that the ApoE ε4 carriers had 10 atrophic brain areas compared with the ε4 non-carriers (P < 0.005,uncorrected,10 continuous voxels),which mainly located in the right anterior cingulate,the bilateral caudates,parietal lobes and lateral temporal lobes.Conclusions The influence of ApoE gene polymorphisms on brain volume has appeared in the youth.The ε4 gene is related to the reductions of the gray matter volume in multiple brain areas.%目的 探讨载脂蛋白E基因多态性对健康青年人群脑容积的影响.方法 于2013年8月至2014年5月在中国医科大学附属盛京医院招募年龄为20 ~ 40岁的健康志愿者193名.采集其外周血2 ml,应用PCR产物直接测序法检测志愿者的载脂蛋白E(apoliprotein E,ApoE)基因型.同时对志愿者进行头颅MRI扫描,采用三维T1加权成像梯度回波序列获得高分辨率头颅磁共振数据.以ApoE e3/e4及ε4/ε4基因型为ε4携带者组,以ApoE最常见的基因型e3/e3型为对照组,运用基于体素

  6. The in vitro loose dimer structure and rearrangements of the HIV-2 leader RNA

    OpenAIRE

    Purzycka, Katarzyna J.; Pachulska-Wieczorek, Katarzyna; Adamiak, Ryszard W.

    2011-01-01

    RNA dimerization is an essential step in the retroviral life cycle. Dimerization and encapsidation signals, closely linked in HIV-2, are located in the leader RNA region. The SL1 motif and nucleocapsid protein are considered important for both processes. In this study, we show the structure of the HIV-2 leader RNA (+1–560) captured as a loose dimer. Potential structural rearrangements within the leader RNA were studied. In the loose dimer form, the HIV-2 leader RNA strand exists in vitro as a...

  7. Radiation-induced tetramer-to-dimer transition of Escherichia coli lactose repressor

    International Nuclear Information System (INIS)

    The wild type lactose repressor of Escherichia coli is a tetrameric protein formed by two identical dimers. They are associated via a C-terminal 4-helix bundle (called tetramerization domain) whose stability is ensured by the interaction of leucine zipper motifs. Upon in vitro γ-irradiation the repressor losses its ability to bind the operator DNA sequence due to damage of its DNA-binding domains. Using an engineered dimeric repressor for comparison, we show here that irradiation induces also the change of repressor oligomerisation state from tetramer to dimer. The splitting of the tetramer into dimers can result from the oxidation of the leucine residues of the tetramerization domain.

  8. Dimer and String Formation during Low Temperature Silicon Deposition on Si(100)

    DEFF Research Database (Denmark)

    Smith, A. P.; Jonsson, Hannes

    1996-01-01

    We present theoretical results based on density functional theory and kinetic Monte Carlo simulations of silicon deposition and address observations made in recently reported low temperature scanning tunneling microscopy studies. A mechanism is presented which explains dimer formation on top of the...... substrate's dimer rows at 160 K and up to room temperature, while between-row dimers and longer strings of adatoms (''diluted dimer rows'') form at higher temperature. A crossover occurs at around room temperature between two different mechanisms for adatom diffusion in our model....

  9. Adventures in Holographic Dimer Models

    Energy Technology Data Exchange (ETDEWEB)

    Kachru, Shamit; /Stanford U., Phys. Dept. /SLAC; Karch, Andreas; /Washington U., Seattle; Yaida, Sho; /Stanford U., Phys. Dept.

    2011-08-12

    We abstract the essential features of holographic dimer models, and develop several new applications of these models. Firstly, semi-holographically coupling free band fermions to holographic dimers, we uncover novel phase transitions between conventional Fermi liquids and non-Fermi liquids, accompanied by a change in the structure of the Fermi surface. Secondly, we make dimer vibrations propagate through the whole crystal by way of double trace deformations, obtaining nontrivial band structure. In a simple toy model, the topology of the band structure experiences an interesting reorganization as we vary the strength of the double trace deformations. Finally, we develop tools that would allow one to build, in a bottom-up fashion, a holographic avatar of the Hubbard model.

  10. UV laser multiphoton ionization--dissociation of phenylsilane and its homogeneous dimers

    Science.gov (United States)

    Kosmidis, Constantine; Philis, John G.

    1998-01-01

    Homogeneous dimers of phenylsilane, formed in a rare-gas seeded supersonic expansion have been studied by laser resonant two-photon ionization combined with a time-of-flight mass spectrometer. The resonant intermediate states are the S1 (270 nm) and S2 (210 nm) ones. The ionization of phenylsilane monomer is inefficient at 210 nm whereas phenylsilane homo-dimers are resonantly ionized with high efficiency at this wavelength region. The wavelength dependence of the dimer at S1<-- S0 origin region implies the existence of at least two, almost isoenergetic, dimer conformers in the molecular beam. Photoionization of phenylsilane dimer induces chemical reactions within the dimer. The detected dissociation channels have to do with -SiH3 and -C6H6 loss and proton-transfer. Van der Waals fragmentation (evaporation of a neutral phenylsilane) is also taking place.

  11. DNA melting properties of the dityrosine cross-linked dimer of Ribonuclease A.

    Science.gov (United States)

    Dinda, Amit Kumar; Chattaraj, Saparya; Ghosh, Sudeshna; Tripathy, Debi Ranjan; Dasgupta, Swagata

    2016-09-01

    Several DNA binding proteins exist in dimeric form when bound with DNA to be able to exhibit various biological processes such as DNA repair, DNA replication and gene expression. Various dimeric forms of Ribonuclease A (RNase A) and other members of the ribonuclease A superfamily are endowed with a multitude of biological activities such as antitumor and antiviral activity. In the present study, we have compared the DNA binding properties between the RNase A monomer and the dityrosine (DT) cross-linked RNase A dimer, and checked the inhibitory effect of DNA on the ribonucleolytic activity of the dimeric protein. An agarose gel based assay shows that like the monomer, the dimer also binds with DNA. The number of nucleotides bound per monomer unit of the dimer is higher than the number of nucleotides that bind with the each monomer. From fluorescence measurements, the association constant (Ka) values for complexation of the monomer and the dimer with ct-DNA are (4.95±0.45)×10(4)M(-1) and (1.29±0.05)×10(6)M(-1) respectively. Binding constant (Kb) values for the binding of the monomer and the dimer with ct-DNA were determined using UV-vis spectroscopy and were found to be (4.96±1.67)×10(4)M(-1) and (4.32±0.31)×10(5)M(-1) respectively. Circular dichroism studies shows that the dimer possesses significant effect on DNA conformation. The melting profile for the ct-DNA-dimer indicated that the melting temperature (Tm) for the ct-DNA-dimer complex is lower compared to the ct-DNA-monomer complex. The ribonucleolytic activity of the dimer, like the monomer, diminishes upon binding with DNA. PMID:27475778

  12. Rotational Spectrum of Propargyl Alcohol Dimer

    Science.gov (United States)

    Mani, Devendra; Arunan, E.

    2013-06-01

    Propargyl alcohol is a molecule of interest to astrophysics as well as combustion studies. Rotational-tunneling spectra of propargyl alcohol monomer is well known and shows that the molecule exists in gauche form. Recently we reported microwave spectra of Ar...propargyl alcohol complex. Propargyl alcochol exists in gauche form in the complex as well. In this study we have recorded pure rotational spectra of propargyl alcohol dimer between 4-13 GHz range.A total of 47 transitions, 24 a-type, 16 b-type and 7 c-type, have been observed and fitted with semi rigid rotor asymmetric top hamiltonian. The fitted rotational constants are: A = 2321.83323(47) MHz, B = 1150.47726(24) MHz and C = 1124.89000(20) MHz. The standard deviation for the fit is 2.5 kHz. The experimental rotational constants are very close to the structure predicted by ab-initio calculations in which two gauche-propargyl alcohol moieties are in three point contact stabilized by O-H...O, O-H...pi and C-H...pi interactions. Few transitions for duterated isotopologues of the dimer have also been observed and search for the remaining transitions is in progress. Details will be presented in the talk. E. Hirota,J. Mol. Spectrosc. 26 (1968) 335-350. J.C. Pearson, B.J. Drouin, J. Mol. Spectrosc. 234 (2005) 149-156. D. Mani, E. Arunan, ChemPhysChem 14 (2013) 754-763.

  13. Salt bridge residues between I-Ak dimer of dimers alpha-chains modulate antigen presentation.

    Science.gov (United States)

    Yadati, S; Nydam, T; Demian, D; Wade, T K; Gabriel, J L; Barisas, B G; Wade, W F

    1999-03-15

    Class II dimers of dimers are predicted to have functional significance in antigen presentation. The putative contact amino acids of the I-Ak class II dimer of dimers have been identified by molecular modeling based on the DR1 crystal structure (Nydam et al., Int. Immunol. 10, 1237,1998). We have previously reported the role in antigen presentation of dimer of dimers contact amino acids located in the C-terminal domains of the alpha- and beta-chains of class II. Our calculations show that residues Ealpha89 and Ralpha145 in the alpha2-domain form an inter alpha-chain salt bridge between pairs of alphabeta-heterodimers. Other residues, Qalpha92 and Nalpha115, may be involved in close association in that part of the alpha-chain. We investigated the role of these amino acids on class II expression and antigen presentation. Class II composed of an Ealpha89K substituted alpha-chain paired with a wt beta-chain exhibited inhibited antigen presentation and expression of alpha-chain serologic epitopes. In contrast, mutation of Ralpha145E had less affect on antigen presentation and did not affect I-Ak serologic epitopes. Interchanging charges of the salt bridge residues by expressing both Ralpha145E and Ealpha89K on the same chain obviated the large negative effect of the Ealpha89K mutation on antigen presentation but not on the serologic epitopes. Our results are similar for those reported for mutation of DR3's inter-chain salt bridge with the exception that double mutants did not moderate the DR3 defect. Interestingly, the amino acids differences between I-A and DR change the location of the inter-chain salt bridges. In DR1 these residues are located at positions Ealpha88 and Kalpha111; in I-Ak these residues are located at position Ealpha89 and Ralpha145. Inter alpha-chain salt bridges are thus maintained in various class II molecules by amino acids located in different parts of the alpha2-domain. This conservation of structure suggests that considerable functional

  14. A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis.

    OpenAIRE

    Jenne, D. E.; Denzel, K; Blätzinger, P; Winter, P.; Obermaier, B; Linke, R P; Altland, K

    1996-01-01

    The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium, with polyneuropathy and cardiomyopathy as major clinical manifes...

  15. High-Resolution Rotational Spectroscopy Study of the Smallest Sugar Dimer: Interplay of Hydrogen Bonds in the Glycolaldehyde Dimer.

    Science.gov (United States)

    Zinn, Sabrina; Medcraft, Chris; Betz, Thomas; Schnell, Melanie

    2016-05-10

    Molecular recognition of carbohydrates plays an important role in nature. The aggregation of the smallest sugar, glycolaldehyde, was studied in a conformer-selective manner using high-resolution rotational spectroscopy. Two different dimer structures were observed. The most stable conformer reveals C2 -symmetry by forming two intermolecular hydrogen bonds, giving up the strong intramolecular hydrogen bonds of the monomers and thus showing high hydrogen bond selectivity. By analyzing the spectra of the (13) C and (18) O isotopologues of the dimer in natural abundance, we could precisely determine the heavy backbone structure of the dimer. Comparison to the monomer structure and the complex with water provides insight into intermolecular interactions. Despite hydrogen bonding being the dominant interaction, precise predictions from quantum-chemical calculations highly rely on the consideration of dispersion. PMID:27060475

  16. Fiber optic D dimer biosensor

    Science.gov (United States)

    Glass, Robert S.; Grant, Sheila A.

    1999-01-01

    A fiber optic sensor for D dimer (a fibrinolytic product) can be used in vivo (e.g., in catheter-based procedures) for the diagnosis and treatment of stroke-related conditions in humans. Stroke is the third leading cause of death in the United States. It has been estimated that strokes and stroke-related disorders cost Americans between $15-30 billion annually. Relatively recently, new medical procedures have been developed for the treatment of stroke. These endovascular procedures rely upon the use of microcatheters. These procedures could be facilitated with this sensor for D dimer integrated with a microcatheter for the diagnosis of clot type, and as an indicator of the effectiveness, or end-point of thrombolytic therapy.

  17. Dimer models and crepant resolutions

    OpenAIRE

    Ishii, Akira; Ueda, Kazushi

    2013-01-01

    We study variations of tautological bundles on moduli spaces of representations of quivers with relations associated with dimer models under a change of stability parameters. We prove that if the tautological bundle induces a derived equivalence for some stability parameter, then the same holds for any generic stability parameter, and any projective crepant resolution can be obtained as the moduli space for some stability parameter. This result is used in 0905.0059 to prove the abelian McKay ...

  18. Distinct conformations of the kinesin Unc104 neck regulate a monomer to dimer motor transition

    OpenAIRE

    Al-Bassam, Jawdat; Cui, Yujia; Klopfenstein, Dieter; Carragher, Bridget O.; Vale, Ronald D.; Milligan, Ronald A.

    2003-01-01

    Caenhorhabditis elegans Unc104 kinesin transports synaptic vesicles at rapid velocities. Unc104 is primarily monomeric in solution, but recent motility studies suggest that it may dimerize when concentrated on membranes. Using cryo-electron microscopy, we observe two conformations of microtubule-bound Unc104: a monomeric state in which the two neck helices form an intramolecular, parallel coiled coil; and a dimeric state in which the neck helices form an intermolecular coiled coil. The intram...

  19. Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization

    DEFF Research Database (Denmark)

    Vinther, Tine N.; Norrman, Mathias; Strauss, Holger M.;

    2012-01-01

    An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers in...... oligomerization and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further...

  20. Synthesis of steroidal dimers: Selective amine catalysed steroidal dimerization

    Indian Academy of Sciences (India)

    Shamsuzzaman; Mohd Gulfam Aalam; Tabassum Siddiqui

    2011-07-01

    Some new dimeric steroids namely cholest-5-en-3-spiro-[6',5'-oxa]-5'-cholest-3'-one (2), cholest-5-en-7-spiro-[4',5'-oxa]-5'-cholest-7'-one (4a) and 3-substitutedcholest-5-en-7-spiro-[4',5'-oxa]-3'-substituted-5'-cholestan-7'-ones (4b, c) are synthesized starting from cholest-5-en-3-one (1), cholest-5-en-7-one (3a) and 3-substituted-cholest-5-en-7-ones (3b, c) respectively by using DMAP and xylene. All the synthesized compounds were characterized by using IR, MS and 1H, 13C NMR spectral and elemental analysis.

  1. Data on dimer formation between importin α subtypes.

    Science.gov (United States)

    Miyamoto, Yoichi; Oka, Masahiro

    2016-06-01

    This article describes data related to the research article titled "Functional characterization of importin α8 as a classical nuclear localization signal receptor" [1]. A GST pull-down assay showed that both importin α1 and α8, which are classical nuclear localization signal (cNLS) receptors, can form a dimer with importin α6, α7, or α8. Importin α8 has higher dimer-forming ability than importin α1. In addition, our data show that either importin α1 or importin α8 can form a heterodimer with importin α3, which exists in a preformed complex with cNLS substrates such as the conventional SV40TNLS or the p53 protein, resulting in the release of the cNLS substrates from importin α3. PMID:27222842

  2. Cold-active alkaline phosphatase is irreversibly transformed into an inactive dimer by low urea concentrations.

    Science.gov (United States)

    Hjörleifsson, Jens Guðmundur; Ásgeirsson, Bjarni

    2016-07-01

    Alkaline phosphatase is a homodimeric metallo-hydrolase where both Zn(2+) and Mg(2+) are important for catalysis and stability. Cold-adapted alkaline phosphatase variants have high activity at low temperatures and lower thermal stability compared with variants from mesophilic hosts. The instability, and thus inactivation, could be due to loose association of the dimers and/or loosely bound Mg(2)(+) in the active site, but this has not been studied in detail for the cold-adapted variants. Here, we focus on using the intrinsic fluorescence of Trp in alkaline phosphatase from the marine bacterium Vibrio splendidus (VAP) to probe for dimerization. Trp→Phe substitutions showed that two out of the five native Trp residues contributed mostly to the fluorescence emission. One residue, 15Å away from the active site (W460) and highly solvent excluded, was phosphorescent and had a distant role in substrate binding. An additional Trp residue was introduced to the dimer interface to act as a possible probe for dimerization. Urea denaturation curves indicated that an inactive dimer intermediate, structurally equivalent to the native state, was formed before dimer dissociation took place. This is the first example of the transition of a native dimer to an inactive dimer intermediate for alkaline phosphatase without using mutagenesis, ligands, or competitive inhibition. PMID:27043172

  3. Synchronized oscillations of dimers in biphasic charged fd-virus suspensions

    Science.gov (United States)

    Kang, K.; Piao, S. H.; Choi, H. J.

    2016-08-01

    Micron-sized colloidal spheres that are dispersed in an isotropic-nematic biphasic host suspension of charged rods (fd-virus particles) are shown to spontaneously form dimers, which exhibit a synchronized oscillatory motion. Dimer formation is not observed in the monophase of isotropic and nematic suspensions. The synchronized oscillations of dimers are connected to the inhomogeneous state of the host suspension of charged rods (fd viruses) where nematic domains are in coexistence with isotropic regions. The synchronization of oscillations occurs in bulk states, in the absence of an external field. With a low field strength of an applied electric field, the synchronization is rather reduced, but it recovers again when the field is turned off. In this Rapid Communication, we report this observation as an example of the strange attractor, occurring in the mixture of PS (polystyrene) dimers in an isotropic-nematic coexistence biphasic fd-virus network. Furthermore, we highlight that the synchronization of PS-dimer oscillations is the result of a global bifurcation diagram, driven by a delicate balance between the short-attractive "twisted" interaction of PS dimers and long-ranged electrostatic repulsive interactions of charged fd rods. The interest is then in the local enhancement of "twist-nematic" elasticity in reorientation of the dimer oscillations. An analysis of image-time correlations is provided with the data movies and Fourier transforms of averaged orientations for the synchronized oscillations of dimers in the biphasic I -N coexistence concentration of charged fd-virus suspensions.

  4. Dimerization of Human Growth Hormone by Zinc

    Science.gov (United States)

    Cunningham, Brian C.; Mulkerrin, Michael G.; Wells, James A.

    1991-08-01

    Size-exclusion chromatography and sedimentation equilibrium studies demonstrated that zinc ion (Zn2+) induced the dimerization of human growth hormone (hGH). Scatchard analysis of 65Zn2+ binding to hGH showed that two Zn2+ ions associate per dimer of hGH in a cooperative fashion. Cobalt (II) can substitute for Zn2+ in the hormone dimer and gives a visible spectrum characteristic of cobalt coordinated in a tetrahedral fashion by oxygen- and nitrogen-containing ligands. Replacement of potential Zn2+ ligands (His18, His21, and Glu174) in hGH with alanine weakened both Zn2+ binding and hGH dimer formation. The Zn2+-hGH dimer was more stable than monomeric hGH to denaturation in guanidine-HCl. Formation of a Zn2+-hGH dimeric complex may be important for storage of hGH in secretory granules.

  5. Does Dimeric Melittin Occur in Aqueous Solutions?

    OpenAIRE

    Schubert, D; Pappert, G.; Boss, K.

    1985-01-01

    Melittin, a peptide from bee venom, is known to undergo a monomer / tetramer conversion in aqueous solutions. We have studied the possible participation of dimers in the association equilibrium of melittin by sedimentation equilibrium experiments in the analytical ultracentrifuge and subsequent mathematical analysis of the concentration distributions obtained. It was found that the dimeric state is not significantly populated, the contribution of dimer to the total peptide weight probably bei...

  6. Dimerization of norbornene on zeolite catalysts

    Institute of Scientific and Technical Information of China (English)

    N. G. Grigor’eva; S. V. Bubennov; L. M. Khalilov; B. I. Kutepov

    2015-01-01

    The high activity and selectivity of H‐Beta and H‐ZSM‐12 zeolites in the dimerization of norbornene was established. The norbornene conversion reached 100%in chlorinated paraffin and argon gas medium, with a selectivity of dimer formation of 88%–98%. Four stereo‐isomers of the bis‐2,2’‐norbornylidene structure were identified in the dimer fraction, with the (Z)‐anti‐bis‐2,2’‐norbornylidene prevailing over the others.

  7. Monomer-dimer problem on some networks

    Science.gov (United States)

    Wu, Ruijuan; Yan, Weigen

    2016-09-01

    Zhang et al. (2012) obtained the exact formula for the number of all possible monomer-dimer arrangements and the asymptotic growth constant on a scale-free small-world network. In this note, we generalize this result and obtain the exact solution on the monomer-dimer model on many networks. Particularly, we prove that these networks have the same asymptotic growth constant of the number of monomer-dimer arrangements.

  8. Enhanced Chiral Recognition by Cyclodextrin Dimers

    Directory of Open Access Journals (Sweden)

    Bart Jan Ravoo

    2011-07-01

    Full Text Available In this article we investigate the effect of multivalency in chiral recognition. To this end, we measured the host-guest interaction of a β-cyclodextrin dimer with divalent chiral guests. We report the synthesis of carbohydrate-based water soluble chiral guests functionalized with two borneol, menthol, or isopinocampheol units in either (+ or (– configuration. We determined the interaction of these divalent guests with a β-cyclodextrin dimer using isothermal titration calorimetry. It was found that—in spite of a highly unfavorable conformation—the cyclodextrin dimer binds to guest dimers with an increased enantioselectivity, which clearly reflects the effect of multivalency.

  9. Sputtering of dimers off a silicon surface

    Science.gov (United States)

    Nietiadi, Maureen L.; Rosandi, Yudi; Kopnarski, Michael; Urbassek, Herbert M.

    2012-10-01

    We present experimental and molecular-dynamics simulation results of the sputtering of a Si surface by 2 keV Ar ions. Results on both the monomer and dimer distributions are presented. In simulation, these distributions follow a generalized Thompson law with power exponent n=2 and n=3, respectively. The experimental data, obtained via plasma post-ionization in an SNMS (secondary neutral mass spectrometry) apparatus, show good agreement with respect to the dimer fraction, and the relative energy distributions of dimers and monomers. The consequences for the dimer sputtering mechanism are discussed.

  10. Sputtering of dimers off a silicon surface

    Energy Technology Data Exchange (ETDEWEB)

    Nietiadi, Maureen L. [Physics Department, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Research Center OPTIMAS, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Rosandi, Yudi [Physics Department, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Research Center OPTIMAS, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Department of Physics, Universitas Padjadjaran, Jatinangor, Sumedang 45363 (Indonesia); Kopnarski, Michael [Physics Department, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Research Center OPTIMAS, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Institut fuer Oberflaechen- und Schichtanalytik IFOS GmbH, Trippstadter Strasse 120, D-67663 Kaiserslautern (Germany); Urbassek, Herbert M., E-mail: urbassek@rhrk.uni-kl.de [Physics Department, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany); Research Center OPTIMAS, University Kaiserslautern, Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern (Germany)

    2012-10-15

    We present experimental and molecular-dynamics simulation results of the sputtering of a Si surface by 2 keV Ar ions. Results on both the monomer and dimer distributions are presented. In simulation, these distributions follow a generalized Thompson law with power exponent n=2 and n=3, respectively. The experimental data, obtained via plasma post-ionization in an SNMS (secondary neutral mass spectrometry) apparatus, show good agreement with respect to the dimer fraction, and the relative energy distributions of dimers and monomers. The consequences for the dimer sputtering mechanism are discussed.

  11. Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers

    Directory of Open Access Journals (Sweden)

    Ichiro N. Maruyama

    2014-04-01

    Full Text Available Receptor tyrosine kinases (RTKs play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights.

  12. Angle-Resolved Plasmonic Properties of Single Gold Nanorod Dimers

    Institute of Scientific and Technical Information of China (English)

    Jian Wu; Xuxing Lu; Qiannan Zhu; Junwei Zhao; Qishun Shen; Li Zhan; Weihai Ni

    2014-01-01

    Through wet-chemical assembly methods, gold nanorods were placed close to each other and formed a dimer with a gap distance*1 nm, and hence degenerated plasmonic dipole modes of individual nanorods coupled together to produce hybridized bonding and antibonding resonance modes. Previous studies using a condenser for illumination result in averaged signals over all excitation angles. By exciting an individual dimer obliquely at different angles, we demonstrate that these two new resonance modes are highly tunable and sensitive to the angle between the excitation polarization and the dimer orientation, which follows cos2u dependence. Moreover, for dimer structures with various structure angles, the resonance wavelengths as well as the refractive index sensitivities were found independent of the structure angle. Cal-culated angle-resolved plasmonic properties are in good agreement with the measurements. The assembled nanostructures investigated here are important for fundamental researches as well as potential applications when they are used as building blocks in plasmon-based optical and optoelectronic devices.

  13. Morphological and physiological retinal degeneration induced by intravenous delivery of vitamin A dimers in rabbits

    Directory of Open Access Journals (Sweden)

    Jackie Penn

    2015-02-01

    Full Text Available The eye uses vitamin A as a cofactor to sense light and, during this process, some vitamin A molecules dimerize, forming vitamin A dimers. A striking chemical signature of retinas undergoing degeneration in major eye diseases such as age-related macular degeneration (AMD and Stargardt disease is the accumulation of these dimers in the retinal pigment epithelium (RPE and Bruch’s membrane (BM. However, it is not known whether dimers of vitamin A are secondary symptoms or primary insults that drive degeneration. Here, we present a chromatography-free method to prepare gram quantities of the vitamin A dimer, A2E, and show that intravenous administration of A2E to the rabbit results in retinal degeneration. A2E-damaged photoreceptors and RPE cells triggered inflammation, induced remolding of the choroidal vasculature and triggered a decline in the retina’s response to light. Data suggest that vitamin A dimers are not bystanders, but can be primary drivers of retinal degeneration. Thus, preventing dimer formation could be a preemptive strategy to address serious forms of blindness.

  14. Apolipoprotein E gene polymorphism in children with primary nephritic syndrome between Zhuang and Han races in Guangxi%广西壮、汉族原发性肾病综合征患儿载脂蛋白E基因多态性研究

    Institute of Scientific and Technical Information of China (English)

    胡鹏; 覃远汉; 李铭芳

    2006-01-01

    目的研究广西壮、汉族原发性肾病综合征(primary nephritic syndrome,PNS)患儿载脂蛋白E(apolipoprotein E,ApoE)主要等位基因和基因型的分布规律,进一步探讨种族因素对PNS患儿ApoE基因多态性的影响.方法应用聚合酶链反应-单链构象的多态性(single-strand conformation polymorphism,PCR-SSCP)并结合测序的方法确定20例壮族、26例汉族PNSS患儿ApoE基因型,并根据平衡法计算出各等位基因频率.结果肾病组壮、汉族患儿ApoE等位基因和基因型的分布未见明显差异.结论尚不能认为种族因素对广西壮、汉族PNS患儿ApoE基因多态性构成影响.

  15. Glycine transporter dimers: evidence for occurrence in the plasma membrane

    DEFF Research Database (Denmark)

    Bartholomäus, Ingo; Milan-Lobo, Laura; Nicke, Annette;

    2008-01-01

    membrane based on hydrodynamic and native gel electrophoretic studies. Here, we used cysteine substitution and oxidative cross-linking to show that of GlyT1 and GlyT2 also form dimeric complexes within the plasma membrane. GlyT oligomerization at the cell surface was confirmed for both GlyT1 and GlyT2 by......Different Na(+)/Cl(-)-dependent neurotransmitter transporters of the SLC6a family have been shown to form dimers or oligomers in both intracellular compartments and at the cell surface. In contrast, the glycine transporters (GlyTs) GlyT1 and -2 have been reported to exist as monomers in the plasma...

  16. Dimerization of the thyrotropin-releasing hormone receptor potentiates hormone-dependent receptor phosphorylation.

    Science.gov (United States)

    Song, Gyun Jee; Jones, Brian W; Hinkle, Patricia M

    2007-11-13

    The G protein-coupled thyrotropin (TSH)-releasing hormone (TRH) receptor forms homodimers. Regulated receptor dimerization increases TRH-induced receptor endocytosis. These studies test whether dimerization increases receptor phosphorylation, which could potentiate internalization. Phosphorylation at residues 355-365, which is critical for internalization, was measured with a highly selective phospho-site-specific antibody. Two strategies were used to drive receptor dimerization. Dimerization of a TRH receptor-FK506-binding protein (FKBP) fusion protein was stimulated by a dimeric FKBP ligand. The chemical dimerizer caused a large increase in TRH-dependent phosphorylation within 1 min, whereas a monomeric FKBP ligand had no effect. The dimerizer did not alter phoshorylation of receptors lacking the FKBP domain. Dimerization of receptors containing an N-terminal HA epitope also was induced with anti-HA antibody. Anti-HA IgG strongly increased TRH-induced phosphorylation, whereas monomeric Fab fragments had no effect. Anti-HA antibody did not alter phosphorylation in receptors lacking an HA tag. Furthermore, two phosphorylation-defective TRH receptors functionally complemented one another and permitted phosphorylation. Receptors with a D71A mutation in the second transmembrane domain do not signal, whereas receptors with four Ala mutations in the 355-365 region signal normally but lack phosphorylation sites. When D71A- and 4Ala-TRH receptors were expressed alone, neither underwent TRH-dependent phosphorylation. When they were expressed together, D71A receptor was phosphorylated by G protein-coupled receptor kinases in response to TRH. These results suggest that the TRH receptor is phosphorylated preferentially when it is in dimers or when preexisting receptor dimers are driven into microaggregates. Increased receptor phosphorylation may amplify desensitization. PMID:17989235

  17. Dynamic dimer formation between superionic fluorines in PbF2

    Science.gov (United States)

    Nakamura, Nobutaka; Tsumuraya, Kazuo

    2013-03-01

    Recently Tsumuraya et al .(J. Phys. Soc. Jpn. 81,055603(2012).) have elucidated the formation of the dynamic dimers in the superionic conductor α-CuI with the first principles molecular dynamics (MD) method. They, for the first time in research, confirmed the dimer formation through the analyses the origin of the correlation peaks of the partial pair distribution functions and the partial angle distribution functions. The present study elucidates the dynamic structure of the superionc fluorines in PbF2 crystal with the MD method through identifying the origins of the correlation peaks. The fluorines form the dynamic 32 f-8 c and 4 b-8 c dimers.

  18. Requirements for kissing-loop-mediated dimerization of human immunodeficiency virus RNA.

    OpenAIRE

    Clever, J L; Wong, M L; Parslow, T G

    1996-01-01

    Sequences from the 5' end of type 1 human immunodeficiency virus RNA dimerize spontaneously in vitro in a reaction thought to mimic the initial step of genomic dimerization in vivo. Dimer initiation has been proposed to occur through a "kissing-loop" interaction involving a specific RNA stem-loop element designated SL1: the RNA strands first interact by base pairing through a six-base GC-rich palindrome in the loop of SL1, whose stems then isomerize to form a longer interstrand duplex. We now...

  19. Self-assembled rows of Ni porphyrin dimers on the Ag(111) surface

    OpenAIRE

    SENGE, Mathias; SERGEEVA, NATALIA

    2010-01-01

    PUBLISHED The growth and ordering of 5-(10,15,20-triphenylporphyrinatonickel(II))dimer (NiTPP-dimer) molecules on the Ag(111) surface have been investigated using scanning tunnelling microscopy/spectroscopy (STM/STS) and low-energy electron diffraction (LEED). At one monolayer (ML) coverage the NiTPP-dimer forms a well-ordered close-packed molecular layer in which the porphyrin molecules have a flat orientation with the molecular plane lying parallel to the substrate. STM and LEED data obt...

  20. Antimicrobial peptide protegrin-3 adopt an antiparallel dimer in the presence of DPC micelles: a high-resolution NMR study

    International Nuclear Information System (INIS)

    A tendency to dimerize in the presence of lipids was found for the protegrin. The dimer formation by the protegrin-1 (PG-1) is the first step for further oligomeric membrane pore formation. Generally there are two distinct model of PG-1 dimerization in either a parallel or antiparallel β-sheet. But despite the wealth of data available today, protegrin dimer structure and pore formation is still not completely understood. In order to investigate a more detailed dimerization process of PG-1 and if it will be the same for another type of protegrins, in this work we used a high-resolution NMR spectroscopy for structure determination of protegrin-3 (RGGGL-CYCRR-RFCVC-VGR) in the presence of perdeuterated DPC micelles and demonstrate that PG-3 forms an antiparallel NCCN dimer with a possible association of these dimers. This structural study complements previously published solution, solid state and computational studies of PG-1 in various environments and validate the potential of mean force simulations of PG-1 dimers and association of dimers to form octameric or decameric β-barrels

  1. PREPARATION AND APPLICATION OF DIMER ACID/LIGNIN GRAFT COPOLYMER

    OpenAIRE

    Run Fang; Xiansu Cheng; Wu-shi Lin

    2011-01-01

    Dimer acid (DA) was grafted onto lignin (EHL) to form a graft copolymer DA-g-EHL. The selection of the reaction type and the optimization of the reaction conditions for the grafting reaction were conducted through orthogonal and single factor experiments. FT-IR and thermal analysis were used to characterize the graft product. It was found that, compared with free radical grafting, DA can be grafted onto EHL more effectively by ester condensation with strongly acidic cation exchange resin as a...

  2. A computational model for the dimerization of allene.

    Science.gov (United States)

    Skraba, Sarah L; Johnson, Richard P

    2012-12-21

    Computations at the CCSD(T)/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory support long-held beliefs that allene dimerization to 1,2-dimethylenecyclobutane proceeds through diradical intermediates rather than a concerted (π)2(s) + (π)2(a) mechanism. Two diastereomeric transition states with orthogonal and skew geometries have been located for C2-C2 dimerization of allene, with predicted barriers of 34.5 and 40.3 kcal/mol, respectively. In dimerization, the outward-facing ligands rotate in a sense opposite to the forming C-C bond. Both transition states lead to nearly orthogonal (D(2)) singlet bisallyl (or tetramethyleneethane) diradical. This diradical has a barrier to planarization of 3.2 kcal/mol through a planar D(2h) geometry and a barrier to methylene rotation of 14.3 kcal/mol. Bisallyl diradical closes through one of four degenerate paths by a conrotatory motion of the methylene groups with a predicted barrier of 15.7 kcal/mol. The low barrier to planarization of bisallyl, and similar barriers for methylene rotation and conrotatory closure are consistent with a stepwise dimerization process which can still maintain stereochemical elements of reactants. These computations support the observation that racemic 1,3-disubstituted allenes, with access to an orthogonal transition state which minimizes steric strain, will dimerize more readily than enantiopure materials and by a mechanism that preferentially bonds M and P enantiomers. PMID:23198916

  3. Mahler Measure, Eisenstein Series and Dimers

    NARCIS (Netherlands)

    Stienstra, J.

    2007-01-01

    This note reveals a mysterious link between the partition function of certain dimer models on 2-dimensional tori and the L-function of their spectral curves. It also relates the partition function in certain families of dimer models to Eisenstein series. http://www.arxiv.org/abs/math.NT/0502197

  4. Enzymatic oxidative dimerization of silymarin flavonolignans

    Czech Academy of Sciences Publication Activity Database

    Gavezzotti, P.; Vavříková, Eva; Valentová, Kateřina; Fronza, G.; Kudanga, T.; Kuzma, Marek; Riva, S.; Biedermann, David; Křen, Vladimír

    2014-01-01

    Roč. 109, NOV 2014 (2014), s. 24-30. ISSN 1381-1177 R&D Projects: GA MŠk(CZ) LD13041; GA ČR(CZ) GP14-14373P Institutional support: RVO:61388971 Keywords : Silybin dimers * Silydianin dimer * Silymarin Subject RIV: CE - Biochemistry Impact factor: 2.128, year: 2014

  5. Dimerization of the glucan phosphatase laforin requires the participation of cysteine 329.

    Directory of Open Access Journals (Sweden)

    Pablo Sánchez-Martín

    Full Text Available Laforin, encoded by a gene that is mutated in Lafora Disease (LD, OMIM 254780, is a modular protein composed of a carbohydrate-binding module and a dual-specificity phosphatase domain. Laforin is the founding member of the glucan-phosphatase family and regulates the levels of phosphate present in glycogen. Multiple reports have described the capability of laforin to form dimers, although the function of these dimers and their relationship with LD remains unclear. Recent evidence suggests that laforin dimerization depends on redox conditions, suggesting that disulfide bonds are involved in laforin dimerization. Using site-directed mutagenesis we constructed laforin mutants in which individual cysteine residues were replaced by serine and then tested the ability of each protein to dimerize using recombinant protein as well as a mammalian cell culture assay. Laforin-Cys329Ser was the only Cys/Ser mutant unable to form dimers in both assays. We also generated a laforin truncation lacking the last three amino acids, laforin-Cys329X, and this truncation also failed to dimerize. Interestingly, laforin-Cys329Ser and laforin-Cys329X were able to bind glucans, and maintained wild type phosphatase activity against both exogenous and biologically relevant substrates. Furthermore, laforin-Cys329Ser was fully capable of participating in the ubiquitination process driven by a laforin-malin complex. These results suggest that dimerization is not required for laforin phosphatase activity, glucan binding, or for the formation of a functional laforin-malin complex. Cumulatively, these results suggest that cysteine 329 is specifically involved in the dimerization process of laforin. Therefore, the C329S mutant constitutes a valuable tool to analyze the physiological implications of laforin's oligomerization.

  6. Disulphide bridges of phospholipase C of Chlamydomonas reinhardtii modulates lipid interaction and dimer stability.

    Directory of Open Access Journals (Sweden)

    Mayanka Awasthi

    Full Text Available BACKGROUND: Phospholipase C (PLC is an enzyme that plays pivotal role in a number of signaling cascades. These are active in the plasma membrane and triggers cellular responses by catalyzing the hydrolysis of membrane phospholipids and thereby generating the secondary messengers. Phosphatidylinositol-PLC (PI-PLC specifically interacts with phosphoinositide and/or phosphoinositol and catalyzes specific cleavage of sn-3- phosphodiester bond. Several isoforms of PLC are known to form and function as dimer but very little is known about the molecular basis of the dimerization and its importance in the lipid interaction. PRINCIPAL FINDINGS: We herein report that, the disruption of disulphide bond of a novel PI-specific PLC of C. reinhardtii (CrPLC can modulate its interaction affinity with a set of phospholipids and also the stability of its dimer. CrPLC was found to form a mixture of higher oligomeric states with monomer and dimer as major species. Dimer adduct of CrPLC disappeared in the presence of DTT, which suggested the involvement of disulphide bond(s in CrPLC oligomerization. Dimer-monomer equilibrium studies with the isolated fractions of CrPLC monomer and dimer supported the involvement of covalent forces in the dimerization of CrPLC. A disulphide bridge was found to be responsible for the dimerization and Cys7 seems to be involved in the formation of the disulphide bond. This crucial disulphide bond also modulated the lipid affinity of CrPLC. Oligomers of CrPLC were also captured in in vivo condition. CrPLC was mainly found to be localized in the plasma membrane of the cell. The cell surface localization of CrPLC may have significant implication in the downstream regulatory function of CrPLC. SIGNIFICANCE: This study helps in establishing the role of CrPLC (or similar proteins in the quaternary structure of the molecule its affinities during lipid interactions.

  7. Stochastic Flips on Dimer Tilings

    CERN Document Server

    Fernique, Thomas

    2011-01-01

    This paper introduces a Markov process inspired by the problem of quasicrystal growth. It acts over dimer tilings of the triangular grid by randomly performing local transformations, called {\\em flips}, which do not increase the number of identical adjacent tiles (this number can be thought as the tiling energy). Fixed-points of such a process play the role of quasicrystals. We are here interested in the worst-case expected number of flips to converge towards a fixed-point. Numerical experiments suggest a bound quadratic in the number n of tiles of the tiling. We prove a O(n^2.5) upper bound and discuss the gap between this bound and the previous one. We also briefly discuss the average-case.

  8. STM observation of sulfur dimerization in alkanethiol self-assembled monolayers on Au{111}

    OpenAIRE

    O'Dwyer, Colm

    2005-01-01

    We present for the first time, direct microscopical observation by STM of sulfur dimer formation on alkanethiol self-assembled monolayers (SAM) on sputtered Au substrates. The sulfur dimers are observed when imaging at a bias where the tip-molecule interaction occurs, and are formed by displacement of sulfur atoms from their normal three-fold hollow site residence of the (4 × 2) superlattice to nearest-neighbor bridge-site residence between two Au atoms. The displacement is ...

  9. Investigation of UVC Induced DNA Damage Formation and Photolyase Catalyzed Repair of Cyclobutane Pyrimidine Dimers

    OpenAIRE

    Kundu, Lal Mohan

    2005-01-01

    Gradual depletion of the ozone layer and consequently, increased ultraviolet (UV) radiation on the Earth's surface induces DNA-lesions inside the genome, thereby causing mutations. Three kinds of photoproducts are mainly formed, namely: cyclobutane pyrimidine dimers (CPD), pyrimidine-(6-4)-pyrimidone dimer [(6-4)PP] and the Dewar valence isomer of (6-4)PP lesion. The formation of these photolesions is a major cause of cell death (aging) and fatal disease like skin cancer. ...

  10. Multistep π dimerization of tetrakis(n-decyl)heptathienoacene radical cations: a combined experimental and theoretical study.

    Science.gov (United States)

    Ferrón, Cristina Capel; Capdevila-Cortada, Marçal; Balster, Russell; Hartl, František; Niu, Weijun; He, Mingqian; Novoa, Juan J; López Navarrete, Juan T; Hernández, Víctor; Ruiz Delgado, M Carmen

    2014-08-11

    Radical cations of a heptathienoacene α,β-substituted with four n-decyl side groups (D4T7(.) (+) ) form exceptionally stable π-dimer dications already at ambient temperature (Chem. Comm. 2011, 47, 12622). This extraordinary π-dimerization process is investigated here with a focus on the ultimate [D4T7(.) (+) ]2 π-dimer dication and yet-unreported transitory species formed during and after the oxidation. To this end, we use a joint experimental and theoretical approach that combines cyclic voltammetry, in situ spectrochemistry and spectroelectrochemistry, EPR spectroscopy, and DFT calculations. The impact of temperature, thienoacene concentration, and the nature and concentration of counteranions on the π-dimerization process is also investigated in detail. Two different transitory species were detected in the course of the one-electron oxidation: 1) a different transient conformation of the ultimate [D4T7(.) (+) ]2 π-dimer dications, the stability of which is strongly affected by the applied experimental conditions, and 2) intermediate [D4T7]2 (.) (+) π-dimer radical cations formed prior to the fully oxidized [D4T7]2 (.) (+) π-dimer dications. Thus, this comprehensive work demonstrates the formation of peculiar supramolecular species of heptathienoacene radical cations, the stability, nature, and structure of which have been successfully analyzed. We therefore believe that this study leads to a deeper fundamental understanding of the mechanism of dimer formation between conjugated aromatic systems. PMID:25043826

  11. Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain

    Directory of Open Access Journals (Sweden)

    Cowburn David

    2011-05-01

    Full Text Available Abstract Background The C-terminal domain (CTD of HIV-1 capsid (CA, like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs. Results Due to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC, sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease. Conclusions These preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind

  12. Stochastic Optimization Based Study of Dimerization Kinetics

    CERN Document Server

    Talukder, Srijeeta; Metzler, Ralf; Banik, Suman K; Chaudhury, Pinaki

    2013-01-01

    We investigate the potential of numerical algorithms to decipher the kinetic parameters involved in multi-step chemical reactions. To this end we study a dimerization kinetics of protein as a model system. We follow the dimerization kinetics using a stochastic simulation algorithm and combine it with three different optimization techniques (Genetic Algorithm, Simulated Annealing and Parallel Tempering) to obtain the rate constants involved in each reaction step. We find good convergence of the numerical scheme to the rate constants of the process. We also perform a sensitivity test on the reaction kinetic parameters to see the relative effects of the parameters for the associated profile of the monomer/dimer distribution.

  13. T-shaped dimer of coronene

    OpenAIRE

    Obolensky, O. I.; Semenikhina, V. V.; Solov'yov, A. V.; Greiner, W.

    2005-01-01

    An evidence of importance of the T-shaped configuration of coronene dimer is presented. That is, the dimer's lowest energy configuration is not necessarily a stack, as it might had been expected a priori. This is a surprising result for dimer of such a large polycyclic aromatic hydrocarbon (PAH) as coronene. The energy of the T-shaped configuration at all considered levels of density functional theory (B3LYP,PBE/6-31+G(d),D95,cc-pVDZ,cc-pVTZ) was systematically lower than the energies of thre...

  14. Effects of moxa and cigarette smoke on behavioral changes and brainβamyloid deposition in apoli-poprotein E-deficient mice%艾烟与香烟对载脂蛋白E基因敲除小鼠学习记忆功能与海马β淀粉样蛋白沉淀的影响

    Institute of Scientific and Technical Information of China (English)

    刘钧天; 崔莹雪; 黄玉海; 黄畅; 黄剑; 赵百孝; 韩丽; 杨佳; 王磊

    2015-01-01

    Objective To investigate the influence of moxa smoke and cigarette smoke on the apo-lipoprotein E-deficient ( ApoE-/-) male mice’ learning and memory ability andβamyloid deposition in brain hippocampus. Method 13 eight weeks old C57BL/6 mice were assigned to control group;27 eight weeks old ApoE-/- mice were randomly divided into 3 groups ( n=9/group): model group, moxa smoke group, cigarette smoke group. Mice in the two smoke groups were exposed to smoke, which concentration is con-trolled within 5~15 mg/m3;mice in model group and control group were exposed to normal air. The step-down test was conducted in the 13th week. Level ofβamyloid deposition was determined by congo red stai-ning. Results Compared with the model group, mice in control group, moxa smoke group and cigarette smoke group showed decreased learning latency, increased memory latency and made less mistakes in the step-down test (P< 0. 05). Compared with the model group,βamyloid deposition of control group, moxa smoke group and cigarette smoke group was significantly decreased ( P< 0. 05 ) . Conclusion Our find-ings suggest that moxa smoke may have effect on protecting nerve function and anti-aging by reducing the deposition of β amyloid in hippocampus.%目的:观察艾烟与香烟对载脂蛋白E基因敲除( apolipoprotein E-deficient,ApoE-/-)小鼠学习记忆能力与海马β淀粉样蛋白(β-Amyloid)沉淀的影响。方法将13只8周龄C57BL/6小鼠作为空白对照组,27只同龄ApoE-/-小鼠随机分为ApoE-/-模型组、艾烟组、香烟组。香烟与艾烟组小鼠分别暴露于5~15 mg/m3的香烟与艾烟环境。各组小鼠每天干预20分钟,每周6天,共干预12周。于第13周进行行为学测试,之后处死动物、取材,对其脑组织海马中Aβ沉淀进行刚果红染色。结果与模型组对比,空白对照组、艾烟组、香烟组小鼠均表现出学习潜伏期缩短,记忆潜伏期增长,记忆错误次数减少,差别有统计学意义( P<0.05)

  15. Association between ε2/3/4, Promoter Polymorphism (−491A/T, −427T/C, and −219T/G at the Apolipoprotein E Gene, and Mental Retardation in Children from an Iodine Deficiency Area, China

    Directory of Open Access Journals (Sweden)

    Jun Li

    2014-01-01

    Full Text Available Background. Several common single-nucleotide polymorphisms (SNPs at apolipoprotein E (ApoE have been linked with late onset sporadic Alzheimer’s disease and declining normative cognitive ability in elder people, but we are unclear about their relationship with cognition in children. Results. We studied -491A/T, -427T/C, and -219G/T promoter polymorphisms and ε2/ε3/ε4 at ApoE among children with mental retardation (MR, n=130, borderline MR (n=124, and controls (n=334 from an iodine deficiency area in China. The allelic and genotypic distribution of individual locus did not significantly differ among three groups with Mantel-Haenszel χ2 test (P>0.05. However, frequencies of haplotype of -491A/-427T/-219T/ε4 were distributed as MR > borderline MR > controls (P uncorrected = 0.004, indicating that the presence of this haplotype may increase the risk of disease. Conclusions. In this large population-based study in children, we did not find any significant association between single locus of the four common ApoE polymorphisms (-491A/T, -427T/C, -219T/G, and ε2/3/4 and MR or borderline MR. However, we found that the presence of ATTε4 haplotype was associated with an increased risk of MR and borderline MR. Our present work may help enlarge our knowledge of the cognitive role of ApoE across the lifespan and the mechanisms of human cognition.

  16. Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer.

    Science.gov (United States)

    Xue, Li; Rovira, Xavier; Scholler, Pauline; Zhao, Han; Liu, Jianfeng; Pin, Jean-Philippe; Rondard, Philippe

    2015-02-01

    G protein-coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane α helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers. PMID:25503927

  17. Environment assisted energy transfer in dimer system

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Salman, E-mail: sksafi@comsats.edu.pk [Department of Physics, COMSATS Institute of Information Technology, Chak Shahzad, Islamabad (Pakistan); Ibrahim, M.; Khan, M.K. [Department of Physics, Quaid-i-Azam University, Islamabad (Pakistan)

    2014-02-15

    The influence of collective and multilocal environments on the energy transfer between the levels of a dimer is studied. The dynamics of energy transfer are investigated by considering coupling of collective environment with the levels of the dimer in the presence of both two individuals and mutually correlated multilocal environments. It is shown that every way of coupling we consider assists, though differently, the probability of transition between the levels of dimer. The probability of transition is strongly enhanced when the two local environments are mutually correlated. -- Highlights: • The dynamics of energy transfer between the levels of a dimer are studied. • Coupling of collective as well as individual environments are considered. • The environments are in spin star configurations. • The environment assists the energy transfer between the levels. • For correlated multilocal environments, the transition probability is almost 100%.

  18. Synthesis of new dimeric carvacrol compounds

    OpenAIRE

    Uttam B. More; Hemant P. Narkhede; Mahulikar, Pramod P.

    2008-01-01

    The polymer supported carvacrol anion was reacted with 1,2-dibromoethane, 1,4-dibromoethane, oxalyl dichloride, malonyl dichloride, succinyl dichloride, glutaroyl dichloride, and adipoyl dichloride to afford the corresponding dimeric carvacryl ethers or esters

  19. Synthesis of new dimeric carvacrol compounds

    Directory of Open Access Journals (Sweden)

    Uttam B. More

    2008-12-01

    Full Text Available The polymer supported carvacrol anion was reacted with 1,2-dibromoethane, 1,4-dibromoethane, oxalyl dichloride, malonyl dichloride, succinyl dichloride, glutaroyl dichloride, and adipoyl dichloride to afford the corresponding dimeric carvacryl ethers or esters

  20. Modeling dimer structure for efficient singlet fission

    Czech Academy of Sciences Publication Activity Database

    Havlas, Zdeněk; Jovanovic, M.; Michl, Josef

    Kyoto: -, 2013. Oa1. [JCS International Symposium on Theoretical Chemistry /5./. 02.12.2013-06.12.2013, Nara] Institutional support: RVO:61388963 Keywords : singlet fission * dimer structure Subject RIV: CF - Physical ; Theoretical Chemistry

  1. Formation of cystine slipknots in dimeric proteins.

    Science.gov (United States)

    Sikora, Mateusz; Cieplak, Marek

    2013-01-01

    We consider mechanical stability of dimeric and monomeric proteins with the cystine knot motif. A structure based dynamical model is used to demonstrate that all dimeric and some monomeric proteins of this kind should have considerable resistance to stretching that is significantly larger than that of titin. The mechanisms of the large mechanostability are elucidated. In most cases, it originates from the induced formation of one or two cystine slipknots. Since there are four termini in a dimer, there are several ways of selecting two of them to pull by. We show that in the cystine knot systems, there is strong anisotropy in mechanostability and force patterns related to the selection. We show that the thermodynamic stability of the dimers is enhanced compared to the constituting monomers whereas machanostability is either lower or higher. PMID:23520470

  2. Water dimer and the atmospheric continuum

    International Nuclear Information System (INIS)

    The physical origin of humidity-related atmospheric continuum absorption is examined. The existence of double water molecules (dimers) in equilibrium water vapor at room temperature is proved by direct spectroscopic experiments supported by ab initio calculations. It is demonstrated that diluting water vapor with air does not significantly reduce the abundance of dimers. Numerous previous studies have predicted the presence of water dimers in the atmosphere and their influence on chemical reactions, homogeneous condensation, and Earth's radiation balance. Our results provide experimental proof of the presence of dimers in the atmosphere, thus enabling a detailed study of their role in natural processes. Prospects for future research are discussed. (reviews of topical problems)

  3. Reductive dimerization mechanisms of some streptocyanine dyes

    International Nuclear Information System (INIS)

    Cyclic voltammetric studies of streptocyanine dyes were carried out on a glassy carbon electrode. For dye electroreduction, logarithmic analysis of the convoluted current indicates an EC2 mechanism with dimerization following electron transfer. Relevant kinetic and thermodynamic values are reported

  4. Designing Stable Antiparallel Coiled Coil Dimers

    Institute of Scientific and Technical Information of China (English)

    曾宪纲; 周海梦

    2001-01-01

    The history of antiparallel coiled coil dimer design is briefly reviewed and the main principles governing the successful designs are explained. They include analysis of the inter-subunit electrostatic repulsion for determining partners for dimerization and of the buried polar interaction for determining the relative orientation of the partners. A theory is proposed to explain the lack of antiparallel coiled coil homodimers in nature.

  5. Formation of Cystine Slipknots in Dimeric Proteins

    OpenAIRE

    Sikora, Mateusz; Cieplak, Marek

    2013-01-01

    We consider mechanical stability of dimeric and monomeric proteins with the cystine knot motif. A structure based dynamical model is used to demonstrate that all dimeric and some monomeric proteins of this kind should have considerable resistance to stretching that is significantly larger than that of titin. The mechanisms of the large mechanostability are elucidated. In most cases, it originates from the induced formation of one or two cystine slipknots. Since there are four termini in a dim...

  6. Structure and dimerization of translation initiation factor aIF5B in solution

    International Nuclear Information System (INIS)

    Highlights: ► aIF5B forms maximum 5.0–6.8% irreversible dimers in solution. ► Sedimentation coefficients for monomer and dimer are 3.64 and 5.51 ± 0.29 S. ► Adding only 2% glycerol prevents dimerization. ► SAXS on aIF5B monomer gave an Rg of 37.5 ± 0.2 Å and a Dmax of ∼130 Å. ► There are universal structural differences between aIF5B and Escherichia coli IF2. -- Abstract: Translation initiation factor 5B (IF5B) is required for initiation of protein synthesis. The solution structure of archaeal IF5B (aIF5B) was analysed by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) and was indicated to be in both monomeric and dimeric form. Sedimentation equilibrium (SE) analytical ultracentrifugation (AUC) of aIF5B indicated that aIF5B forms irreversible dimers in solution but only to a maximum of 5.0–6.8% dimer. Sedimentation velocity (SV) AUC at higher speed also indicated the presence of two species, and the sedimentation coefficients s20,w0 were determined to be 3.64 and 5.51 ± 0.29 S for monomer and dimer, respectively. The atomic resolution (crystallographic) structure of aIF5B (Roll-Mecak et al. ) was used to model monomer and dimer, and theoretical sedimentation coefficients for these models were computed (3.89 and 5.63 S, respectively) in good agreement with the sedimentation coefficients obtained from SV analysis. Thus, the structure of aIF5B in solution must be very similar to the atomic resolution structure of aIF5B. SAXS data were acquired in the same buffer with the addition of 2% glycerol to inhibit dimerization, and the resultant monomeric aIF5B in solution did indeed adopt a structure very similar to the one reported earlier for the protein in crystalline form. The p(r) function indicated an elongated conformation supported by a radius of gyration of 37.5 ± 0.2 Å and a maximum dimension of ∼130 Å. The effects of glycerol on the formation of dimers are discussed. This new model of aIF5B in solution shows that

  7. Direct assessment of the effect of the Gly380Arg achondroplasia mutation on FGFR3 dimerization using quantitative imaging FRET.

    Directory of Open Access Journals (Sweden)

    Jesse Placone

    Full Text Available The Gly380Arg mutation in FGFR3 is the genetic cause for achondroplasia (ACH, the most common form of human dwarfism. The mutation has been proposed to increase FGFR3 dimerization, but the dimerization propensities of wild-type and mutant FGFR3 have not been compared. Here we use quantitative imaging FRET to characterize the dimerization of wild-type FGFR3 and the ACH mutant in plasma membrane-derived vesicles from HEK293T cells. We demonstrate a small, but statistically significant increase in FGFR3 dimerization due to the ACH mutation. The data are consistent with the idea that the ACH mutation causes a structural change which affects both the stability and the activity of FGFR3 dimers in the absence of ligand.

  8. Nonadiabatic dynamics of floppy hydrogen bonded complexes: the case of the ionized ammonia dimer.

    Science.gov (United States)

    Chalabala, Jan; Slavíček, Petr

    2016-07-27

    In the case of the ammonia dimer, we address the following questions: how ultrafast ionization dynamics is controlled by hydrogen bonding and whether we can control the products via selective ionization of a specific electron. We use quantum chemical calculations and ab initio non-adiabatic molecular dynamics simulations to model the femtosecond dynamics of the ammonia dimer upon ionization. The role of nuclear quantum effects and thermal fluctuations in predicting the structure of the dimer is emphasized; it is shown that the minimum energy and vibrationally averaged structures are rather different. The ground state structure subsequently controls the ionization dynamics. We describe reaction pathways, electronic population transfers and reaction yields with respect to ionization from different molecular orbitals. The simulations showed that the ionized ammonia dimer is highly unstable and its decay rate is primarily driven by the position of the electron hole. In the case of ground state ionization (i.e. the HOMO electron is ionized), the decay is likely to be preceded by a proton transfer (PT) channel yielding NH4(+) and NH2˙ fragments. The PT is less intense and slower compared with the ionized water dimer. After ionizing deeper lying electrons, mainly NH3(+)˙ and NH3 fragments are formed. Overall, our results show that the ionization dynamics of the ammonia and water dimers differ due to the nature of the hydrogen bond in these systems. PMID:27402376

  9. Structure of a Rabbit Muscle Fructose-1,6-Bisphosphate Aldolase A Dimer Variant

    Energy Technology Data Exchange (ETDEWEB)

    Sherawat,M.; Tolan, D.; Allen, K.

    2008-01-01

    Fructose-1,6-bisphosphate aldolase (aldolase) is an essential enzyme in glycolysis and gluconeogenesis. In addition to this primary function, aldolase is also known to bind to a variety of other proteins, a property that may allow it to perform 'moonlighting' roles in the cell. Although monomeric and dimeric aldolases possess full catalytic activity, the enzyme occurs as an unusually stable tetramer, suggesting a possible link between the oligomeric state and these noncatalytic cellular roles. Here, the first high-resolution X-ray crystal structure of rabbit muscle D128V aldolase, a dimeric form of aldolase mimicking the clinically important D128G mutation in humans associated with hemolytic anemia, is presented. The structure of the dimer was determined to 1.7 Angstroms resolution with the product DHAP bound in the active site. The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase. The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer. The tertiary structure of the dimer does not significantly differ from the structure of half of the tetramer. Analytical ultracentrifugation confirms the occurrence of the enzyme as a dimer in solution. The highly stable structure of aldolase with an independent active site is consistent with a model in which aldolase has evolved as a multimeric scaffold to perform other noncatalytic functions.

  10. Dimeric 2G12 as a potent protection against HIV-1.

    Directory of Open Access Journals (Sweden)

    Xin M Luo

    Full Text Available We previously showed that broadly neutralizing anti-HIV-1 antibody 2G12 (human IgG1 naturally forms dimers that are more potent than monomeric 2G12 in in vitro neutralization of various strains of HIV-1. In this study, we have investigated the protective effects of monomeric versus dimeric 2G12 against HIV-1 infection in vivo using a humanized mouse model. Our results showed that passively transferred, purified 2G12 dimer is more potent than 2G12 monomer at preventing CD4 T cell loss and suppressing the increase of viral load following HIV-1 infection of humanized mice. Using humanized mice bearing IgG "backpack" tumors that provided 2G12 antibodies continuously, we found that a sustained dimer concentration of 5-25 µg/ml during the course of infection provides effective protection against HIV-1. Importantly, 2G12 dimer at this concentration does not favor mutations of the HIV-1 envelope that would cause the virus to completely escape 2G12 neutralization. We have therefore identified dimeric 2G12 as a potent prophylactic reagent against HIV-1 in vivo, which could be used as part of an antibody cocktail to prevent HIV-1 infection.

  11. Quantitation of pyrimidine dimers in DNA from UVB-irradiated alfalfa (Medicago sativa L.) seedlings

    International Nuclear Information System (INIS)

    Depletion of stratospheric ozone will increase the solar ultraviolet radiation in the range from 290-320 nm (UVB) that reaches the surface of the earth, placing an increased UV burden on exposed organisms. One consequence of increased UVB may be decreased productivity of crop plants. A principal lesion caused by UV in DNA is the cyclobutyl pyrimidine dimer. We have adapted a method for measuring these dimers in nanogram quantities of non-radioactive DNA for use in UV-irradiated plants. We find that biologically relevant doses of broad band UVB radiation induce easily detectable frequencies of pyrimidine dimers in the DNA of irradiated alfalfa sprout leaves and that the dose response for dimer formation is linear up to doses of at least 690 J/m2. We also find easily measurable frequencies of dimers in the leaves of seedlings grown in glass filtered sunlight but not exposed to additional UVB, suggesting that significant number of dimers are formed in plants exposed to normal sunlight. 27 refs., 3 figs., 1 tab

  12. Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate.

    Directory of Open Access Journals (Sweden)

    Yingzhi Xu

    Full Text Available 3-Hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35 is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60-80 that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects.

  13. Shear-response of the spectrin dimer-tetramer equilibrium in the red blood cell membrane

    Energy Technology Data Exchange (ETDEWEB)

    An, Xiuli; Lecomte, M. Christine; Chasis, Joel Anne; Mohandas, Narla; Gratzer, Walter

    2003-06-18

    The red cell membrane derives its elasticity and resistance to mechanical stresses from the membrane skeleton, a network composed of spectrin tetramers. These are formed by the head-to-head association of pairs of heterodimers attached at their ends to junctional complexes of several proteins. Here we examine the dynamics of the spectrin dimer-dimer association in the intact membrane. We show that univalent fragments of spectrin, containing the dimer self-association site, will bind to spectrin on the membrane and thereby disrupt the continuity of the protein network. This results in impairment of the mechanical stability of the membrane. When, moreover, the cells are subjected to a continuous low level of shear, even at room temperature, the incorporation of the fragments and the consequent destabilization of the membrane are greatly accentuated. It follows that a modest shearing force, well below that experienced by the red cell in the circulation, is sufficient to sever dimer-dimer links in the network. Our results imply (1) that the membrane accommodates the enormous distortions imposed on it during the passage of the cell through the micro vasculature by means of local dissociation of spectrin tetramers to dimers, (2) that the network in situ is in a dynamic state and under goes a ''breathing'' action of tetramer dissociation and re-formation.

  14. Dislocations and vacancies in two-dimensional mixed crystals of spheres and dimers

    KAUST Repository

    Gerbode, Sharon J.

    2010-10-15

    In colloidal crystals of spheres, dislocation motion is unrestricted. On the other hand, recent studies of relaxation in crystals of colloidal dimer particles have demonstrated that the dislocation dynamics in such crystals are reminiscent of glassy systems. The observed glassy dynamics arise as a result of dislocation cages formed by certain dimer orientations. In the current study, we use experiments and simulations to investigate the transition that arises when a pure sphere crystal is doped with an increasing concentration of dimers. Specifically, we focus on both dislocation caging and vacancy motion. Interestingly, we find that any nonzero fraction of dimers introduces finite dislocation cages, suggesting that glassy dynamics are present for any mixed crystal. However, we have also identified a vacancy-mediated uncaging mechanism for releasing dislocations from their cages. This mechanism is dependent on vacancy diffusion, which slows by orders of magnitude as the dimer concentration is increased. We propose that in mixed crystals with low dimer concentrations vacancy diffusion is fast enough to uncage dislocations and delay the onset of glassy dislocation dynamics. © 2010 The American Physical Society.

  15. Independent relationship between amyloid precursor protein (APP dimerization and γ-secretase processivity.

    Directory of Open Access Journals (Sweden)

    Joo In Jung

    Full Text Available Altered production of β-amyloid (Aβ from the amyloid precursor protein (APP is closely associated with Alzheimer's disease (AD. APP has a number of homo- and hetero-dimerizing domains, and studies have suggested that dimerization of β-secretase derived APP carboxyl terminal fragment (CTFβ, C99 impairs processive cleavage by γ-secretase increasing production of long Aβs (e.g., Aβ1-42, 43. Other studies report that APP CTFβ dimers are not γ-secretase substrates. We revisited this issue due to observations made with an artificial APP mutant referred to as 3xK-APP, which contains three lysine residues at the border of the APP ectodomain and transmembrane domain (TMD. This mutant, which dramatically increases production of long Aβ, was found to form SDS-stable APP dimers, once again suggesting a mechanistic link between dimerization and increased production of long Aβ. To further evaluate how multimerization of substrate affects both initial γ-secretase cleavage and subsequent processivity, we generated recombinant wild type- (WT and 3xK-C100 substrates, isolated monomeric, dimeric and trimeric forms of these proteins, and evaluated both ε-cleavage site utilization and Aβ production. These show that multimerization significantly impedes γ-secretase cleavage, irrespective of substrate sequence. Further, the monomeric form of the 3xK-C100 mutant increased long Aβ production without altering the initial ε-cleavage utilization. These data confirm and extend previous studies showing that dimeric substrates are not efficient γ-secretase substrates, and demonstrate that primary sequence determinants within APP substrate alter γ-secretase processivity.

  16. Camelliin B and nobotanin I, macrocyclic ellagitannin dimers and related dimers, and their antitumor activity.

    Science.gov (United States)

    Yoshida, T; Chou, T; Haba, K; Okano, Y; Shingu, T; Miyamoto, K; Koshiura, R; Okuda, T

    1989-11-01

    Camelliin B and nobotanin I, dimeric hydrolyzable tannins of a new class having macrocyclic structures, were isolated from Camellia japonica and Heterocentron roseum, respectively. Nobotanin G and H of the structures related to nobotanin I, were also obtained from H. roseum. Camelliin B and also woodfordin C, a macrocyclic dimer from Woodfordia fruticosa, exhibited marked host-mediated antitumor activities. PMID:2632067

  17. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.

    Science.gov (United States)

    Mahley, Robert W

    2016-07-01

    Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer's disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12-29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders. PMID:27277824

  18. Apolipoprotein E polymorphism in German patients with frontotemporal degeneration

    OpenAIRE

    Riemenschneider, M.; Diehl, J; Muller, U; Forstl, H.; Kurz, A.

    2002-01-01

    Methods: the frequencies of the ε2 and ε4 alleles and the effect of these alleles on the age at onset in 52 patients with frontotemporal degeneration who underwent a thorough diagnostic examination and in 182 cognitively healthy age matched controls were assessed. Genotype comparisons between the groups were performed using multiple logistic regression analysis. Ages at onset according to the apoE genotype were compared by linear regression analysis.

  19. IL-25 inhibits atherosclerosis development in apolipoprotein E deficient mice.

    Directory of Open Access Journals (Sweden)

    Polyxeni T Mantani

    Full Text Available IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice.Administration of 1 μg IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apoE deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 μg IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease.The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.

  20. Apolipoprotein E genotype in patients with Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    罗本燕; 陈智; 张艳艳; 潘小平; 李霞; 陈峰

    2003-01-01

    Objective To explore the frequency and significance of ApoE gene polymorphisms in patients with sporadic Alzheimer's disease (AD).Methods Single nucleotide polymorphisms of the ApoE gene were analyzed in 32 cases of AD and 26 controls, using PCR and gene sequencing.Results The single nucleotide polymorphism of ApoE gene 462C/G was significantly associated with AD (P<0.05).Conclusions The 462C/G polymorphism might be a specific genotype in Chinese patients with sporadic AD.

  1. Apolipoprotein E*3-Leiden transgenic mice mode for hypolipidaemic drugs

    OpenAIRE

    Vlijmen, B.J.M. van; Pearce, N.J.; Bergö, M.; Staels, B.; Yates, J.W.; Gribble, A.D.; Bond, B.C.; Hofker, M H; Havekes, L. M.; Groot, P H E

    1998-01-01

    Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a novel compound, SB 204990 (the 5- ring lactone of ±(3R*,5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5- dihydroxyundecanoic acid, CAS 154566-12-8), a poten...

  2. Genetic susceptibility to traumatic brain injury and apolipoprotein E gene

    Institute of Scientific and Technical Information of China (English)

    SUN Xiao-chuan; JIANG Yong

    2008-01-01

    @@ Traumatic brain injury (TBI) is defined as an injury caused by a blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. It is a common emergency and severe case in neurosurgery field. Nowadays, there are more and more evidences showing that TBI, which is apparently similar in pathology and severity in the acute stage, may have different outcomes.

  3. Expression of apolipoprotein E during nerve degeneration and regeneration

    OpenAIRE

    Ignatius, M J; Gebicke-Härter, P J; Skene, J H; Schilling, J W; Weisgraber, K H; Mahley, R. W.; Shooter, E M

    1986-01-01

    A 37-kDa glycoprotein has been described recently, whose synthesis is dramatically increased after injury of the rat sciatic and optic nerves. Cells in the nerve sheath, distal to the site of injury, produce and secrete large amounts of this protein, so that by 3 weeks after injury, it represents 2-5% of the total soluble extracellular protein in the regenerating sciatic nerve sheath, although it fails to accumulate in damaged optic nerve. Results presented here reveal extensive homology betw...

  4. Formation of H-type liquid crystal dimer at air-water interface

    International Nuclear Information System (INIS)

    We have formed the Langmuir monolayer of H-shaped Azo linked liquid crystal dimer molecule at the air-water interface. Isocycles of the molecule showed hysteresis suggesting the ir-reversible nature of the monolayer formed. The thin film deposited on the silicon wafer was characterized using Atomic Force Microscopy (AFM) and Field Emission Scanning Electron Microscopy (FESEM). The images showed uniform domains of the dimer molecule. We propose that these molecules tend to take book shelf configuration in the liquid phase

  5. Formation of H-type liquid crystal dimer at air-water interface

    Energy Technology Data Exchange (ETDEWEB)

    Karthik, C., E-mail: karthik.c@pilani.bits-pilani.ac.in; Gupta, Adbhut, E-mail: karthik.c@pilani.bits-pilani.ac.in; Joshi, Aditya, E-mail: karthik.c@pilani.bits-pilani.ac.in; Manjuladevi, V., E-mail: karthik.c@pilani.bits-pilani.ac.in; Gupta, Raj Kumar, E-mail: karthik.c@pilani.bits-pilani.ac.in [Department of Physics, Birla Institute of Technology and Science, Pilani, Rajasthan -333031 (India); Varia, Mahesh C.; Kumar, Sandeep [Raman Research Institute, Sadashivanagar, Bangalore - 560080 (India)

    2014-04-24

    We have formed the Langmuir monolayer of H-shaped Azo linked liquid crystal dimer molecule at the air-water interface. Isocycles of the molecule showed hysteresis suggesting the ir-reversible nature of the monolayer formed. The thin film deposited on the silicon wafer was characterized using Atomic Force Microscopy (AFM) and Field Emission Scanning Electron Microscopy (FESEM). The images showed uniform domains of the dimer molecule. We propose that these molecules tend to take book shelf configuration in the liquid phase.

  6. Solution structure of the dimeric cytoplasmic domain of syndecan-4

    DEFF Research Database (Denmark)

    Shin, J; Lee, W; Lee, D;

    2001-01-01

    cytoplasmic domain is dependent on its oligomeric status, the conformation of the syndecan-4 cytoplasmic domain itself is important in the understanding of its biological roles. Gel filtration results show that the syndecan-4 cytoplasmic domain (4L) itself forms a dimer stabilized by ionic interactions...... is affected by the presence of C1 and C2 regions. Therefore, we propose that although the 4V region in the full cytoplasmic domain has a tendency for strong peptide--peptide interaction, it may not be enough to overcome the repulsion of the C1 regions of syndecan-4L....

  7. Structure of a rabbit muscle fructose-1, 6-bisphosphate aldolase A dimer variant

    Energy Technology Data Exchange (ETDEWEB)

    Sherawat, Manashi [Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2394 (United States); Tolan, Dean R., E-mail: tolan@bu.edu [Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215 (United States); Allen, Karen N., E-mail: tolan@bu.edu [Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2394 (United States)

    2008-05-01

    The X-ray crystallographic structure of a dimer variant of fructose-1, 6-bisphosphate aldolase demonstrates a stable oligomer that mirrors half of the native tetramer. The presence of product demonstrates that this is an active form. Fructose-1, 6-bisphosphate aldolase (aldolase) is an essential enzyme in glycolysis and gluconeogenesis. In addition to this primary function, aldolase is also known to bind to a variety of other proteins, a property that may allow it to perform ‘moonlighting’ roles in the cell. Although monomeric and dimeric aldolases possess full catalytic activity, the enzyme occurs as an unusually stable tetramer, suggesting a possible link between the oligomeric state and these noncatalytic cellular roles. Here, the first high-resolution X-ray crystal structure of rabbit muscle D128V aldolase, a dimeric form of aldolase mimicking the clinically important D128G mutation in humans associated with hemolytic anemia, is presented. The structure of the dimer was determined to 1.7 Å resolution with the product DHAP bound in the active site. The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase. The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer. The tertiary structure of the dimer does not significantly differ from the structure of half of the tetramer. Analytical ultracentrifugation confirms the occurrence of the enzyme as a dimer in solution. The highly stable structure of aldolase with an independent active site is consistent with a model in which aldolase has evolved as a multimeric scaffold to perform other noncatalytic functions.

  8. Structure of a rabbit muscle fructose-1, 6-bisphosphate aldolase A dimer variant

    International Nuclear Information System (INIS)

    The X-ray crystallographic structure of a dimer variant of fructose-1, 6-bisphosphate aldolase demonstrates a stable oligomer that mirrors half of the native tetramer. The presence of product demonstrates that this is an active form. Fructose-1, 6-bisphosphate aldolase (aldolase) is an essential enzyme in glycolysis and gluconeogenesis. In addition to this primary function, aldolase is also known to bind to a variety of other proteins, a property that may allow it to perform ‘moonlighting’ roles in the cell. Although monomeric and dimeric aldolases possess full catalytic activity, the enzyme occurs as an unusually stable tetramer, suggesting a possible link between the oligomeric state and these noncatalytic cellular roles. Here, the first high-resolution X-ray crystal structure of rabbit muscle D128V aldolase, a dimeric form of aldolase mimicking the clinically important D128G mutation in humans associated with hemolytic anemia, is presented. The structure of the dimer was determined to 1.7 Å resolution with the product DHAP bound in the active site. The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase. The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer. The tertiary structure of the dimer does not significantly differ from the structure of half of the tetramer. Analytical ultracentrifugation confirms the occurrence of the enzyme as a dimer in solution. The highly stable structure of aldolase with an independent active site is consistent with a model in which aldolase has evolved as a multimeric scaffold to perform other noncatalytic functions

  9. Radiation chemistry of aromatic dimer radical cations

    International Nuclear Information System (INIS)

    π-π Interactions of aromatic molecules are paid attention much in many fields, especially biology, chemistry, and applied physics, represented as protein, DNA, electron donor-accepter complexes, charge transfers, and self assembly molecules. Aromatic molecules including benzene rings are the simplest case to study the π-π interactions. To interpret the charge resonance (CR) structure in the dimer radical cations, spectroscopic and ESR methods have been carried out. The spectroscopic study on the dimer radical ion of molecules with two chromophores would be profitable to identify the electronic and configurational properties. In this article, dynamics of the dimer radical cation of benzenes, polystyrenes, and resist polymers is described on the basis of direct observation of CR band by the nanosecond pulse radiolysis and low temperature γ-radiolysis methods. (author)

  10. Photoionization of helium dimers; Photoionisation von Heliumdimeren

    Energy Technology Data Exchange (ETDEWEB)

    Havermeier, Tilo

    2010-06-09

    The helium dimer is one of the most weakly bound systems in the universe. This makes it an interesting quantum mechanical object for investigation. These Van der Waals Clusters can be produced in an expansion of a cryogenic gas jet through a small nozzle into vacuum. In the present experiment we examine the interaction of He dimers with synchrotron radiation at an energy range from 64 to 78 eV. We observed different pathways leading to single ionization of both He atoms of the dimer compound. This two close standing ions begin now to dissociate in cause of their coulomb potential. All charged fragments were detected in coincidence with a COLTRIMS system. Especially Interatomic Coulombic Decay (ICD) and the two step process (TS1) were clearly identified. Furthermore a distribution of the internuclear distance was obtained from the measured Kinetic Energy Release (KER). (orig.)

  11. Non-cysteine linked MUC1 cytoplasmic dimers are required for Src recruitment and ICAM-1 binding induced cell invasion

    Directory of Open Access Journals (Sweden)

    Gunasekara Nirosha

    2011-07-01

    Full Text Available Abstract Background The mucin MUC1, a type I transmembrane glycoprotein, is overexpressed in breast cancer and has been correlated with increased metastasis. We were the first to report binding between MUC1 and Intercellular adhesion molecule-1 (ICAM-1, which is expressed on stromal and endothelial cells throughout the migratory tract of a metastasizing breast cancer cell. Subsequently, we found that MUC1/ICAM-1 binding results in pro-migratory calcium oscillations, cytoskeletal reorganization, and simulated transendothelial migration. These events were found to involve Src kinase, a non-receptor tyrosine kinase also implicated in breast cancer initiation and progression. Here, we further investigated the mechanism of MUC1/ICAM-1 signalling, focusing on the role of MUC1 dimerization in Src recruitment and pro-metastatic signalling. Methods To assay MUC1 dimerization, we used a chemical crosslinker which allowed for the detection of dimers on SDS-PAGE. We then generated MUC1 constructs containing an engineered domain which allowed for manipulation of dimerization status through the addition of ligands to the engineered domain. Following manipulation of dimerization, we immunoprecipitated MUC1 to investigate recruitment of Src, or assayed for our previously observed ICAM-1 binding induced events. To investigate the nature of MUC1 dimers, we used both non-reducing SDS-PAGE and generated a mutant construct lacking cysteine residues. Results We first demonstrate that the previously observed MUC1/ICAM-1signalling events are dependent on the activity of Src kinase. We then report that MUC1 forms constitutive cytoplasmic domain dimers which are necessary for Src recruitment, ICAM-1 induced calcium oscillations and simulated transendothelial migration. The dimers are not covalently linked constitutively or following ICAM-1 binding. In contrast to previously published reports, we found that membrane proximal cysteine residues were not involved in

  12. Dimerization and DNA recognition rules of mithramycin and its analogues.

    Science.gov (United States)

    Weidenbach, Stevi; Hou, Caixia; Chen, Jhong-Min; Tsodikov, Oleg V; Rohr, Jürgen

    2016-03-01

    The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me(2+))-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM=MTM SDK>MTM SA-Trp>MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents. PMID:26760230

  13. A redox-dependent dimerization switch regulates activity and tolerance for reactive oxygen species of barley seed glutathione peroxidase

    DEFF Research Database (Denmark)

    Navrot, Nicolas; Skjoldager, Nicklas; Bunkenborg, Jakob;

    2015-01-01

    Monomeric and dimeric forms of recombinant barley (Hordeum vulgare subsp. vulgare) glutathione peroxidase 2 (HvGpx2) are demonstrated to display distinctly different functional properties in vitro. Monomeric HvGpx2 thus has five fold higher catalytic efficiency than the dimer towards tert......-butyl hydroperoxide, but is more sensitive to inactivation by hydrogen peroxide. Treatment of the monomer with hydrogen peroxide results in dimer formation. This observed new behavior of a plant glutathione peroxidase suggests a mechanism involving a switch from a highly catalytically competent monomer to a less...

  14. Direct Assessment of the Effect of the Gly380Arg Achondroplasia Mutation on FGFR3 Dimerization Using Quantitative Imaging FRET

    OpenAIRE

    Placone, Jesse; Hristova, Kalina

    2012-01-01

    The Gly380Arg mutation in FGFR3 is the genetic cause for achondroplasia (ACH), the most common form of human dwarfism. The mutation has been proposed to increase FGFR3 dimerization, but the dimerization propensities of wild-type and mutant FGFR3 have not been compared. Here we use quantitative imaging FRET to characterize the dimerization of wild-type FGFR3 and the ACH mutant in plasma membrane-derived vesicles from HEK293T cells. We demonstrate a small, but statistically significant increase...

  15. Photosynthetic reaction center mimicry of a "special pair" dimer linked to electron acceptors by a supramolecular approach: self-assembled cofacial zinc porphyrin dimer complexed with fullerene(s).

    Science.gov (United States)

    D'Souza, Francis; Chitta, Raghu; Gadde, Suresh; Rogers, Lisa M; Karr, Paul A; Zandler, Melvin E; Sandanayaka, Atula S D; Araki, Yasuyaki; Ito, Osamu

    2007-01-01

    Biomimetic bacterial photosynthetic reaction center complexes have been constructed using well-defined self-assembled supramolecular approaches. The "special pair" donor, a cofacial porphyrin dimer, was formed via potassium ion induced dimerization of meso-(benzo-[15]crown-5)porphyrinatozinc. The dimer was subsequently self-assembled with functionalized fullerenes via axial coordination and crown ether-alkyl ammonium cation complexation to form the donor-acceptor pairs, mimicking the noncovalently bound entities of the photosynthetic reaction center. The adopted self-assembly methodology yielded supramolecular complexes of higher stability, with defined geometry and orientation. Efficient forward electron transfer from the singlet excited zinc porphyrin dimer to the fullerene entity and relatively slow reverse electron transfer, important steps in the photosynthetic light energy conversion have been achieved in these novel biomimetic model systems. PMID:17066393

  16. Surprising Impact of Remote Groups on the Folding-Unfolding and Dimer-Chain Equilibria of Bifunctionl H-Bonding Unimers

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Rui; Cheng, Shuang; Baker, Erin Shammel; Smith, Richard D.; Zeng, Xiao Cheng; Gong, Bing

    2016-01-28

    Oligoamide 1, consisting of two H-bonding units linked by a trimethylene linker, was previously found to form a very stable, folded dimer. In this work, replacing the side chains and end groups of 1 led to derivatives that show the surprising impact of end groups on the folding and dimer-chain equilibria of the resultant molecules.

  17. Close Packing of Listeria monocytogenes ActA, a Natively Unfolded Protein, Enhances F-actin Assembly without Dimerization*

    OpenAIRE

    Footer, Matthew J.; Lyo, John K; Theriot, Julie A.

    2008-01-01

    Studies of the biochemistry of Listeria monocytogenes virulence protein ActA have typically focused on the behavior of bacteria in complex systems or on the characterization of the protein after expression and purification. Although prior in vivo work has proposed that ActA forms dimers on the surface of L. monocytogenes, dimerization has not been demonstrated in vitro, and little consideration has been given to the surface environment where ActA performs its pivotal r...

  18. Failure of matrix metalloproteinase-9 dimer induction by phorbol 12-myristate 13-acetate in normal human cell lines

    OpenAIRE

    WAHEED ROOMI, MOHD; KALINOVSKY, TATIANA; RATH, MATTHIAS; NIEDZWIECKI, ALEKSANDRA

    2015-01-01

    Increasing experimental and clinical data has identified an association between increased levels of matrix metalloproteinase (MMP)-9 and shortened patient survival, cancer progression and metastasis. MMP-9 has a significant role in tumor cell invasion and metastasis, as it digests the basement membrane and components of the extracellular matrix. MMP-9 is secreted in either a monomeric or dimeric form. Although limited evidence exists concerning MMP-9 dimers, certain studies have demonstrated ...

  19. A New Diterpenoid Dimer from Annona glabra

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Anew diterpenoid dimer annonebinide A has been isolated from the stems ofAnnona glabra. Its structure was determined to be ent-16α-hydroxykauran-17-yl ent- 16β-kauran- 17-oate on the basis ofspectroscopic and chemical evidence.

  20. The hyperfine spectrum of hydrogen dimers

    International Nuclear Information System (INIS)

    The authors' aim was to obtain the level scheme for the hydrogen dimers and to investigate the angle dependent interactions by analyzing the zero magnetic field hyperfine spectrum of the ortho-ortho and ortho-para species. The results were tested by several recent semi-empirical and ab initio potentials. (Auth.)

  1. Alkali atoms, dimers, exciplexes and clusters in 4He crystals

    International Nuclear Information System (INIS)

    Full text: A closed-shell He atom and a single-electron alkali atom strongly repel each other because of the Pauli principle. As a consequence, an alkali atom immersed into condensed (superfluid or solid) 4He forms a spherical bubble state, in which the alkali repels the He quantum fluid/solid by imposing its own symmetry on the local He environment. For 15 years we have investigated such atomic bubbles in solid 4He using optical and magnetic resonance spectroscopy. In this talk I will first review our high resolution magnetic resonance studies performed on solid He matrix-isolated alkali atoms in the radio-frequency and microwave domains with special emphasis on their sensitive dependence on the crystalline structure (body-centered cubic, bcc, versus hexagonally close-packed, hcp) of the helium matrix. In recent years we have extended the purely atomic studies to larger bound complexes, such as exciplexes, dimers and clusters. I will present some of our intriguing recent results: in their respective ground states, alkali and He atoms are the worst enemies in the periodic table and strongly repel each other. Excited alkali atoms, however, attract He atoms and form bound states (so-called exciplexes), in which up to 7 He atoms can be attached to one alkali atom. Cs2 and Rb2 dimers in solid He can be excited via a large variety of absorption bands, and the deexcitation proceeds either by photodissociation or by emission of radiation. We made the strange observation that, irrespective of the excitation band, dimer fluorescence is only emitted on the (1)3Πu → X1Σg triplet-singlet transition which is forbidden in the free dimer. When the first excited P1/2 state of an alkali atom is populated by direct atomic excitation, it fluoresces at 879 nm (1.7 % blueshifted from the free atomic transition at 894 nm), a quantitatively well explained fact. However, when the same state is populated by photodissociation of the dimer, the emission wavelength is 885 nm. We attribute

  2. Hydrogen bond mediated stabilization of the salt bridge structure for the glycine dimer anion

    NARCIS (Netherlands)

    S. Heiles; R.J. Cooper; G. Berden; J. Oomens; E.R. Williams

    2015-01-01

    The formation of a salt bridge in deprotonated glycine dimer anions in a solvent-free environment is investigated using both infrared multiple photon dissociation spectroscopy between 600 and 1800 cm(-1) and theory. The zwitterionic and nonzwitterionic forms of glycine in this complex are computed t

  3. Disulfide bond-mediated dimerization of HLA-G on the cell surface.

    Science.gov (United States)

    Boyson, Jonathan E; Erskine, Robert; Whitman, Mary C; Chiu, Michael; Lau, Julie M; Koopman, Louise A; Valter, Markus M; Angelisova, Pavla; Horejsi, Vaclav; Strominger, Jack L

    2002-12-10

    HLA-G is a nonclassical class I MHC molecule with an unknown function and with unusual characteristics that distinguish it from other class I MHC molecules. Here, we demonstrate that HLA-G forms disulfide-linked dimers that are present on the cell surface. Immunoprecipitation of HLA-G from surface biotinylated transfectants using the anti-beta2-microglobulin mAb BBM.1 revealed the presence of an approximately equal 78-kDa form of HLA-G heavy chain that was reduced by using DTT to a 39-kDa form. Mutation of Cys-42 to a serine completely abrogated dimerization of HLA-G, suggesting that the disulfide linkage formed exclusively through this residue. A possible interaction between the HLA-G monomer or dimer and the KIR2DL4 receptor was also investigated, but no interaction between these molecules could be detected through several approaches. The cell-surface expression of dimerized HLA-G molecules may have implications for HLA-Greceptor interactions and for the search for specific receptors that bind HLA-G. PMID:12454284

  4. Universal bosonic tetramers of dimer-atom-atom structure

    OpenAIRE

    Deltuva, A.

    2012-01-01

    Unstable four-boson states having an approximate dimer-atom-atom structure are studied using momentum-space integral equations for the four-particle transition operators. For a given Efimov trimer the universal properties of the lowest associated tetramer are determined. The impact of this tetramer on the atom-trimer and dimer-dimer collisions is analyzed. The reliability of the three-body dimer-atom-atom model is studied.

  5. Dimerization of visual pigments in vivo.

    Science.gov (United States)

    Zhang, Tao; Cao, Li-Hui; Kumar, Sandeep; Enemchukwu, Nduka O; Zhang, Ning; Lambert, Alyssia; Zhao, Xuchen; Jones, Alex; Wang, Shixian; Dennis, Emily M; Fnu, Amrita; Ham, Sam; Rainier, Jon; Yau, King-Wai; Fu, Yingbin

    2016-08-01

    It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S-opsin(+)Lrat(-/-)) expressing, transgenically, short-wavelength-sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor's outer segment. In R-opsin's absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin's presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptide-competition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling. PMID:27462111

  6. Mutant human immunodeficiency virus type 1 genomes with defects in RNA dimerization or encapsidation.

    OpenAIRE

    Clever, J L; Parslow, T G

    1997-01-01

    Retrovirus particles each contain two copies of the viral genome in the form of a noncovalently linked RNA dimer. Earlier studies have mapped a cis-acting region near the 5' end of the human immunodeficiency virus type 1 (HIV-1) genome, termed the psi locus, which appears essential for initiation of genomic dimerization, as well as for interactions with the HIV-1 Gag protein that are thought to target the RNA into nascent virions. This HIV-1 psi locus is proposed to be organized in four indep...

  7. Hydrogen bonding inside and outside carbon nanotubes: HF dimer as a case study.

    Science.gov (United States)

    Roztoczyńska, Agnieszka; Kozłowska, Justyna; Lipkowski, Paweł; Bartkowiak, Wojciech

    2016-01-28

    In this theoretical work we analyze the noncovalent interactions of molecular complexes formed between the hydrogen bonded HF dimer and single-walled carbon nanotubes (SWCNTs) of different diameters. In particular, the interaction energies of: (i) spatially confined hydrogen fluoride molecules and (ii) HF dimer and the exterior or interior of SWCNTs are investigated. The computations are carried out in a supermolecular manner using the M06-2X exchange-correlation functional. In order to establish the influence of mutual orientation of the hydrogen fluoride dimer and molecular carbon cages on the analyzed energetic parameters energy scans are performed. Furthermore, changes in the charge distribution of the investigated endo- and exohedral complexes are studied employing the Natural Bond Orbital analysis. Among others, the position of the HF dimer with respect to the carbon cages proves to have a significant influence on the analyzed quantities. The results of our study also indicate that the HF dimer interacts stronger with the interior rather than the exterior of SWCNTs. Moreover, a substantial enhancement of the basis set superposition error is disclosed. PMID:26701220

  8. Dimer formation of receptor activator of nuclear factor κB induces incomplete osteoclast formation

    International Nuclear Information System (INIS)

    Receptor activator of nuclear factor κB-ligand (RANKL) transduces a differentiation signal appropriate to osteoclasts likely through induction a receptor homotrimer; however, biological importance of RANK-trimerizarion is unknown. To address the signaling mechanism of the RANK receptor, we analyzed the effect of two different types of homodimer inducers RANK-TM-FKBP36v and hEpoR-RANK-TM on osteoclastogenesis. Dimerizing component FKBP36v or extracellular portion of human erythropoietin receptor (hEpoR) was fused to RANK lacking the extracellular domain, and the dimerization of this fusion protein was induced by addition of the chemical inducer of dimerization AP20187 or erythropoietin, respectively. Such treatment resulted in induction of TRAP-activity, a marker of osteoclast in a dose dependent manner, with an efficiency equivalent to that of induction by RANKL. However, dimerized-RANK-induced osteoclasts showed relatively low levels of multinucleation, pit forming activity, and expression of calcitonin receptor and cathepsin K, compared with osteoclasts which were induced in the presence of RANKL. As expression of nuclear factor of activated T cells 1 (NFATc1) was also reduced in dimerized-RANK-induced osteoclasts, RANK oligomerization by RANKL is a critical event to generate fully matured osteoclasts through upregulation of NFATc1

  9. Mutagenesis of the human IgA1 heavy chain tailpiece that prevents dimer assembly.

    Science.gov (United States)

    Atkin, J D; Pleass, R J; Owens, R J; Woof, J M

    1996-07-01

    The structural features of the human IgA1 tailpiece required for interaction with J chain in IgA dimer assembly were investigated using a protein engineering approach. Wild-type and mutant forms of IgA1 were expressed in the mouse myeloma cell line, J558L, which endogenously expresses J chain. Wild-type IgA1 was secreted as a mixture of dimers and monomers. Deletion of the entire tailpiece by stop codon introduction completely prevented dimer formation. Similarly, substitution of the penultimate residue of the tailpiece, Cys471, with serine resulted in the secretion of IgA monomers alone. Substitution of Asn459 with alanine to prevent attachment of N-linked carbohydrate to the tailpiece also resulted in markedly reduced dimer assembly. These results indicate the critical role played by the tailpiece, and Cys471 in particular, in IgA dimerization. In addition, we found tailpiece-deleted IgA1 and the Cys to Ser471 mutant IgA1 were secreted as mixtures of covalently associated monomers (alpha 2L2) and alpha L half-molecules. The tailpiece may thus play some role in promoting the association of alpha-chains required for IgA monomer assembly. PMID:8683109

  10. Self-assembly of channel type β-CD dimers induced by dodecane.

    Science.gov (United States)

    Zhou, Chengcheng; Cheng, Xinhao; Zhao, Qiang; Yan, Yun; Wang, Jide; Huang, Jianbin

    2014-01-01

    Cyclodextrins (CDs) can hardly self-assemble into well-defined structures. Here we report if they preassemble into channel type dimers assisted by dodecane, well-defined vesicles and bricks can be formed. Unlike the traditional self-assembly of amphiphilic molecules driven by hydrophobic effect, the self-assembly of the channel type dodecane@2β-CD supramolecular building block is predoninantly driven by hydrogen-bonds. More water molecules are found in the lyophilized vesicles than in the bricks, suggesting water molecules play an important role in the self-assembly of the channel-type dimers of β-CD. The amount of structural water in the self-assembly is closely related to the curvature of the final self-assembled structures. Our work reveals that the channel-type dimer of β-CD may represent a new sort of building block for advanced structures. PMID:25532046

  11. A structure-based approach for targeting the HIV-1 genomic RNA dimerization initiation site.

    Science.gov (United States)

    Ennifar, Eric; Paillart, Jean-Christophe; Bernacchi, Serena; Walter, Philippe; Pale, Patrick; Decout, Jean-Luc; Marquet, Roland; Dumas, Philippe

    2007-10-01

    Dimerization of the genomic RNA is an important step of the HIV-1 replication cycle. The Dimerization Initiation Site (DIS) promotes dimerization of the viral genome by forming a loop-loop complex between two DIS hairpins. Crystal structures of the DIS loop-loop complex revealed an unexpected and strong similitude with the bacterial 16S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics. As a consequence of these structural and sequence similarities, the HIV-1 DIS also binds some aminoglycosides, not only in vitro, but also ex vivo, in lymphoid cells and in viral particles. Crystal structures of the DIS loop-loop in complex with several aminoglycoside antibiotics provide a detailed-view of the DIS/drug interaction and reveal some hints about possible modifications to increase the drug affinity and/or specificity. PMID:17434658

  12. Rapid dimerization of quercetin through an oxidative mechanism in the presence of serum albumin decreases its ability to induce cytotoxicity in MDA-MB-231 cells.

    Science.gov (United States)

    Pham, Anh; Bortolazzo, Anthony; White, J Brandon

    2012-10-19

    Quercetin is a member of the flavonoid family and has been previously shown to have a variety of anti-cancer activities. We and others have reported anti-proliferation, cell cycle arrest, and induction of apoptosis of cancer cells after treatment with quercetin. Quercetin has also been shown to undergo oxidation. However, it is unclear if quercetin or one of its oxidized forms is responsible for cell death. Here we report that quercetin rapidly oxidized in cell culture media to form a dimer. The quercetin dimer is identical to a dimer that is naturally produced by onions. The quercetin dimer and quercetin-3-O-glucopyranoside are unable to cross the cell membrane and do not kill MDA-MB-231 cells. Finally, supplementing the media with ascorbic acid increases quercetin's ability to induce cell death probably by reduction oxidative dimerization. Our results suggest that an unmodified quercetin is the compound that elicits cell death. PMID:23000408

  13. Oligomerization of the SARS-CoV S glycoprotein: dimerization of the N-terminus and trimerization of the ectodomain

    International Nuclear Information System (INIS)

    Viral envelope glycoproteins are oligomeric and the quaternary structure is critical for their membrane fusion activity. Typically the transmembrane glycoproteins of class I fusion proteins contain the oligomerization domains and the surface glycoproteins (SU) are monomeric. However, it has been previously demonstrated [J. Biol. Chem. 277 (2002) 19727] that the SU of a murine hepatitis coronavirus (MHV) forms dimers, the dimerization domain overlaps the receptor-binding domain (RBD) and that this dimeric state is important for binding to receptor molecules that initiates entry into cells. We have previously expressed various soluble fragments of the SARS-CoV SU and identified stably folded fragments (residues 272-537) that contain the RBD [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Here, we further characterize these and other fragments in an attempt to identify possible dimerization domains and their role for membrane fusion. We demonstrate that the SU and a shorter 260-amino acid N-terminal fragment (residues 17-276), which folds independently, form dimers. In contrast to the previously characterized MHV SU dimerization, this fragment is upstream and distinct from the RBD. Its deletion abolished S-mediated cell membrane fusion but retained the SU-receptor-binding function indicating the possibility for a role in post-receptor binding steps of the virus entry mechanism. Interestingly, the whole soluble S ectodomain (Se) that contains the dimerization domain but not the transmembrane domain and the cytoplasmic tail forms trimers suggesting the existence of a trimerization domain in the TM subunit in its prefusion state that may lead to a conformation unfavorable for formation of higher-order multimeric structures. These results demonstrate the existence of SU dimers and Se trimers, and indicate the possibility for an unknown mechanism of their role in entry. They also further characterize the S-mediated membrane fusion and could be important for understanding

  14. Dimerization of Np(V) and media effects in concentrated solutions

    International Nuclear Information System (INIS)

    Highly concentrated (up to 3.56 mol L-1) binary solutions of NpO2NO3 were prepared to investigate the self-association of Np(V). By using visible/NIR absorption spectrophotometry and chemometric techniques, Np(V) was shown to be only monomeric below 0.2 mol L-1, to exist under its monomeric and dimeric forms between 0.2 and 2 mol L-1, to begin to form self-associates of higher degrees above 2 mol L-1. In the range 0.2 mol L-1 Np(V) -1, the neptunium distribution between the free NpO2+ and dimeric (NpO2)22+ forms was determined by Raman spectroscopy. The simple solution concept was used to establish the activity function for the reaction of dimerization. Such a water activity function can be used to calculate the apparent dimer formation constant for any solution of known composition and water activity, provided that this solution is simple. (orig.)

  15. Dimerization of Np(V) and media effects in concentrated solutions

    Energy Technology Data Exchange (ETDEWEB)

    Gregoire-Kappenstein, A.C.; Moisy, Ph.; Blanc, P. [Commissariat a l' Energie Atomique, Bagnols-sur-Ceze (France); Cote, G. [ENSCP Lab. d' Electrochimie et de Chimie Analytique, Paris (France)

    2003-07-01

    Highly concentrated (up to 3.56 mol L{sup -1}) binary solutions of NpO{sub 2}NO{sub 3} were prepared to investigate the self-association of Np(V). By using visible/NIR absorption spectrophotometry and chemometric techniques, Np(V) was shown to be only monomeric below 0.2 mol L{sup -1}, to exist under its monomeric and dimeric forms between 0.2 and 2 mol L{sup -1}, to begin to form self-associates of higher degrees above 2 mol L{sup -1}. In the range 0.2 mol L{sup -1} < C{sub Np(V)} < 2 mol L{sup -1}, the neptunium distribution between the free NpO{sub 2}{sup +} and dimeric (NpO{sub 2}){sub 2}{sup 2+} forms was determined by Raman spectroscopy. The simple solution concept was used to establish the activity function for the reaction of dimerization. Such a water activity function can be used to calculate the apparent dimer formation constant for any solution of known composition and water activity, provided that this solution is simple. (orig.)

  16. Dimerization of a Viral SET Protein Endows its Function

    Energy Technology Data Exchange (ETDEWEB)

    H Wei; M Zhou

    2011-12-31

    Histone modifications are regarded as the most indispensible phenomena in epigenetics. Of these modifications, lysine methylation is of the greatest complexity and importance as site- and state-specific lysine methylation exerts a plethora of effects on chromatin structure and gene transcription. Notably, paramecium bursaria chlorella viruses encode a conserved SET domain methyltransferase, termed vSET, that functions to suppress host transcription by methylating histone H3 at lysine 27 (H3K27), a mark for eukaryotic gene silencing. Unlike mammalian lysine methyltransferases (KMTs), vSET functions only as a dimer, but the underlying mechanism has remained elusive. In this study, we demonstrate that dimeric vSET operates with negative cooperativity between the two active sites and engages in H3K27 methylation one site at a time. New atomic structures of vSET in the free form and a ternary complex with S-adenosyl homocysteine and a histone H3 peptide and biochemical analyses reveal the molecular origin for the negative cooperativity and explain the substrate specificity of H3K27 methyltransferases. Our study suggests a 'walking' mechanism, by which vSET acts all by itself to globally methylate host H3K27, which is accomplished by the mammalian EZH2 KMT only in the context of the Polycomb repressive complex.

  17. Ankyrin-G Inhibits Endocytosis of Cadherin Dimers.

    Science.gov (United States)

    Cadwell, Chantel M; Jenkins, Paul M; Bennett, Vann; Kowalczyk, Andrew P

    2016-01-01

    Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Therefore, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. However, the mechanisms that control junctional plasticity are not fully understood. Vascular endothelial cadherin (VE-cadherin) is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE-cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with β- and α-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of cadherin and stabilizes it at the plasma membrane. Here we report that induced cis dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin-actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VE-cadherin cis dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions. PMID:26574545

  18. Elastic properties of the degenerate f.c.c. crystal of polydisperse soft dimers at zero temperature

    CERN Document Server

    Narojczyk, J W

    2015-01-01

    Elastic properties of soft, three-dimensional dimers, interacting through site-site n-inverse-power potential, are determined by computer simulations at zero temperature. The degenerate crystal of dimers exhibiting (Gaussian) size distribution of atomic diameters - i.e. size polydispersity - is studied at the molecular number density $1/\\sqrt{2}$; the distance between centers of atoms forming dimers is considered as a length unit. It is shown that, at the fixed number density of the dimers, increasing polydispersity causes, typically, an increase of pressure, elastic constants and Poisson's ratio; the latter is positive in most direction. A direction is found, however, in which the size polydispersity causes substantial decrease of Poisson's ratio, down to negative values for large $n$. Thus, the system is partially auxetic for large polydispersity and large n.

  19. Conformation of self-assembled porphyrin dimers in liposome vesicles by phase-modulation 2D fluorescence spectroscopy

    CERN Document Server

    Lott, Geoffrey A; Utterback, James K; Widom, Julia R; Aspuru-Guzik, Alán; Marcus, Andrew H

    2011-01-01

    By applying a phase-modulation fluorescence approach to 2D electronic spectroscopy, we studied the conformation-dependent exciton-coupling of a porphyrin dimer embedded in a phospholipid bilayer membrane. Our measurements specify the relative angle and separation between interacting electronic transition dipole moments, and thus provide a detailed characterization of dimer conformation. Phase-modulation 2D fluorescence spectroscopy (PM-2D FS) produces 2D spectra with distinct optical features, similar to those obtained using 2D photon-echo spectroscopy (2D PE). Specifically, we studied magnesium meso tetraphenylporphyrin dimers, which form in the amphiphilic regions of 1,2-distearoyl-sn-glycero-3-phosphocholine liposomes. Comparison between experimental and simulated spectra show that while a wide range of dimer conformations can be inferred by either the linear absorption spectrum or the 2D spectrum alone, consideration of both types of spectra constrains the possible structures to a "T-shaped" geometry. The...

  20. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  1. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  2. An introduction to the dimer model

    International Nuclear Information System (INIS)

    A perfect matching of a graph is a subset of edges which covers every vertex exactly once, that is, for every vertex there is exactly one edge in the set with that vertex as endpoint. The dimer model is the study of the set of perfect matchings of a (possibly infinite) graph. The most well-known example is when the graph is Z2, for which perfect matchings are equivalent (via a simple duality) to domino tilings, that is, tilings of the plane with 2 x 1 and 1 x 2 rectangles. In the first three sections we study domino tilings of the plane and of finite polygonal regions, or equivalently, perfect matchings on Z2 and subgraphs of Z2. In the last two sections we study the FK-percolation model and the dimer model on a more general family of planar graphs

  3. Revisiting the optical $PT$-symmetric dimer

    CERN Document Server

    Morales, J D Huerta; López-Aguayo, S; Rodríguez-Lara, B M

    2016-01-01

    Optics has proved a fertile ground for the experimental simulation of quantum mechanics. Most recently, optical realizations of $\\mathcal{PT}$-symmetric quantum mechanics have been shown, both theoretically and experimentally, opening the door to international efforts aiming at the design of practical optical devices exploiting this symmetry. Here, we focus on the optical $\\mathcal{PT}$-symmetric dimer, a two-waveguide coupler were the materials show symmetric effective gain and loss, and provide a review of the linear and nonlinear optical realizations from a symmetry based point of view. We go beyond a simple review of the literature and show that the dimer is just the smallest of a class of planar $N$-waveguide couplers that are the optical realization of Lorentz group in 2+1 dimensions. Furthermore, we provide a formulation to describe light propagation through waveguide couplers described by non-Hermitian mode coupling matrices based on a non-Hermitian generalization of Ehrenfest theorem.

  4. Alcohol dimers - how much diagonal OH anharmonicity?

    OpenAIRE

    Kollipost, Franz; Papendorf, Kim; Lee, Yu-Fang; Lee, Yuan-Pern; Suhm, Martin A

    2014-01-01

    The OH bond of methanol, ethanol and t-butyl alcohol becomes more anharmonic upon hydrogen bonding and the infrared intensity ratio between the overtone and the fundamental transition of the bridging OH stretching mode decreases drastically. FTIR spectroscopy of supersonic slit jet expansions allows to quantify these effects for isolated alcohol dimers, enabling a direct comparison to anharmonic vibrational predictions. The diagonal anharmonicity increase amounts to 15-18%, growing with incre...

  5. Dimer models and quiver gauge theories

    Science.gov (United States)

    Pichai, Ramadevi

    2013-12-01

    = 1 quiver gauge theories on coincident D3 branes placed at a tip of a Calabi-Yau singularity C are dual to string theories on AdS5×X5 where X5 are Sasaki-Einstein spaces. We present a neat combinatorial approach called dimer model to understand interrelations between toric quiver gauge theories and toric data representing the Calabi-Yau singularities.

  6. Entanglement and decoherence in a quantum dimer

    Institute of Scientific and Technical Information of China (English)

    Hou Xi-Wen; Hui Zi; Ding Rui-Min; Chen Xiao-Yang; Gao Yu

    2006-01-01

    The dynamical properties of quantum entanglement in an integrable quantum dimer are studied in terms of the reduced-density linear entropy with various coupling parameters and total boson numbers. The characteristic time of decoherence process in the early-time evolution of the linear entropy is obtained, indicating that the characteristic time and the corresponding entropy exhibit a maximum near the position of the corresponding classical separatrix energy.

  7. Temperature-sensitive protein–DNA dimerizers

    OpenAIRE

    Hauschild, Karl E.; Metzler, Renee E.; Arndt, Hans-Dieter; Moretti, Rocco; Raffaelle, Marni; Dervan, Peter B.; Ansari, Aseem Z.

    2005-01-01

    Programmable DNA-binding polyamides coupled to short peptides have led to the creation of synthetic artificial transcription factors. A hairpin polyamide–YPWM tetrapeptide conjugate facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. Such small molecules function as protein–DNA dimerizers that stabilize complexes at composite DNA binding sites. Here we investigate the role of the linker that connects the polyamide to the peptide. We find that a substantial d...

  8. Repair of DNA-containing pyrimidine dimers

    International Nuclear Information System (INIS)

    Ultraviolet light-induced pyrimidine dimers in DNA are recognized and repaired by a number of unique cellular surveillance systems. The most direct biochemical mechanism responding to this kind of genotoxicity involves direct photoreversal by flavin enzymes that specifically monomerize pyrimidine:pyrimidine dimers monophotonically in the presence of visible light. Incision reactions are catalyzed by a combined pyrimidine dimer DNA-glycosylase:apyrimidinic endonuclease found in some highly UV-resistant organisms. At a higher level of complexity, Escherichia coli has a uvr DNA repair system comprising the UvrA, UvrB, and UvrC proteins responsible for incision. There are several preincision steps governed by this pathway, which includes an ATP-dependent UvrA dimerization reaction required for UvrAB nucleoprotein formation. This complex formation driven by ATP binding is associated with localized topological unwinding of DNA. This same protein complex can catalyze an ATPase-dependent 5'----3'-directed strand displacement of D-loop DNA or short single strands annealed to a single-stranded circular or linear DNA. This putative translocational process is arrested when damaged sites are encountered. The complex is now primed for dual incision catalyzed by UvrC. The remainder of the repair process involves UvrD (helicase II) and DNA polymerase I for a coordinately controlled excision-resynthesis step accompanied by UvrABC turnover. Furthermore, it is proposed that levels of repair proteins can be regulated by proteolysis. UvrB is converted to truncated UvrB* by a stress-induced protease that also acts at similar sites on the E. coli Ada protein. Although UvrB* can bind with UvrA to DNA, it cannot participate in helicase or incision reactions. It is also a DNA-dependent ATPase.21 references

  9. Repair of DNA-containing pyrimidine dimers

    Energy Technology Data Exchange (ETDEWEB)

    Grossman, L.; Caron, P.R.; Mazur, S.J.; Oh, E.Y.

    1988-08-01

    Ultraviolet light-induced pyrimidine dimers in DNA are recognized and repaired by a number of unique cellular surveillance systems. The most direct biochemical mechanism responding to this kind of genotoxicity involves direct photoreversal by flavin enzymes that specifically monomerize pyrimidine:pyrimidine dimers monophotonically in the presence of visible light. Incision reactions are catalyzed by a combined pyrimidine dimer DNA-glycosylase:apyrimidinic endonuclease found in some highly UV-resistant organisms. At a higher level of complexity, Escherichia coli has a uvr DNA repair system comprising the UvrA, UvrB, and UvrC proteins responsible for incision. There are several preincision steps governed by this pathway, which includes an ATP-dependent UvrA dimerization reaction required for UvrAB nucleoprotein formation. This complex formation driven by ATP binding is associated with localized topological unwinding of DNA. This same protein complex can catalyze an ATPase-dependent 5'----3'-directed strand displacement of D-loop DNA or short single strands annealed to a single-stranded circular or linear DNA. This putative translocational process is arrested when damaged sites are encountered. The complex is now primed for dual incision catalyzed by UvrC. The remainder of the repair process involves UvrD (helicase II) and DNA polymerase I for a coordinately controlled excision-resynthesis step accompanied by UvrABC turnover. Furthermore, it is proposed that levels of repair proteins can be regulated by proteolysis. UvrB is converted to truncated UvrB* by a stress-induced protease that also acts at similar sites on the E. coli Ada protein. Although UvrB* can bind with UvrA to DNA, it cannot participate in helicase or incision reactions. It is also a DNA-dependent ATPase.21 references.

  10. Nanoradar based on nonlinear dimer nanoantenna.

    Science.gov (United States)

    Lapshina, Nadezhda; Noskov, Roman; Kivshar, Yuri

    2012-09-15

    We introduce the concept of a nanoradar based on the operation of a nonlinear plasmonic nanoantenna. The nanoradar action originates from modulational instability occurring in a dimer nanoantenna consisting of two subwavelength nonlinear nanoparticles. Modulation instability causes a dynamical energy exchange between the nanoantenna eigenmodes resulting in periodic scanning of the nanoantenna scattering pattern. Such nanoradar demonstrates a wide scanning sector, low operation threshold, and ultrafast time response being potentially useful for many applications in nanophotonics circuitry. PMID:23041904

  11. Fractionalization in dimerized graphene and graphene bilayer

    OpenAIRE

    Milovanović, M. V.

    2008-01-01

    We show that the fractional statistics of quasiparticles in dimerized graphene, in recent proposals for charge and statistics fractionalization, can have two realizations depending whether elementary objects can be considered as point-like or extended objects. Therefore, there are two phases of proposed excitations and we give their topological descriptions with their respective statistics. We propose that a natural setting for fractionalization are certain systems with excitonic instabilitie...

  12. On the dimerization of linear polymers

    International Nuclear Information System (INIS)

    We use the continuum limit of the Su-Schrieffer-Heeger model for linear polymers to construct its effective potential (Gibbs free energy) both at zero and finite temperature. We study both trans and cis-polymers. Our results show that, depending on a renormalization condition to be extracted from experiment, there are several possibilities for the minima of the dimerized ground state of cis-polymers. All calculations are done in the one-loop approximation. (author). 16 refs, 3 figs

  13. T-shaped dimer of coronene

    CERN Document Server

    Obolensky, O I; Semenikhina, V V; Solovyov, A V

    2005-01-01

    An evidence of importance of the T-shaped configuration of coronene dimer is presented. Thus, the dimer's lowest energy configuration is not necessarily a stack, as it might had been expected a priori. This is a surprising result for the dimer of such a large polycyclic aromatic hydrocarbon (PAH) as coronene for which a graphite-like stack.The energy of the T-shaped configuration at all considered levels of density functional theory (B3LYP,PBE/6-31+G(d),D95,cc-pVDZ,cc-pVTZ) was systematically lower than the energy of the three plausible stack configurations. In order to get a better description of the van der Waals interaction,the density functional theory (DFT) results were adjusted by adding a phenomenological Lennard-Jones-type term into the total energy of the system. However, the van der Waals correction is somewhat arbitrary and its magnitude can not be rigorously justified. Depending on the choice of the parameters in the phenomenological term both the T-shaped and the parallel-displaced (PD) stack con...

  14. Kinetics of the monomer-dimer reaction of yeast hexokinase PI.

    Science.gov (United States)

    Hoggett, J G; Kellett, G L

    1992-10-15

    Kinetic studies of the glucose-dependent monomer-dimer reaction of yeast hexokinase PI at pH 8.0 in the presence of 0.1 M-KCl have been carried out using the fluorescence temperature-jump technique. A slow-relaxation effect was observed which was attributed from its dependence on enzyme concentration to the monomer-dimer reaction; the reciprocal relaxation times tau-1 varied from 3 s-1 at low concentrations of glucose to 42 s-1 at saturating concentrations. Rate constants for association (kass.) and dissociation (kdiss.) were determined as a function of glucose concentration using values of the equilibrium association constant of the monomer-dimer reaction derived from sedimentation ultracentrifugation studies under similar conditions, and also from the dependence of tau-2 on enzyme concentration. kass. was almost independent of glucose concentration and its value (2 x 10(5) M-1.s-1) was close to that expected for a diffusion-controlled process. The influence of glucose on the monomer-dimer reaction is entirely due to effects on kdiss., which increases from 0.21 s-1 in the absence of glucose to 25 s-1 at saturating concentrations. The monomer and dimer forms of hexokinase have different affinities and Km values for glucose, and the results reported here imply that there may be a significant lag in the response of the monomer-dimer reaction to changes in glucose concentrations in vivo with consequent hysteretic effects on the hexokinase activity. PMID:1445216

  15. Lysozyme dimer association: Similarities and differences compared with lysozyme monomer association

    Science.gov (United States)

    Onuma, Kazuo; Inaka, Koji

    2008-03-01

    The protein with a molecular weight of 28.6 kDa in lysozyme solution, which has been recognized as a lysozyme dimer, was purified and its association was observed using time-resolved static light scattering and dynamic light scattering under the same buffer condition as that used in lysozyme monomer association. The chromatography results and SDS-PAGE analysis showed that the bonding state of each molecule in a dimer unit was not uniform, i.e., there were at least two kinds of bonds, strong and weak. Some of the weak-bonded dimmers dissociated to monomers (molecular weight: 14.3 kDa) in the SDS-PAGE process. The relative amount of weak-bonded dimers greatly affected the association kinetics. With a 99% pure dimer solution (1% monomers in SDS-PAGE), association proceeded in the same manner as that of a monomer solution: the Zimm-square plot had a concave shape with a maximum at a particular q2 for apparent protein concentrations, up to 2.4 mg/mL. The dynamic light-scattering data showed clear bimodal (dimer and aggregate), distributions. With a 95% pure dimer solution, the association behavior drastically changed when the apparent concentration exceeded 2.0 mg/mL. The Zimm-square plot had a bending point at a low q2, and two discrete lines fitted the plot. The particles in the solution were either oligomers or large aggregates, both of which had polydispersity distributions, and an amorphous phase formed from the aggregates. This was not observed for monomer association.

  16. Effect of acidic pH on the stability of α-synuclein dimers.

    Science.gov (United States)

    Lv, Zhengjian; Krasnoslobodtsev, Alexey V; Zhang, Yuliang; Ysselstein, Daniel; Rochet, Jean Christophe; Blanchard, Scott C; Lyubchenko, Yuri L

    2016-10-01

    Environmental factors, such as acidic pH, facilitate the assembly of α-synuclein (α-Syn) in aggregates, but the impact of pH on the very first step of α-Syn aggregation remains elusive. Recently, we developed a single-molecule approach that enabled us to measure directly the stability of α-Syn dimers. Unlabeled α-Syn monomers were immobilized on a substrate, and fluorophore-labeled monomers were added to the solution to allow them to form dimers with immobilized α-Syn monomers. The dimer lifetimes were measured directly from the fluorescence bursts on the time trajectories. Herein, we applied the single-molecule tethered approach for probing of intermolecular interaction to characterize the effect of acidic pH on the lifetimes of α-Syn dimers. The experiments were performed at pH 5 and 7 for wild-type α-Syn and for two mutants containing familial type mutations E46K and A53T. We demonstrate that a decrease of pH resulted in more than threefold increase in the α-Syn dimers lifetimes with some variability between the α-Syn species. We hypothesize that the stabilization effect is explained by neutralization of residues 96-140 of α-Syn and this electrostatic effect facilitates the association of the two monomers. Given that dimerization is the first step of α-Syn aggregation, we posit that the electrostatic effect thereby contributes to accelerating α-Syn aggregation at acidic pH. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 715-724, 2016. PMID:27177831

  17. Functional equivalence of monomeric (shark) and dimeric (bovine) cytochrome c oxidase.

    Science.gov (United States)

    Bickar, D; Lehninger, A; Brunori, M; Bonaventura, J; Bonaventura, C

    1985-01-01

    Cytochrome c oxidase isolated from hammerhead shark red muscle is monomeric in relation to the dimeric form of isolated bovine cytochrome c oxidase but in other ways bears a close resemblance to the enzyme isolated from mammalian tissue [1, 2]. Comparative studies of shark and bovine cytochrome c oxidase were extended to address the degree of functional similarity between the monomeric (shark) and dimeric (bovine) enzymes in the kinetics of peroxide binding and in the extent to which the catalytic action of the enzymes in vesicles can establish a proton gradient. Although the kinetics of peroxide binding and the proton pumping processes are complex, the dimeric and monomeric forms are quite similar with respect to these functional attributes. The kinetic heterogeneity of the process of peroxide binding is expressed in the shark enzyme as well as in the bovine enzyme, and both types of enzymes in vesicles can generate transmembrane proton gradients. On this basis we conclude that the dimeric state of isolated cytochrome c oxidase from mammalian sources is not essential for its function in vitro. PMID:2410569

  18. Dimer formation and transcription activation in the sporulation response regulator Spo0A.

    Science.gov (United States)

    Lewis, Richard J; Scott, David J; Brannigan, James A; Ladds, Joanne C; Cervin, Marguerite A; Spiegelman, George B; Hoggett, James G; Barák, Imrich; Wilkinson, Anthony J

    2002-02-15

    The response regulator Spo0A is the master control element in the initiation of sporulation in Bacillus subtilis. Like many other multi-domain response regulators, the latent activity of the effector, C-terminal domain is stimulated by phosphorylation on a conserved aspartic acid residue in the regulatory, N-terminal domain. If a threshold concentration of phosphorylated Spo0A is achieved, the transcription of genes required for sporulation is activated, whereas the genes encoding stationary phase sentinels are repressed, and sporulation proceeds. Despite detailed genetic, biochemical and structural characterisation, it is not understood how the phosphorylation signal in the receiver domain is transduced into DNA binding and transcription activation in the distal effector domain. An obstacle to our understanding of Spo0A function is the uncertainty concerning changes in quaternary structure that accompany phosphorylation. Here we have revisited this question and shown unequivocally that Spo0A forms dimers upon phosphorylation and that the subunit interactions in the dimer are mediated principally by the receiver domain. Purified dimers of two mutants of Spo0A, in which the phosphorylatable aspartic acid residue has been substituted, activate transcription from the spoIIG promoter in vitro, whereas monomers do not. This suggests that dimers represent the activated form of Spo0A. PMID:11851334

  19. The importance of alfalfa mosaic virus coat protein dimers in the initiation of replication.

    Science.gov (United States)

    Choi, Jiwon; Kim, Bong-Suk; Zhao, Xiaoxia; Loesch-Fries, Sue

    2003-01-01

    Deletion and substitution mutations affecting the oligomerization of alfalfa mosaic virus (AMV) coat protein (CP) were studied in protoplasts to determine their effect on genome activation, an early step in AMV replication. The CP mutants that formed dimers, CPDeltaC9 and CPC-A(R)F, were highly active in initiating replication with 63-84% of wild-type (wt) CP activity. However, all mutants that did not form dimers, CPDeltaC18, CPDeltaC19, CPC-WFP, and CPC-W, were much less active with 19-33% of wt CP activity. The accumulation and solubility of mutant CPs expressed from a virus-based vector in Nicotiana benthamiana were similar to that of wt CP. Analysis of CP-RNA interactions indicated that CP dimers and CP monomers interacted very differently with AMV RNA 3' ends. These results suggest that CP dimers are more efficient for replication than CP monomers because of differences in RNA binding rather than differences in expression and accumulation of the mutant CPs in infected cells. PMID:12504539

  20. Van der Waals bond in dimers: H2Ne, H2Ar, H2Kr

    International Nuclear Information System (INIS)

    The H2-inert gas dimers H2X, and particularly H2Ne, H2Ar and H2Kr, form the subject of this thesis and are loosely bound van der Waals complexes, which is reflected in the low number of bound states and the small anisotropic interaction. The H2X dimers studied are formed in a supersonic nozzle expansion, in which the internal energy is converted into the macroscopic flow energy, establishing an internal temperature drop to 3 K, which favours dimer formation. Because of this cooling the H2X dimers relax to the lowest rotational states. The hyperfine transitions have been measured using magnetic beam resonance and yield information about the isotropic as well as the anisotropic intermolecular potential in the range between the classical turning points and in the adjacent part of the repulsive branch. The sensitivity of the method is very high and slight changes in the intermolecular potential cause significant effects. The analysis of the measured hyperfine transitions incorporates all interacting states of the molecule, bound as well as unbound (continuum) states. For H2Ne, which is the best studied H2-inert gas system from the experimental point of view, the author succeeded in establishing an intermolecular potential, that provides a solid ground for comparison with future ab initio calculations. (Auth.)

  1. DFT study of small fullerene dimer complexes C20-Nm@Cn (m = 1-6 and n = 24, 28, 32, 36 and 40)

    Science.gov (United States)

    Kaur, Sandeep; Sharma, Amrish; Mudahar, Isha

    2016-05-01

    First principle calculations based on density functional theory were performed to calculate the structural and electronic properties of C20-Nm@Cn dimer complexes. The calculated binding energies of the complexes formed are comparable to C60 dimer which ensures their stability. The bond lengths of these dimer complexes were found to be nearly same as pure complexes C20-Cn. Further, nitrogen (N) atoms were encapsulated inside the secondary cage (Cn) of dimer complexes and the number of N atoms depends on diameter of the cage. The HOMO-LUMO gaps of new proposed complexes indicate the increase in gap as compared to pure complexes. Mulliken charge analysis of these complexes has been studied which shows the significant charge transfer from the N atoms to the secondary cage of these complexes. The study propose the formation of the new dimer complexes which are stable and are able to encapsulate atoms which are otherwise reactive in free space.

  2. Monomer-dimer tatami tilings of square regions

    CERN Document Server

    Erickson, Alejandro

    2011-01-01

    We prove that the number of monomer-dimer tilings of an $n\\times n$ square grid, with $mform $2^{n-1}(3n-4)+2$ and, curiously, this is equal to the sum of the squares of all parts in all compositions of $n$. We also describe two algorithms and a Gray code ordering for generating the $n2^{n-1}$ tilings with $n$ monomers, which are both based on our new proof.

  3. The Structure of the Poxvirus A33 Protein Reveals a Dimer of Unique C-Type Lectin-Like Domains

    Energy Technology Data Exchange (ETDEWEB)

    Su, Hua-Poo; Singh, Kavita; Gittis, Apostolos G.; Garboczi, David N. (NIH)

    2010-11-03

    The current vaccine against smallpox is an infectious form of vaccinia virus that has significant side effects. Alternative vaccine approaches using recombinant viral proteins are being developed. A target of subunit vaccine strategies is the poxvirus protein A33, a conserved protein in the Chordopoxvirinae subfamily of Poxviridae that is expressed on the outer viral envelope. Here we have determined the structure of the A33 ectodomain of vaccinia virus. The structure revealed C-type lectin-like domains (CTLDs) that occur as dimers in A33 crystals with five different crystal lattices. Comparison of the A33 dimer models shows that the A33 monomers have a degree of flexibility in position within the dimer. Structural comparisons show that the A33 monomer is a close match to the Link module class of CTLDs but that the A33 dimer is most similar to the natural killer (NK)-cell receptor class of CTLDs. Structural data on Link modules and NK-cell receptor-ligand complexes suggest a surface of A33 that could interact with viral or host ligands. The dimer interface is well conserved in all known A33 sequences, indicating an important role for the A33 dimer. The structure indicates how previously described A33 mutations disrupt protein folding and locates the positions of N-linked glycosylations and the epitope of a protective antibody.

  4. Low-temperature pulse radiolysis and γ-irradiated matrix studies of dimer anions of olefin derivatives

    International Nuclear Information System (INIS)

    Intense IR absorptions were found for irradiated methyltetrahydrofuran solutions of various olefin derivatives using low-temperature pulse radiolysis and γ-irradiated matrix techniques. The compounds investigated were fumaronitrile, maleic anhydride, citraconic anhydride, dimethylmaleic anhydride, methyl vinyl ketone, acrolein, crotononitrile, methacrylonitrile, methyl acrylate, methyl methacrylate, and methyl crotonate. The IR absorptions increased gradually with time in pulse radiolysis and also increased by warming solutions via the γ-irradiated matrix method. The growth was always in parallel with the decay of the anion radical of each compound in both experiments. The IR absorptions, therefore, are concluded to be due to dimer anions produced by reactions of anion radicals with neutral parent molecules. Growth rates were determined from the formation curves of dimer anions. In many cases, IR spectra changed in shape by repeated warming and their peaks shifted to shorter wavelengths. These results are attributed to conformational changes of the dimer anions which occur in warmed solutions. Dimer anions were not observed for acrylamide, methacrylamide, 1,3-butadiene, and styrene, although their anion radicals were produced in irradiated solutions. The electron affinity of a functional group seems to be an important factor for dimer anion formation. Aromatic compounds such as phthalonitrile and phthalic anhydride did not form dimer anions under similar conditions

  5. Dimerization of the human papillomavirus type 16 E2 N terminus results in DNA looping within the upstream regulatory region.

    Science.gov (United States)

    Hernandez-Ramon, Elena E; Burns, Julie E; Zhang, Wenke; Walker, Hannah F; Allen, Stephanie; Antson, Alfred A; Maitland, Norman J

    2008-05-01

    Papillomavirus E2 proteins play a central role in regulating viral gene expression and replication. DNA-binding activity is associated with the C-terminal domain of E2, which forms a stable dimer, while the N-terminal domain is responsible for E2's replication and transactivation functions. The crystal structure of the latter domain revealed a second dimerization interface on E2 which may be responsible for DNA loop formation in the regulatory region of the human papillomavirus (HPV) genome. We investigated the biological significance of the N-terminal dimerization by introducing single amino acid substitutions into the dimerization interface. As expected, these substitutions did not influence the C-terminal dimerization and DNA-binding functions of E2. However, the mutations led to reduced transactivation of a synthetic E2-responsive reporter gene, while HPV DNA replication was unaffected. The effect of the mutations on DNA looping was visualized by atomic force microscopy. While wild-type E2 was able to generate DNA loops, all three mutant E2 proteins were defective in this ability. Our results suggest that N-terminal dimerization plays a role in E2-mediated transactivation, probably via DNA looping, a common mechanism for remote regulation of gene transcription. PMID:18337573

  6. Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+

    Directory of Open Access Journals (Sweden)

    Nigou Jérôme

    2007-08-01

    Full Text Available Abstract Background The cell wall of Mycobacterium tuberculosis contains a wide range of phosphatidyl inositol-based glycolipids that play critical structural roles and, in part, govern pathogen-host interactions. Synthesis of phosphatidyl inositol is dependent on free myo-inositol, generated through dephosphorylation of myo-inositol-1-phosphate by inositol monophosphatase (IMPase. Human IMPase, the putative target of lithium therapy, has been studied extensively, but the function of four IMPase-like genes in M. tuberculosis is unclear. Results We determined the crystal structure, to 2.6 Å resolution, of the IMPase M. tuberculosis SuhB in the apo form, and analysed self-assembly by analytical ultracentrifugation. Contrary to the paradigm of constitutive dimerization of IMPases, SuhB is predominantly monomeric in the absence of the physiological activator Mg2+, in spite of a conserved fold and apparent dimerization in the crystal. However, Mg2+ concentrations that result in enzymatic activation of SuhB decisively promote dimerization, with the inhibitor Li+ amplifying the effect of Mg2+, but failing to induce dimerization on its own. Conclusion The correlation of Mg2+-driven enzymatic activity with dimerization suggests that catalytic activity is linked to the dimer form. Current models of lithium inhibition of IMPases posit that Li+ competes for one of three catalytic Mg2+ sites in the active site, stabilized by a mobile loop at the dimer interface. Our data suggest that Mg2+/Li+-induced ordering of this loop may promote dimerization by expanding the dimer interface of SuhB. The dynamic nature of the monomer-dimer equilibrium may also explain the extended concentration range over which Mg2+ maintains SuhB activity.

  7. Interaction of the αβ dimers of the insulin-like growth factor I receptor required for receptor autophosphorylation

    International Nuclear Information System (INIS)

    The authors have recently found that association of the two αβ dimers of the insulin-like growth factor I (IGF I) receptor is required for formation of a high-affinity binding site for IGF I. To determine the structural requirements for IGF I activated kinase activity, they have examined the effect of dissociation of the two αβ dimers of the IGF I receptor on β subunit autophosphorylation. The αβ dimers formed after treatment with 2 mM dithiothreitol (DTT) at pH 8.75 for 5 min were separated from IGF I receptor remaining as tetramers after DTT treatment by fast protein liquid chromatography on a Superose 6 gel filtration column. Purification of the αβ dimers was confirmed by Western blot analysis using 125I-labeled αIR-3, a monoclonal antibody to the IGF I receptor. Autophosphorylation of the IGF I receptor (αβ)2 tetramer, treated without DTT or remaining after DTT treatment, is stimulated 1.6-2.9-fold by IGF I. In contrast, autophosporylation of the αβ dimers incubated in the presence or absence of IGF I (100 ng/mL) does not occur. Both IGF I receptor dimers and tetramers exhibit similar kinase activities using the synthetic substrate Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly, indicating that the failure to detect autophosphorylation of the IGF I receptor dimers does not result from inactivation of the kinase by DTT treatment. They conclude that autophosphorylation of the IGF I receptor depends upon the interaction of the two αβ dimers

  8. Evaluation of performance including influence by interfering substances of the Innovance D-dimer assay on the Sysmex coagulation analyzer.

    Science.gov (United States)

    Park, Seo-Jin; Chi, Hyun-Sook; Chun, Soh Hyun; Jang, Seongsoo; Park, Chan-Jeoung

    2011-01-01

    D-dimer is formed during activation of the coagulation system and is commonly assayed in order to diagnose disseminated intravascular coagulation, deep vein thrombosis, and pulmonary embolism. Enzyme-linked immunosorbent assay has been validated as the reference method, but it is a time-consuming procedure. The objective of this study was to evaluate a new immunoturbidimetric, particle-enhanced, Innovance(®) D-dimer immunoassay. A total of 129 plasma samples from apparently healthy individuals and 298 samples from patients were collected for linearity, precision, and correlation studies. Testing the precision of low- and high-controls yielded CV values of 2.08% and 1.76%, respectively. The central 95% non-parametric reference interval estimated from healthy controls was 0.093-0.68 mg/L Fibrinogen Equivalent Units (FEU; median, 0.26 mg/L FEU). Comparison analysis yielded acceptable correlation with the STA Liatest(®) D-dimer assay (R(2) = 0.9471). At a cut-off level of FEU, the sensitivity and specificity indices of the Innovance D-dimer assay were 99.7% and 89.1%, respectively. Thus the Innovance D-dimer method showed acceptable precision and linearity, and the assay results showed acceptable correlation with the STA Liatest D-dimer method. The Innovance method was relatively unaffected by potential interfering substances such as bilirubin and hemoglobin. In conclusion, the Innovance D-dimer assay is suitable for monitoring D-dimer concentrations in various clinical conditions and should be useful in clinical laboratories. PMID:21325250

  9. A study of hydrogen bonded vibrational spectra of (R)-(+)-Methylsuccinic acid, as aided by DFT dimer analysis

    Science.gov (United States)

    Tonannavar, J.; Chavan, Yashaswita B.; Yenagi, Jayashree

    2016-05-01

    Infrared and Raman spectral measurements in the region 4000-400 cm- 1 have been carried out for (R)-(+)-Methylsuccinic acid. The vibrational band structures near 3100-3040 cm- 1 in the IR and near 1650 cm- 1 in the Raman spectra have indicated the presence of an inter-molecular hydrogen bonding. A DFT dimer model has been proposed that involves O-H ⋯ OC type of hydrogen bonding. The proposed dimer model has been derived from the three stable monomers computed at RHF/3-21G and B3LYP/6-311 + G(d,p) levels of theory. A total of six dimer structures have been considered with a Boltzmann population of 38% for the most stable dimer and 62% for the remaining five dimer populations. A Boltzmann population weighted vibration spectrum has predicted bands, among others, for O-H ⋯ OC group that are in very good agreement with experiment. All the dimers have the same structure in that the two pairs of -O-H and -OC form a closed cyclic structure with a local center of inversion. This dimer geometry has given rise to one asymmetric mode at 1683 and one symmetric -CO mode at 1637 cm- 1 corresponding to mutually exclusive an experimental IR band at 1700 and a Raman band at 1651 cm- 1. Further, the bond length, H ⋯ O, for the most stable dimer is 1.686 Å, being shorter than the sums of van der Waals radii, 2.72 Å and the angle between O-H and H ⋯ O is almost linear (179°) suggesting that the hydrogen bonding is fairly strong.

  10. Extended quantum dimer model and novel valence-bond phases

    International Nuclear Information System (INIS)

    We extend the quantum dimer model (QDM) introduced by Rokhsar and Kivelson so as to construct a concrete example of the model which exhibits the first-order phase transition between different valence-bond solids suggested recently by Batista and Trugman and look for the possibility of other exotic dimer states. We show that our model contains three exotic valence-bond phases (herringbone, checkerboard and dimer smectic) in the ground-state phase diagram and that it realizes the phase transition from the staggered valence-bond solid to the herringbone. The checkerboard phase has four-fold rotational symmetry, while the dimer smectic, in the absence of quantum fluctuations, has massive degeneracy originating from partial ordering only in one of the two spatial directions. A resonance process involving three dimers resolves this massive degeneracy and the dimer smectic becomes ordered (order from disorder)

  11. Computational reference data for the photochemistry of cyclobutane pyrimidine dimers.

    Science.gov (United States)

    Barbatti, Mario

    2014-10-20

    The cis-syn cyclobutane pyrimidine dimer is one of the major classes of carcinogenic UV-induced DNA photoproducts. In this work, diverse high-level quantum-chemical methods were used to determine the spectroscopic properties of neutral (singlet and triplet) and charged (cation and anion) species of thymine dimers. Maps of potential energy, charge distribution, electron affinity, and ionization potential of the thymidine dimers were computed along the two dimerization coordinates for neutral and charged species, as well as for the singlet excited state. This set of data aims at providing consistent results computed with the same methods as for photodamage and repair. Based on these results, several different photo-, heat-, and charge-induced mechanisms of dimerization and repair are characterized and discussed. Additionally, a new stable dimer with methylmethylidene-hexahydropyrimidine structure was found in the S0 state. PMID:25044616

  12. Atomic resolution crystal structure of VcLMWPTP-1 from Vibrio cholerae O395: Insights into a novel mode of dimerization in the low molecular weight protein tyrosine phosphatase family

    International Nuclear Information System (INIS)

    Highlights: • VcLMWPTP-1 forms dimer in solution. • The dimer is catalytically active unlike other reported dimeric LMWPTPs. • The formation of extended dimeric surface excludes the active site pocket. • The surface bears closer resemblance to eukaryotic LMWPTPs. - Abstract: Low molecular weight protein tyrosine phosphatase (LMWPTP) is a group of phosphotyrosine phosphatase ubiquitously found in a wide range of organisms ranging from bacteria to mammals. Dimerization in the LMWPTP family has been reported earlier which follows a common mechanism involving active site residues leading to an enzymatically inactive species. Here we report a novel form of dimerization in a LMWPTP from Vibrio cholera 0395 (VcLMWPTP-1). Studies in solution reveal the existence of the dimer in solution while kinetic study depicts the active form of the enzyme. This indicates that the mode of dimerization in VcLMWPTP-1 is different from others where active site residues are not involved in the process. A high resolution (1.45 Å) crystal structure of VcLMWPTP-1 confirms a different mode of dimerization where the active site is catalytically accessible as evident by a tightly bound substrate mimicking ligand, MOPS at the active site pocket. Although being a member of a prokaryotic protein family, VcLMWPTP-1 structure resembles very closely to LMWPTP from a eukaryote, Entamoeba histolytica. It also delineates the diverse surface properties around the active site of the enzyme

  13. Atomic resolution crystal structure of VcLMWPTP-1 from Vibrio cholerae O395: Insights into a novel mode of dimerization in the low molecular weight protein tyrosine phosphatase family

    Energy Technology Data Exchange (ETDEWEB)

    Nath, Seema; Banerjee, Ramanuj; Sen, Udayaditya, E-mail: udayaditya.sen@saha.ac.in

    2014-07-18

    Highlights: • VcLMWPTP-1 forms dimer in solution. • The dimer is catalytically active unlike other reported dimeric LMWPTPs. • The formation of extended dimeric surface excludes the active site pocket. • The surface bears closer resemblance to eukaryotic LMWPTPs. - Abstract: Low molecular weight protein tyrosine phosphatase (LMWPTP) is a group of phosphotyrosine phosphatase ubiquitously found in a wide range of organisms ranging from bacteria to mammals. Dimerization in the LMWPTP family has been reported earlier which follows a common mechanism involving active site residues leading to an enzymatically inactive species. Here we report a novel form of dimerization in a LMWPTP from Vibrio cholera 0395 (VcLMWPTP-1). Studies in solution reveal the existence of the dimer in solution while kinetic study depicts the active form of the enzyme. This indicates that the mode of dimerization in VcLMWPTP-1 is different from others where active site residues are not involved in the process. A high resolution (1.45 Å) crystal structure of VcLMWPTP-1 confirms a different mode of dimerization where the active site is catalytically accessible as evident by a tightly bound substrate mimicking ligand, MOPS at the active site pocket. Although being a member of a prokaryotic protein family, VcLMWPTP-1 structure resembles very closely to LMWPTP from a eukaryote, Entamoeba histolytica. It also delineates the diverse surface properties around the active site of the enzyme.

  14. Dimeric assembly of enterocyte brush border enzymes

    DEFF Research Database (Denmark)

    Danielsen, E M

    1994-01-01

    appearance of the liposome-reconstituted enzyme [Norén et al. (1986) J. Biol. Chem. 261, 12306-12309], showing only the inner, membrane-anchored domains of the monomers to be in close contact with one another while the outer domains are far apart. In contrast to the other brush border enzymes studied......The noncovalent, dimeric assembly of small intestinal brush border enzymes was studied by sedimentation analysis in density gradients of extracts of pulse-labeled pig jejunal mucosal explants. Like aminopeptidase N (EC 3.4.11.2), sucrase-isomaltase (EC 3.2.1.48-10), aminopeptidase A (EC 3...

  15. Equivalence between XY and dimerized models

    Science.gov (United States)

    Campos Venuti, Lorenzo; Roncaglia, Marco

    2010-06-01

    The spin-1/2 chain with XY anisotropic coupling in the plane and the XX isotropic dimerized chain are shown to be equivalent in the bulk. For finite systems, we prove that the equivalence is exact in given parity sectors, after taking care of the precise boundary conditions. The proof is given constructively by finding unitary transformations that map the models onto each other. Moreover, we considerably generalized our mapping and showed that even in the case of fully site-dependent couplings the XY chain can be mapped onto an XX model. This result has potential application in the study of disordered systems.

  16. Equivalence between XY and dimerized models

    International Nuclear Information System (INIS)

    The spin-1/2 chain with XY anisotropic coupling in the plane and the XX isotropic dimerized chain are shown to be equivalent in the bulk. For finite systems, we prove that the equivalence is exact in given parity sectors, after taking care of the precise boundary conditions. The proof is given constructively by finding unitary transformations that map the models onto each other. Moreover, we considerably generalized our mapping and showed that even in the case of fully site-dependent couplings the XY chain can be mapped onto an XX model. This result has potential application in the study of disordered systems.

  17. Water dimer absorption of visible light

    OpenAIRE

    Hargrove, J

    2007-01-01

    International audience Laboratory measurements of water vapor absorption using cavity ring-down spectroscopy revealed a broad absorption at 405 nm with a quadratic dependence on water monomer concentration, a similar absorption with a linear component at 532 nm, and only linear absorption at 570 nm in the vicinity of water monomer peaks. D2O absorption is weaker and linear at 405 nm. Van't Hoff plots constructed at 405.26 nm suggest that for dimerization, Keq=0.056±0.02 atm?1, ?H°301 K=?16...

  18. Mono- and Dimeric Phosphine Complexes of Cyclopentadienylvanadium(II) Halides

    NARCIS (Netherlands)

    Nieman, J.; Teuben, J.H.

    1986-01-01

    Reduction of CpVX2(PR3)2 (X = Cl, R = Me, Et; X = Br, R = Et) with Al or Zn in THF gives dimeric vanadium(II) complexes [CpVX(PR3)]2. Methylcyclopentadienyl compounds are accessible by the same method. Treating the dimers with an excess of PR3 gives CpVx(PR3)2, and treating the dimers with bidentate

  19. Extended Quantum Dimer Model and novel valence-bond phases

    OpenAIRE

    Nakata, Kouki; Totsuka, Keisuke

    2011-01-01

    We extend the quantum dimer model (QDM) introduced by Rokhsar and Kivelson so as to construct a concrete example of the model which exhibits the first-order phase transition between different valence-bond solids suggested recently by Batista and Trugman and look for the possibility of other exotic dimer states. We show that our model contains three exotic valence-bond phases (herringbone, checkerboard and dimer smectic) in the ground-state phase diagram and that it realizes the phase transiti...

  20. Mathematical and experimental approaches to the dimer catastrophe theory

    OpenAIRE

    Field, Christopher Martyn

    2011-01-01

    Multicopy plasmids rely on random distribution for stable inheritance by daughter cells at division. Threats to plasmid copy number increase the probability of plasmid loss, which can be detrimental to both plasmid and host. Plasmid dimers emerge through homologous recombination. Dimers have two independent origins of replication and thus have a replicative advantage and reduced copy number. Models of plasmid behaviour suggest that dimers would overtake a cell population, but that this can be...

  1. Theory and Simulations of Adhesion Receptor Dimerization on Membrane Surfaces

    OpenAIRE

    Wu, Yinghao; Honig, Barry; Ben-Shaul, Avinoam

    2013-01-01

    The equilibrium constants of trans and cis dimerization of membrane bound (2D) and freely moving (3D) adhesion receptors are expressed and compared using elementary statistical-thermodynamics. Both processes are mediated by the binding of extracellular subdomains whose range of motion in the 2D environment is reduced upon dimerization, defining a thin reaction shell where dimer formation and dissociation take place. We show that the ratio between the 2D and 3D equilibrium constants can be exp...

  2. Multicritical tensor models and hard dimers on spherical random lattices

    OpenAIRE

    Bonzom, Valentin

    2012-01-01

    Random tensor models which display multicritical behaviors in a remarkably simple fashion are presented. They come with entropy exponents \\gamma = (m-1)/m, similarly to multicritical random branched polymers. Moreover, they are interpreted as models of hard dimers on a set of random lattices for the sphere in dimension three and higher. Dimers with their exclusion rules are generated by the different interactions between tensors, whose coupling constants are dimer activities. As an illustrati...

  3. Conformational stability of dimeric proteins: quantitative studies by equilibrium denaturation.

    OpenAIRE

    Neet, K. E.; Timm, D. E.

    1994-01-01

    The conformational stability of dimeric globular proteins can be measured by equilibrium denaturation studies in solvents such as guanidine hydrochloride or urea. Many dimeric proteins denature with a 2-state equilibrium transition, whereas others have stable intermediates in the process. For those proteins showing a single transition of native dimer to denatured monomer, the conformational stabilities, delta Gu (H2O), range from 10 to 27 kcal/mol, which is significantly greater than the conf...

  4. Nature of telomere dimers and chromosome looping in human spermatozoa

    OpenAIRE

    Solov'eva, Lyudmila; Svetlova, Maria; Bodinski, Dawn; Zalensky, Andrei O.

    2004-01-01

    Specific and well-organized chromosome architecture in human sperm cells is supported by the prominent interactions between centromeres and between telomeres. The telomere-telomere interactions result in telomere dimers that are positioned at the nuclear periphery. It is unknown whether composition of sperm telomere dimers is random or specific. We now report that telomere dimers result from specific interactions between the two ends of each chromosome. FISH using pairs of subtelomeric DNA pr...

  5. Kinetics of the dimerization of retroviral proteases: The "fireman's grip" and dimerization

    Czech Academy of Sciences Publication Activity Database

    Ingr, Marek; Kondrová, Taťána; Stříšovský, Kvido; Majerová, E.; Konvalinka, Jan

    2003-01-01

    Roč. 12, - (2003), s. 2173-2182. ISSN 0961-8368 R&D Projects: GA MZd NI6339 Institutional research plan: CEZ:AV0Z4055905 Keywords : retroviral protease * dimerization * HIV protease Subject RIV: CE - Biochemistry Impact factor: 3.787, year: 2003

  6. The expressions and clinical significance of complements 3, 4B1 and apolipoprotein E in pancreatic cancer%补体3、补体4B1及载脂蛋白E在胰腺癌中的表达及临床意义

    Institute of Scientific and Technical Information of China (English)

    陈炯; 郑春生; 汤厚阔

    2011-01-01

    Objective To investigate the expressions of complements 3 (C3), 4B1 (C4B1) and apolipoprotein E (ApoE) in pancreatic cancer and relations with TNM staging and lymph node metastasis of pancreatic cancer. Methods Thirty-eight pancreatic cancer biopsy specimens, 20 fresh pancreatic cancer specimens and 20 adjacent normal tissues of pancreatic cancer were collected. The expressions of C3, C4B1, ApoE in pancreatic cancers and normal pancreatic tissues were detected by immunohistochemistry and Western-Blot, the positive expression rates of C3, C4B1, ApoE and the differences in gray scale were also observed. Their association with pancreatic cancer TNM staging and lymph node metastasis were analyzed by SPSS 13.0. Results The expression rates of C3, C4B1, ApoE in pancreatic cancer were 73.68% (28/38), 86.84%(29/38) and 76.31% (33/38) respectively, higher than those in normal pancreatic tissues which were 42.11% (16/38), 26.32% (10/38) and 42.11% (16/38) accordingly, the differences were statistically significant (χ2 was 7.77, 19.01, 16.6, and P value were 0.01, 0.00, 0.00 respectively). The gray scale of C3, C4B1 and ApoE in pancreatic cancer were 1.63±0.28,1.25±0.18 and 2.57±0.22 respectively, higher than those in normal pancreatic tissue (0.88±0.19,0.65±0.13,1.28±0.24 respectively), the differences were statistically significant (t value were 9.93,11.81,17.71 and all P value were 0.00, respectively). There was no association between C3 and TNM staging or lymphatic metastasis of pancreatic cancer. C4B1 and ApoE were closely related with TNM stage and lymph node metastases. The expressions of C4B1 and ApoE in stage Ⅱ to Ⅳ pancreatic cancer or with lymphatic metastasis were significantly higher than those in stage Ⅰpancreatic cancer and those without lymph node metastasis. Conclusion C3, C4B1 and ApoE were all highly expressed in pancreatic cancer. C3 was only involved in early event in pancreatic cancer, not related with development of pancreatic cancer. C4B1

  7. Possible Formation of Metastable PAH Dimers upon Pickup by Helium Droplets.

    Science.gov (United States)

    Calvo, F; Yurtsever, E; Birer, Ö

    2016-03-17

    Using path-integral molecular dynamics simulations and two quantum-mechanical-based force fields, we have investigated the conformational stability of dimers of a polycyclic aromatic hydrocarbon, perylene (C20H12), produced under typical experimental conditions of successive pick-up under helium nanodroplet environment. The most stable configurations are found to be of the stacked form with different relative orientations of the main molecular axes, perpendicular or T-shaped dimers being energetically much disfavored; however, in the presence of helium our simulations suggest that the time for rearrangement and π-stacking may be rather long and exceed hundreds of picoseconds. In addition, highly metastable dimers that are stacked but with a helium monolayer sandwiched between the two molecules are also found as likely products upon successive pickup. This stabilization occurs owing to the stronger localization of the helium atoms facing the aromatic rings, which is further enhanced in the dimer. The implications of the present results are discussed in the perspective of possible identification by spectroscopic methods. PMID:26890583

  8. FAK dimerization controls its kinase-dependent functions at focal adhesions

    KAUST Repository

    Brami-Cherrier, Karen

    2014-01-30

    Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK\\'s kinase-dependent functions-autophosphorylation of tyrosine-397-requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation. © 2014 The Authors.

  9. Structure of cobalt protoporphyrin chloride and its dimer, observation and DFT modeling.

    Science.gov (United States)

    de la Lande, Aurélien; Ha-Thi, Minh-Huong; Chen, Shufeng; Soep, Benoît; Shafizadeh, Niloufar

    2016-06-22

    In this article we present a joint study by time-of-flight mass spectroscopy and density functional theory of cobalt protoporphyrin dimer complexes. The main novelty of the experimental part is to reveal the formation of porphyrin dimers that eventually include a chlorine atom. Density functional theory calculations have been performed to shed light on the structural and electronic properties of monomers and dimers that may be formed experimentally. Various geometries of the monomers are analyzed in the two lowest spin states. The electronic structures are examined by means of population analysis relying on the iterative Hirshfeld scheme and the topological analyses of the electron localization function. It is shown that the cobalt ligand bond is purely ionic in the triplet states but shows a noticeable covalent character in the singlet state. Ionization potential of Co-protoporphyrin and binding energies of the chlorine ligand are also reported. Concerning the dimers, several association patterns are investigated for the chlorinated and non-chlorinated complexes. It is found that the structures of the most stable complexes involve four hydrogen bonds between the carboxylic acid moieties of the protoporphyrins. However other association modes are likely to be possible in the experiments. PMID:27270590

  10. Configurational entropy and cooperativity between ligand binding and dimerization in glycopeptide antibiotics.

    Science.gov (United States)

    Jusuf, Sutjano; Loll, Patrick J; Axelsen, Paul H

    2003-04-01

    Oligomerization and ligand binding are thermodynamically cooperative processes in many biochemical systems, and the mechanisms giving rise to cooperative behavior are generally attributed to changes in structure. In glycopeptide antibiotics, however, these cooperative processes are not accompanied by significant structural changes. To investigate the mechanism by which cooperativity arises in these compounds, fully solvated molecular dynamics simulations and quasiharmonic normal-mode analysis were performed on chloroeremomycin, vancomycin, and dechlorovancomycin. Configurational entropies were derived from the vibrational modes recovered from ligand-free and ligand-bound forms of the monomeric and dimeric species. Results indicate that both ligand binding and dimerization incur an entropic cost as vibrational activity in the central core of the antibiotic is shifted to higher frequencies with lower amplitudes. Nevertheless, ligand binding and dimerization are cooperative because the entropic cost of both processes occurring together is less than the cost of these processes occurring separately. These reductions in configurational entropy are more than sufficient in magnitude to account for the experimentally observed cooperativity between dimerization and ligand binding. We conclude that biochemical cooperativity can be mediated through changes in vibrational activity, irrespective of the presence or absence of concomitant structural change. This may represent a general mechanism of allostery underlying cooperative phenomena in diverse macromolecular systems. PMID:12656635

  11. A note on dimer models and D-brane gauge theories

    International Nuclear Information System (INIS)

    The connection between quiver gauge theories and dimer models has been well studied. It is known that the matter fields of the quiver gauge theories can be represented using the perfect matchings of the corresponding dimer model. We conjecture that a subset of perfect matchings associated with an internal point in the toric diagram is sufficient to give information about the charge matrix of the quiver gauge theory. Further, we perform explicit computations on some aspects of partial resolutions of toric singularities using dimer models. We analyse these with graph theory techniques, using the perfect matchings of orbifolds of the form C3/Γ, where the orbifolding group Γ may be noncyclic. Using these, we study the construction of the superpotential of gauge theories living on D-branes which probe these singularities, including the case where one or more adjoint fields are present upon partial resolution. Applying a combination of open and closed string techniques to dimer models, we also study some aspects of their symmetries.

  12. Insights into Strand Exchange in BTB Domain Dimers from the Crystal Structures of FAZF and Miz1

    Energy Technology Data Exchange (ETDEWEB)

    Stogios, Peter J.; Cuesta-Seijo, Jose Antonio; Chen, Lu; Pomroy, Neil C.; Privé, Gilbert G. (Toronto); (OCI)

    2010-09-22

    The BTB domain is a widely distributed protein-protein interaction motif that is often found at the N-terminus of zinc finger transcription factors. Previous crystal structures of BTB domains have revealed tightly interwound homodimers, with the N-terminus from one chain forming a two-stranded anti-parallel {beta}-sheet with a strand from the other chain. We have solved the crystal structures of the BTB domains from Fanconi anemia zinc finger (FAZF) and Miz1 (Myc-interacting zinc finger 1) to resolutions of 2.0 {angstrom} and 2.6 {angstrom}, respectively. Unlike previous examples of BTB domain structures, the FAZF BTB domain is a nonswapped dimer, with each N-terminal {beta}-strand associated with its own chain. As a result, the dimerization interface in the FAZF BTB domain is about half as large as in the domain-swapped dimers. The Miz1 BTB domain resembles a typical swapped BTB dimer, although it has a shorter N-terminus that is not able to form the interchain sheet. Using cysteine cross-linking, we confirmed that the promyelocytic leukemia zinc finger (PLZF) BTB dimer is strand exchanged in solution, while the FAZF BTB dimer is not. A phylogenic tree of the BTB fold based on both sequence and structural features shows that the common ancestor of the BTB domain in BTB-ZF (bric a brac, tramtrack, broad-complex zinc finger) proteins was a domain-swapped dimer. The differences in the N-termini seen in the FAZF and Miz1 BTB domains appear to be more recent developments in the structural evolution of the domain.

  13. Dimeric Labdane Diterpenes: Synthesis and Antiproliferative Effects

    Directory of Open Access Journals (Sweden)

    Guillermo Schmeda-Hirschmann

    2013-05-01

    Full Text Available Several diterpenes with the labdane skeleton show biological activity, including antiproliferative effects. Most of the research work on bioactive labdanes has been carried out on naturally occurring diterpenes and semisynthetic derivatives, but much less is known on the effects of diterpene dimers. The aim of the present work was to synthesize dimeric diterpenes from the labdane imbricatolic acid using esters, ethers and the triazole ring as linkers. Some 18 new derivatives were prepared and the compounds were evaluated for antiproliferative activity on human normal fibroblasts (MRC-5 and the following human tumor cell lines: AGS, SK-MES-1, J82 and HL-60. The diethers 8–10, differing in the number of CH2 units in the linker, presented better antiproliferative activity with a maximum effect for the derivative 9. The best antiproliferative effect against HL-60 cells was found for compounds 3 and 17, with IC50 values of 22.3 and 23.2 μM, lower than that found for the reference compound etoposide (2.23 μM. The compounds 9, 17 and 11 were the most active derivatives towards AGS cells with IC50 values of 17.8, 23.4 and 26.1 μM. A free carboxylic acid function seems relevant for the effect as several of the compounds showed less antiproliferative effect after methylation.

  14. Water dimer absorption of visible light

    Directory of Open Access Journals (Sweden)

    J. Hargrove

    2007-07-01

    Full Text Available Laboratory measurements of water vapor absorption using cavity ring-down spectroscopy revealed a broad absorption at 405 nm with a quadratic dependence on water monomer concentration, a similar absorption with a linear component at 532 nm, and only linear absorption at 570 nm in the vicinity of water monomer peaks. D2O absorption is weaker and linear at 405 nm. Van't Hoff plots constructed at 405.26 nm suggest that for dimerization, Keq=0.056±0.02 atm−1, ΔH°301 K=−16.6±2 kJ mol−1 and ΔS°301 K=−80±10 J mol−1 K−1. This transition peaks at 409.5 nm, could be attributed to the 8th overtone of water dimer and the 532 nm absorption to the 6th overtone. It is possible that some lower overtones previously searched for are less enhanced. These absorptions could increase water vapor feed back calculations leading to higher global temperature projections with currently projected greenhouse gas levels or greater cooling from greenhouse gas reductions.

  15. Modelling study of dimerization in mammalian defensins

    Directory of Open Access Journals (Sweden)

    Verma Chandra

    2006-12-01

    Full Text Available Abstract Background Defensins are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. Their cationicity, amphipathicity and ability to oligomerize are considered key factors for their action. Based on structural information on human β-defensin 2, we examine homologous defensins from various mammalian species for conserved functional physico-chemical characteristics. Results Based on homology greater than 40%, structural models of 8 homologs of HBD-2 were constructed. A conserved pattern of electrostatics and dynamics was observed across 6 of the examined defensins; models backed by energetics suggest that the defensins in these 6 organisms are characterized by dimerization-linked enhanced functional potentials. In contrast, dimerization is not energetically favoured in the sheep, goat and mouse defensins, suggesting that they function efficiently as monomers. Conclusion β-defensin 2 from some mammals may work as monomers while those in others, including humans, work as oligomers. This could potentially be used to design human defensins that may be effective at lower concentrations and hence have therapeutic benefits.

  16. Ionization dynamics of water dimer on ice surface

    Science.gov (United States)

    Tachikawa, Hiroto

    2016-05-01

    The solid surface provides an effective two-dimensional reaction field because the surface increases the encounter probability of bi-molecular collision reactions. Also, the solid surface stabilizes a reaction intermediate because the excess energy generated by the reaction dissipates into the bath modes of surface. The ice surface in the universe is one of the two dimensional reaction fields. However, it is still unknown how the ice surface affects to the reaction mechanism. In the present study, to elucidate the specific property of the ice surface reaction, ionization dynamics of water dimer adsorbed on the ice surface was theoretically investigated by means of direct ab-initio molecular dynamics (AIMD) method combined with ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) technique, and the result was compared with that of gas phase reaction. It was found that a proton is transferred from H2O+ to H2O within the dimer and the intermediate complex H3O+(OH) is formed in both cases. However, the dynamic features were different from each other. The reaction rate of the proton transfer on the ice surface was three times faster than that in the gas phase. The intermediate complex H3O+(OH) was easily dissociated to H3O+ and OH radical on the ice surface, and the lifetime of the complex was significantly shorter than that of gas phase (100 fs vs. infinite). The reason why the ice surface accelerates the reaction was discussed in the present study.

  17. FRET-based dimeric aptamer probe for selective and sensitive Lup an 1 allergen detection.

    Science.gov (United States)

    Mairal, T; Nadal, P; Svobodova, M; O'Sullivan, C K

    2014-04-15

    A sensitive method for the rapid and sensitive detection of the anaphylactic food allergen Lup an 1 (β-conglutin) exploiting fluorescence resonance energy transfer (FRET) has been developed. A high affinity dimeric form of a truncated 11-mer aptamer against β-conglutin was used, with each monomeric aptamer being flanked by donor/acceptor moieties. The dimeric form in the absence of target yields fluorescence emission due to the FRET from the excited fluorophore to the proximal second fluorophore. However, upon addition of β-conglutin, the specific interaction induces a change in the bi-aptameric structure resulting in an increase in fluorescence emission. The method is highly specific and sensitive, with a detection limit of 150 pM, providing an effective tool for the direct detection of the toxic β-conglutin subunit in foodstuffs in just 1 min at room temperature. PMID:24280051

  18. Hydrogen Recombination and Dimer Formation on Graphite from Ab Initio Molecular Dynamics Simulations.

    Science.gov (United States)

    Casolo, S; Tantardini, G F; Martinazzo, R

    2016-07-14

    We studied Eley-Rideal molecular hydrogen formation on graphite using ab initio molecular dynamics, in the energy range relevant for the chemistry of the interstellar medium and for terrestrial experiments employing cold plasma (0.02-1 eV). We found substantial projectile steering effects that prevent dimer formation at low energies, thereby ruling out any catalytic synthetic pathways that form hydrogen molecules. Ortho and para dimers do form efficiently thanks to preferential sticking, but only at energies that are too high to be relevant for the chemistry of the interstellar medium. Computed reaction cross sections and ro-vibrational product populations are in good agreement with available experimental data and capable of generating adsorbate configurations similar to those observed with scanning tunneling microscopy techniques. PMID:26905385

  19. Dimerization of translationally controlled tumor protein is essential for its cytokine-like activity.

    Directory of Open Access Journals (Sweden)

    Miyoung Kim

    Full Text Available BACKGROUND: Translationally Controlled Tumor Protein (TCTP found in nasal lavage fluids of allergic patients was named IgE-dependent histamine-releasing factor (HRF. Human recombinant HRF (HrHRF has been recently reported to be much less effective than HRF produced from activated mononuclear cells (HRFmn. METHODS AND FINDINGS: We found that only NH(2-terminal truncated, but not C-terminal truncated, TCTP shows cytokine releasing activity compared to full-length TCTP. Interestingly, only NH(2-terminal truncated TCTP, unlike full-length TCTP, forms dimers through intermolecular disulfide bonds. We tested the activity of dimerized full-length TCTP generated by fusing it to rabbit Fc region. The untruncated-full length protein (Fc-HrTCTP was more active than HrTCTP in BEAS-2B cells, suggesting that dimerization of TCTP, rather than truncation, is essential for the activation of TCTP in allergic responses. We used confocal microscopy to evaluate the affinity of TCTPs to its putative receptor. We detected stronger fluorescence in the plasma membrane of BEAS-2B cells incubated with Del-N11TCTP than those incubated with rat recombinant TCTP (RrTCTP. Allergenic activity of Del-N11TCTP prompted us to see whether the NH(2-terminal truncated TCTP can induce allergic airway inflammation in vivo. While RrTCTP had no influence on airway inflammation, Del-N11TCTP increased goblet cell hyperplasia in both lung and rhinal cavity. The dimerized protein was found in sera from allergic patients, and bronchoalveolar lavage fluids from airway inflamed mice. CONCLUSIONS: Dimerization of TCTP seems to be essential for its cytokine-like activity. Our study has potential to enhance the understanding of pathogenesis of allergic disease and provide a target for allergic drug development.

  20. Exact Solution of a Generalized Nonlinear Schrodinger Equation Dimer

    DEFF Research Database (Denmark)

    Christiansen, Peter Leth; Maniadis, P.; Tsironis, G.P.

    1998-01-01

    We present exact solutions for a nonlinear dimer system defined throught a discrete nonlinear Schrodinger equation that contains also an integrable Ablowitz-Ladik term. The solutions are obtained throught a transformation that maps the dimer into a double Sine-Gordon like ordinary nonlinear...

  1. Spin dynamics of quantum and classical Heisenberg dimers

    OpenAIRE

    Mentrup, D.; Schnack, J.; Luban, Marshall

    1999-01-01

    Analytical solutions for the time-dependent autocorrelation function of the classical and quantum mechanical spin dimer with arbitrary spin are presented and compared. For large spin quantum numbers or high temperature the classical and the quantum dimer become more and more similar, yet with the major difference that the quantum autocorrelation function is periodic in time whereas the classical is not.

  2. Local field enhancement: comparing self-similar and dimer nanoantennas

    CERN Document Server

    Pellegrini, Giovanni; Finazzi, Marco; Biagioni, Paolo

    2016-01-01

    We study the local field enhancement properties of self-similar nanolenses and compare the obtained results with the performance of standard dimer nanoantennas. We report that, despite the additional structural complexity, self-similar nanolenses are unable to provide significant improvements over the field enhancement performance of standard plasmonic dimers.

  3. Dimer representations of the Temperley–Lieb algebra

    International Nuclear Information System (INIS)

    A new spin-chain representation of the Temperley–Lieb algebra TLn(β=0) is introduced and related to the dimer model. Unlike the usual XXZ spin-chain representations of dimension 2n, this dimer representation is of dimension 2n−1. A detailed analysis of its structure is presented and found to yield indecomposable zigzag modules

  4. Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes.

    Directory of Open Access Journals (Sweden)

    Jonathan W Nelson

    Full Text Available The epoxyeicosatrienoic acid (EET neutralizing enzyme soluble epoxide hydrolase (sEH is a neuronal enzyme, which has been localized in both the cytosol and peroxisomes. The molecular basis for its dual localization remains unclear as sEH contains a functional peroxisomal targeting sequence (PTS. Recently, a missense polymorphism was identified in human sEH (R287Q that enhances its peroxisomal localization. This same polymorphism has also been shown to generate weaker sEH homo-dimers. Taken together, these observations suggest that dimerization may mask the sEH PTS and prevent peroxisome translocation. In the current study, we test the hypothesis that dimerization is a key regulator of sEH subcellular localization. Specifically, we altered the dimerization state of sEH by introducing substitutions in amino acids responsible for the dimer-stabilizing salt-bridge. Green Fluorescent Protein (GFP fusions of each of mutants were co-transfected into mouse primary cultured cortical neurons together with a PTS-linked red fluorescent protein to constitutively label peroxisomes. Labeled neurons were analyzed using confocal microscopy and co-localization of sEH with peroxisomes was quantified using Pearson's correlation coefficient. We find that dimer-competent sEH constructs preferentially localize to the cytosol, whereas constructs with weakened or disrupted dimerization were preferentially targeted to peroxisomes. We conclude that the sEH dimerization status is a key regulator of its peroxisomal localization.

  5. Synthesis of novel organo-phosphorus C60 dimers

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Carbon bridged organophosphorus C60 dimers were obtained by the reaction of aminome- thylenebisphosphonate anion with C60 and fully characterized by 1HNMR, 31PNMR, 13CNMR, FT- MALDI-MS, FT-IR, UV-Vis, DEPT and HMBC, and the dimeric compounds undergo hydrolysis by using TMSI.

  6. Dimeric Surfactants: Promising Ingredients of Cosmetics and Toiletries

    OpenAIRE

    Naveen Kumar; Rashmi Tyagi

    2013-01-01

    Surfactants are an essential ingredient for cosmetic, toiletries and personal care products for enhancing their performance. Dimeric surfactants demonstrate superiority compared to conventional surfactants in all areas of application. Dimeric surfactants are extremely promising for utilization in various cosmetic formulations viz. shampoo, lotions, creams, conditioners etc. These surfactants possess extremely unique surface properties viz. lower surface tension, unique micellization, low crit...

  7. Mechanism of hairpin-duplex conversion for the HIV-1 dimerization initiation site.

    Science.gov (United States)

    Bernacchi, Serena; Ennifar, Eric; Tóth, Katalin; Walter, Philippe; Langowski, Jörg; Dumas, Philippe

    2005-12-01

    We have used the dimerization initiation site of HIV-1 genomic RNA as a model to investigate hairpin-duplex interconversion with a combination of fluorescence, UV melting, gel electrophoresis, and x-ray crystallographic techniques. Fluorescence studies with molecular beacons and crystallization experiments with 23-nucleotide dimerization initiation site fragments showed that the ratio of hairpin to duplex formed after annealing in water essentially depends on RNA concentration and not on cooling kinetics. With natural sequences allowing to form the most stable duplex, and thus also the loop-loop complex (or "kissing complex"), concentrations as low as 3 mum in strands are necessary to obtain a majority of the hairpin form. With a mutated sequence preventing kissing complex formation, a majority of hairpins was even obtained at 80 mum in strands. However, this did not prevent an efficient conversion from hairpin to duplex in the presence of salts. Kinetic considerations are in favor of duplex formation from intermediates involving hairpins engaged in cruciform dimers rather than from free strands. The very first step of formation of such a cruciform intermediate could be trapped in a crystal structure. This mechanism might be significant for the dynamics of small RNAs beyond the strict field of HIV-1. PMID:16169845

  8. Gravidade da lesão angiográfica coronariana e polimorfismo da APOE nas síndromes coronarianas agudas Severidad de la lesión angiográfica coronaria y polimorfismo de la APOE en los síndromes coronarios agudos Severity of angiographic coronary obstruction and the apolipoprotein E polymorphism in acute coronary syndromes

    Directory of Open Access Journals (Sweden)

    Arlisa Monteiro de Castro Dias

    2009-09-01

    afectados por obstrucción significativa definida por angiografía, el polimorfismo de la APOE y las variables clínicas. MÉTODOS: Estudio transversal multicéntrico que implicó a 207 pacientes (138 varones con síndrome coronario agudo (SCA en la ciudad de Niterói (RJ - Brasil, los que realizaron angiografía coronaria, y determinación del genotipo para el polimorfismo APOE *2*3*4 mediante el método de Restriction Fragment Length Polymorphism (RFLP. RESULTADOS: La frecuencia de los alelos APOE *2 fue del 6,8%, *3 fue del 82,5%, y *4 fue del 10,7%. En cuanto al número de vasos lesionados, el 27% de los pacientes presentaban obstrucción uniarterial, el 33,8%, biarterial, y el 39,1%, triarterial o de tronco de la coronaria izquierda. El grado de lesión multivascular no se relacionó con la presencia del alelo *4 (p = 0,78, sino con la edad > 55 años (p = 0,025, el ex tabaquismo (p = 0,004 y la dislipidemia (p = 0,05 en el análisis multivariado y con la enfermedad arterial coronaria previa (p = 0,05, la diabetes (p = 0,038 y el síndrome metabólico (p = 0,021 en el análisis univariado. La prevalencia de dislipidemia, diabetes e hipertensión arterial sistémica (HAS fue elevada con relación a estudios semejantes, con aumento progresivo de la prevalencia de HAS (p = 0,59 y de diabetes (p = 0,06, según el número de vasos lesionados. CONCLUSIÓN: El polimorfismo de la APOE no se asoció al número de vasos coronarios con obstrucción significativa en cualquier grupo de edad. Por otro lado, la edad > 55 años, el ex tabaquismo y la dislipidemia se asociaron a la lesión multivascular.BACKGROUND: There is evidence of the association between the apolipoprotein E (APOE and coronary disease; however, there are controversies. OBJECTIVE: To evaluate the association between the number of coronary vessels with significant obstruction defined by angiography, the APOE polymorphism and clinical variables. METHODS: This was a cross-sectional, multicenter study with 207 patients

  9. Vertically-oriented nanoparticle dimer based on focused plasmonic trapping.

    Science.gov (United States)

    Shen, Zhe; Su, Lei; Shen, Yao-Chun

    2016-07-11

    We proposed a vertically-oriented dimer structure based on focused plasmonic trapping of metallic nanoparticle. Quantitative FDTD calculations and qualitative analysis by simplified dipole approximation revealed that localized surface plasmon coupling dominates in the plasmon hybridization, and the vertically-oriented dimer can effectively make use of the dominant longitudinal component of the surface plasmon virtual probe thus providing much stronger electric field in the gap. Furthermore, for practical application the top nanoparticle of the dimer can be replaced with an atomic force microscope tip which enables the precise control of the gap distance of the dimer. Therefore the proposed vertically-oriented dimer structure provides both the scanning capability and the extremely-high electrical field necessary for the high sensitivity Raman imaging. PMID:27410874

  10. Molecular Dynamics Simulation of Amyloid Beta Dimer Formation

    CERN Document Server

    Urbanc, B; Ding, F; Sammond, D; Khare, S; Buldyrev, S V; Stanley, H E; Dokholyan, N V

    2004-01-01

    Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40...

  11. Pseudo-two-dimensional random dimer lattices

    Energy Technology Data Exchange (ETDEWEB)

    Naether, U., E-mail: naether@unizar.es [Instituto de Ciencia de Materiales de Aragón and Departamento de Física de la Materia Condensada, CSIC – Universidad de Zaragoza, 50009 Zaragoza (Spain); Mejía-Cortés, C.; Vicencio, R.A. [Departamento de Física and MSI – Nucleus for Advanced Optics, Center for Optics and Photonics (CEFOP), Facultad de Ciencias, Universidad de Chile, Santiago (Chile)

    2015-06-05

    We study the long-time wave transport in correlated and uncorrelated disordered 2D arrays. When a separation of dimensions is applied to the model, we find that the previously predicted 1D random dimer phenomenology also appears in so-called pseudo-2D arrays. Therefore, a threshold behavior is observed in terms of the effective size for eigenmodes, as well as in long-time dynamics. A minimum system size is required to observe this threshold, which is very important when considering a possible experimental realization. For the long-time evolution, we find that for correlated lattices a super-diffusive long-range transport is observed. For completely uncorrelated disorder 2D transport becomes sub-diffusive within the localization length and for random binary pseudo-2D arrays localization is observed.

  12. Pseudo-two-dimensional random dimer lattices

    International Nuclear Information System (INIS)

    We study the long-time wave transport in correlated and uncorrelated disordered 2D arrays. When a separation of dimensions is applied to the model, we find that the previously predicted 1D random dimer phenomenology also appears in so-called pseudo-2D arrays. Therefore, a threshold behavior is observed in terms of the effective size for eigenmodes, as well as in long-time dynamics. A minimum system size is required to observe this threshold, which is very important when considering a possible experimental realization. For the long-time evolution, we find that for correlated lattices a super-diffusive long-range transport is observed. For completely uncorrelated disorder 2D transport becomes sub-diffusive within the localization length and for random binary pseudo-2D arrays localization is observed

  13. Monomer-dimer model explains the results of radiation inactivation: binding characteristics of insulin receptor purified from human placenta

    International Nuclear Information System (INIS)

    The technique of radiation inactivation has been used on highly purified human placental insulin receptor in order to determine the functional molecular size responsible for the insulin binding and to evaluate the affinity regulator hypothesis, which has been proposed to explain the increase in specific insulin binding to rat liver membranes observed at low radiation does. Three different types of inactivation curves were observed: (1) biphasic with an enhanced binding activity after exposure to low radiation doses, (2) nonlinear with no change in binding activity after exposure to low radiation doses, and (3) linear with a loss in the binding activity with increasing radiation exposures. A monomer-dimer model was the simplest model that best described the three types of radiation inactivation curves observed. The model predicts that an increase in insulin binding activity would result after exposure to low radiation doses when the initial dimer/monomer ratio is equal to or greater than 1 and a monomer is more active than a dimer. The monomer size of the binding activity was estimated to be 227,000 daltons by this model. To substantiate this model, the purified receptor was fractionated by Sepharose CL-6B chromatography. The insulin binding profile of this column indicated two peaks. These studies suggest that the affinity regulator does not exist as a separate structural protein but is due to the dimeric form of the receptor. The dimeric form (α2β2) possesses a much lower specific activity for insulin binding than does the monomeric αβ form (under the standard conditions), but the dimeric structure is necessary to observe the negative cooperative binding isotherm

  14. Teaching Form as Form

    DEFF Research Database (Denmark)

    Keiding, Tina Bering

    2012-01-01

    understanding of form per se, or, to use an expression from this text, of form as form. This challenge can be reduced to one question: how can design teaching support students in achieving not only the ability to recognize and describe different form-related concepts in existing design (i.e. analytical and...

  15. Preparation of gold nanoparticle dimers via streptavidin-induced interlinking

    Energy Technology Data Exchange (ETDEWEB)

    Zon, Vera B.; Sachsenhauser, Matthias; Rant, Ulrich, E-mail: rant@wsi.tum.de [Technische Universitaet Muenchen, Walter Schottky Institut (Germany)

    2013-10-15

    There is great interest in establishing efficient means of organizing nanoparticles into complex structures, especially in fields like nano-optical devices. One of the demonstrated routes uses biomolecular scaffolds, like the streptavidin-biotin system, to deterministically separate and structure particle complexes. However, controlled formation of streptavidin-linked nanoparticle dimers or trimers is challenging, and large aggregates are often formed under conditions that are difficult to regulate. Here, we studied the aggregates and interlinking kinetics of biotin-functionalized 20 nm gold nanoparticles in the presence of the interlinking protein, streptavidin. We found two different protein-linker concentration regions where small stable particle aggregates are formed: when the protein and nanoparticle concentrations are similar and when the protein to nanoparticle concentration ratio exceeds intermediate concentrations (10:1-100:1) that promote precipitation of large aggregates. We attribute this behavior to the limited availability of free-linker molecules and the limited availability of free ligand (biotin) on the particle surface for low and high protein concentrations, respectively. Furthermore, we show that the product can be additionally enriched up to 25 % through either centrifugation in sucrose or size-exclusion chromatography. These results provide additional understanding into the assembly of ligand-functionalized nanoparticles with water-soluble linkers and provide a facile way to produce well-defined small aggregates for potential use in, for instance, surface-enhanced spectroscopy.

  16. Luminal and parenteral TFF2 and TFF3 dimer and monomer in two models of experimental colitis in the rat

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Kissow, Hannelouise; Hare, Kristine; Hartmann, Bolette; Thim, Lars

    2005-01-01

    , and both injected and orally administered TFF peptide have protective and healing functions in the gastric mucosa. AIM: To investigate the possible treatment effect of luminally and parenterally administered TFF peptides in experimental colitis in rats. METHODS: Colitis was induced by administration...... dimer 5 mg/kg twice per day throughout the study [dextran sulphate sodium (DSS)] or from day 4 to 7 (mitomycin C). Colitis severity was scored in a stereomicroscope and histologically. RESULTS: Luminal treatment with TFF3 in its dimeric form significantly improved the colitis score in both colitis...

  17. Quantum chemical investigation of linear hydrogen bonding in ONCCN···HX (X = F, Cl, Br) dimers

    Science.gov (United States)

    Varadwaj, Pradeep R.

    Linear hydrogen bonding formed between the nitrogen end of cyanogen-N-oxide (ONCCN) and hydrogen halides HX (X = F, Cl, Br) has been observed in their ground ? states. The order of agreement of energetic stabilities between the correlated functionals used in this calculation is: B3LYP bonds in these dimers follows the conventional trend: ONCCN···HF > ONCCN···HCl > ONCCN···HBr in the series, except H-bond lengths and static dipole polarizabilities which are in reverse order. The atomic charges obtained from the Mulliken and natural population analysis is used to assess the charge transfer effects that accompany the dimer formation. It is found from the investigation that the dimers having highest binding energy are accompanied by the highest transfer of charge. The 14N nuclear quadrupole coupling constants of the monomer ON1CCN2 are found to be decreased upon complection and in the series it increases from F through Br. We observed enhancements in the values of the dimer dipole moment and intrinsic dipole polarizabilities compared with the sum of the monomer values by intermolecular electrical interaction. Investigation reveals vibrational spectral shifts of HX and CN stretching modes similar to the conventional red-shifted H-bonded dimers; for the former case, the infrared band intensity increases significantly. Finally, the new vibrational modes originated from the intermolecular interaction are outlined.

  18. Relativistic time-dependent density functional theory, a study of the ground and excited states of the zinc dimer

    Energy Technology Data Exchange (ETDEWEB)

    Kullie, Ossama [CNRS et Universite de Strasbourg, Institut de Chimie, Laboratoire de Chimie Quantique, 1 Rue Blaise Pascal, F- 67008 Strasbourg cedex (France)

    2012-07-01

    In this poster I present a (time-dependent) density functional study of the 20 low-lying excited states as well the ground states of the zinc dimer Zn{sub 2}. I analyze the spectrum of the dimer obtained form all electrons calculations which are performed using time-depended density functional with a relativistic 4-components-, and spin-free-Hamiltonian. I show results for different well-known density functional approximations, in comparing with literature and experimental values, the results are very encouraging, especially for the lowest excited states of these dimers. However, the results show that only the long-range corrected functionals such CAMB3LYP gives the correct asymptotic behavior for the higher states, for which the best result is obtained, and a comparable result is obtained from PBE0 functional.

  19. An asymmetric dimer in a periodic potential: a minimal model for friction of graphene flakes

    Science.gov (United States)

    Hens, Remco; Fasolino, Annalisa

    2016-07-01

    We discuss the friction and motion of a model of a dimer with asymmetric interactions with a substrate potential. Starting from the consideration that a rigid dimer with spacing equal to half of the period of the potential has exactly zero static friction like the infinite incommensurate Frenkel Kontorova model, we show how stick-slip behaviour and friction arise as a function of asymmetry. We argue that this model can yield a simple yet insightful description of the frictional behaviour of graphene flakes on graphite and of superlubricity. The results can also be of interest for diatomic molecules on surfaces. Supplementary material in the form of three mp4 files available from the Journal web page at http://dx.doi.org/10.1140/epjb/e2016-70273-5

  20. α-Helix-peptides comprising the human nuclear receptor ERRγ competitively provoke inhibition of functional homomeric dimerization.

    Science.gov (United States)

    Liu, Xiaohui; Nishimura, Hirokazu; Fujiyama, Akina; Matsushima, Ayami; Shimohigashi, Miki; Shimohigashi, Yasuyuki

    2016-11-01

    Estrogen-related receptor γ (ERRγ) is a constitutively active nuclear receptor functioning as a transcription factor. ERRγ binds to a single half site designated as ERRE that has only a single DNA-binding motif. However, with regard to the subunit structure, it remains a matter of controversy whether ERRγ binds as a monomer or dimer. Because the ligand-binding domain (LBD) of ERRγ was in a homodimer form in its X-ray crystal structure, the peptide fragments present in the dimer interfaces would perturb or destabilize the dimer structure by inhibiting the mutual interaction among ERRγ molecules. Thus, to demonstrate the essential homodimer structure of ERRγ, we utilized the peptides corresponding to the α-helix peptides 7 (H7), H9, and H10/11 in order to test such inhibitor activity. These selections were done based on a structural analysis of the X-ray crystal structures of ERRγ-LBD, which forms a head-to-head dimer structure. Peptides were evaluated by means of a luciferase reporter gene assay, in which ERRγ exhibited a high constitutive activity with no ligand. When the peptide was expressed in the HeLa cells together with ERRγ, these peptides clearly showed a concentration-dependent activity inhibition, indicating that ERRγ is indeed homodimerized as required for DNA transcription activity. The present results strongly suggest that human nuclear receptor ERRγ functions as a genuine homomeric dimer with symmetrical dimeric interface regions. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 547-554, 2016. PMID:26662629

  1. Pair density wave superconducting states and statistical mechanics of dimers

    Science.gov (United States)

    Soto Garrido, Rodrigo Andres

    spectrum in detail. We show that the quasiparticle spectrum can be fully gapped or nodal in the uniform SC phase and also in the coexisting phase of the uniform SC and PDW parameters. In the pure PDW state, the excitation spectrum has a reconstructed Fermi surface in the form of Fermi pockets of Bogoliubov quasiparticles. In chapter 5 we study the octahedron relation, obeyed in particular by the partition function for dimer coverings of the Aztec Diamond graph. For a suitable class of doubly periodic initial conditions, we find exact solutions with a particularly simple factorized form. For these, we show that the density function that measures the average dimer occupation of a face of the Aztec graph, obeys a system of linear recursion relations with periodic coefficients. This allows us to explore the thermodynamic limit of the corresponding dimer models and to derive exact "arctic" curves separating the various phases of the system. (Abstract shortened by UMI.).

  2. Mono- and Dimeric Phosphine Complexes of Cyclopentadienylvanadium(II) Halides

    OpenAIRE

    Nieman, J.; Teuben, J.H.

    1986-01-01

    Reduction of CpVX2(PR3)2 (X = Cl, R = Me, Et; X = Br, R = Et) with Al or Zn in THF gives dimeric vanadium(II) complexes [CpVX(PR3)]2. Methylcyclopentadienyl compounds are accessible by the same method. Treating the dimers with an excess of PR3 gives CpVx(PR3)2, and treating the dimers with bidentate phosphines, CpVCl(DMPE) and CpVCl(DPPE) are obtained. All compounds are paramagnetic with, in principle, three unpaired electrons on the metal atom. 1H NMR spectra of the complexes show large down...

  3. Electric and magnetic hotspots in dielectric nanowire dimers.

    Science.gov (United States)

    Mirzaei, Ali; Miroshnichenko, Andrey E

    2015-04-14

    We study the formation of the electric and magnetic near-field hotspots in dielectric cylindrical dimers. We compare dielectric and metallic dimers by using experimental data for all materials and consider both TM and TE polarizations of light. We demonstrate that dielectric dimers allow us to simultaneously achieve pure magnetic and electric near-field hotspots for both polarizations in contrast to plasmonic structures. This offers new approaches for near-field engineering such as sensing, control of spontaneous emission, and enhanced Raman scattering. PMID:25773044

  4. Dimeric Surfactants: Promising Ingredients of Cosmetics and Toiletries

    Directory of Open Access Journals (Sweden)

    Naveen Kumar

    2013-11-01

    Full Text Available Surfactants are an essential ingredient for cosmetic, toiletries and personal care products for enhancing their performance. Dimeric surfactants demonstrate superiority compared to conventional surfactants in all areas of application. Dimeric surfactants are extremely promising for utilization in various cosmetic formulations viz. shampoo, lotions, creams, conditioners etc. These surfactants possess extremely unique surface properties viz. lower surface tension, unique micellization, low critical micelle concentration (CMC and antimicrobial activity, higher solubilization etc. Dimerics enhance the performances of cosmetics in an extraordinary manner and provide eco-friendly preparations for human epidermis.

  5. Stochastic optimization-based study of dimerization kinetics

    Indian Academy of Sciences (India)

    Srijeeta Talukder; Shrabani Sen; Ralf Metzler; Suman K Banik; Pinaki Chaudhury

    2013-11-01

    We investigate the potential of numerical algorithms to decipher the kinetic parameters involved in multi-step chemical reactions. To this end, we study dimerization kinetics of protein as a model system. We follow the dimerization kinetics using a stochastic simulation algorithm and combine it with three different optimization techniques (genetic algorithm, simulated annealing and parallel tempering) to obtain the rate constants involved in each reaction step. We find good convergence of the numerical scheme to the rate constants of the process. We also perform a sensitivity test on the reaction kinetic parameters to see the relative effects of the parameters for the associated profile of the monomer/dimer distribution.

  6. Asymmetric and connected graphene dimers for a tunable plasmonic response

    Science.gov (United States)

    Rosolen, G.; Maes, B.

    2015-11-01

    We investigate the infrared response of graphene dimers with various doping and polarization configurations. The interaction between the plasmonic resonances of graphene nanodisks leads to a rich, tunable behavior. The hybridization of the nanodisk modes enables the excitation of resonances that would be invisible or dark in a single disk. The simulation results show various anticrossings that depend on dark-bright or bright-bright mode coupling, which we can describe via a simple Hamiltonian model. In addition, we determine the response of a dimer bridged by a tunable graphene junction. This structure leads to charge transfer plasmons, with an even higher absorption efficiency and tunability than nonbridged dimers.

  7. Host-Guest Chemistry in the Gas Phase: Complex Formation of Cucurbit[6]uril with Proton-bound Water Dimer

    Science.gov (United States)

    Noh, Dong Hun; Lee, Shin Jung C.; Lee, Jong Wha; Kim, Hugh I.

    2014-03-01

    The hydration of cucurbit[6]uril (CB[6]) in the gas phase is investigated using electrospray ionization traveling wave ion mobility mass spectrometry (ESI-TWIM-MS). Highly abundant dihydrated and tetrahydrated species of diprotonated CB[6] are found in the ESI-TWIM-MS spectrum. The hydration patterns of the CB[6] ion and the dissociation patterns of the hydrated CB[6] ion indicate that two water molecules are bound to each other, forming a water dimer in the CB[6] complex. Ion mobility studies combined with the structures calculated by density functional theory suggest that the proton-bound water dimer is present as a Zundel-like structure in the CB[6] portal, forming a hydrogen bond network with carbonyl groups of the CB[6]. When a large guest molecule is bound to a CB[6] portal, water molecules cannot bind to the portal. In addition, the strong binding energy of the water dimer blocks the portal, hindering the insertion of the long alkyl chain of the guest molecule into the CB[6] cavity. With small alkali metal cations, such as Li+ and Na+, a single water molecule interacts with the CB[6] portal, forming hydrogen bonds with the carbonyl groups of CB[6]. A highly stable Zundel-like structure of the proton-bound water dimer or a metal-bound water molecule at the CB[6] portal is suggested as an initial hydration process for CB[6], which is only dissolved in aqueous solution with acid or alkali metal ions.

  8. Immunoglobulin-free light chain monomer-dimer patterns help to distinguish malignant from premalignant monoclonal gammopathies: a pilot study.

    Science.gov (United States)

    Kaplan, Batia; Golderman, Sizilia; Aizenbud, Boris; Esev, Konstantin; Kukuy, Olga; Leiba, Merav; Livneh, Avi; Ben-Zvi, Ilan

    2014-09-01

    Multiple myeloma (MM) and AL amyloidosis (AL) are two malignant forms of monoclonal gammopathies. For the purposes of prognosis and treatment, it is important to distinguish these diseases from the premalignant forms of monoclonal gammopathies, such as monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM). Routine serum/urine tests for monoclonal protein are insufficient for differential diagnosis. Thus, invasive procedures, such as tissue aspiration or biopsy, are applied. In this study, we aimed at characterization of serum-free light chain (FLC) monomer-dimer patterns to distinguish the malignant from the premalignant forms of monoclonal gammopathies. A quantitative Western blotting was applied to estimate the FLC monomer and dimer levels in AL, MM, MGUS, and SMM patients, and in control subjects (healthy individuals and patients with AA amyloidosis). AL and MM patients displayed an abnormally increased dimerization of monoclonal FLC, accompanied by higher clonality values of FLC dimers, as compared to that of monomers. These abnormalities of FLC patterns were not observed in patients with MGUS, SMM, AA amyloidosis, and healthy individuals. Analysis of FLC patterns helped to differentiate AL and MM from MGUS and SMM, a goal difficult to achieve using routine serum tests. Also, our technique might serve as a complimentary diagnostic tool in the cases with suspected AL amyloidosis, where the diagnosis of MM is excluded, while the results of amyloid typing by routine immunohistochemical techniques are inconclusive. PMID:24866208

  9. Polymeric architectures of bismuth citrate based on dimeric building blocks

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Four bismuth complexes, (H2En)[Bi2(cit)2(H2O)4/3]·(H2O)x (1), (H2En)3[Bi2(cit)2Cl4]·(H2O)x (2), (HPy)2[Bi2(cit)2(H2O)8/5]·(H2O)x (3) and (H2En)[Bi2(cit)2](H2O)x (4) [cit = citrate4-; En = ethylenediamine; Py = pyridine] have been synthesized and crystallized. The crystal structures reveal that the basic building blocks in all of these complexes are bismuth citrate dimeric units which combine to form polymeric architectures. The embedded protonated ethylenediamine and pyridine moieties in the polymeric frameworks have been identified by X-ray crystallography and solid-state cross polarization/magic angle spinning (CP/MAS) 13C NMR. Based on the framework of complex 1, a structural model of a clinically used antiulcer drug, ranitidine bismuth citrate (RBC) was generated. The behavior of the protonated amine-bismuth citrate complexes in acidic aqueous solution has been studied by electrospray ionization-mass spectrometry (ESI-MS).

  10. Self-Assembling Multifunctional Peptide Dimers for Gene Delivery Systems

    Directory of Open Access Journals (Sweden)

    Kitae Ryu

    2015-01-01

    Full Text Available Self-assembling multifunctional peptide was designed for gene delivery systems. The multifunctional peptide (MP consists of cellular penetrating peptide moiety (R8, matrix metalloproteinase-2 (MMP-2 specific sequence (GPLGV, pH-responsive moiety (H5, and hydrophobic moiety (palmitic acid (CR8GPLGVH5-Pal. MP was oxidized to form multifunctional peptide dimer (MPD by DMSO oxidation of thiols in terminal cysteine residues. MPD could condense pDNA successfully at a weight ratio of 5. MPD itself could self-assemble into submicron micelle particles via hydrophobic interaction, of which critical micelle concentration is about 0.01 mM. MPD showed concentration-dependent but low cytotoxicity in comparison with PEI25k. MPD polyplexes showed low transfection efficiency in HEK293 cells expressing low level of MMP-2 but high transfection efficiency in A549 and C2C12 cells expressing high level of MMP-2, meaning the enhanced transfection efficiency probably due to MMP-induced structural change of polyplexes. Bafilomycin A1-treated transfection results suggest that the transfection of MPD is mediated via endosomal escape by endosome buffering ability. These results show the potential of MPD for MMP-2 targeted gene delivery systems due to its multifunctionality.

  11. PREPARATION AND APPLICATION OF DIMER ACID/LIGNIN GRAFT COPOLYMER

    Directory of Open Access Journals (Sweden)

    Run Fang

    2011-06-01

    Full Text Available Dimer acid (DA was grafted onto lignin (EHL to form a graft copolymer DA-g-EHL. The selection of the reaction type and the optimization of the reaction conditions for the grafting reaction were conducted through orthogonal and single factor experiments. FT-IR and thermal analysis were used to characterize the graft product. It was found that, compared with free radical grafting, DA can be grafted onto EHL more effectively by ester condensation with strongly acidic cation exchange resin as a catalyst. Under optimum reaction conditions, the increase of acid value and the yield of graft copolymer can reach about 9.3% and 83%, respectively. The application of DA-g-EHL in preparing modified phenolic aldehyde amine curing agent (PAA was studied. Results showed that the flexibility of the epoxy resin cured by DA-g-EHL modified PAA is significant higher than that of the resin cured by EHL modified PAA. The graft of DA onto EHL may reduce the rigidity of EHL and the chain stiffness of the PAA modified by EHL.

  12. RACK1 and β-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5.

    Science.gov (United States)

    Bolger, Graeme B

    2016-07-01

    PDE4 family cAMP-selective cyclic nucleotide phosphodiesterases are important in the regulation of cAMP abundance in numerous systems, and thereby play an important role in the regulation of PKA and EPAC activity and the phosphorylation of CREB. We have used the yeast 2-hybrid system to demonstrate recently that long PDE4 isoforms form homodimers, consistent with data obtained recently by structural studies. The long PDE4 isoform PDE4D5 interacts selectively with β-arrestin2, implicated in the regulation of G-protein-coupled receptors and other cell signaling components, and also with the β-propeller protein RACK1. In the present study, we use 2-hybrid approaches to demonstrate that RACK1 and β-arrestin2 inhibit the dimerization of PDE4D5. We also show that serine-to-alanine mutations at PKA and ERK1/2 phosphorylation sites on PDE4D5 detectably ablate dimerization. Conversely, phospho-mimic serine-to-aspartate mutations at the MK2 and oxidative stress kinase sites ablate dimerization. Analysis of PDE4D5 that is locked into the dimeric configuration by the formation of a trans disulfide bond between Ser261 and Ser602 shows that RACK1 interacts strongly with both the monomeric and dimeric forms, but that β-arrestin2 interacts exclusively with the monomeric form. This is consistent with the concept that β-arrestin2 can preferentially recruit the monomeric, or "open," form of PDE4D5 to β2-adrenergic receptors, where it can regulate cAMP signaling. PMID:26257302

  13. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

    Directory of Open Access Journals (Sweden)

    Yun Seong-Jo

    2012-01-01

    Full Text Available Abstract Background Dimeric human erythropoietin (dHuEPO peptides are reported to exhibit significantly higher biological activity than the monomeric form of recombinant EPO. The objective of this study was to produce transgenic (tg mice expressing dHuEPO and to investigate the characteristics of these mice. Methods A dHuEPO-expressing vector under the control of the goat beta-casein promoter, which produced a dimer of human EPO molecules linked by a 2-amino acid peptide linker (Asp-Ile, was constructed and injected into 1-cell fertilized embryos by microinjection. Mice were screened using genomic DNA samples obtained from tail biopsies. Blood samples were obtained by heart puncture using heparinized tubes, and hematologic parameters were assessed. Using the microarray analysis tool, we analyzed differences in gene expression in the spleens of tg and control mice. Results A high rate of spontaneous abortion or death of the offspring was observed in the recipients of dHuEPO embryos. We obtained 3 founder lines (#4, #11, and #47 of tg mice expressing the dHuEPO gene. However, only one founder line showed stable germline integration and transmission, subsequently establishing the only transgenic line (#11. We obtained 2 F1 mice and 3 F2 mice from line #11. The dHuEPO protein could not be obtained because of repeated spontaneous abortions in the tg mice. Tg mice exhibited symptoms such as short lifespan and abnormal blood composition. The red blood cell count, white blood cell count, and hematocrit levels in the tg mice were remarkably higher than those in the control mice. The spleens of the tg mice (F1 and F2 females were 11- and -21-fold larger than those of the control mice. Microarray analysis revealed 2,672 spleen-derived candidate genes; more genes were downregulated than upregulated (849/764. Reverse transcriptase-polymerase chain reaction (RT-PCR and quantitative real-time PCR (qRT-PCR were used for validating the results of the microarray

  14. Metal membrane with dimer slots as a universal polarizer

    DEFF Research Database (Denmark)

    Zhukovsky, Sergei; Zalkovskij, Maksim; Malureanu, Radu;

    2014-01-01

    electromagnetic response of an arbitrary dimer based on the Green functions approach. The theory confirms that a great variety of polarization properties, such as birefringence, chirality and elliptical dichroism, can be achieved in a metal layer with such slot-dimer patterning (i.e. in a metasurface). Optical...... properties of the metasurface can be extensively tuned by varying the geometry (shape and dimensions) of the dimer, for example, by adjusting the sizes and mutual placement of the slots (e.g. inter-slot distance and alignment angle). Three basic shapes of dimers are analyzed: II-shaped (parallel slots), V...... UV lithography with subsequent Ni growth. Such metasurfaces were characterized using time-domain THz spectroscopy. The samples exhibit pronounced optical activity (500 degrees per wavelength) and high transmission: even though the slots cover only 4.3 % of the total membrane area the amplitude...

  15. A New Benzosesquiterpenoid Dimer from Polyalthia cheliensis Hu

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A new benzosesquiterpenoid dimer, 3",3"-bispolycerasoidol (1), along with its monomer, polycerasoidol, were isolated from the dried leaves of Polyalthia cheliensis Hu. The structure of 1 was established by spectroscopic methods.

  16. Binding Affinity of Novel Cyclodextrin Dimers to Ethyl Orange

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The interaction between ethyl orange (Eto, guest) and β-cyclodextrin dimers (1a~d, host) bridged with 2-t-butoxycarbonyl(Boc)-amino diacid was investigated. A remarkable synergic complexation of two cavities in host molecule was observed.

  17. Glassy dislocation dynamics in 2D colloidal dimer crystals.

    Science.gov (United States)

    Gerbode, Sharon J; Agarwal, Umang; Ong, Desmond C; Liddell, Chekesha M; Escobedo, Fernando; Cohen, Itai

    2010-08-13

    Although glassy relaxation is typically associated with disorder, here we report on a new type of glassy dynamics relating to dislocations within 2D crystals of colloidal dimers. Previous studies have demonstrated that dislocation motion in dimer crystals is restricted by certain particle orientations. Here, we drag an optically trapped particle through such dimer crystals, creating dislocations. We find a two-stage relaxation response where initially dislocations glide until encountering particles that cage their motion. Subsequent relaxation occurs logarithmically slowly through a second process where dislocations hop between caged configurations. Finally, in simulations of sheared dimer crystals, the dislocation mean squared displacement displays a caging plateau typical of glassy dynamics. Together, these results reveal a novel glassy system within a colloidal crystal. PMID:20868079

  18. How to use D-dimer in acute cardiovascular care

    DEFF Research Database (Denmark)

    Giannitsis, Evangelos; Mair, Johannes; Christersson, Christina;

    2015-01-01

    and subsequent degradation of cross-linked fibrin by plasmin. Many different assays for D-dimer testing are currently used in routine care. However, these tests are neither standardized nor harmonized. Consequently, only clinically validated assays and assay specific decision limits should be used for routine...... testing. For the exclusion of pulmonary embolism/deep vein thrombosis, age-adjusted cut-offs are recommend. Clinicians must be aware of the validated use of their hospital's D-dimer assay to avoid inappropriate use of this biomarker in routine care.......D-dimer testing is important to aid in the exclusion of venous thromboembolic events (VTEs), including deep venous thrombosis and pulmonary embolism, and it may be used to evaluate suspected aortic dissection. D-dimer is produced upon activation of the coagulation system with the generation...

  19. DNA target selectivity by the vitamin D3 receptor: mechanism of dimer binding to an asymmetric repeat element.

    OpenAIRE

    Towers, T L; Luisi, B F; Asianov, A; Freedman, L P

    1993-01-01

    The 1,25-dihydroxyvitamin D3 receptor, like other members of the nuclear receptor superfamily, forms dimers in solution that are probably stabilized by a dyad symmetrical interface formed by the ligand-binding domain. This receptor, however, recognizes DNA targets that are not dyad symmetric but rather are organized as direct repeats of a hexameric sequence with a characteristic 3-bp spacing. Using molecular modeling and site-directed mutagenesis, we have identified regions within the vitamin...

  20. Dimer representations of the Temperley-Lieb algebra

    CERN Document Server

    Morin-Duchesne, Alexi; Ruelle, Philippe

    2014-01-01

    A new spin-chain representation of the Temperley-Lieb algebra $TL_n(\\beta=0)$ is introduced and related to the dimer model. Unlike the usual XXZ spin-chain representations of dimension $2^n$, this dimer representation is of dimension $2^{n-1}$. A detailed analysis of its structure is presented and found to yield indecomposable zigzag modules not appearing in traditional spin-chain scenarios.