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Sample records for cholesterol trafficking parallels

  1. NPC1, intracellular cholesterol trafficking and atherosclerosis.

    PubMed

    Yu, Xiao-Hua; Jiang, Na; Yao, Ping-Bo; Zheng, Xi-Long; Cayabyab, Francisco S; Tang, Chao-Ke

    2014-02-15

    Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking. Liver X receptor (LXR) is the major positive regulator of NPC1 expression. Atherosclerosis is the pathological basis of coronary heart disease, one of the major causes of death worldwide. NPC1 has been shown to play a critical role in the atherosclerotic progression. In this review, we have summarized the role of NPC1 in regulating intracellular cholesterol trafficking and atherosclerosis.

  2. Early steps in steroidogenesis: intracellular cholesterol trafficking

    PubMed Central

    Miller, Walter L.; Bose, Himangshu S.

    2011-01-01

    Steroid hormones are made from cholesterol, primarily derived from lipoproteins that enter cells via receptor-mediated endocytosis. In endo-lysosomes, cholesterol is released from cholesterol esters by lysosomal acid lipase (LAL; disordered in Wolman disease) and exported via Niemann-Pick type C (NPC) proteins (disordered in NPC disease). These diseases are characterized by accumulated cholesterol and cholesterol esters in most cell types. Mechanisms for trans-cytoplasmic cholesterol transport, membrane insertion, and retrieval from membranes are less clear. Cholesterol esters and “free” cholesterol are enzymatically interconverted in lipid droplets. Cholesterol transport to the cholesterol-poor outer mitochondrial membrane (OMM) appears to involve cholesterol transport proteins. Cytochrome P450scc (CYP11A1) then initiates steroidogenesis by converting cholesterol to pregnenolone on the inner mitochondrial membrane (IMM). Acute steroidogenic responses are regulated by cholesterol delivery from OMM to IMM, triggered by the steroidogenic acute regulatory protein (StAR). Chronic steroidogenic capacity is determined by CYP11A1 gene transcription. StAR mutations cause congenital lipoid adrenal hyperplasia, with absent steroidogenesis, potentially lethal salt loss, and 46,XY sex reversal. StAR mutations initially destroy most, but not all steroidogenesis; low levels of StAR-independent steroidogenesis are lost later due to cellular damage, explaining the clinical findings. Rare P450scc mutations cause a similar syndrome. This review addresses these early steps in steroid biosynthesis. PMID:21976778

  3. Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

    PubMed Central

    McIntosh, Avery L.; Atshaves, Barbara P.; Huang, Huan; Gallegos, Adalberto M.; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Cholesterol itself has very few structural/chemical features suitable for real-time imaging in living cells. Thus, the advent of dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol, DHE] the fluorescent sterol most structurally and functionally similar to cholesterol to date, has proven to be a major asset for real-time probing/elucidating the sterol environment and intracellular sterol trafficking in living organisms. DHE is a naturally-occurring, fluorescent sterol analog that faithfully mimics many of the properties of cholesterol. Because these properties are very sensitive to sterol structure and degradation, such studies require the use of extremely pure (>98%) quantities of fluorescent sterol. DHE is readily bound by cholesterol-binding proteins, is incorporated into lipoproteins (from the diet of animals or by exchange in vitro), and for real-time imaging studies is easily incorporated into cultured cells where it co-distributes with endogenous sterol. Incorporation from an ethanolic stock solution to cell culture media is effective, but this process forms an aqueous dispersion of dehydroergosterol crystals which can result in endocytic cellular uptake and distribution into lysosomes which is problematic in imaging DHE at the plasma membrane of living cells. In contrast, monomeric DHE can be incorporated from unilamellar vesicles by exchange/fusion with the plasma membrane or from DHE-methyl-β-cyclodextrin (DHE-MβCD) complexes by exchange with the plasma membrane. Both of the latter techniques can deliver large quantities of monomeric dehydroergosterol with significant distribution into the plasma membrane. The properties and behavior of DHE in protein-binding, lipoproteins, model membranes, biological membranes, lipid rafts/caveolae, and real-time imaging in living cells indicate that this naturally-occurring fluorescent sterol is a useful mimic for probing the properties of cholesterol in these systems. PMID:18536950

  4. Box C/D Small Nucleolar RNA (snoRNA) U60 Regulates Intracellular Cholesterol Trafficking*

    PubMed Central

    Brandis, Katrina A.; Gale, Sarah; Jinn, Sarah; Langmade, Stephen J.; Dudley-Rucker, Nicole; Jiang, Hui; Sidhu, Rohini; Ren, Aileen; Goldberg, Anna; Schaffer, Jean E.; Ory, Daniel S.

    2013-01-01

    Mobilization of plasma membrane (PM) cholesterol to the endoplasmic reticulum is essential for cellular cholesterol homeostasis. The mechanisms regulating this retrograde, intermembrane cholesterol transfer are not well understood. Because mutant cells with defects in PM to endoplasmic reticulum cholesterol trafficking can be isolated on the basis of resistance to amphotericin B, we conducted an amphotericin B loss-of-function screen in Chinese hamster ovary (CHO) cells using insertional mutagenesis to identify genes that regulate this trafficking mechanism. Mutant line A1 displayed reduced cholesteryl ester formation from PM-derived cholesterol and increased de novo cholesterol synthesis, indicating a deficiency in retrograde cholesterol transport. Genotypic analysis revealed that the A1 cell line contained one disrupted allele of the U60 small nucleolar RNA (snoRNA) host gene, resulting in haploinsufficiency of the box C/D snoRNA U60. Complementation and mutational studies revealed the U60 snoRNA to be the essential feature from this locus that affects cholesterol trafficking. Lack of alteration in predicted U60-mediated site-directed methylation of 28 S rRNA in the A1 mutant suggests that the U60 snoRNA modulates cholesterol trafficking by a mechanism that is independent of this canonical function. Our study adds to a growing body of evidence for participation of small noncoding RNAs in cholesterol homeostasis and is the first to implicate a snoRNA in this cellular function. PMID:24174535

  5. Box C/D small nucleolar RNA (snoRNA) U60 regulates intracellular cholesterol trafficking.

    PubMed

    Brandis, Katrina A; Gale, Sarah; Jinn, Sarah; Langmade, Stephen J; Dudley-Rucker, Nicole; Jiang, Hui; Sidhu, Rohini; Ren, Aileen; Goldberg, Anna; Schaffer, Jean E; Ory, Daniel S

    2013-12-13

    Mobilization of plasma membrane (PM) cholesterol to the endoplasmic reticulum is essential for cellular cholesterol homeostasis. The mechanisms regulating this retrograde, intermembrane cholesterol transfer are not well understood. Because mutant cells with defects in PM to endoplasmic reticulum cholesterol trafficking can be isolated on the basis of resistance to amphotericin B, we conducted an amphotericin B loss-of-function screen in Chinese hamster ovary (CHO) cells using insertional mutagenesis to identify genes that regulate this trafficking mechanism. Mutant line A1 displayed reduced cholesteryl ester formation from PM-derived cholesterol and increased de novo cholesterol synthesis, indicating a deficiency in retrograde cholesterol transport. Genotypic analysis revealed that the A1 cell line contained one disrupted allele of the U60 small nucleolar RNA (snoRNA) host gene, resulting in haploinsufficiency of the box C/D snoRNA U60. Complementation and mutational studies revealed the U60 snoRNA to be the essential feature from this locus that affects cholesterol trafficking. Lack of alteration in predicted U60-mediated site-directed methylation of 28 S rRNA in the A1 mutant suggests that the U60 snoRNA modulates cholesterol trafficking by a mechanism that is independent of this canonical function. Our study adds to a growing body of evidence for participation of small noncoding RNAs in cholesterol homeostasis and is the first to implicate a snoRNA in this cellular function.

  6. Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense.

    PubMed

    Gabor, Kristin A; Fessler, Michael B

    2017-01-01

    The mevalonic acid synthesis pathway, cholesterol, and lipoproteins play fundamental roles in lung physiology and the innate immune response. Recent literature investigating roles for cholesterol synthesis and trafficking in host defense against respiratory infection was critically reviewed. The innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense in the lung. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate replication and evade immunity. Emerging literature suggests the potential for harnessing these insights towards therapeutic development. Given that >50% of adults in the U.S. have serum cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance and warrants further mechanistic and translational investigation.

  7. Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer’s disease

    PubMed Central

    Marzolo, Maria-Paz; Bu, Guojun

    2009-01-01

    Amyloid-β (Aβ) peptide accumulation in the brain is central to the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through proteolytic processing of a transmembrane protein, β-amyloid precursor protein (APP), by β- and γ-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Aβ. Members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apoER2, interact with APP and regulate its endocytic trafficking. Additionally, APP trafficking and processing are greatly affected by cellular cholesterol content. In this review, we summarize the current understanding of the roles of lipoprotein receptors and cholesterol in APP trafficking and processing and their implication for AD pathogenesis and therapy. PMID:19041409

  8. Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism.

    PubMed

    Shim, Joong Sup; Li, Ruo-Jing; Lv, Junfang; Head, Sarah A; Yang, Eun Ju; Liu, Jun O

    2015-06-28

    Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

  9. Sterol O-Acyltransferase 2 Contributes to the Yolk Cholesterol Trafficking during Zebrafish Embryogenesis

    PubMed Central

    Lee, Yen-Hua; HuangFu, Wei-Chun

    2016-01-01

    To elucidate whether Sterol O-acyltransferase (Soat) mediates the absorption and transportation of yolk lipids to the developing embryo, zebrafish soat1 and soat2 were cloned and studied. In the adult zebrafish, soat1 was detected ubiquitously while soat2 mRNA was detected specifically in the liver, intestine, brain and testis. Whole mount in situ hybridization demonstrated that both soat1 and soat2 expressed in the yolk syncytial layer, hatching gland and developing cardiovascular as well as digestive systems, suggesting that Soats may play important roles in the lipid trafficking and utilization during embryonic development. The enzymatic activity of zebrafish Soat2 was confirmed by Oil Red O staining in the HEK293 cells overexpressing this gene, and could be quenched by Soat2 inhibitor Pyripyropene A (PPPA). The zebrafish embryos injected with PPPA or morpholino oligo against soat2 in the yolk showed significantly larger yolk when compared with wild-type embryos, especially at 72 hpf, indicating a slower rate of yolk consumption. Our result indicated that zebrafish Soat2 is catalytically active in synthesizing cholesteryl esters and contributes to the yolk cholesterol trafficking during zebrafish embryogenesis. PMID:27936201

  10. Synthesis and validation of novel cholesterol-based fluorescent lipids designed to observe the cellular trafficking of cationic liposomes.

    PubMed

    Kim, Bieong-Kil; Seu, Young-Bae; Choi, Jong-Soo; Park, Jong-Won; Doh, Kyung-Oh

    2015-09-15

    Cholesterol-based fluorescent lipids with ether linker were synthesized using NBD (Chol-E-NBD) or Rhodamine B (Chol-E-Rh), and the usefulnesses as fluorescent probes for tracing cholesterol-based liposomes were validated. The fluorescent intensities of liposomes containing these modified lipids were measured and observed under a microscope. Neither compound interfered with the expression of GFP plasmid, and live cell images were obtained without interferences. Changes in the fluorescent intensity of liposomes containing Chol-E-NBD were followed by flow cytometry for up to 24h. These fluorescent lipids could be useful probes for trafficking of cationic liposome-mediated gene delivery.

  11. Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking.

    PubMed

    Liu, Rui; Li, Jingyi; Zhang, Tao; Zou, Linzhi; Chen, Yi; Wang, Kui; Lei, Yunlong; Yuan, Kefei; Li, Yi; Lan, Jiang; Cheng, Lin; Xie, Na; Xiang, Rong; Nice, Edouard C; Huang, Canhua; Wei, Yuquan

    2014-07-01

    Glioblastoma is one of the most aggressive human cancers with poor prognosis, and therefore a critical need exists for novel therapeutic strategies for management of glioblastoma patients. Itraconazole, a traditional antifungal drug, has been identified as a novel potential anticancer agent due to its inhibitory effects on cell proliferation and tumor angiogenesis; however, the molecular mechanisms involved are still unclear. Here, we show that itraconazole inhibits the proliferation of glioblastoma cells both in vitro and in vivo. Notably, we demonstrate that treatment with itraconazole induces autophagic progression in glioblastoma cells, while blockage of autophagy markedly reverses the antiproliferative activities of itraconazole, suggesting an antitumor effect of autophagy in response to itraconazole treatment. Functional studies revealed that itraconazole retarded the trafficking of cholesterol from late endosomes and lysosomes to the plasma membrane by reducing the levels of SCP2, resulting in repression of AKT1-MTOR signaling, induction of autophagy, and finally inhibition of cell proliferation. Together, our studies provide new insights into the molecular mechanisms regarding the antitumor activities of itraconazole, and may further assist both the pharmacological investigation and rational use of itraconazole in potential clinical applications.

  12. Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis*

    PubMed Central

    Wu, Zhi-Yuan; Yu, De-Jie; Soong, Tuck Wah; Dawe, Gavin S.; Bian, Jin-Song

    2011-01-01

    The prolongation of QT intervals in both mothers and fetuses during the later period of pregnancy implies that higher levels of progesterone may regulate the function of the human ether-a-go-go-related gene (HERG) potassium channel, a key ion channel responsible for controlling the length of QT intervals. Here, we studied the effect of progesterone on the expression, trafficking, and function of HERG channels and the underlying mechanism. Treatment with progesterone for 24 h decreased the abundance of the fully glycosylated form of the HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells, a cell line stably expressing HERG channels. Progesterone also concentration-dependently decreased HERG current density, but had no effect on voltage-gated L-type Ca2+ and K+ channels. Immunofluorescence microscopy and Western blot analysis show that progesterone preferentially decreased HERG channel protein abundance in the plasma membrane, induced protein accumulation in the dilated endoplasmic reticulum (ER), and increased the protein expression of C/EBP homologous protein, a hallmark of ER stress. Application of 2-hydroxypropyl-β-cyclodextrin (a sterol-binding agent) or overexpression of Rab9 rescued the progesterone-induced HERG trafficking defect and ER stress. Disruption of intracellular cholesterol homeostasis with simvastatin, imipramine, or exogenous application of cholesterol mimicked the effect of progesterone on HERG channel trafficking. Progesterone may impair HERG channel folding in the ER and/or block its trafficking to the Golgi complex by disrupting intracellular cholesterol homeostasis. Our findings may reveal a novel molecular mechanism to explain the QT prolongation and high risk of developing arrhythmias during late pregnancy. PMID:21525004

  13. Cholesterol and phospholipids in frontal cortex and synaptosomes of suicide completers: relationship with endosomal lipid trafficking genes.

    PubMed

    Freemantle, Erika; Mechawar, Naguib; Turecki, Gustavo

    2013-02-01

    Cholesterol (CHL) and phospholipid (PL) levels in synaptosomal membranes in particular can have an impact on cell signalling. Alterations in peripheral CHL measures have been consistently reported in suicidal behaviour. As CHL and PL turnover in the brain are important in synapse maintenance and function, the objective of this study was to determine if differences exist in synaptosomal cholesterol and phospholipid levels between suicide completers and controls. Expression measures of genes involved in lipid trafficking suggest an association between Lysosomal acid lipase A, cholesteryl ester hydrolase (LIPA) and brain PL levels, with LIPA being significantly increased in violent suicides and associated with alterations in brain PL. The results of this study suggest an altered PL content mediated by LIPA expression in violent suicides in the prefrontal cortex, which would have important consequences for inhibitory neurotransmission.

  14. The Dynamin Chemical Inhibitor Dynasore Impairs Cholesterol Trafficking and Sterol-Sensitive Genes Transcription in Human HeLa Cells and Macrophages

    PubMed Central

    Girard, Emmanuelle; Paul, Jean Louis; Fournier, Natalie; Beaune, Philippe; Johannes, Ludger

    2011-01-01

    Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL) in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC) within the endolysosomal network. The measure of cholesterol esters (CE) further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER) was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2), 3-hydroxy-3-methyl-coenzymeA reductase (HMGCoAR), and low-density lipoprotein receptor (LDLR). The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol. PMID:22205993

  15. Electrochemiluminescence imaging for parallel single-cell analysis of active membrane cholesterol.

    PubMed

    Zhou, Junyu; Ma, Guangzhong; Chen, Yun; Fang, Danjun; Jiang, Dechen; Chen, Hong-Yuan

    2015-08-18

    Luminol electrochemiluminescence (ECL) imaging was developed for the parallel measurement of active membrane cholesterol at single living cells, thus establishing a novel electrochemical detection technique for single cells with high analysis throughput and low detection limit. In our strategy, the luminescence generated from luminol and hydrogen peroxide upon the potential was recorded in one image so that hydrogen peroxide at the surface of multiple cells could be simultaneously analyzed. Compared with the classic microelectrode array for the parallel single-cell analysis, the plat electrode only was needed in our ECL imaging, avoiding the complexity of electrode fabrication. The optimized ECL imaging system showed that hydrogen peroxide as low as 10 μM was visible and the efflux of hydrogen peroxide from cells could be determined. Coupled with the reaction between active membrane cholesterol and cholesterol oxidase to generate hydrogen peroxide, active membrane cholesterol at cells on the electrode was analyzed at single-cell level. The luminescence intensity was correlated with the amount of active membrane cholesterol, validating our system for single-cell cholesterol analysis. The relative high standard deviation on the luminescence suggested high cellular heterogeneities on hydrogen peroxide efflux and active membrane cholesterol, which exhibited the significance of single-cell analysis. This success in ECL imaging for single-cell analysis opens a new field in the parallel measurement of surface molecules at single cells.

  16. Cholesterol Biosynthesis and Trafficking in Cortisol-Producing Lesions of the Adrenal Cortex

    PubMed Central

    Wassif, Christopher A.; Horvath, Anelia; Tatsi, Christina; Angelousi, Anna; Karageorgiadis, Alexander S.; Porter, Forbes D.; Stratakis, Constantine A.

    2015-01-01

    Context: Cortisol-producing adenomas (CPAs), primary pigmented nodular adrenocortical disease (PPNAD), and primary macronodular adrenocortical hyperplasia (PMAH) cause ACTH-independent Cushing syndrome (CS). Investigation of their pathogenesis has demonstrated their integral link to the cAMP-dependent protein kinase signaling pathway. Objective: The aim of this study was to identify differences in cholesterol biosynthesis among different CS-causing adrenocortical tumors. Because of the concomitant associations of cAMP levels with cholesterol and with steroid biosynthesis, we hypothesized that benign cortisol-producing tumors would display aberration of these pathways. Design and Setting: Twenty-three patients with CPA, PPNAD, or PMAH who underwent adrenalectomy for CS were included in the study. Preoperative biochemical analyses were performed, and excised adrenal tissues were studied. Main Outcome Measures: Serum, urinary hormone levels, serum lipid profiles, and anthropometric data were obtained preoperatively. Adrenal tissues were analyzed for total protein, cholesterol, and neutral sterol content by mass spectrometry and expression of HMGCR, LDLR, ABCA1, DHCR24, and STAR genes. Results: There were differences in cholesterol content and markers of cholesterol biosynthesis and metabolism that distinguished CPAs from PMAH and PPNAD; cholesterol, lathosterol, and lathosterol/cholesterol ratio were significantly higher in CPAs. ABCA1 mRNA was lower among CPAs compared to tissues from bilateral adrenocortical hyperplasia (PMAH and PPNAD), and mRNA expression of LDL-R, DCHR24, and HMGCR tended to be higher in CPA tumor tissues. Conclusion: CPAs displayed characteristics of “cholesterol-starved” tissues when compared to PPNAD and PMAH and appeared to have increased intrinsic cholesterol production and uptake from the periphery, as well as decreased cholesterol efflux. This has implications for a potential new way of treating these tumors. PMID:26204136

  17. The cross-talk of LDL-cholesterol with cell motility: Insights from the Niemann Pick Type C1 mutation and altered integrin trafficking

    PubMed Central

    Hoque, Monira; Rentero, Carles; Conway, James R; Murray, Rachael Z; Timpson, Paul; Enrich, Carlos; Grewal, Thomas

    2015-01-01

    Cholesterol is considered indispensible for the recruitment and functioning of integrins in focal adhesions for cell migration. However, the physiological cholesterol pools that control integrin trafficking and focal adhesion assembly remain unclear. Using Niemann Pick Type C1 (NPC) mutant cells, which accumulate Low Density lipoprotein (LDL)-derived cholesterol in late endosomes (LE), several recent studies indicate that LDL-cholesterol has multiple roles in regulating focal adhesion dynamics. Firstly, targeting of endocytosed LDL-cholesterol from LE to focal adhesions controls their formation at the leading edge of migrating cells. Other newly emerging literature suggests that this may be coupled to vesicular transport of integrins, Src kinase and metalloproteases from the LE compartment to focal adhesions. Secondly, our recent work identified LDL-cholesterol as a key factor that determines the distribution and ability of several Soluble NSF Attachment Protein (SNAP) Receptor (SNARE) proteins, key players in vesicle transport, to control integrin trafficking to the cell surface and extracellular matrix (ECM) secretion. Collectively, dietary, genetic and pathological changes in cholesterol metabolism may link with efficiency and speed of integrin and ECM cell surface delivery in metastatic cancer cells. This commentary will summarize how direct and indirect pathways enable LDL-cholesterol to modulate cell motility. PMID:26366834

  18. Role of cholesterol in SNARE-mediated trafficking on intracellular membranes.

    PubMed

    Enrich, Carlos; Rentero, Carles; Hierro, Aitor; Grewal, Thomas

    2015-03-15

    The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.

  19. EhNPC1 and EhNPC2 Proteins Participate in Trafficking of Exogenous Cholesterol in Entamoeba histolytica Trophozoites: Relevance for Phagocytosis

    PubMed Central

    Bolaños, Jeni; Betanzos, Abigail; Javier-Reyna, Rosario; García- Rivera, Guillermina; Huerta, Miriam; Pais-Morales, Jonnatan; González-Robles, Arturo; Rodríguez, Mario A.

    2016-01-01

    Entamoeba histolytica, the highly phagocytic protozoan causative of human amoebiasis lacks the machinery to synthesize cholesterol. Here, we investigated the presence of NPC1 and NPC2 proteins in this parasite, which are involved in cholesterol trafficking in mammals. Bioinformatics analysis revealed one Ehnpc1 and two Ehnpc2 genes. EhNPC1 appeared as a transmembrane protein and both EhNPC2 as peripheral membrane proteins. Molecular docking predicted that EhNPC1 and EhNPC2 bind cholesterol and interact with each other. Genes and proteins were identified in trophozoites. Serum pulse-chase and confocal microscopy assays unveiled that after trophozoites sensed the cholesterol source, EhNPC1 and EhNPC2 were organized around the plasma membrane in a punctuated pattern. Vesicles emerged and increased in number and size and some appeared full of cholesterol with EhNPC1 or EhNPC2 facing the extracellular space. Both proteins, but mostly EhNPC2, were found out of the cell associated with cholesterol. EhNPC1 and cholesterol formed networks from the plasma membrane to the nucleus. EhNPC2 appeared in erythrocytes that were being ingested by trophozoites, co-localizing with cholesterol of erythrocytes, whereas EhNPC1 surrounded the phagocytic cup. EhNPC1 and EhNPC2 co-localized with EhSERCA in the endoplasmic reticulum and with lysobisphosphatidic acid and EhADH (an Alix protein) in phagolysosomes. Immunoprecipitation assays confirmed the EhNPC1 and EhNPC2 association with cholesterol, EhRab7A and EhADH. Serum starved and blockage of cholesterol trafficking caused a low rate of phagocytosis and incapability of trophozoites to produce damage in the mouse colon. Ehnpc1 and Ehnpc2 knockdown provoked in trophozoites a lower intracellular cholesterol concentration and a diminished rate of phagocytosis; and Ehnpc1 silencing also produced a decrease of trophozoites movement. Trafficking of EhNPC1 and EhNPC2 during cholesterol uptake and phagocytosis as well as their association with

  20. Desipramine induces disorder in cholesterol-rich membranes: implications for viral trafficking.

    PubMed

    Pakkanen, Kirsi; Salonen, Emppu; Mäkelä, Anna R; Oker-Blom, Christian; Vattulainen, Ilpo; Vuento, Matti

    2009-09-10

    In this study, the effect of desipramine (DMI) on phospholipid bilayers and parvoviral entry was elucidated. In atomistic molecular dynamics simulations, DMI was found to introduce disorder in cholesterol-rich phospholipid bilayers. This was manifested by a decrease in the deuterium order parameter S(CD) as well as an increase in the membrane area. Disordering of the membrane suggested DMI to destabilize cholesterol-rich membrane domains (rafts) in cellular conditions. To relate the raft disrupting ability of DMI with novel biological relevance, we studied the intracellular effect of DMI using canine parvovirus (CPV), a virus known to interact with endosomal membranes and sphingomyelin, as an intracellular probe. DMI was found to cause retention of the virus in intracellular vesicular structures leading to the inhibition of viral proliferation. This implies that DMI has a deleterious effect on the viral traffic. As recycling endosomes and the internal vesicles of multivesicular bodies are known to contain raft components, the effect of desipramine beyond the plasma membrane step could be caused by raft disruption leading to impaired endosomal function and possibly have direct influence on the penetration of the virus through an endosomal membrane.

  1. Desipramine induces disorder in cholesterol-rich membranes: implications for viral trafficking

    NASA Astrophysics Data System (ADS)

    Pakkanen, Kirsi; Salonen, Emppu; Mäkelä, Anna R.; Oker-Blom, Christian; Vattulainen, Ilpo; Vuento, Matti

    2009-12-01

    In this study, the effect of desipramine (DMI) on phospholipid bilayers and parvoviral entry was elucidated. In atomistic molecular dynamics simulations, DMI was found to introduce disorder in cholesterol-rich phospholipid bilayers. This was manifested by a decrease in the deuterium order parameter SCD as well as an increase in the membrane area. Disordering of the membrane suggested DMI to destabilize cholesterol-rich membrane domains (rafts) in cellular conditions. To relate the raft disrupting ability of DMI with novel biological relevance, we studied the intracellular effect of DMI using canine parvovirus (CPV), a virus known to interact with endosomal membranes and sphingomyelin, as an intracellular probe. DMI was found to cause retention of the virus in intracellular vesicular structures leading to the inhibition of viral proliferation. This implies that DMI has a deleterious effect on the viral traffic. As recycling endosomes and the internal vesicles of multivesicular bodies are known to contain raft components, the effect of desipramine beyond the plasma membrane step could be caused by raft disruption leading to impaired endosomal function and possibly have direct influence on the penetration of the virus through an endosomal membrane.

  2. Modulation of intrahepatic cholesterol trafficking: evidence by in vivo antisense treatment for the involvement of sterol carrier protein-2 in newly synthesized cholesterol transport into rat bile.

    PubMed Central

    Puglielli, L; Rigotti, A; Amigo, L; Nuñez, L; Greco, A V; Santos, M J; Nervi, F

    1996-01-01

    Biliary cholesterol represents one of the two major excretory pathways for sterol elimination from the body and plays a central role in cholesterol gallstone formation. Biliary cholesterol originates from a precursor pool of preformed and newly synthesized free cholesterol. Although it has been suggested that newly synthesized and preformed biliary cholesterol are secreted by independent pathways, the specific cellular and molecular mechanisms are unknown. We used male Wistar rats to study the time-course of the appearance of newly synthesized cholesterol, phosphatidylcholine and protein into bile. The specific role of sterol carrier protein-2 (SCP-2) in the transport of newly synthesized biliary cholesterol was evaluated by an in vivo antisense oligonucleotide approach. In contrast to [14C]phosphatidylcholine and [35S]proteins, the time-course of [14C]cholesterol appearance into bile was rapid, and microtubule- and Golgi-independent. In vivo SCP-2 antisense treatment reduced and delayed the appearance of biliary [14C]cholesterol. Furthermore, hepatic SCP-2 expression increased more than 3-fold over control values in rats that had been treated with diosgenin to increase biliary secretion of newly synthesized cholesterol. These results suggest that SCP-2 is necessary for the rapid transport of newly synthesized cholesterol into bile and that hepatocytes can induce SCP-2 expression according to the rate of biliary secretion of newly synthesized cholesterol. PMID:8760350

  3. Regulation of the high-affinity choline transporter activity and trafficking by its association with cholesterol-rich lipid rafts.

    PubMed

    Cuddy, Leah K; Winick-Ng, Warren; Rylett, Rebecca Jane

    2014-03-01

    The sodium-coupled, hemicholinium-3-sensitive, high-affinity choline transporter (CHT) is responsible for transport of choline into cholinergic nerve terminals from the synaptic cleft following acetylcholine release and hydrolysis. In this study, we address regulation of CHT function by plasma membrane cholesterol. We show for the first time that CHT is concentrated in cholesterol-rich lipid rafts in both SH-SY5Y cells and nerve terminals from mouse forebrain. Treatment of SH-SY5Y cells expressing rat CHT with filipin, methyl-β-cyclodextrin (MβC) or cholesterol oxidase significantly decreased choline uptake. In contrast, CHT activity was increased by addition of cholesterol to membranes using cholesterol-saturated MβC. Kinetic analysis of binding of [(3)H]hemicholinium-3 to CHT revealed that reducing membrane cholesterol with MβC decreased both the apparent binding affinity (KD) and maximum number of binding sites (Bmax ); this was confirmed by decreased plasma membrane CHT protein in lipid rafts in cell surface protein biotinylation assays. Finally, the loss of cell surface CHT associated with lipid raft disruption was not because of changes in CHT internalization. In summary, we provide evidence that CHT association with cholesterol-rich rafts is critical for transporter function and localization. Alterations in plasma membrane cholesterol cholinergic nerve terminals could diminish cholinergic transmission by reducing choline availability for acetylcholine synthesis. The sodium-coupled choline transporter CHT moves choline into cholinergic nerve terminals to serve as substrate for acetylcholine synthesis. We show for the first time that CHT is concentrated in cholesterol-rich lipid rafts, and decreasing membrane cholesterol significantly reduces both choline uptake activity and cell surface CHT protein levels. CHT association with cholesterol-rich rafts is critical for its function, and alterations in plasma membrane cholesterol could diminish cholinergic

  4. Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism.

    PubMed

    Chen, Guoli; Liu, Ping; Pattar, Guruprasad R; Tackett, Lixuan; Bhonagiri, Padma; Strawbridge, Andrew B; Elmendorf, Jeffrey S

    2006-04-01

    Evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that trivalent chromium in the chloride (CrCl3) or picolinate (CrPic) salt forms mobilize the glucose transporter, GLUT4, to the plasma membrane in 3T3-L1 adipocytes. Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment. In contrast, the chromium-mobilized pool of transporters was not active in the absence of insulin. Microscopic analysis of an exofacially Myc-tagged enhanced green fluorescent protein-GLUT4 construct revealed that the chromium-induced accumulation of GLUT4-containing vesicles occurred adjacent to the inner cell surface membrane. With insulin these transporters physically incorporated into the plasma membrane. Regulation of GLUT4 translocation by chromium did not involve known insulin signaling proteins such as the insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt. Consistent with a reported effect of chromium on increasing membrane fluidity, we found that chromium treatment decreased plasma membrane cholesterol. Interestingly, cholesterol add-back to the plasma membrane prevented the beneficial effect of chromium on both GLUT4 mobilization and insulin-stimulated glucose transport. Furthermore, chromium action was absent in methyl-beta-cyclodextrin-pretreated cells already displaying reduced plasma membrane cholesterol and increased GLUT4 translocation. Together, these data reveal a novel mechanism by which chromium may enhance GLUT4 trafficking and insulin-stimulated glucose transport. Moreover, these findings at the level of the cell are consistent with in vivo observations of improved glucose tolerance and decreased circulating cholesterol levels after chromium supplementation.

  5. Haptoglobin increases with age in rat hippocampus and modulates Apolipoprotein E mediated cholesterol trafficking in neuroblastoma cell lines

    PubMed Central

    Spagnuolo, Maria Stefania; Maresca, Bernardetta; Mollica, Maria Pina; Cavaliere, Gina; Cefaliello, Carolina; Trinchese, Giovanna; Esposito, Maria Grazia; Scudiero, Rosaria; Crispino, Marianna; Abrescia, Paolo; Cigliano, Luisa

    2014-01-01

    Alteration in cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative disorders. Apolipoprotein E (ApoE) is the major component of brain lipoproteins supporting cholesterol transport. We previously reported that the acute-phase protein Haptoglobin (Hpt) binds ApoE, and influences its function in blood cholesterol homeostasis. Major aim of this study was to investigate whether Hpt influences the mechanisms by which cholesterol is shuttled from astrocytes to neurons. In detail it was studied Hpt effect on ApoE-dependent cholesterol efflux from astrocytes and ApoE-mediated cholesterol incorporation in neurons. We report here that Hpt impairs ApoE-mediated cholesterol uptake in human neuroblastoma cell line SH-SY5Y, and limits the toxicity of a massive concentration of cholesterol for these cells, while it does not affect cholesterol efflux from the human glioblastoma-astrocytoma cell line U-87 MG. As aging is the most important non-genetic risk factor for various neurodegenerative disorders, and our results suggest that Hpt modulates ApoE functions, we evaluated the Hpt and ApoE expression profiles in cerebral cortex and hippocampus of adolescent (2 months), adult (5 and 8 months), and middle-aged (16 months) rats. Hpt mRNA level was higher in hippocampus of 8 and 16 month-old than in 2-month old rats (p < 0.05), and Hpt concentration increased with the age from adolescence to middle-age (p < 0.001). ApoE concentration, in hippocampus, was higher (p < 0.001) in 5 month-old rats compared to 2 month but did not further change with aging. No age-related changes of Hpt (protein and mRNA) were found in the cortex. Our results suggest that aging is associated with changes, particularly in the hippocampus, in the Hpt/ApoE ratio. Age-related changes in the concentration of Hpt were also found in human cerebrospinal fluids. The age-related changes might affect neuronal function and survival in brain, and have important implications in brain

  6. Phosphatidylcholine: Greasing the Cholesterol Transport Machinery

    PubMed Central

    Lagace, Thomas A.

    2015-01-01

    Negative feedback regulation of cholesterol metabolism in mammalian cells ensures a proper balance of cholesterol with other membrane lipids, principal among these being the major phospholipid phosphatidylcholine (PC). Processes such as cholesterol biosynthesis and efflux, cholesteryl ester storage in lipid droplets, and uptake of plasma lipoproteins are tuned to the cholesterol/PC ratio. Cholesterol-loaded macrophages in atherosclerotic lesions display increased PC biosynthesis that buffers against elevated cholesterol levels and may also facilitate cholesterol trafficking to enhance cholesterol sensing and efflux. These same mechanisms could play a generic role in homeostatic responses to acute changes in membrane free cholesterol levels. Here, I discuss the established and emerging roles of PC metabolism in promoting intracellular cholesterol trafficking and membrane lipid homeostasis. PMID:27081313

  7. Human Trafficking

    ERIC Educational Resources Information Center

    Wilson, David McKay

    2011-01-01

    The shadowy, criminal nature of human trafficking makes evaluating its nature and scope difficult. The U.S. State Department and anti-trafficking groups estimate that worldwide some 27 million people are caught in a form of forced servitude today. Public awareness of modern-day slavery is gaining momentum thanks to new abolitionist efforts. Among…

  8. Cholesterol Test

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Cholesterol Share this page: Was this page helpful? Also known as: Blood Cholesterol Formal name: Total Cholesterol Related tests: HDL Cholesterol , ...

  9. What's Cholesterol?

    MedlinePlus

    ... los dientes Video: Getting an X-ray What's Cholesterol? KidsHealth > For Kids > What's Cholesterol? Print A A ... thing for food to be low in it? Cholesterol and Your Body Cholesterol (say: kuh-LES-tuh- ...

  10. What's Cholesterol?

    MedlinePlus

    ... Room? What Happens in the Operating Room? What's Cholesterol? KidsHealth > For Kids > What's Cholesterol? A A A ... thing for food to be low in it? Cholesterol and Your Body Cholesterol (say: kuh-LES-tuh- ...

  11. About Cholesterol

    MedlinePlus

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More About Cholesterol Updated:Apr 3,2017 It may surprise you ... our bodies to keep us healthy. What is cholesterol and where does it come from? Cholesterol is ...

  12. The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

    PubMed Central

    Horner, Michael A.; Pardee, Keith; Liu, Suya; King-Jones, Kirst; Lajoie, Gilles; Edwards, Aled; Krause, Henry M.; Thummel, Carl S.

    2009-01-01

    Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis. PMID:19952106

  13. The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis.

    PubMed

    Horner, Michael A; Pardee, Keith; Liu, Suya; King-Jones, Kirst; Lajoie, Gilles; Edwards, Aled; Krause, Henry M; Thummel, Carl S

    2009-12-01

    Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis.

  14. Economics of human trafficking.

    PubMed

    Wheaton, Elizabeth M; Schauer, Edward J; Galli, Thomas V

    2010-01-01

    Because freedom of choice and economic gain are at the heart of productivity, human trafficking impedes national and international economic growth. Within the next 10 years, crime experts expect human trafficking to surpass drug and arms trafficking in its incidence, cost to human well-being, and profitability to criminals (Schauer and Wheaton, 2006: 164-165). The loss of agency from human trafficking as well as from modern slavery is the result of human vulnerability (Bales, 2000: 15). As people become vulnerable to exploitation and businesses continually seek the lowest-cost labour sources, trafficking human beings generates profit and a market for human trafficking is created. This paper presents an economic model of human trafficking that encompasses all known economic factors that affect human trafficking both across and within national borders. We envision human trafficking as a monopolistically competitive industry in which traffickers act as intermediaries between vulnerable individuals and employers by supplying differentiated products to employers. In the human trafficking market, the consumers are employers of trafficked labour and the products are human beings. Using a rational-choice framework of human trafficking we explain the social situations that shape relocation and working decisions of vulnerable populations leading to human trafficking, the impetus for being a trafficker, and the decisions by employers of trafficked individuals. The goal of this paper is to provide a common ground upon which policymakers and researchers can collaborate to decrease the incidence of trafficking in humans.

  15. Cholesterol (image)

    MedlinePlus

    Cholesterol is a soft, waxy substance that is present in all parts of the body including the ... and obtained from animal products in the diet. Cholesterol is manufactured in the liver and is needed ...

  16. Cellular Localization and Trafficking of the Human ABCG1 Transporter

    PubMed Central

    Neufeld, Edward B.; O’Brien, Katherine; Walts, Avram D.; Stonik, John A.; Demosky, Steven J.; Malide, Daniela; Combs, Christian A.; Remaley, Alan T.

    2014-01-01

    We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not apoA-I. Delivery of ABCG1 to the PM and LE was required for ABCG1-mediated cellular cholesterol efflux. ABCG1 LEs frequently contacted the PM, providing a collisional mechanism for transfer of ABCG1-mobilized cholesterol, similar to ABCG1-mediated PM cholesterol efflux to lipoproteins. ABCG1-mobilized LE cholesterol also trafficked to the PM by a non-vesicular pathway. Transfer of ABCG1-mobilized cholesterol from the cytoplasmic face of LEs to the PM and concomitant removal of cholesterol from the outer leaflet of the PM bilayer by extracellular acceptors suggests that ABCG1 mobilizes cholesterol on both sides of the lipid bilayer for removal by acceptors. ABCG1 increased uptake of HDL into LEs, consistent with a potential ABCG1-mediated cholesterol efflux pathway involving HDL resecretion. Thus, ABCG1 at the PM mobilizes PM cholesterol and ABCG1 in LE/LYS generates mobile pools of cholesterol that can traffic by both vesicular and non-vesicular pathways to the PM where it can also be transferred to extracellular acceptors with a lipid surface. PMID:25405320

  17. The Antifungal Drug Itraconazole Inhibits Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, Trafficking, and Signaling in Endothelial Cells*

    PubMed Central

    Nacev, Benjamin A.; Grassi, Paola; Dell, Anne; Haslam, Stuart M.; Liu, Jun O.

    2011-01-01

    Itraconazole is a safe and widely used antifungal drug that was recently found to possess potent antiangiogenic activity. Currently, there are four active clinical trials evaluating itraconazole as a cancer therapeutic. Tumor growth is dependent on angiogenesis, which is driven by the secretion of growth factors from the tumor itself. We report here that itraconazole significantly inhibited the binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 (VEGFR2) and that both VEGFR2 and an immediate downstream substrate, phospholipase C γ1, failed to become activated after VEGF stimulation. These effects were due to a defect in VEGFR2 trafficking, leading to a decrease in cell surface expression, and were associated with the accumulation of immature N-glycans on VEGFR2. Small molecule inducers of lysosomal cholesterol accumulation and mammalian target of rapamycin (mTOR) inhibition, two previously reported itraconazole activities, failed to recapitulate itraconazole's effects on VEGFR2 glycosylation and signaling. Likewise, glycosylation inhibitors did not alter cholesterol trafficking or inhibit mTOR. Repletion of cellular cholesterol levels, which was known to rescue the effects of itraconazole on mTOR and cholesterol trafficking, was also able to restore VEGFR2 glycosylation and signaling. This suggests that the new effects of itraconazole occur in parallel to those previously reported but are downstream of a common target. We also demonstrated that itraconazole globally reduced poly-N-acetyllactosamine and tetra-antennary complex N-glycans in endothelial cells and induced hypoglycosylation of the epidermal growth factor receptor in a renal cell carcinoma line, suggesting that itraconazole's effects extend beyond VEGFR2. PMID:22025615

  18. Lipid content in hepatic and gonadal adipose tissue parallel aortic cholesterol accumulation in mice fed diets with different omega-6 PUFA to EPA plus DHA ratios

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diets with low omega (u)-6 polyunsaturated fatty acids (PUFA) to eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) ratios have been shown to decrease aortic cholesterol accumulation and have been suggested to promote weight loss. The involvement of the liver and gonadal adipose tissue (GAT...

  19. Good vs. Bad Cholesterol

    MedlinePlus

    ... Venous Thromboembolism Aortic Aneurysm More Good vs. Bad Cholesterol Updated:Apr 3,2017 Cholesterol can't dissolve ... test . View an animation of cholesterol . LDL (Bad) Cholesterol LDL cholesterol is considered the “bad” cholesterol because ...

  20. 25-Hydroxycholesterol Increases the Availability of Cholesterol in Phospholipid Membranes

    SciTech Connect

    Olsen, Brett N.; Schlesinger, Paul H.; Ory, Daniel S.; Baker, Nathan A.

    2011-02-01

    Side-chain oxysterols are enzymatically generated oxidation products of cholesterol that serve a central role in mediating cholesterol homeostasis. Recent work has shown that side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), alter membrane structure in very different ways from cholesterol, suggesting a possible mechanism for how these oxysterols regulate cholesterol homeostasis. Here we extend our previous work, using molecular dynamics simulations of 25-HC and cholesterol mixtures in 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers to examine interactions between 25-HC and cholesterol in the same bilayer. When added to cholesterol-containing membranes, 25-HC causes larger changes in membrane structure than when added to cholesterol-free membranes, demonstrating interactions between the two sterols. We also find that the presence of 25-HC changes the position, orientation, and solvent accessibility of cholesterol, shifting it into the water interface and therefore its availability to external acceptors. This is consistent with experimental results showing that oxysterols can trigger cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. These interactions provide a potential mechanism for 25-HC-mediated regulation of cholesterol trafficking and homeostasis through direct modulation of cholesterol availability.

  1. The Structural Basis of Cholesterol Activity in Membranes

    SciTech Connect

    Olsen, Brett N.; Bielska, Agata; Lee, Tiffany; Daily, Michael D.; Covey, Douglas F.; Schlesinger, Paul H.; Baker, Nathan A.; Ory, Daniel S.

    2013-10-15

    Although the majority of free cellular cholesterol is present in the plasma membrane, cholesterol homeostasis is principally regulated through sterol-sensing proteins that reside in the cholesterol-poor endoplasmic reticulum (ER). In response to acute cholesterol loading or depletion, there is rapid equilibration between the ER and plasma membrane cholesterol pools, suggesting a biophysical model in which the availability of plasma membrane cholesterol for trafficking to internal membranes modulates ER membrane behavior. Previous studies have predominantly examined cholesterol availability in terms of binding to extramembrane acceptors, but have provided limited insight into the structural changes underlying cholesterol activation. In this study, we use both molecular dynamics simulations and experimental membrane systems to examine the behavior of cholesterol in membrane bilayers. We find that cholesterol depth within the bilayer provides a reasonable structural metric for cholesterol availability and that this is correlated with cholesterol-acceptor binding. Further, the distribution of cholesterol availability in our simulations is continuous rather than divided into distinct available and unavailable pools. This data provide support for a revised cholesterol activation model in which activation is driven not by saturation of membrane-cholesterol interactions but rather by bulk membrane remodeling that reduces membrane-cholesterol affinity.

  2. Cholesterol distribution in living cells: fluorescence imaging using dehydroergosterol as a fluorescent cholesterol analog.

    PubMed Central

    Mukherjee, S; Zha, X; Tabas, I; Maxfield, F R

    1998-01-01

    Cholesterol is an important constituent of most mammalian cell membranes and its concentration in various cellular membranes is tightly regulated. Although there is much information about cholesterol distribution and trafficking in cells, it is primarily derived from indirect measurements, and the results obtained using different approaches are often conflicting. A cholesterol analog that faithfully mimics the properties of cholesterol and can be followed in living cells would thus be very useful. In this study, we report the fluorescence imaging of such an analog, dehydroergosterol (DHE), in living cells. DHE differs from cholesterol in having three additional double bonds and an extra methyl group. In model systems, DHE closely mimics the behavior of native cholesterol. Using triple-labeling studies, we show that DHE colocalizes extensively with endocytosed transferrin, an endocytic recycling compartment marker, and with a marker for the trans-Golgi network, Tac-TGN38. This distribution of DHE is qualitatively similar to that observed when cells are labeled with the fluorescent cholesterol-binding polyene antibiotic, filipin, although there are differences in apparent proportions of DHE and filipin that are localized at the plasma membrane. Another cholesterol derivative, 25-NBD-cholesterol, has a structure that is compromised by the presence of a bulky NBD group and does not distribute to the same organelles as DHE or filipin. In addition, we show in this manuscript that kinetic processes can be followed in living cells by monitoring recovery of DHE fluorescence in a photobleached region over time. Our observations provide evidence for the presence of a large intracellular cholesterol pool in the endocytic recycling compartment and the trans-Golgi network that might play important roles in the trafficking of lipids, lipid-anchored proteins, and transmembrane proteins that preferentially partition into cholesterol-enriched membrane domains. In addition, this

  3. SNAREs and cholesterol movement for steroidogenesis.

    PubMed

    Kraemer, Fredric B; Shen, Wen-Jun; Azhar, Salman

    2017-02-05

    Steroidogenesis is a complex process through which cholesterol traffics to mitochondria and is converted via a series of enzymatic steps to steroid hormones. Although the rate-limiting step in this process is the movement of cholesterol from the outer to the inner mitochondrial membrane via the actions of StAR, a continuous supply of cholesterol must be delivered to the outer mitochondrial membrane during active steroidogenesis and this is derived from multiple sources, including lipoprotein uptake, endogenous cholesterol synthesis and release from stores within cytoplasmic lipid droplets. A number of mechanisms have been suggested to contribute to cholesterol trafficking to mitochondria; however, there is no definitive consensus and this is particularly so in regards to trafficking from cytoplasmic lipid droplets. In this paper we review experiments in which we have surveyed the expression of SNARE proteins in steroidogenic tissue and cells and examined the role of SNAREs in mediating cholesterol movement from lipid droplets to the mitochondria based on multiple studies that identified SNAREs as components of cytoplasmic lipid droplets. We established and characterized an in vitro mitochondria reconstitution assay system that enabled us to examine the impact of adding recombinant SNARE proteins specifically on the movement of cholesterol from model lipid droplets to the outer mitochondrial membrane. Using this reconstitution assay system in combination with siRNA knockdown experiments in rat primary granulosa cells or in steroidogenic cell lines, we showed that several SNARE proteins are important components in the trafficking of cholesterol from lipid droplets to the mitochondria for steroidogenesis.

  4. Cholesterol self-powered biosensor.

    PubMed

    Sekretaryova, Alina N; Beni, Valerio; Eriksson, Mats; Karyakin, Arkady A; Turner, Anthony P F; Vagin, Mikhail Yu

    2014-10-07

    Monitoring the cholesterol level is of great importance, especially for people with high risk of developing heart disease. Here we report on reagentless cholesterol detection in human plasma with a novel single-enzyme, membrane-free, self-powered biosensor, in which both cathodic and anodic bioelectrocatalytic reactions are powered by the same substrate. Cholesterol oxidase was immobilized in a sol-gel matrix on both the cathode and the anode. Hydrogen peroxide, a product of the enzymatic conversion of cholesterol, was electrocatalytically reduced, by the use of Prussian blue, at the cathode. In parallel, cholesterol oxidation catalyzed by mediated cholesterol oxidase occurred at the anode. The analytical performance was assessed for both electrode systems separately. The combination of the two electrodes, formed on high surface-area carbon cloth electrodes, resulted in a self-powered biosensor with enhanced sensitivity (26.0 mA M(-1) cm(-2)), compared to either of the two individual electrodes, and a dynamic range up to 4.1 mM cholesterol. Reagentless cholesterol detection with both electrochemical systems and with the self-powered biosensor was performed and the results were compared with the standard method of colorimetric cholesterol quantification.

  5. High Blood Cholesterol

    MedlinePlus

    ... page from the NHLBI on Twitter. What Is Cholesterol? To understand high blood cholesterol (ko-LES-ter- ... cholesterol from your body. What Is High Blood Cholesterol? High blood cholesterol is a condition in which ...

  6. Structure of Cholesterol in Lipid Rafts

    NASA Astrophysics Data System (ADS)

    Toppozini, Laura; Meinhardt, Sebastian; Armstrong, Clare L.; Yamani, Zahra; Kučerka, Norbert; Schmid, Friederike; Rheinstädter, Maikel C.

    2014-11-01

    Rafts, or functional domains, are transient nano-or mesoscopic structures in the plasma membrane and are thought to be essential for many cellular processes such as signal transduction, adhesion, trafficking, and lipid or protein sorting. Observations of these membrane heterogeneities have proven challenging, as they are thought to be both small and short lived. With a combination of coarse-grained molecular dynamics simulations and neutron diffraction using deuterium labeled cholesterol molecules, we observe raftlike structures and determine the ordering of the cholesterol molecules in binary cholesterol-containing lipid membranes. From coarse-grained computer simulations, heterogenous membranes structures were observed and characterized as small, ordered domains. Neutron diffraction was used to study the lateral structure of the cholesterol molecules. We find pairs of strongly bound cholesterol molecules in the liquid-disordered phase, in accordance with the umbrella model. Bragg peaks corresponding to ordering of the cholesterol molecules in the raftlike structures were observed and indexed by two different structures: a monoclinic structure of ordered cholesterol pairs of alternating direction in equilibrium with cholesterol plaques, i.e., triclinic cholesterol bilayers.

  7. Peptide mediators of cholesterol efflux

    DOEpatents

    Bielicki, John K.; Johansson, Jan

    2013-04-09

    The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABAC1 that parallels that of full-length apolipoproteins. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia and inflammation.

  8. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism

    PubMed Central

    Korolnek, Tamara; Hamza, Iqbal

    2014-01-01

    Heme is an iron-containing porphyrin ring that serves as a prosthetic group in proteins that function in diverse metabolic pathways. Heme is also a major source of bioavailable iron in the human diet. While the synthesis of heme has been well-characterized, the pathways for heme trafficking remain poorly understood. It is likely that heme transport across membranes is highly regulated, as free heme is toxic to cells. This review outlines the requirement for heme delivery to various subcellular compartments as well as possible mechanisms for the mobilization of heme to these compartments. We also discuss how these trafficking pathways might function during physiological events involving inter- and intra-cellular mobilization of heme, including erythropoiesis, erythrophagocytosis, heme absorption in the gut, as well as heme transport pathways supporting embryonic development. Lastly, we aim to question the current dogma that heme, in toto, is not mobilized from one cell or tissue to another, outlining the evidence for these pathways and drawing parallels to other well-accepted paradigms for copper, iron, and cholesterol homeostasis. PMID:24926267

  9. Cholesterol and Your Child

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Cholesterol and Your Child KidsHealth > For Parents > Cholesterol and ... child's risk of developing heart disease later. About Cholesterol Cholesterol is a waxy substance produced by the ...

  10. Women and Cholesterol

    MedlinePlus

    ... Disease Venous Thromboembolism Aortic Aneurysm More Women and Cholesterol Updated:Apr 1,2016 The female sex hormone ... 2014. Related Sites Nutrition Center My Life Check Cholesterol • Home • About Cholesterol • Why Cholesterol Matters • Understand Your ...

  11. LDL Cholesterol Test

    MedlinePlus

    ... products and services. Advertising & Sponsorship: Policy | Opportunities LDL Cholesterol Share this page: Was this page helpful? Also ... LDL; LDL-C Formal name: Low-Density Lipoprotein Cholesterol Related tests: Cholesterol ; HDL Cholesterol ; Triglycerides ; Lipid Profile ; ...

  12. Common Misconceptions about Cholesterol

    MedlinePlus

    ... Venous Thromboembolism Aortic Aneurysm More Common Misconceptions about Cholesterol Updated:Apr 3,2017 Cholesterol can be both ... misconceptions about cholesterol. Click on each misconception about cholesterol to see the truth: My choices about diet ...

  13. Lifestyle Changes and Cholesterol

    MedlinePlus

    ... Venous Thromboembolism Aortic Aneurysm More Lifestyle Changes and Cholesterol Updated:Sep 26,2016 As part of a ... to the Terms and Conditions and Privacy Policy Cholesterol • Home • About Cholesterol • Why Cholesterol Matters • Understand Your ...

  14. HDL Cholesterol Test

    MedlinePlus

    ... products and services. Advertising & Sponsorship: Policy | Opportunities HDL Cholesterol Share this page: Was this page helpful? Also ... HDL; HDL-C Formal name: High-density Lipoprotein Cholesterol Related tests: Cholesterol ; LDL Cholesterol ; Triglycerides ; Lipid Profile ; ...

  15. Cholesterol IQ Quiz

    MedlinePlus

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Cholesterol IQ Quiz Updated:Feb 2,2015 Begin the quiz Cholesterol • Home • About Cholesterol Introduction Good vs. Bad Cholesterol ...

  16. Sex Trafficking of Minors.

    PubMed

    Moore, Jessica L; Kaplan, Dana M; Barron, Christine E

    2017-04-01

    Sex trafficking is an increasingly recognized global health crisis affecting every country and region in the world. Domestic minor sex trafficking is a subset of commercial sexual exploitation of children, defined as engagement of minors (<18 years of age) in sexual acts for items of value (eg, food, shelter, drugs, money) involving children victimized within US borders. These involved youth are at risk for serious immediate and long-term physical and mental health consequences. Continued efforts are needed to improve preventive efforts, identification, screening, appropriate interventions, and subsequent resource provision for victimized and high-risk youth.

  17. Potential of BODIPY-cholesterol for analysis of cholesterol transport and diffusion in living cells.

    PubMed

    Wüstner, Daniel; Lund, Frederik W; Röhrl, Clemens; Stangl, Herbert

    2016-01-01

    Cholesterol is an abundant and important lipid component of cellular membranes. Analysis of cholesterol transport and diffusion in living cells is hampered by the technical challenge of designing suitable cholesterol probes which can be detected for example by optical microscopy. One strategy is to use intrinsically fluorescent sterols, as dehydroergosterol (DHE), having minimal chemical alteration compared to cholesterol but giving low fluorescence signals in the UV region of the spectrum. Alternatively, one can use dye-tagged cholesterol analogs and in particular BODIPY-cholesterol (BChol), whose synthesis and initial characterization was pioneered by Robert Bittman. Here, we give a general overview of the properties and applications but also limitations of BODIPY-tagged cholesterol probes for analyzing intracellular cholesterol trafficking. We describe our own experiences and collaborative efforts with Bob Bittman for studying diffusion in the plasma membrane (PM) and uptake of BChol in a quantitative manner. For that purpose, we used a variety of fluorescence approaches including fluorescence correlation spectroscopy and its imaging variants, fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP). We also describe pulse-chase studies from the PM using BChol in direct comparison to DHE. Based on the gathered imaging data, we present a two-step kinetic model for sterol transport between PM and recycling endosomes. In addition, we highlight the suitability of BChol for determining transport of lipoprotein-derived sterol using electron microscopy (EM) and show that this approach ideally complements fluorescence studies.

  18. Measurement of Mitochondrial Cholesterol Import Using a Mitochondria-Targeted CYP11A1 Fusion Construct.

    PubMed

    Kennedy, Barry E; Charman, Mark; Karten, Barbara

    2017-01-01

    All animal membranes require cholesterol as an essential regulator of biophysical properties and function, but the levels of cholesterol vary widely among different subcellular compartments. Mitochondria, and in particular the inner mitochondrial membrane, have the lowest levels of cholesterol in the cell. Nevertheless, mitochondria need cholesterol for membrane maintenance and biogenesis, as well as oxysterol, steroid, and hepatic bile acid production. Alterations in mitochondrial cholesterol have been associated with a range of pathological conditions, including cancer, hepatosteatosis, cardiac ischemia, Alzheimer's, and Niemann-Pick Type C Disease. The mechanisms of mitochondrial cholesterol import are not fully elucidated yet, and may vary in different cell types and environmental conditions. Measuring cholesterol trafficking to the mitochondrial membranes is technically challenging because of its low abundance; for example, traditional pulse-chase experiments with isotope-labeled cholesterol are not feasible. Here, we describe improvements to a method first developed by the Miller group at the University of California to measure cholesterol trafficking to the inner mitochondrial membrane (IMM) through the conversion of cholesterol to pregnenolone. This method uses a mitochondria-targeted, ectopically expressed fusion construct of CYP11A1, ferredoxin reductase and ferredoxin. Pregnenolone is formed exclusively from cholesterol at the IMM, and can be analyzed with high sensitivity and specificity through ELISA or radioimmunoassay of the medium/buffer to reflect mitochondrial cholesterol import. This assay can be used to investigate the effects of genetic or pharmacological interventions on mitochondrial cholesterol import in cultured cells or isolated mitochondria.

  19. What Is Cholesterol?

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Cholesterol KidsHealth > For Teens > Cholesterol Print A A A ... High Cholesterol? en español ¿Qué es el colesterol? Cholesterol Is a Fat in the Blood Cholesterol (kuh- ...

  20. What Is Cholesterol?

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Cholesterol KidsHealth > For Teens > Cholesterol A A A What's ... High Cholesterol? en español ¿Qué es el colesterol? Cholesterol Is a Fat in the Blood Cholesterol (kuh- ...

  1. Get Your Cholesterol Checked

    MedlinePlus

    ... Checked Print This Topic En español Get Your Cholesterol Checked Browse Sections The Basics Overview Cholesterol Test ... How often do I need to get my cholesterol checked? The general recommendation is to get your ...

  2. Cholesterol Facts and Statistics

    MedlinePlus

    ... Blood Pressure Salt Million Hearts® WISEWOMAN Program High Cholesterol Facts Recommend on Facebook Tweet Share Compartir As ... the facts about high cholesterol [PDF-281K] . High Cholesterol in the United States 73.5 million adults ( ...

  3. Dietary Fat and Cholesterol

    MedlinePlus

    ... Conditions Nutrition & Fitness Emotional Health Dietary Fat and Cholesterol Posted under Health Guides . Updated 7 March 2017. + ... saturated fat found in red meat. What is cholesterol? Cholesterol is a fatlike substance that’s found in ...

  4. Cellular Cholesterol Homeostasis in Alzheimer's Disease.

    PubMed

    Chang, Ta Yuan; Yamauchi, Yoshio; Hasan, Mazahir; Chang, Catherine Cy

    2017-03-15

    Alzheimer's disease [AD] is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid beta peptides [Abeta; especially Abeta1-42], and neurofibrillary tangles, composed of hyper-phosphorylated tau, accompanied with chronic neuroinflammation. Abeta are derived from the amyloid precursor protein APP. The oligomeric form of Abeta is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major cholesterol transport protein in the CNS that has three alleles, of which the Apoe4 allele constitutes the major risk factor for late onset AD [LOAD]. In this review we describe the complex relationship between ApoE4, oligomeric Abeta peptides, and cholesterol homeostasis. The review consists of four parts: 1. Key elements involved in cellular cholesterol metabolism and regulation; II. Key elements involved in intracellular cholesterol trafficking; III. Links between ApoE4, Abeta, and disturbance of cholesterol homeostasis in the CNS; IV. Potential lipid based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.

  5. Cell Cholesterol Homeostasis: Mediation by Active Cholesterol

    PubMed Central

    Steck, Theodore L.; Lange, Yvonne

    2010-01-01

    Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is that fraction which exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol prompts several feedback responses thereby. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol. PMID:20843692

  6. Arms Trafficking and Colombia

    DTIC Science & Technology

    2003-01-01

    September 20, 2000. 8Bedoya Lima , Jineth, “La Autopista De Las Farc En Plena Selva," El Espectador, April 27, 2001. Although the authors could not...are simply augmenting the normal “trickle” pattern as their operations, and therefore their demand, grow. For example, Lima La Republica reported that...Trafficking,” Lima La Republica, September 21, 2000. 11See the appendix. Interestingly, some reports claim that the criminal working with the AUC then

  7. Trafficking in Persons Report

    DTIC Science & Technology

    2009-06-01

    causes retardation, blindness, kidney damage, and tremors. To a lesser extent, child mine laborers are also exposed to cyanide and sulfur. A 2006 Harvard...Medical School study found that children in gold mining communities in Ecuador showed neurological abnormalities resulting from mercury and cyanide ...trafficked for the purposes of commercial sexual exploitation and forced labor, including domestic servitude and forced labor in the tobacco , cotton

  8. Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function.

    PubMed

    Martin, Laura A; Kennedy, Barry E; Karten, Barbara

    2016-04-01

    Mitochondria require cholesterol for biogenesis and membrane maintenance, and for the synthesis of steroids, oxysterols and hepatic bile acids. Multiple pathways mediate the transport of cholesterol from different subcellular pools to mitochondria. In steroidogenic cells, the steroidogenic acute regulatory protein (StAR) interacts with a mitochondrial protein complex to mediate cholesterol delivery to the inner mitochondrial membrane for conversion to pregnenolone. In non-steroidogenic cells, several members of a protein family defined by the presence of a StAR-related lipid transfer (START) domain play key roles in the delivery of cholesterol to mitochondrial membranes. Subdomains of the endoplasmic reticulum (ER), termed mitochondria-associated ER membranes (MAM), form membrane contact sites with mitochondria and may contribute to the transport of ER cholesterol to mitochondria, either independently or in conjunction with lipid-transfer proteins. Model systems of mitochondria enriched with cholesterol in vitro and mitochondria isolated from cells with (patho)physiological mitochondrial cholesterol accumulation clearly demonstrate that mitochondrial cholesterol levels affect mitochondrial function. Increased mitochondrial cholesterol levels have been observed in several diseases, including cancer, ischemia, steatohepatitis and neurodegenerative diseases, and influence disease pathology. Hence, a deeper understanding of the mechanisms maintaining mitochondrial cholesterol homeostasis may reveal additional targets for therapeutic intervention. Here we give a brief overview of mitochondrial cholesterol import in steroidogenic cells, and then focus on cholesterol trafficking pathways that deliver cholesterol to mitochondrial membranes in non-steroidogenic cells. We also briefly discuss the consequences of increased mitochondrial cholesterol levels on mitochondrial function and their potential role in disease pathology.

  9. Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes

    PubMed Central

    Storey, Stephen M.; McIntosh, Avery L.; Huang, Huan; Landrock, Kerstin K.; Martin, Gregory G.; Landrock, Danilo; Payne, H. Ross; Atshaves, Barbara P.; Kier, Ann B.

    2012-01-01

    A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in <1 min and initial rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2

  10. Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes.

    PubMed

    Storey, Stephen M; McIntosh, Avery L; Huang, Huan; Landrock, Kerstin K; Martin, Gregory G; Landrock, Danilo; Payne, H Ross; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm

    2012-04-15

    A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in <1 min and initial rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2

  11. Cooking for Lower Cholesterol

    MedlinePlus

    ... Venous Thromboembolism Aortic Aneurysm More Cooking for Lower Cholesterol Updated:Oct 28,2016 A heart-healthy eating ... content was last reviewed on 04/21/2014. Cholesterol • Home • About Cholesterol • Why Cholesterol Matters • Understand Your ...

  12. Health implications of human trafficking.

    PubMed

    Richards, Tiffany A

    2014-01-01

    Freedom is arguably the most cherished right in the United States. But each year, approximately 14,500 to 17,500 women, men and children are trafficked into the United States for the purposes of forced labor or sexual exploitation. Human trafficking has significant effects on both physical and mental health. This article describes the features of human trafficking, its physical and mental health effects and the vital role nurses can play in providing care to this vulnerable population.

  13. Interactions between Ether Phospholipids and Cholesterol as Determined by Scattering and Molecular Dynamics Simulations

    SciTech Connect

    Pan, Jianjun; Cheng, Xiaolin; Heberle, Frederick A; Mostofian, Barmak; Kucerka, Norbert; Drazba, Paul; Katsaras, John

    2012-01-01

    Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol s molecular interactions with ether lipids as determined using a combination of small-angle neutron and Xray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid-mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.

  14. Intracellular trafficking of hybrid gene delivery vectors.

    PubMed

    Keswani, Rahul K; Lazebnik, Mihael; Pack, Daniel W

    2015-06-10

    Viral and non-viral gene delivery vectors are in development for human gene therapy, but both exhibit disadvantages such as inadequate efficiency, lack of cell-specific targeting or safety concerns. We have recently reported the design of hybrid delivery vectors combining retrovirus-like particles with synthetic polymers or lipids that are efficient, provide sustained gene expression and are more stable compared to native retroviruses. To guide further development of this promising class of gene delivery vectors, we have investigated their mechanisms of intracellular trafficking. Moloney murine leukemia virus-like particles (M-VLPs) were complexed with chitosan (Chi) or liposomes (Lip) comprising DOTAP, DOPE and cholesterol to form the hybrid vectors (Chi/M-VLPs and Lip/M-VLPs, respectively). Transfection efficiency and cellular internalization of the vectors were quantified in the presence of a panel of inhibitors of various endocytic pathways. Intracellular transport and trafficking kinetics of the hybrid vectors were dependent on the synthetic component and used a combination of clathrin- and caveolar-dependent endocytosis and macropinocytosis. Chi/M-VLPs were slower to transfect compared to Lip/M-VLPs due to the delayed detachment of the synthetic component. The synthetic component of hybrid gene delivery vectors plays a significant role in their cellular interactions and processing and is a key parameter for the design of more efficient gene delivery vehicles.

  15. Controlling Cholesterol with Statins

    MedlinePlus

    ... For Consumers Home For Consumers Consumer Updates Controlling Cholesterol with Statins Share Tweet Linkedin Pin it More ... not, the following tips can help keep your cholesterol in check: Talk with your healthcare provider about ...

  16. Cholesterol - drug treatment

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000314.htm Cholesterol - drug treatment To use the sharing features on ... treatment; Hardening of the arteries - statin Statins for Cholesterol Statins reduce your risk of heart disease, stroke, ...

  17. Cholesterol testing and results

    MedlinePlus

    Cholesterol test results; LDL test results; VLDL test results; HDL test results; Coronary risk profile results; Hyperlipidemia- ... Some cholesterol is considered good and some is considered bad. Different blood tests can be done to measure each ...

  18. Cholesterol and Statins

    MedlinePlus

    ... away from cells and back to the liver. saturated fat and cholesterol in the food you eat can ... care professionals advise a program of reduced dietary saturated fat and cholesterol, together with physical activity and weight ...

  19. Potent and selective mediators of cholesterol efflux

    DOEpatents

    Bielicki, John K; Johansson, Jan

    2015-03-24

    The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABAC1 that parallels that of full-length apolipoproteins. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia and inflammation.

  20. All about Cholesterol

    MedlinePlus

    Toolkit No. 6 All About Cholesterol Managing your cholesterol and other blood fats (also called blood lipids) can help you prevent health problems. ... it’s likely that your cholesterol may be off. All of these are risk factors for diabetes, heart ...

  1. Cholesterol and Plants

    ERIC Educational Resources Information Center

    Behrman, E. J.; Gopalan, Venkat

    2005-01-01

    There is a widespread belief among the public and even among chemist that plants do not contain cholesterol. This wrong belief is the result of the fact that plants generally contain only small quantities of cholesterol and that analytical methods for the detection of cholesterol in this range were not developed until recently.

  2. Detecting Elevated Cholesterol Levels

    PubMed Central

    Reimer, H.L.; Elford, R.W.; Shumak, S.

    1991-01-01

    To assess accuracy of blood cholesterol measurements in the office, fingerprick blood cholesterol assays by a dry reagent chemistry analyzer were compared in 151 patients with simultaneous venipuncture cholesterol assays by standard laboratory methods. Compared with the laboratory assay, seven of eight analyzers had total absolute biases less than 5%. Variability in results was comparable to that of community laboratories. PMID:21229050

  3. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  4. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Narcotics trafficking. 536.311... OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any...

  5. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  6. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  7. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  8. What Your Cholesterol Levels Mean

    MedlinePlus

    ... Disease Venous Thromboembolism Aortic Aneurysm More What Your Cholesterol Levels Mean Updated:Apr 3,2017 Keeping your ... content was last reviewed on 04/21/2014. Cholesterol • Home • About Cholesterol Introduction Good vs. Bad Cholesterol ...

  9. Home-Use Tests - Cholesterol

    MedlinePlus

    ... Medical Procedures In Vitro Diagnostics Home Use Tests Cholesterol Share Tweet Linkedin Pin it More sharing options ... a home-use test kit to measure total cholesterol. What cholesterol is: Cholesterol is a fat (lipid) ...

  10. Luminol electrochemiluminescence for the analysis of active cholesterol at the plasma membrane in single mammalian cells.

    PubMed

    Ma, Guangzhong; Zhou, Junyu; Tian, Chunxiu; Jiang, Dechen; Fang, Danjun; Chen, Hongyuan

    2013-04-16

    A luminol electrochemiluminescence assay was reported to analyze active cholesterol at the plasma membrane in single mammalian cells. The cellular membrane cholesterol was activated by the exposure of the cells to low ionic strength buffer or the inhibition of intracellular acyl-coA/cholesterol acyltransferase (ACAT). The active membrane cholesterol was reacted with cholesterol oxidase in the solution to generate a peak concentration of hydrogen peroxide on the electrode surface, which induced a measurable luminol electrochemiluminescence. Further treatment of the active cells with mevastatin decreased the active membrane cholesterol resulting in a drop in luminance. No change in the intracellular calcium was observed in the presence of luminol and voltage, which indicated that our analysis process might not interrupt the intracellular cholesterol trafficking. Single cell analysis was performed by placing a pinhole below the electrode so that only one cell was exposed to the photomultiplier tube (PMT). Twelve single cells were analyzed individually, and a large deviation on luminance ratio observed exhibited the cell heterogeneity on the active membrane cholesterol. The smaller deviation on ACAT/HMGCoA inhibited cells than ACAT inhibited cells suggested different inhibition efficiency for sandoz 58035 and mevastatin. The new information obtained from single cell analysis might provide a new insight on the study of intracellular cholesterol trafficking.

  11. Illicit Trafficking of Natural Radionuclides

    NASA Astrophysics Data System (ADS)

    Friedrich, Steinhäusler; Lyudmila, Zaitseva

    2008-08-01

    Natural radionuclides have been subject to trafficking worldwide, involving natural uranium ore (U 238), processed uranium (yellow cake), low enriched uranium (<20% U 235) or highly enriched uranium (>20% U 235), radium (Ra 226), polonium (Po 210), and natural thorium ore (Th 232). An important prerequisite to successful illicit trafficking activities is access to a suitable logistical infrastructure enabling an undercover shipment of radioactive materials and, in case of trafficking natural uranium or thorium ore, capable of transporting large volumes of material. Covert en route diversion of an authorised uranium transport, together with covert diversion of uranium concentrate from an operating or closed uranium mines or mills, are subject of case studies. Such cases, involving Israel, Iran, Pakistan and Libya, have been analyzed in terms of international actors involved and methods deployed. Using international incident data contained in the Database on Nuclear Smuggling, Theft and Orphan Radiation Sources (DSTO) and international experience gained from the fight against drug trafficking, a generic Trafficking Pathway Model (TPM) is developed for trafficking of natural radionuclides. The TPM covers the complete trafficking cycle, ranging from material diversion, covert material transport, material concealment, and all associated operational procedures. The model subdivides the trafficking cycle into five phases: (1) Material diversion by insider(s) or initiation by outsider(s); (2) Covert transport; (3) Material brokerage; (4) Material sale; (5) Material delivery. An Action Plan is recommended, addressing the strengthening of the national infrastructure for material protection and accounting, development of higher standards of good governance, and needs for improving the control system deployed by customs, border guards and security forces.

  12. Illicit Trafficking of Natural Radionuclides

    SciTech Connect

    Friedrich, Steinhaeusler; Lyudmila, Zaitseva

    2008-08-07

    Natural radionuclides have been subject to trafficking worldwide, involving natural uranium ore (U 238), processed uranium (yellow cake), low enriched uranium (<20% U 235) or highly enriched uranium (>20% U 235), radium (Ra 226), polonium (Po 210), and natural thorium ore (Th 232). An important prerequisite to successful illicit trafficking activities is access to a suitable logistical infrastructure enabling an undercover shipment of radioactive materials and, in case of trafficking natural uranium or thorium ore, capable of transporting large volumes of material. Covert en route diversion of an authorised uranium transport, together with covert diversion of uranium concentrate from an operating or closed uranium mines or mills, are subject of case studies. Such cases, involving Israel, Iran, Pakistan and Libya, have been analyzed in terms of international actors involved and methods deployed. Using international incident data contained in the Database on Nuclear Smuggling, Theft and Orphan Radiation Sources (DSTO) and international experience gained from the fight against drug trafficking, a generic Trafficking Pathway Model (TPM) is developed for trafficking of natural radionuclides. The TPM covers the complete trafficking cycle, ranging from material diversion, covert material transport, material concealment, and all associated operational procedures. The model subdivides the trafficking cycle into five phases: (1) Material diversion by insider(s) or initiation by outsider(s); (2) Covert transport; (3) Material brokerage; (4) Material sale; (5) Material delivery. An Action Plan is recommended, addressing the strengthening of the national infrastructure for material protection and accounting, development of higher standards of good governance, and needs for improving the control system deployed by customs, border guards and security forces.

  13. Sex trafficking in South Asia.

    PubMed

    Huda, S

    2006-09-01

    Economic and social inequalities and political conflicts have led to the movement of persons within each country and across the borders in South Asia. Globalization has encouraged free mobility of capital, technology, experts and sex tourism. Illiteracy, dependency, violence, social stigma, cultural stereotypes, gender disparity and endemic poverty, among other factors, place women and children in powerless, non-negotiable situations that have contributed to the emergence and breeding of the cavernous problem of sex trafficking in the entire region. This alarming spread of sex trafficking has fuelled the spread of HIV infection in South Asia, posing a unique and serious threat to community health, poverty alleviation and other crucial aspects of human development. Although the SAARC (South Asian Association for Regional Cooperation) Convention on Trafficking in Women and Children has been an important breakthrough, most of the countries in the region do not have anti-trafficking legislation or means to protect the victims. Countries of the region should make a concerted effort to treat trafficking victims as "victims" of human rights violations in all anti-trafficking strategies and actions.

  14. To discuss illicit nuclear trafficking

    SciTech Connect

    Balatsky, Galya I; Severe, William R; Wallace, Richard K

    2010-01-01

    The Illicit nuclear trafficking panel was conducted at the 4th Annual INMM workshop on Reducing the Risk from Radioactive and Nuclear Materials on February 2-3, 2010 in Washington DC. While the workshop occurred prior to the Nuclear Security Summit, April 12-13 2010 in Washington DC, some of the summit issues were raised during the workshop. The Communique of the Washington Nuclear Security Summit stated that 'Nuclear terrorism is one of the most challenging threats to international security, and strong nuclear security measures are the most effective means to prevent terrorists, criminals, or other unauthorized actors from acquiring nuclear materials.' The Illicit Trafficking panel is one means to strengthen nuclear security and cooperation at bilateral, regional and multilateral levels. Such a panel promotes nuclear security culture through technology development, human resources development, education and training. It is a tool which stresses the importance of international cooperation and coordination of assistance to improve efforts to prevent and respond to incidents of illicit nuclear trafficking. Illicit trafficking panel included representatives from US government, an international organization (IAEA), private industry and a non-governmental organization to discuss illicit nuclear trafficking issues. The focus of discussions was on best practices and challenges for addressing illicit nuclear trafficking. Terrorism connection. Workshop discussions pointed out the identification of terrorist connections with several trafficking incidents. Several trafficking cases involved real buyers (as opposed to undercover law enforcement agents) and there have been reports identifying individuals associated with terrorist organizations as prospective plutonium buyers. Some specific groups have been identified that consistently search for materials to buy on the black market, but no criminal groups were identified that specialize in nuclear materials or isotope smuggling

  15. Regulation of cholesterol homeostasis.

    PubMed

    van der Wulp, Mariëtte Y M; Verkade, Henkjan J; Groen, Albert K

    2013-04-10

    Hypercholesterolemia is an important risk factor for cardiovascular disease. It is caused by a disturbed balance between cholesterol secretion into the blood versus uptake. The pathways involved are regulated via a complex interplay of enzymes, transport proteins, transcription factors and non-coding RNA's. The last two decades insight into underlying mechanisms has increased vastly but there are still a lot of unknowns, particularly regarding intracellular cholesterol transport. After decades of concentration on the liver, in recent years the intestine has come into focus as an important control point in cholesterol homeostasis. This review will discuss current knowledge of cholesterol physiology, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and new (possible) therapeutic options for hypercholesterolemia.

  16. Assessing Cholesterol Storage in Live Cells and C. elegans by Stimulated Raman Scattering Imaging of Phenyl-Diyne Cholesterol

    NASA Astrophysics Data System (ADS)

    Lee, Hyeon Jeong; Zhang, Wandi; Zhang, Delong; Yang, Yang; Liu, Bin; Barker, Eric L.; Buhman, Kimberly K.; Slipchenko, Lyudmila V.; Dai, Mingji; Cheng, Ji-Xin

    2015-01-01

    We report a cholesterol imaging method using rationally synthesized phenyl-diyne cholesterol (PhDY-Chol) and stimulated Raman scattering (SRS) microscope. The phenyl-diyne group is biologically inert and provides a Raman scattering cross section that is 88 times larger than the endogenous C = O stretching mode. SRS microscopy offers an imaging speed that is faster than spontaneous Raman microscopy by three orders of magnitude, and a detection sensitivity of 31 μM PhDY-Chol (~1,800 molecules in the excitation volume). Inside living CHO cells, PhDY-Chol mimics the behavior of cholesterol, including membrane incorporation and esterification. In a cellular model of Niemann-Pick type C disease, PhDY-Chol reflects the lysosomal accumulation of cholesterol, and shows relocation to lipid droplets after HPβCD treatment. In live C. elegans, PhDY-Chol mimics cholesterol uptake by intestinal cells and reflects cholesterol storage. Together, our work demonstrates an enabling platform for study of cholesterol storage and trafficking in living cells and vital organisms.

  17. Cholesterol - what to ask your doctor

    MedlinePlus

    ... your doctor; What to ask your doctor about cholesterol ... What is my cholesterol level? What should my cholesterol level be? What are HDL ("good") cholesterol and LDL ("bad") cholesterol? Does my cholesterol ...

  18. Improved Coarse-Grained Modeling of Cholesterol-Containing Lipid Bilayers

    PubMed Central

    2015-01-01

    Cholesterol trafficking, which is an essential function in mammalian cells, is intimately connected to molecular-scale interactions through cholesterol modulation of membrane structure and dynamics and interaction with membrane receptors. Since these effects of cholesterol occur on micro- to millisecond time scales, it is essential to develop accurate coarse-grained simulation models that can reach these time scales. Cholesterol has been shown experimentally to thicken the membrane and increase phospholipid tail order between 0 and 40% cholesterol, above which these effects plateau or slightly decrease. Here, we showed that the published MARTINI coarse-grained force-field for phospholipid (POPC) and cholesterol fails to capture these effects. Using reference atomistic simulations, we systematically modified POPC and cholesterol bonded parameters in MARTINI to improve its performance. We showed that the corrections to pseudobond angles between glycerol and the lipid tails and around the oleoyl double bond particle (the “angle-corrected model”) slightly improves the agreement of MARTINI with experimentally measured thermal, elastic, and dynamic properties of POPC membranes. The angle-corrected model improves prediction of the thickening and ordering effects up to 40% cholesterol but overestimates these effects at higher cholesterol concentration. In accordance with prior work that showed the cholesterol rough face methyl groups are important for limiting cholesterol self-association, we revised the coarse-grained representation of these methyl groups to better match cholesterol-cholesterol radial distribution functions from atomistic simulations. In addition, by using a finer-grained representation of the branched cholesterol tail than MARTINI, we improved predictions of lipid tail order and bilayer thickness across a wide range of concentrations. Finally, transferability testing shows that a model incorporating our revised parameters into DOPC outperforms other

  19. Complementary probes reveal that phosphatidylserine is required for the proper transbilayer distribution of cholesterol.

    PubMed

    Maekawa, Masashi; Fairn, Gregory D

    2015-04-01

    Cholesterol is an essential component of metazoan cellular membranes and it helps to maintain the structural integrity and fluidity of the plasma membrane. Here, we developed a cholesterol biosensor, termed D4H, based on the fourth domain of Clostridium perfringens theta-toxin, which recognizes cholesterol in the cytosolic leaflet of the plasma membrane and organelles. The D4H probe disassociates from the plasma membrane upon cholesterol extraction and after perturbations in cellular cholesterol trafficking. When used in combination with a recombinant version of the biosensor, we show that plasmalemmal phosphatidylserine is essential for retaining cholesterol in the cytosolic leaflet of the plasma membrane. In vitro experiments reveal that 1-stearoy-2-oleoyl phosphatidylserine can induce phase separation in cholesterol-containing lipid bilayers and shield cholesterol from cholesterol oxidase. Finally, the altered transbilayer distribution of cholesterol causes flotillin-1 to relocalize to endocytic organelles. This probe should be useful in the future to study pools of cholesterol in the cytosolic leaflet of the plasma membrane and organelles.

  20. Plant sterol consumption frequency affects plasma lipid levels and cholesterol kinetics in humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background/Objectives: To compare the efficacy of single versus multiple doses of plant sterols on circulating lipid level and cholesterol trafficking. Subjects/Methods: A randomized, placebo-controlled, three-phase (6 days/phase) crossover, supervised feeding trial was conducted in 19 subjects. Sub...

  1. Cholesterol and Kir channels

    PubMed Central

    Levitan, Irena

    2009-01-01

    To date, most of the major types of Kir channels, Kir2s, Kir3s, Kir4s and Kir6s, have been found to partition into cholesterol-rich membrane domains and/or to be regulated by changes in the level of membrane cholesterol. Surprisingly, however, in spite of the structural similarities between different Kirs, effects of cholesterol on different types of Kir channels vary from cholesterol-induced decrease in the current density (Kir2 channels) to the loss of channel activity by cholesterol depletion (Kir4 channels) and loss of channel coupling by different mediators (Kir3 and Kir6 channels). Recently, we have gained initial insights into the mechanisms responsible for cholesterol-induced suppression Kir2 channels, but mechanisms underlying cholesterol sensitivity of other Kir channels are mostly unknown. The goal of this review is to present a summary of the current knowledge of the distinct effects of cholesterol on different types of Kir channels in vitro and in vivo. PMID:19548316

  2. Cholesterol and prostate cancer.

    PubMed

    Freeman, Michael R; Solomon, Keith R

    2004-01-01

    Cholesterol is a neutral lipid that accumulates in liquid-ordered, detergent-resistant membrane domains called lipid rafts. Lipid rafts serve as membrane platforms for signal transduction mechanisms that mediate cell growth, survival, and a variety of other processes relevant to cancer. A number of studies, going back many years, demonstrate that cholesterol accumulates in solid tumors and that cholesterol homeostasis breaks down in the prostate with aging and with the transition to the malignant state. This review summarizes the established links between cholesterol and prostate cancer (PCa), with a focus on how accumulation of cholesterol within the lipid raft component of the plasma membrane may stimulate signaling pathways that promote progression to hormone refractory disease. We propose that increases in cholesterol in prostate tumor cell membranes, resulting from increases in circulating levels or from dysregulation of endogenous synthesis, results in the coalescence of raft domains. This would have the effect of sequestering positive regulators of oncogenic signaling within rafts, while maintaining negative regulators in the liquid-disordered membrane fraction. This approach toward examining the function of lipid rafts in prostate cancer cells may provide insight into the role of circulating cholesterol in malignant growth and on the potential relationship between diet and aggressive disease. Large-scale characterization of proteins that localize to cholesterol-rich domains may help unveil signaling networks and pathways that will lead to identification of new biomarkers for disease progression and potentially to novel targets for therapeutic intervention.

  3. Electrochemical oxidation of cholesterol

    PubMed Central

    2015-01-01

    Summary Indirect cholesterol electrochemical oxidation in the presence of various mediators leads to electrophilic addition to the double bond, oxidation at the allylic position, oxidation of the hydroxy group, or functionalization of the side chain. Recent studies have proven that direct electrochemical oxidation of cholesterol is also possible and affords different products depending on the reaction conditions. PMID:25977713

  4. Kids and Cholesterol.

    ERIC Educational Resources Information Center

    Ficklen, Ellen

    1992-01-01

    According to a 1991 National Cholesterol Education Program report, the best way to avoid heart trouble is to take early preventive measures. This means that children over age two should follow the same low-fat, low-cholesterol guidelines already recommended for adults. Sidebars contain a fat glossary and tips for cutting fat in school lunches.…

  5. Understanding human trafficking in the United States.

    PubMed

    Logan, T K; Walker, Robert; Hunt, Gretchen

    2009-01-01

    The topic of modern-day slavery or human trafficking has received increased media and national attention. However, to date there has been limited research on the nature and scope of human trafficking in the United States. This article describes and synthesizes nine reports that assess the U.S. service organizations' legal representative knowledge of, and experience with, human trafficking cases, as well as information from actual cases and media reports. This article has five main goals: (a) to define what human trafficking is, and is not; (b) to describe factors identified as contributing to vulnerability to being trafficked and keeping a person entrapped in the situation; (c) to examine how the crime of human trafficking differs from other kinds of crimes in the United States; (d) to explore how human trafficking victims are identified; and, (e) to provide recommendations to better address human trafficking in the United States.

  6. What Causes High Blood Cholesterol?

    MedlinePlus

    ... the NHLBI on Twitter. What Causes High Blood Cholesterol? Many factors can affect the cholesterol levels in your blood. You can control some ... but not others. Factors You Can Control Diet Cholesterol is found in foods that come from animal ...

  7. Bile acid sequestrants for cholesterol

    MedlinePlus

    ... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

  8. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  9. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  10. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  11. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  12. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Narcotics trafficking. 598.310... OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any...

  13. Barriers to Combating Human Trafficking in Colombia

    DTIC Science & Technology

    2015-03-01

    EFFORTS ..............25 A. THE COLOMBIAN LEGAL FRAMEWORK AGAINST HUMAN TRAFFICKING...severe forms of trafficking in persons.”20 The second and third standards deal exclusively with the legal status of human trafficking in, requiring...problems involving definitions and victim identification; quantifying the problem; victimization factors; the legal system; and demand, corruption, and

  14. Cholesterol and Ion Channels

    PubMed Central

    Levitan, Irena; Fang, Yun; Rosenhouse-Dantsker, Avia; Romanenko, Victor

    2010-01-01

    A variety of ion channels, including members of all major ion channel families, have been shown to be regulated by changes in the level of membrane cholesterol and partition into cholesterol-rich membrane domains. In general, several types of cholesterol effects have been described. The most common effect is suppression of channel activity by an increase in membrane cholesterol, an effect that was described for several types of inwardly-rectifying K+ channels, voltage-gated K+ channels, Ca+2 sensitive K+ channels, voltage-gated Na+ channels, N-type voltage-gated Ca+2 channels and volume-regulated anion channels. In contrast, several types of ion channels, such as epithelial amiloride-sensitive Na+ channels and Transient Receptor Potential channels, as well as some of the types of inwardly-rectifying and voltage-gated K+ channels were shown to be inhibited by cholesterol depletion. Cholesterol was also shown to alter the kinetic properties and current-voltage dependence of several voltage-gated channels. Finally, maintaining membrane cholesterol level is required for coupling ion channels to signalling cascades. In terms of the mechanisms, three general mechanisms have been proposed: (i) specific interactions between cholesterol and the channel protein, (ii) changes in the physical properties of the membrane bilayer and (iii) maintaining the scaffolds for protein-protein interactions. The goal of this review is to describe systematically the role of cholesterol in regulation of the major types of ion channels and to discuss these effects in the context of the models proposed. PMID:20213557

  15. Diacylglycerol kinases in membrane trafficking

    PubMed Central

    Xie, Shuwei; Naslavsky, Naava; Caplan, Steve

    2015-01-01

    Diacylglycerol kinases (DGKs) belong to a family of cytosolic kinases that regulate the phosphorylation of diacylglycerol (DAG), converting it into phosphatidic acid (PA). There are 10 known mammalian DGK isoforms, each with a different tissue distribution and substrate specificity. These differences allow regulation of cellular responses by fine-tuning the delicate balance of cellular DAG and PA. DGK isoforms are best characterized as mediators of signal transduction and immune function. However, since recent studies reveal that DAG and PA are also involved in the regulation of endocytic trafficking, it is therefore anticipated that DGKs also plays an important role in membrane trafficking. In this review, we summarize the literature discussing the role of DGK isoforms at different stages of endocytic trafficking, including endocytosis, exocytosis, endocytic recycling, and transport from/to the Golgi apparatus. Overall, these studies contribute to our understanding of the involvement of PA and DAG in endocytic trafficking, an area of research that is drawing increasing attention in recent years. PMID:27057419

  16. Detecting Elevated Cholesterol Levels

    PubMed Central

    Reimer, H.L.; Elford, R.W.; Shumak, S.

    1991-01-01

    The Reflotron dry chemistry reflectance photometer was studied as a case-finding method in physicians' offices. A total of 713 adult patients had their risk factor profiles determined along with fingerprick blood cholesterol measurements. Blood cholesterol levels were classified into three categories, (<5.2 mmol/L), 51%; borderline high (5.2 to 6.1 mmol/L), 28%; and high (≥6.2 mmol/L), 21%. The physicians' predictions from clinical risk factor profiles of which patients had elevated serum cholesterol levels were inaccurate. PMID:21229051

  17. Regulation of Adaptive Immunity in Health and Disease by Cholesterol Metabolism

    PubMed Central

    Fessler, Michael B.

    2015-01-01

    Four decades ago, it was observed that stimulation of T cells induces rapid changes in cellular cholesterol that are required before proliferation can commence. Investigators returning to this phenomenon have finally revealed its molecular underpinnings. Cholesterol trafficking and its dysregulation are now also recognized to strongly influence dendritic cell function, T cell polarization, and antibody responses. In this review, the state of the literature is reviewed on how cholesterol and its trafficking regulate the cells of the adaptive immune response and in vivo disease phenotypes of dysregulated adaptive immunity, including allergy, asthma, and autoimmune disease. Emerging evidence supporting a potential role for statins and other lipid-targeted therapies in the treatment of these diseases is presented. Just as vascular biologists have embraced immunity in the pathogenesis and treatment of atherosclerosis, so should basic and clinical immunologists in allergy, pulmonology, and other disciplines seek to encompass a basic understanding of lipid science. PMID:26149587

  18. Domain 4 (D4) of Perfringolysin O to Visualize Cholesterol in Cellular Membranes—The Update

    PubMed Central

    Maekawa, Masashi

    2017-01-01

    The cellular membrane of eukaryotes consists of phospholipids, sphingolipids, cholesterol and membrane proteins. Among them, cholesterol is crucial for various cellular events (e.g., signaling, viral/bacterial infection, and membrane trafficking) in addition to its essential role as an ingredient of steroid hormones, vitamin D, and bile acids. From a micro-perspective, at the plasma membrane, recent emerging evidence strongly suggests the existence of lipid nanodomains formed with cholesterol and phospholipids (e.g., sphingomyelin, phosphatidylserine). Thus, it is important to elucidate how cholesterol behaves in membranes and how the behavior of cholesterol is regulated at the molecular level. To elucidate the complexed characteristics of cholesterol in cellular membranes, a couple of useful biosensors that enable us to visualize cholesterol in cellular membranes have been recently developed by utilizing domain 4 (D4) of Perfringolysin O (PFO, theta toxin), a cholesterol-binding toxin. This review highlights the current progress on development of novel cholesterol biosensors that uncover new insights of cholesterol in cellular membranes. PMID:28273804

  19. Domain 4 (D4) of Perfringolysin O to Visualize Cholesterol in Cellular Membranes-The Update.

    PubMed

    Maekawa, Masashi

    2017-03-03

    The cellular membrane of eukaryotes consists of phospholipids, sphingolipids, cholesterol and membrane proteins. Among them, cholesterol is crucial for various cellular events (e.g., signaling, viral/bacterial infection, and membrane trafficking) in addition to its essential role as an ingredient of steroid hormones, vitamin D, and bile acids. From a micro-perspective, at the plasma membrane, recent emerging evidence strongly suggests the existence of lipid nanodomains formed with cholesterol and phospholipids (e.g., sphingomyelin, phosphatidylserine). Thus, it is important to elucidate how cholesterol behaves in membranes and how the behavior of cholesterol is regulated at the molecular level. To elucidate the complexed characteristics of cholesterol in cellular membranes, a couple of useful biosensors that enable us to visualize cholesterol in cellular membranes have been recently developed by utilizing domain 4 (D4) of Perfringolysin O (PFO, theta toxin), a cholesterol-binding toxin. This review highlights the current progress on development of novel cholesterol biosensors that uncover new insights of cholesterol in cellular membranes.

  20. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport.

    PubMed

    Fernández-Suárez, María E; Escolà-Gil, Joan C; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-09-07

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages.

  1. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

    PubMed Central

    Fernández-Suárez, María E.; Escolà-Gil, Joan C.; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A.; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [3H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  2. How cholesterol interacts with proteins and lipids during its intracellular transport.

    PubMed

    Wüstner, Daniel; Solanko, Katarzyna

    2015-09-01

    Sterols, as cholesterol in mammalian cells and ergosterol in fungi, are indispensable molecules for proper functioning and nanoscale organization of the plasma membrane. Synthesis, uptake and efflux of cholesterol are regulated by a variety of protein-lipid and protein-protein interactions. Similarly, membrane lipids and their physico-chemical properties directly affect cholesterol partitioning and thereby contribute to the highly heterogeneous intracellular cholesterol distribution. Movement of cholesterol in cells is mediated by vesicle trafficking along the endocytic and secretory pathways as well as by non-vesicular sterol exchange between organelles. In this article, we will review recent progress in elucidating sterol-lipid and sterol-protein interactions contributing to proper sterol transport in living cells. We outline recent biophysical models of cholesterol distribution and dynamics in membranes and explain how such models are related to sterol flux between organelles. An overview of various sterol-transfer proteins is given, and the physico-chemical principles of their function in non-vesicular sterol transport are explained. We also discuss selected experimental approaches for characterization of sterol-protein interactions and for monitoring intracellular sterol transport. Finally, we review recent work on the molecular mechanisms underlying lipoprotein-mediated cholesterol import into mammalian cells and describe the process of cellular cholesterol efflux. Overall, we emphasize how specific protein-lipid and protein-protein interactions help overcoming the extremely low water solubility of cholesterol, thereby controlling intracellular cholesterol movement. This article is part of a Special Issue entitled: Lipid-protein interactions.

  3. Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake

    PubMed Central

    Ge, Liang; Qi, Wei; Wang, Li-Juan; Miao, Hong-Hua; Qu, Yu-Xiu; Li, Bo-Liang; Song, Bao-Liang

    2011-01-01

    Dietary absorption is a major way for mammals to obtain cholesterol, which is mediated by Niemann-Pick C1-like 1 (NPC1L1) via vesicular endocytosis. One fundamental question in this process is how free cholesterol is efficiently taken up through the internalization of NPC1L1. Using exogenously expressed NPC1L1-EGFP, we show that the lipid raft proteins flotillins associate with NPC1L1 and their localization is regulated by NPC1L1 during intracellular trafficking. Furthermore, flotillins are essential for NPC1L1-mediated cellular cholesterol uptake, biliary cholesterol reabsorption, and the regulation of lipid levels in mice. Together with NPC1L1, they form cholesterol-enriched membrane microdomains, which function as carriers for bulk of cholesterol. The hypocholesterolemic drug ezetimibe disrupts the association between NPC1L1 and flotillins, which blocks the formation of the cholesterol-enriched microdomains. Our findings reveal a functional role of flotillins in NPC1L1-mediated cholesterol uptake and elucidate the formation of NPC1L1–flotillins-postive cholesterol-enriched membrane microdomains as a mechanism for efficient cholesterol absorption. PMID:21187433

  4. LDL-cholesterol lowering activity of a blend of rice bran oil and safflower oil (8:2) in patients with hyperlipidaemia: a proof of concept, double blind, controlled, randomised parallel group study.

    PubMed

    Malve, Harshad; Kerkar, Prafulla; Mishra, Nidheesh; Loke, Sanjita; Rege, N N; Marwaha-Jaspal, Ankita; Jainani, Kiran J

    2010-11-01

    Cardiovascular diseases have emerged as major health burden worldwide in recent times. Low density lipoprotein cholesterol (LDL-C) serves as the primary marker for cardiovascular diseases. Reports suggest that rice bran oil has antihyperlipidaemic properties. However, current evidence suggests that no single oil can provide the recommended dietary fat ratio. Hence the present study was undertaken in patients with hyperlipidaemia to study effects of substitution of the cooking oil with a blend of 80% rice bran oil and 20% safflower oil on LDL-C levels. The selected patients (n = 73) were randomly assigned either to the study oil group (blend under study) or control oil group (the oil which the patient was using before). The lipid profile was monitored monthly in these patients for 3 months during which they consumed the oil as per the randomisation. At each follow up, LDL-C levels showed a significant reduction from baseline in the study oil group and reduction was more than that observed in the control group. It was also observed that the percentage of the respondents was higher in the study oil group. At the end of the study period, 82% patients from this group had LDL levels less than 150 mg% as against 57% in the control group. Thus, the substitution of usual cooking oil with a blend of rice bran oil and safflower oil (8:2) was found to exert beneficial effects on the LDL-C levels shifting them to low-risk lipid category.

  5. Human trafficking and the healthcare professional.

    PubMed

    Barrows, Jeffrey; Finger, Reginald

    2008-05-01

    Despite the legislation passed in the 19th century outlawing human slavery, it is more widespread today than at the conclusion of the civil war. Modern human slavery, termed human trafficking, comes in several forms. The most common type of human trafficking is sex trafficking, the sale of women and children into prostitution. Labor trafficking is the sale of men, women, and children into hard labor for which they receive little or no compensation. Other forms of trafficking include child soldiering, war brides, and organ removal. Healthcare professionals play a critical role in both finding victims of human trafficking while they are still in captivity, as well as caring for their mental and physical needs upon release. Those working in the healthcare profession need to be educated regarding how a trafficking victim may present, as well as their unique healthcare needs.

  6. Compounds affecting cholesterol absorption

    NASA Technical Reports Server (NTRS)

    Hua, Duy H. (Inventor); Koo, Sung I. (Inventor); Noh, Sang K. (Inventor)

    2004-01-01

    A class of novel compounds is described for use in affecting lymphatic absorption of cholesterol. Compounds of particular interest are defined by Formula I: ##STR1## or a pharmaceutically acceptable salt thereof.

  7. High blood cholesterol levels

    MedlinePlus

    ... Outlook (Prognosis) High cholesterol levels can lead to hardening of the arteries , also called atherosclerosis. This occurs ... and safe drinking Coronary heart disease Cushing syndrome Hardening of the arteries Hypothyroidism Overweight Stroke Triglyceride level ...

  8. MD-2 binds cholesterol.

    PubMed

    Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet; Viriyakosol, Suganya; Miller, Yury I

    2016-02-19

    Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis.

  9. MD-2 binds cholesterol

    PubMed Central

    Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet; Viriyakosol, Suganya; Miller, Yury I.

    2016-01-01

    Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis. PMID:26806306

  10. Design and Synthesis of a Crosslinker for Studying Intracellular Steroid Trafficking Pathways

    PubMed Central

    Byrd, Katherine M.; Arieno, Marcus D.; Kennelly, Megan E.; Estiu, Guillermina; Wiest, Olaf; Helquist, Paul

    2015-01-01

    A crosslinker was designed and synthesized as a molecular tool for potential use in probing the intracellular trafficking pathways of steroids. The design was guided by computational modeling based upon a model for the transfer of cholesterol between two proteins, NPC1 and NPC2. These proteins play critical roles in the transport of low-density lipoprotein-derived cholesterol from the lumen of lysosomes to other subcellular compartments. Two modified cholesterol residues were covalently joined by a tether based on molecular modeling of the transient interaction of NPC1 and NPC2 during the transfer of cholesterol from the binding site of one of these proteins to the other. With two cholesterol molecules appropriately connected, we hypothesize that the cholesterol binding sites of both proteins will be simultaneously occupied in a manner that will stabilize the protein-protein interaction to permit detailed structural analysis of the resulting complex. A photoaffinity label has also been introduced into one of the cholesterol cores to permit covalent attachment of one of the units into its respective protein-binding pocket. The basic design of these crosslinkers should render them useful for examining interactions of the NPC1/NPC2 pair as well as other sterol transport proteins. PMID:25890696

  11. Design and synthesis of a crosslinker for studying intracellular steroid trafficking pathways.

    PubMed

    Byrd, Katherine M; Arieno, Marcus D; Kennelly, Megan E; Estiu, Guillermina; Wiest, Olaf; Helquist, Paul

    2015-07-01

    A crosslinker was designed and synthesized as a molecular tool for potential use in probing the intracellular trafficking pathways of steroids. The design was guided by computational modeling based upon a model for the transfer of cholesterol between two proteins, NPC1 and NPC2. These proteins play critical roles in the transport of low-density lipoprotein-derived cholesterol from the lumen of lysosomes to other subcellular compartments. Two modified cholesterol residues were covalently joined by a tether based on molecular modeling of the transient interaction of NPC1 and NPC2 during the transfer of cholesterol from the binding site of one of these proteins to the other. With two cholesterol molecules appropriately connected, we hypothesize that the cholesterol binding sites of both proteins will be simultaneously occupied in a manner that will stabilize the protein-protein interaction to permit detailed structural analysis of the resulting complex. A photoaffinity label has also been introduced into one of the cholesterol cores to permit covalent attachment of one of the units into its respective protein-binding pocket. The basic design of these crosslinkers should render them useful for examining interactions of the NPC1/NPC2 pair as well as other sterol transport proteins.

  12. Cholesterol through the Looking Glass

    PubMed Central

    Kristiana, Ika; Luu, Winnie; Stevenson, Julian; Cartland, Sian; Jessup, Wendy; Belani, Jitendra D.; Rychnovsky, Scott D.; Brown, Andrew J.

    2012-01-01

    How cholesterol is sensed to maintain homeostasis has been explained by direct binding to a specific protein, Scap, or through altering the physical properties of the membrane. The enantiomer of cholesterol (ent-cholesterol) is a valuable tool in distinguishing between these two models because it shares nonspecific membrane effects with native cholesterol (nat-cholesterol), but not specific binding interactions. This is the first study to compare ent- and nat-cholesterol directly on major molecular parameters of cholesterol homeostasis. We found that ent-cholesterol suppressed activation of the master transcriptional regulator of cholesterol metabolism, SREBP-2, almost as effectively as nat-cholesterol. Importantly, ent-cholesterol induced a conformational change in the cholesterol-sensing protein Scap in isolated membranes in vitro, even when steps were taken to eliminate potential confounding effects from endogenous cholesterol. Ent-cholesterol also accelerated proteasomal degradation of the key cholesterol biosynthetic enzyme, squalene monooxygenase. Together, these findings provide compelling evidence that cholesterol maintains its own homeostasis not only via direct protein interactions, but also by altering membrane properties. PMID:22869373

  13. Biopolitical management, economic calculation and "trafficked women".

    PubMed

    Berman, Jacqueline

    2010-01-01

    Narratives surrounding human trafficking, especially trafficking in women for sex work, employ gendered and racialized tropes that have among their effects, a shrouding of women's economic decision-making and state collusion in benefiting from their labour. This paper explores the operation of these narratives in order to understand the ways in which they mask the economics of trafficking by sensationalizing the sexual and criminal aspects of it, which in turn allows the state to pursue political projects under the guise of a benevolent concern for trafficked women and/or protection of its own citizens. This paper will explore one national example: Article 18 of Italian Law 40 (1998). I argue that its passage has led to an increase in cooperation with criminal prosecution of traffickers largely because it approaches trafficked women as capable of making decisions about how and what they themselves want to do. This paper will also consider a more global approach to trafficking embedded in the concept of "migration management", an International Organization for Migration (IOM) framework that is now shaping EU, US and other national immigration laws and policies that impact trafficking. It will also examine the inherent limitations of both the national and global approach as an occasion to unpack how Article 18 and Migration Management function as forms of biopolitical management that participate in the production of "trafficking victims" into a massified population to be managed, rather than engender a more engaged discussion of what constitutes trafficking and how to redress it.

  14. Protein trafficking in kinetoplastid protozoa.

    PubMed Central

    Clayton, C; Häusler, T; Blattner, J

    1995-01-01

    The kinetoplastid protozoa infect hosts ranging from invertebrates to plants and mammals, causing diseases of medical and economic importance. They are the earliest-branching organisms in eucaryotic evolution to have either mitochondria or peroxisome-like microbodies. Investigation of their protein trafficking enables us to identify characteristics that have been conserved throughout eucaryotic evolution and also reveals how far variations, or alternative mechanisms, are possible. Protein trafficking in kinetoplastids is in many respects similar to that in higher eucaryotes, including mammals and yeasts. Differences in signal sequence specificities exist, however, for all subcellular locations so far examined in detail--microbodies, mitochondria, and endoplasmic reticulum--with signals being more degenerate, or shorter, than those of their higher eucaryotic counterparts. Some components of the normal array of trafficking mechanisms may be missing in most (if not all) kinetoplastids: examples are clathrin-coated vesicles, recycling receptors, and mannose 6-phosphate-mediated lysosomal targeting. Other aspects and structures are unique to the kinetoplastids or are as yet unexplained. Some of these peculiarities may eventually prove to be weak points that can be used as targets for chemotherapy; others may turn out to be much more widespread than currently suspected. PMID:7565409

  15. Viral Subversion of Nucleocytoplasmic Trafficking

    PubMed Central

    Yarbrough, Melanie L.; Mata, Miguel A.; Sakthivel, Ramanavelan; Fontoura, Beatriz M. A.

    2014-01-01

    Trafficking of proteins and RNA into and out of the nucleus occurs through the nuclear pore complex (NPC). Due to its critical function in many cellular processes, the NPC and transport factors are common targets of several viruses that disrupt key constituents of the machinery to facilitate viral replication. Many viruses such as poliovirus and severe acute respiratory syndrome (SARS) virus inhibit protein import into the nucleus, while viruses such as influenza A virus target and disrupt host mRNA nuclear export. Current evidence indicates that these viruses may employ such strategies to avert the host immune response. Conversely, many viruses co-opt nucleocytoplasmic trafficking to facilitate transport of viral RNAs. Since viral proteins interact with key regulators of the host nuclear transport machinery, viruses have served as invaluable tools of discovery that led to the identification of novel constituents of nuclear transport pathways. In addition, this review explores the importance of nucleocytoplasmic trafficking to viral pathogenesis as these studies revealed new antiviral therapeutic strategies and exposed previously unknown cellular mechanisms. Further understanding of nuclear transport pathways will determine whether such therapeutics will be useful treatments for important human pathogens. PMID:24289861

  16. [The food cholesterol controversy].

    PubMed

    Cichosz, Grazyna; Czeczot, Hanna

    2012-07-01

    Arteriosclerosis of blood vessels, the main cause of heart attack and stroke, is a disease of multifactor pathogenesis. Multiple experimental, clinical and epidemiologic studies indicate that free radicals and lipid oxidation products take part in aterogenesis process. Homocysteine possess also cytotoxic activity leading to degradation of elastine of internal membrane of blood vessels. Deficiency of vitamin folic acid, B12 and B6 cause homocysteine accumulation in human organism. Identifying the arteriosclerosis with oxidation of LDL-cholesterol results with faulty conclusions. Metabolism of cholesterol in human organism depends on content of n-6 and n-3 polyunsaturated fatty acids, phospholipids, fitosterols, food fiber, Lactobacillus and antioxidants in the diet. In aterogenesis antioxidant defficiency, especially long-lasting ones, are more important then amount of fat itself. Considering cholesterol intake with average food and its absorption amounting 25-30%, one can conclude that amount of cholesterol in intestine originates in 90% from liver synthesis, which is excreted with bile, and in more than ten percent--from food. This is why reduction of cholesterol intake with food only little improves blood lipid indexes.

  17. Cholesterol depletion induces autophagy

    SciTech Connect

    Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi . E-mail: tfujimot@med.nagoya-u.ac.jp

    2006-12-08

    Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

  18. Characterization of trans-neuronal trafficking of Cbln1.

    PubMed

    Wei, Peng; Rong, Yongqi; Li, Leyi; Bao, Dashi; Morgan, James I

    2009-06-01

    Cbln1, a glycoprotein secreted from granule cells and GluRdelta2 in the postsynaptic densities of Purkinje cells are components of an incompletely understood pathway essential for integrity and plasticity of parallel fiber-Purkinje cell synapses. We show that Cbln1 undergoes anterograde transport from granule cells to Purkinje cells and Bergmann glia, and enters the endolysosomal trafficking system, raising the possibility that Cbln1 exerts its activity on or within Purkinje cells and Bergmann glia. Cbln1 is absent in Purkinje cells and Bergmann glia of GluRdelta2-null mice, suggesting a mechanistic convergence on Cbln1 trafficking. Ectopic expression of Cbln1 in Purkinje cells of L7-cbln1 transgenic mice reveals Cbln1 undergoes anterograde and retrograde trans-neuronal trafficking even across synapses that lack GluRDelta2, indicating that it is not universally essential for Cbln1 transport. The L7-cbln1 transgene also ameliorates the locomotor deficits of cbln1-null mice, indicating that the presence and/or release of Cbln1 from the postsynaptic neuron has functional consequences.

  19. Dynein-mediated trafficking negatively regulates LET-23 EGFR signaling

    PubMed Central

    Skorobogata, Olga; Meng, Jassy; Gauthier, Kimberley; Rocheleau, Christian E.

    2016-01-01

    Epidermal growth factor receptor (EGFR) signaling is essential for animal development, and increased signaling underlies many human cancers. Identifying the genes and cellular processes that regulate EGFR signaling in vivo will help to elucidate how this pathway can become inappropriately activated. Caenorhabditis elegans vulva development provides an in vivo model to genetically dissect EGFR signaling. Here we identified a mutation in dhc-1, the heavy chain of the cytoplasmic dynein minus end–directed microtubule motor, in a genetic screen for regulators of EGFR signaling. Despite the many cellular functions of dynein, DHC-1 is a strong negative regulator of EGFR signaling during vulva induction. DHC-1 is required in the signal-receiving cell and genetically functions upstream or in parallel to LET-23 EGFR. LET-23 EGFR accumulates in cytoplasmic foci in dhc-1 mutants, consistent with mammalian cell studies in which dynein is shown to regulate late endosome trafficking of EGFR with the Rab7 GTPase. However, we found different distributions of LET-23 EGFR foci in rab-7 versus dhc-1 mutants, suggesting that dynein functions at an earlier step of LET-23 EGFR trafficking to the lysosome than RAB-7. Our results demonstrate an in vivo role for dynein in limiting LET-23 EGFR signaling via endosomal trafficking. PMID:27654944

  20. Cholesterol and prostate cancer.

    PubMed

    Pelton, Kristine; Freeman, Michael R; Solomon, Keith R

    2012-12-01

    Prostate cancer risk can be modified by environmental factors, however the molecular mechanisms affecting susceptibility to this disease are not well understood. As a result of a series of recently published studies, the steroidal lipid, cholesterol, has emerged as a clinically relevant therapeutic target in prostate cancer. This review summarizes the findings from human studies as well as animal and cell biology models, which suggest that high circulating cholesterol increases risk of aggressive prostate cancer, while cholesterol lowering strategies may confer protective benefit. Relevant molecular processes that have been experimentally tested and might explain these associations are described. We suggest that these promising results now could be applied prospectively to attempt to lower risk of prostate cancer in select populations.

  1. Cholesterol Metabolism in CKD.

    PubMed

    Reiss, Allison B; Voloshyna, Iryna; De Leon, Joshua; Miyawaki, Nobuyuki; Mattana, Joseph

    2015-12-01

    Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.

  2. Lysosomes, cholesterol and atherosclerosis

    PubMed Central

    Jerome, W Gray

    2011-01-01

    Cholesterol-engorged macrophage foam cells are a critical component of the atherosclerotic lesion. Reducing the sterol deposits in lesions reduces clinical events. Sterol accumulations within lysosomes have proven to be particularly hard to mobilize out of foam cells. Moreover, excess sterol accumulation in lysosomes has untoward effects, including a complete disruption of lysosome function. Recently, we demonstrated that treatment of sterol-engorged macrophages in culture with triglyceride-containing particles can reverse many of the effects of cholesterol on lysosomes and dramatically reduce the sterol burden in these cells. This article describes what is known about lysosomal sterol engorgement, discusses the possible mechanisms by which triglyceride could produce its effects, and evaluates the possible positive and negative effects of reducing the lysosomal cholesterol levels in foam cells. PMID:21643524

  3. Decreasing Human Trafficking through Sex Work Decriminalization.

    PubMed

    Albright, Erin; D'Adamo, Kate

    2017-01-01

    In order to decrease human trafficking, health care workers should support the full decriminalization of prostitution. Similar to trafficking in other forms of labor, preventing trafficking in the sex trade requires addressing the different forms of marginalization that create vulnerable communities. By removing punitive laws that prevent reporting of exploitation and abuse, decriminalization allows sex workers to work more safely, thereby reducing marginalization and vulnerability. Decriminalization can also help destigmatize sex work and help resist political, social, and cultural marginalization of sex workers.

  4. Improvement in Lipid and Protein Trafficking in Niemann-Pick C1 Cells by Correction of a Secondary Enzyme Defect

    PubMed Central

    Devlin, Cecilia; Pipalia, Nina H.; Liao, Xianghai; Schuchman, Edward H.; Maxfield, Frederick R.; Tabas, Ira

    2010-01-01

    Different primary lysosomal trafficking defects lead to common alterations in lipid trafficking, suggesting cooperative interactions among lysosomal lipids. However, cellular analysis of the functional consequences of this phenomenon is lacking. As a test case, we studied cells with defective Niemann-Pick C1 (NPC1) protein, a cholesterol trafficking protein whose defect gives rise to lysosomal accumulation of cholesterol and other lipids, leading to NPC disease. NPC1 cells also develop a secondary defect in acid sphingomyelinase (SMase) activity despite a normal acid SMase gene (SMPD1). When acid SMase activity was restored to normal levels in NPC1-deficient CHO cells through SMPD1 transfection, there was a dramatic reduction in lysosomal cholesterol. Two other defects, excess lysosomal bis-(monoacylglycerol) phosphate (BMP) and defective transferrin receptor (TfR) recycling, were also markedly improved. To test its relevance in human cells, the acid SMase activity defect in fibroblasts from NPC1 patients was corrected by SMPD1 transfection or acid SMase enzyme replacement. Both treatments resulted in a dramatic reduction in lysosomal cholesterol. These data show that correcting one aspect of a complex lysosomal lipid storage disease can reduce the cellular consequences even if the primary genetic defect is not corrected. PMID:20412078

  5. Illicit Trafficking Challenges: Fighting the Good Fight Against Illicit Trafficking Networks

    DTIC Science & Technology

    2012-10-01

    2012 U.S. NAVAL POSTGRADUATE SCHOOL • CENTER ON CONTEMPORARY CONFLICT PASCC REPORT NUMBER 2012 012 ILLICIT TRAFFICKING CHALLENGES FIGHTING THE...GOOD FIGHT AGAINST ILLICIT TRAFFICKING NETWORKS Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection... Trafficking Challenges: Fighting the Good Fight Against Illicit Trafficking Networks 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

  6. Perfringolysin O Theta Toxin as a Tool to Monitor the Distribution and Inhomogeneity of Cholesterol in Cellular Membranes.

    PubMed

    Maekawa, Masashi; Yang, Yanbo; Fairn, Gregory D

    2016-03-08

    Cholesterol is an essential structural component of cellular membranes in eukaryotes. Cholesterol in the exofacial leaflet of the plasma membrane is thought to form membrane nanodomains with sphingolipids and specific proteins. Additionally, cholesterol is found in the intracellular membranes of endosomes and has crucial functions in membrane trafficking. Furthermore, cellular cholesterol homeostasis and regulation of de novo synthesis rely on transport via both vesicular and non-vesicular pathways. Thus, the ability to visualize and detect intracellular cholesterol, especially in the plasma membrane, is critical to understanding the complex biology associated with cholesterol and the nanodomains. Perfringolysin O (PFO) theta toxin is one of the toxins secreted by the anaerobic bacteria Clostridium perfringens and this toxin forms pores in the plasma membrane that causes cell lysis. It is well understood that PFO recognizes and binds to cholesterol in the exofacial leaflets of the plasma membrane, and domain 4 of PFO (D4) is sufficient for the binding of cholesterol. Recent studies have taken advantage of this high-affinity cholesterol-binding domain to create a variety of cholesterol biosensors by using a non-toxic PFO or the D4 in isolation. This review highlights the characteristics and usefulness of, and the principal findings related to, these PFO-derived cholesterol biosensors.

  7. Cholesterol: Up in Smoke.

    ERIC Educational Resources Information Center

    Raloff, Janet

    1991-01-01

    Discussed is the contribution cooked meat makes to air pollution. The dozens of compounds, including cholesterol, that are released when a hamburger is grilled are described. The potential effects of these emissions on humans and the urban environment are discussed. (KR)

  8. Cholesterol, inflammasomes, and atherogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasma cholesterol levels have been strongly associated with atherogenesis, underscoring the role of lipid metabolism in defining cardiovascular disease risk. However, atherosclerotic plaque is highly dynamic and contains elements of both the innate and adaptive immune system that respond to the abe...

  9. Optical Control of Peroxisomal Trafficking

    PubMed Central

    2015-01-01

    The blue-light-responsive LOV2 domain of Avena sativa phototropin1 (AsLOV2) has been used to regulate activity and binding of diverse protein targets with light. Here, we used AsLOV2 to photocage a peroxisomal targeting sequence, allowing light regulation of peroxisomal protein import. We generated a protein tag, LOV-PTS1, that can be appended to proteins of interest to direct their import to the peroxisome with light. This method provides a means to inducibly trigger peroxisomal protein trafficking in specific cells at user-defined times. PMID:26513473

  10. Cholesterol transformations during heat treatment.

    PubMed

    Derewiaka, D; Molińska née Sosińska, E

    2015-03-15

    The aim of the study was to characterise products of cholesterol standard changes during thermal processing. Cholesterol was heated at 120°C, 150°C, 180°C and 220°C from 30 to 180 min. The highest losses of cholesterol content were found during thermal processing at 220°C, whereas the highest content of cholesterol oxidation products was observed at temperature of 150°C. The production of volatile compounds was stimulated by the increase of temperature. Treatment of cholesterol at higher temperatures i.e. 180°C and 220°C led to the formation of polymers and other products e.g. cholestadienes and fragmented cholesterol molecules. Further studies are required to identify the structure of cholesterol oligomers and to establish volatile compounds, which are markers of cholesterol transformations, mainly oxidation.

  11. Cholesterol excretion and colon cancer.

    PubMed

    Broitman, S A

    1981-09-01

    Populations consuming diets high in fat and cholesterol exhibit a greater incidence of colon cancer than those consuming less fat and cholesterol. Lowering elevated serum cholesterol levels experimentally or clinically is associated with increased large-bowel tumorigenesis. Thus, cholesterol lost to the gut, either dietary or endogenously synthesized, appears to have a role in large-bowel cancer. Whether the effect(s) is mediated by increases in fecal bile acid excretion or some other mechanism is not clear.

  12. Preliminary Validation of the Sex Trafficking Attitudes Scale.

    PubMed

    Houston-Kolnik, Jaclyn D; Todd, Nathan R; Wilson, Midge

    2016-09-01

    This study presents the Sex Trafficking Attitudes Scale (STAS), assessing cognitive, behavioral, and affective attitudes toward the sex trafficking of women and girls. Across two studies, exploratory and confirmatory factor analyses revealed and confirmed six subscales: (a) Knowledge About Sex Trafficking, (b) Awareness of Sex Trafficking, (c) Attitudes Toward Ability to Leave Sex Trafficking, (d) Attitudes Toward Helping Survivors, (e) Empathic Reactions Toward Sex Trafficking, and (f) Efficacy to Reduce Sex Trafficking. Results showed support for convergent validity as the subscales were associated with related measures. The STAS holds promise to expand research and inform efforts to support trafficking survivors.

  13. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    PubMed Central

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Oude Elferink, Ronald P. J.; Kuipers, Folkert; Groen, Albert K.

    2009-01-01

    Peroxisome proliferator-activated receptor delta (PPARδ) is involved in regulation of energy homeostasis. Activation of PPARδ markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary cholesterol secretion, nor by reduced cholesterol absorption. To test the hypothesis that PPARδ activation leads to stimulation of transintestinal cholesterol efflux (TICE), we quantified it by intestine perfusions in FVB mice treated with PPARδ agonist GW610742. To exclude the effects on cholesterol absorption, mice were also treated with cholesterol absorption inhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion (∼200%) and TICE (∼100%). GW610742 decreased intestinal Npc1l1 expression but had no effect on Abcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encoding proteins involved in intracellular cholesterol trafficking, was increased upon PPARδ activation. Although treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE. These data show that activation of PPARδ stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis. PMID:19439761

  14. Human Trafficking. Ministering to The 'Invisible' Victim.

    PubMed

    Scanlon, Colleen; Krausa, Laura

    2016-07-01

    Human trafficking is modern-day slavery - an insidious, criminal industry that gener- ates billions of dollars in labor trafficking alone. It knows no boundary of continent, country, race or class; it is a shattering, impartial predator that robs individuals of their basic human dignity.

  15. Facts about Blood Cholesterol. Revised.

    ERIC Educational Resources Information Center

    National Heart, Lung, and Blood Inst. (DHHS/NIH), Bethesda, MD.

    This fact sheet offers information on blood cholesterol and its implications for a healthy heart. An explanation is given of the known facts about cholesterol and how it affects the body. A chart is provided that lists various foods and their fat and cholesterol contents. (JD)

  16. C3N4 Nanosheet Modified Microwell Array with Enhanced Electrochemiluminescence for Total Analysis of Cholesterol at Single Cells.

    PubMed

    Xu, Jingjing; Jiang, Depeng; Qin, Yanling; Xia, Juan; Jiang, Dechen; Chen, Hong-Yuan

    2017-02-21

    Here, a g-C3N4 nanosheet modified microwell array providing enhanced electrochemiluminescence (ECL) and better visible sensitivity was prepared to simultaneously analyze total (membrane and intracellular) cholesterol at single cells. The detection limit for ECL visualization of hydrogen peroxide at microwell array was improved to be 500 nM that guaranteed the detection of low concentration cholesterol at single cells in parallel. To achieve single cell cholesterol analysis, the individual cells cultured at the microwell array were exposed to cholesterol oxidase generating hydrogen peroxide for luminescence analysis of membrane cholesterol, and then treated with triton X-100, cholesterol esterase, and cholesterol oxidase to produce hydrogen peroxide from intracellular cholesterol for luminescence determination. The observation of the luminescence spots at microwells in these two steps confirmed the codetection of membrane and intracellular cholesterol at single cells. The inhibition of intracellular acyl-coA/cholesterol acyltransferase (ACAT) resulted in less intracellular cholesterol storage (less luminescence) and more membrane cholesterol (more luminescence). The correlation of the luminescence intensity with the amount of cholesterol confirmed that our assay could simultaneously monitor membrane and intracellular cholesterol pools at different cellular states, which should offer more information for the study of cholesterol-related pathways at single cells.

  17. Examining the Risk of Nuclear Trafficking

    SciTech Connect

    Balatsky, Galya; Severe, William R; Schoeneck, Jeffery

    2009-01-01

    The need to stop illicit trafficking of nuclear and radioactive materials around the world is undeniable and urgent. This issue is particularly evident due to the highly dangerous consequences of the risks involved, the known interest of terrorist groups in acquiring such materials and the vulnerability of theft and diversion of such materials. Yet the phenomenon of nuclear trafficking remains a subject where the unknown dominates what is known on the subject. The trafficking panel at the Institute for Nuclear Materials Management (INMM) Workshop on Reducing the Risk of Radioactive and Nuclear Materials that took place in Albuquerque, New Mexico, March 10-11, 2009, dealt with some of the issues associated with nuclear trafficking. Different points of view on how to better address trafficking and thwart perpetrator efforts were discussed. This paper presents some of these views and addresses practical measures that should be considered to improve the situation.

  18. How to Get Your Cholesterol Tested

    MedlinePlus

    ... Thromboembolism Aortic Aneurysm More How To Get Your Cholesterol Tested Updated:Apr 3,2017 Cholesterol plays a ... factors for heart disease and stroke . How is cholesterol tested? A cholesterol screening measures your level of ...

  19. Parallel rendering

    NASA Technical Reports Server (NTRS)

    Crockett, Thomas W.

    1995-01-01

    This article provides a broad introduction to the subject of parallel rendering, encompassing both hardware and software systems. The focus is on the underlying concepts and the issues which arise in the design of parallel rendering algorithms and systems. We examine the different types of parallelism and how they can be applied in rendering applications. Concepts from parallel computing, such as data decomposition, task granularity, scalability, and load balancing, are considered in relation to the rendering problem. We also explore concepts from computer graphics, such as coherence and projection, which have a significant impact on the structure of parallel rendering algorithms. Our survey covers a number of practical considerations as well, including the choice of architectural platform, communication and memory requirements, and the problem of image assembly and display. We illustrate the discussion with numerous examples from the parallel rendering literature, representing most of the principal rendering methods currently used in computer graphics.

  20. Analysis of SCAP N-glycosylation and Trafficking in Human Cells.

    PubMed

    Cheng, Chunming; Guo, Jeffrey Yunhua; Geng, Feng; Wu, Xiaoning; Cheng, Xiang; Li, Qiyue; Guo, Deliang

    2016-11-08

    Elevated lipogenesis is a common characteristic of cancer and metabolic diseases. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors controlling the expression of genes important for the synthesis of cholesterol, fatty acids and phospholipids, are frequently upregulated in these diseases. In the process of SREBP nuclear translocation, SREBP-cleavage activating protein (SCAP) plays a central role in the trafficking of SREBP from the endoplasmic reticulum (ER) to the Golgi and in subsequent proteolysis activation. Recently, we uncovered that glucose-mediated N-glycosylation of SCAP is a prerequisite condition for the exit of SCAP/SREBP from the ER and movement to the Golgi. N-glycosylation stabilizes SCAP and directs SCAP/SREBP trafficking. Here, we describe a protocol for the isolation of membrane fractions in human cells and for the preparation of the samples for the detection of SCAP N-glycosylation and total protein by using western blot. We further provide a method to monitor SCAP trafficking by using confocal microscopy. This protocol is appropriate for the investigation of SCAP N-glycosylation and trafficking in mammalian cells.

  1. Cholesterol crystal embolism (atheroembolism).

    PubMed

    Venturelli, Chiara; Jeannin, Guido; Sottini, Laura; Dallera, Nadia; Scolari, Francesco

    2006-01-01

    Cholesterol crystal embolism, known as atheroembolic disease, is caused by showers of cholesterol crystals from an atherosclerotic plaque that occludes small arteries. Embolization can occur spontaneously or as an iatrogenic complication from an invasive vascular procedure (angiography or vascular surgery) and after anticoagulant therapy. The atheroembolism can give rise to different degrees of renal impairment. Some patients show a moderate loss of renal function, others severe renal failure requiring dialysis. Renal outcome can be variable: some patients deteriorate or remain on dialysis, some improve and some remain with chronic renal impairment. Clinically, three types of atheroembolic renal disease have been described: acute, subacute or chronic. More frequently a progressive loss of renal function occurs over weeks. Atheroembolization can involve the skin, gastrointestinal system and central nervous system. The diagnosis is difficult and controversial for the protean extrarenal manifestations. In the past, the diagnosis was often made post-mortem. In the last 10 yrs, awareness of atheroembolic renal disease has improved. The correct diagnosis requires the clinician to be alert. The typical patient is a white male aged >60 yrs with a history of hypertension, smoking and arterial disease. The presence of a classic triad (precipitating event, renal failure and peripheral cholesterol crystal embolization) suggests the diagnosis. This can be confirmed by a biopsy of the target organs. A specific treatment is lacking; however, it is an important diagnosis to make because an aggressive therapeutic approach can be associated with a more favorable clinical outcome.

  2. Cholesterol crystal embolism (atheroembolism)

    PubMed Central

    VENTURELLI, CHIARA; JEANNIN, GUIDO; SOTTINI, LAURA; DALLERA, NADIA; SCOLARI, FRANCESCO

    2006-01-01

    Cholesterol crystal embolism, known as atheroembolic disease, is caused by showers of cholesterol crystals from an atherosclerotic plaque that occludes small arteries. Embolization can occur spontaneously or as an iatrogenic complication from an invasive vascular procedure (angiography or vascular surgery) and after anticoagulant therapy. The atheroembolism can give rise to different degrees of renal impairment. Some patients show a moderate loss of renal function, others severe renal failure requiring dialysis. Renal outcome can be variable: some patients deteriorate or remain on dialysis, some improve and some remain with chronic renal impairment. Clinically, three types of atheroembolic renal disease have been described: acute, subacute or chronic. More frequently a progressive loss of renal function occurs over weeks. Atheroembolization can involve the skin, gastrointestinal system and central nervous system. The diagnosis is difficult and controversial for the protean extrarenal manifestations. In the past, the diagnosis was often made post-mortem. In the last 10 yrs, awareness of atheroembolic renal disease has improved. The correct diagnosis requires the clinician to be alert. The typical patient is a white male aged >60 yrs with a history of hypertension, smoking and arterial disease. The presence of a classic triad (precipitating event, renal failure and peripheral cholesterol crystal embolization) suggests the diagnosis. This can be confirmed by a biopsy of the target organs. A specific treatment is lacking; however, it is an important diagnosis to make because an aggressive therapeutic approach can be associated with a more favorable clinical outcome. PMID:21977265

  3. Trafficking to the Ciliary Membrane

    PubMed Central

    Nachury, Maxence V.; Seeley, E. Scott; Jin, Hua

    2010-01-01

    The primary cilium organizes numerous signal transduction cascades and an understanding of signaling receptors trafficking to cilia is now emerging. A defining feature of cilia is the periciliary diffusion barrier that separates the ciliary and plasma membranes despite the topological continuity between these two membranes. Although lateral transport through this barrier may take place, polarized exocytosis to the base of the cilium has been the prevailing model for delivering membrane proteins to cilia. Key players for this polarized exocytosis model include the GTPases Rab8 and Rab11, the exocyst and possibly the intraflagellar tranport machinery. Sorting membrane proteins to cilia critically relies on the recognition of ciliary targeting signals by sorting machines such as the BBSome coat complex or the GTPase Arf4. Finally, signaling at the cilium entails the bidirectional movement of proteins between cytoplasm and cilia and ubiquitination may promote exit from cilia. PMID:19575670

  4. Improved Coarse-Grained Modeling of Cholesterol-Containing Lipid Bilayers

    SciTech Connect

    Daily, Michael D.; Olsen, Brett N.; Schlesinger, Paul H.; Ory, Daniel S.; Baker, Nathan A.

    2014-03-24

    In mammalian cells cholesterol is essential for membrane function, but in excess can be cytototoxic. The cellular response to acute cholesterol loading involves biophysical-based mechanisms that regulate cholesterol levels, through modulation of the “activity” or accessibility of cholesterol to extra-membrane acceptors. Experiments and united atom (UA) simulations show that at high concentrations of cholesterol, lipid bilayers thin significantly and cholesterol availability to external acceptors increases substantially. Such cholesterol activation is critical to its trafficking within cells. Here we aim to reduce the computational cost to enable simulation of large and complex systems involved in cholesterol regulation, such as those including oxysterols and cholesterol-sensing proteins. To accomplish this, we have modified the published MARTINI coarse-grained force field to improve its predictions of cholesterol-induced changes in both macroscopic and microscopic properties of membranes. Most notably, MARTINI fails to capture both the (macroscopic) area condensation and membrane thickening seen at less than 30% cholesterol and the thinning seen above 40% cholesterol. The thinning at high concentration is critical to cholesterol activation. Microscopic properties of interest include cholesterol-cholesterol radial distribution functions (RDFs), tilt angle, and accessible surface area. First, we develop an “angle-corrected” model wherein we modify the coarse-grained bond angle potentials based on atomistic simulations. This modification significantly improves prediction of macroscopic properties, most notably the thickening/thinning behavior, and also slightly improves microscopic property prediction relative to MARTINI. Second, we add to the angle correction a “volume correction” by also adjusting phospholipid bond lengths to achieve a more accurate volume per molecule. The angle + volume correction substantially further improves the quantitative

  5. Female sex trafficking: conceptual issues, current debates, and future directions.

    PubMed

    Meshkovska, Biljana; Siegel, Melissa; Stutterheim, Sarah E; Bos, Arjan E R

    2015-01-01

    Female sex trafficking is a pressing concern. In this article, we provide a comprehensive overview of relevant issues regarding the concept of female sex trafficking and research in the field of human trafficking, drawing on a variety of disciplines, including economics, gender and sexuality studies, psychology, sociology, law, and social work. We discuss the debates surrounding the definition of human trafficking, compare and contrast it with human smuggling, and outline connections between female sex trafficking and the issue of sex work and prostitution. We further discuss the history and current estimations of female sex trafficking. We then outline the main actors in female sex trafficking, including trafficked persons, traffickers, clients, and service providers, and we overview the trafficking process from recruitment to identification, recovery, and (re)integration. Finally, we conclude with recommendations for future research that tie together the concepts of vulnerability, exploitation, and long-term recovery and (re)integration.

  6. Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis.

    PubMed

    Hendrikx, T; Walenbergh, S M A; Hofker, M H; Shiri-Sverdlov, R

    2014-05-01

    Many studies show an association between the accumulation of cholesterol inside lysosomes and the progression towards inflammatory disease states that are closely related to obesity. While in the past, the knowledge regarding lysosomal cholesterol accumulation was limited to its association with plaque severity during atherosclerosis, recently, a growing body of evidence indicates a causal link between lysosomal cholesterol accumulation and inflammation. These findings make lysosomal cholesterol accumulation an important target for intervention in metabolic diseases that are characterized by the presence of an inflammatory response. In this review, we aim to show the importance of cholesterol trapping inside lysosomes to the development of inflammation by focusing upon cardiovascular disease and non-alcoholic steatohepatitis (NASH) in particular. We summarize current data supporting the hypothesis that lysosomal cholesterol accumulation plays a key role in the development of inflammation during atherosclerosis and NASH. In addition, potential mechanisms by which disturbed lysosomal function can trigger the inflammatory response, the challenges in improving cholesterol trafficking in macrophages and recent successful research directions will be discussed.

  7. Fluorescent Sterols and Cholesteryl Esters as Probes for Intracellular Cholesterol Transport

    PubMed Central

    Solanko, Katarzyna A.; Modzel, Maciej; Solanko, Lukasz M.; Wüstner, Daniel

    2015-01-01

    Cholesterol transport between cellular organelles comprised vesicular trafficking and nonvesicular exchange; these processes are often studied by quantitative fluorescence microscopy. A major challenge for using this approach is producing analogs of cholesterol with suitable brightness and structural and chemical properties comparable with those of cholesterol. This review surveys currently used fluorescent sterols with respect to their behavior in model membranes, their photophysical properties, as well as their transport and metabolism in cells. In the first part, several intrinsically fluorescent sterols, such as dehydroergosterol or cholestatrienol, are discussed. These polyene sterols (P-sterols) contain three conjugated double bonds in the steroid ring system, giving them slight fluorescence in ultraviolet light. We discuss the properties of P-sterols relative to cholesterol, outline their chemical synthesis, and explain how to image them in living cells and organisms. In particular, we show that P-sterol esters inserted into low-density lipoprotein can be tracked in the fibroblasts of Niemann–Pick disease using high-resolution deconvolution microscopy. We also describe fluorophore-tagged cholesterol probes, such as BODIPY-, NBD-, Dansyl-, or Pyrene-tagged cholesterol, and eventual esters of these analogs. Finally, we survey the latest developments in the synthesis and use of alkyne cholesterol analogs to be labeled with fluorophores by click chemistry and discuss the potential of all approaches for future applications. PMID:27330304

  8. Cholesterol metabolism in Huntington disease.

    PubMed

    Karasinska, Joanna M; Hayden, Michael R

    2011-09-06

    The CNS is rich in cholesterol, which is essential for neuronal development and survival, synapse maturation, and optimal synaptic activity. Alterations in brain cholesterol homeostasis are linked to neurodegeneration. Studies have demonstrated that Huntington disease (HD), a progressive and fatal neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin protein, is associated with changes in cellular cholesterol metabolism. Emerging evidence from human and animal studies indicates that attenuated brain sterol synthesis and accumulation of cholesterol in neuronal membranes represent two distinct mechanisms occurring in the presence of mutant huntingtin that influence neuronal survival. Increased knowledge of how changes in intraneuronal cholesterol metabolism influence the pathogenesis of HD will provide insights into the potential application of brain cholesterol regulation as a therapeutic strategy for this devastating disease.

  9. Sex Trafficking of Women and Girls

    PubMed Central

    Deshpande, Neha A; Nour, Nawal M

    2013-01-01

    Sex trafficking involves some form of forced or coerced sexual exploitation that is not limited to prostitution, and has become a significant and growing problem in both the United States and the larger global community. The costs to society include the degradation of human and women’s rights, poor public health, disrupted communities, and diminished social development. Victims of sex trafficking acquire adverse physical and psychological health conditions and social disadvantages. Thus, sex trafficking is a critical health issue with broader social implications that requires both medical and legal attention. Healthcare professionals can work to improve the screening, identification, and assistance of victims of sex trafficking in a clinical setting and help these women and girls access legal and social services. PMID:23687554

  10. Committee opinion no. 507: human trafficking.

    PubMed

    2011-09-01

    Human trafficking is a widespread problem with estimates ranging from 14,000 to 50,000 individuals trafficked into the United States annually. This hidden population involves the commercial sex industry, agriculture, factories, hotel and restaurant businesses, domestic workers, marriage brokers, and some adoption firms. Because 80% of trafficked individuals are women and girls, women’s health care providers may better serve their diverse patient population by increasing their awareness of this problem. The exploitation of people of any race, gender, sexual orientation, or ethnicity is unacceptable at any time, in any place. The members of the American College of Obstetricians and Gynecologists should be aware of this problem and strive to recognize and assist their patients who are victims or who have been victims of human trafficking.

  11. Human trafficking law and social structures.

    PubMed

    Wooditch, Alese

    2012-08-01

    Human trafficking has only recently emerged at the forefront of policy reform, even in developed nations. Yet, heightened awareness of the issue has not translated into effective policy as the majority of nations have ineffective antitrafficking practices; many countries have failed to criminalize human trafficking, whereas others do not actively enforce statutes in place. By applying Black's theory of law, this study offers a preliminary understanding into the variation of global prosecutorial efforts in human trafficking and adequacy of antitrafficking law. To isolate this relationship, the effects of trafficking markets are controlled. As with prior research, the study finds limited support for the theory. The article concludes with a discussion on the implications of the quantity of antitrafficking law and morphology association for policy development.

  12. Ovarian Cystadenoma in a Trafficked Patient.

    PubMed

    Titchen, Kanani E; Katz, Douglas; Martinez, Kidian; White, Krishna

    2016-05-01

    The topic of child sex trafficking is receiving increased attention both in the lay press and in research articles. Recently, a number of physician organizations have issued policy statements calling for the education and involvement of physicians in combating this form of "modern-day slavery." Primary care and emergency medicine physicians have led these efforts, but a number of these victims may present to surgeons. Surgeons are in a unique position to identify trafficked patients; during the process of undraping, intubation, and surgical preparation, signs of trafficking such as tattoos, scars, dental injuries, and bruising may be evident. In addition, these patients may have specific needs in terms of anesthesia and postoperative care due to substance abuse. Here, we report the case of an 18-year-old girl with a history of sexual exploitation who presents for cystadenoma excision. To our knowledge, this is the first report of a sex-trafficked pediatric patient presenting for surgery.

  13. Trafficking in Persons Report 10th Edition

    DTIC Science & Technology

    2010-06-01

    prohibits most forms of human trafficking through its 2007 Organic Law on the Right of Women to a Violence-Free Life . Article 56 of this law...www.timmatsui.com 20: REUTERS 21: (left) Jacqueline Abromeit/bigStockPhoto.com 21: ( right ) Environmental Justice Foundation/ www.ejfoundation.org 22: Jacques-Jean...prosecuted, and more instances of this human rights abuse have been pre- vented. Countries that once denied the existence of human trafficking now work

  14. Specific Cellular Incorporation of a Pyrene-Labelled Cholesterol: Lipoprotein-Mediated Delivery toward Ordered Intracellular Membranes

    PubMed Central

    Gaibelet, Gérald; Azalbert, Vincent; Bertrand-Michel, Justine; Hamdi, Safouane; Collet, Xavier; Orlowski, Stéphane

    2015-01-01

    In the aim of testing tools for tracing cell trafficking of exogenous cholesterol, two fluorescent derivatives of cholesterol, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), with distinctive chemico-physical characteristics, have been compared for their cell incorporation properties, using two cell models differently handling cholesterol, with two incorporation routes. In the Caco-2 cell model, the cholesterol probes were delivered in bile salt micelles, as a model of intestinal absorption. The two probes displayed contrasting behaviors for cell uptake characteristics, cell staining, and efflux kinetics. In particular, Pyr-met-Chol cell incorporation involved SR-BI, while that of NBD-Chol appeared purely passive. In the PC-3 cell model, which overexpresses lipoprotein receptors, the cholesterol probes were delivered via the serum components, as a model of systemic delivery. We showed that Pyr-met-Chol-labelled purified LDL or HDL were able to specifically deliver Pyr-met-Chol to the PC-3 cells, while NBD-Chol incorporation was independent of lipoproteins. Observations by fluorescence microscopy evidenced that, while NBD-Chol readily stained the cytosolic lipid droplets, Pyr-met-Chol labelling led to the intense staining of intracellular structures of membranous nature, in agreement with the absence of detectable esterification of Pyr-met-Chol. A 48 h incubation of PC-3 cells with either Pyr-met-Chol-labelled LDL or HDL gave same staining patterns, mainly colocalizing with Lamp1, caveolin-1 and CD63. These data indicated convergent trafficking downwards their respective receptors, LDL-R and SR-BI, toward the cholesterol-rich internal membrane compartments, late endosomes and multivesicular bodies. Interestingly, Pyr-met-Chol staining of these structures exhibited a high excimer fluorescence emission, revealing their ordered membrane environment, and indicating that Pyr-met-Chol behaves as a fair cholesterol tracer

  15. Food prices and blood cholesterol.

    PubMed

    Rahkovsky, Ilya; Gregory, Christian A

    2013-01-01

    Cardiovascular diseases (CVD) cost Americans billions of dollars per year. High cholesterol levels, which are closely related to dietary habits, are a major contributor to CVD. In this article, we study whether changes in food prices are related to cholesterol levels and whether taxes or subsidies on particular foods would be effective in lowering cholesterol levels and, consequently, CVD costs. We find that prices of vegetables, processed foods, whole milk and whole grains are significantly associated with blood cholesterol levels. Having analyzed the costs and benefits of government interventions, we find that a subsidy of vegetables and whole grains would be an efficient way to reduce CVD expenditures.

  16. Parallel machines: Parallel machine languages

    SciTech Connect

    Iannucci, R.A. )

    1990-01-01

    This book presents a framework for understanding the tradeoffs between the conventional view and the dataflow view with the objective of discovering the critical hardware structures which must be present in any scalable, general-purpose parallel computer to effectively tolerate latency and synchronization costs. The author presents an approach to scalable general purpose parallel computation. Linguistic Concerns, Compiling Issues, Intermediate Language Issues, and hardware/technological constraints are presented as a combined approach to architectural Develoement. This book presents the notion of a parallel machine language.

  17. [The real measurement of non-HDL-cholesterol: Atherogenic cholesterol].

    PubMed

    Millán, Jesús; Hernández-Mijares, Antonio; Ascaso, Juan F; Blasco, Mariano; Brea, Angel; Díaz, Ángel; González-Santos, Pedro; Mantilla, Teresa; Pedro-Botet, Juan; Pintó, Xavier

    Lowe density lipoproteins (LDL) are the causal agent of cardiovascular diseases. In practice, we identify LDL with cholesterol transported in LDL (cLDL). So, cLDL has become the major target for cardiovascular prevention. Howewer, we have progressive evidences about the role of triglycerides rich lipoproteins, particularly those very low density lipoprotein (VLDL) in promotion and progression of atherosclerosis, that leads cholesterol in VLDL and its remanents as a potential therapeutic target. This feature is particularly important and of a great magnitude, in patients with hypertiglyceridemia. We can to considere, that the non-HDL cholesterol -cLDL+cVLDL+c-remmants+Lp(a)- is the real measurement of atherogenic cholesterol. In addition, non-HDL-cholesterol do not show any variations between postprandial states. In fact, non-HDL-cholesterol should be an excellent marker of atherogenic cholesterol, and an major therapeutic target in patients with atherogenic dyslipidaemia. According with different clinical trials and with the epidemiological and mendelian studies, in patients with high cardiovascular risk, optimal level of cLDL will be under 70mg/dl, and under 100 ng/dl for non-HDL-cholesterol; and in high risk patients, 100mg/dl and 130mg/dl, respectively.

  18. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices.

  19. Sex work and sex trafficking.

    PubMed

    Ditmore, M; Saunders, P

    1998-01-01

    Preventing HIV infection and other sexually transmitted diseases (STDs), as well as sexual and physical violence, are major occupational health and safety concerns for prostitutes. Considerable evidence shows that anti-prostitution laws facilitate violence and abuse against prostitutes and may increase their risk of contracting HIV/STDs. For example, police often take advantage of existing laws against prostitution to demand money or sex. In general, the strict enforcement of anti-prostitution laws marginalizes prostitutes from services which could help them avoid abuse and promotes an environment in which prostitutes must take risks to avoid detection and arrest. One strategy to improve prostitutes' lives would therefore be to remove laws which prevent them from working safely and from travelling abroad to work legally. Projects in which prostitutes are actively involved have helped break down stereotypes against prostitutes, while police-sex worker liaison projects in Scotland and Australia have led to higher levels of reporting of crimes against prostitutes. The Network of Sex Work Projects (NSWP), an organization which links sex worker health programs around the world, has found that the incidence of HIV/STDs among prostitutes is lowest when they have control over their work conditions; access to condoms, lubricants, and other safe sex materials; and respect of their basic human and legal rights. People need to understand that consensual involvement in sex work is different from forced sex trafficking.

  20. Lymphatic Regulation of Cellular Trafficking

    PubMed Central

    Jackson, David G.

    2016-01-01

    Lymphatic vessels play vital roles in immune surveillance and immune regulation by conveying antigen loaded dendritic cells, memory T cells, macrophages and neutrophils from the peripheral tissues to draining lymph nodes where they initiate as well as modify immune responses. Until relatively recently however, there was little understanding of how entry and migration through lymphatic vessels is organized or the specific molecular mechanisms that might be involved. Within the last decade, the situation has been transformed by an explosion of knowledge generated largely through the application of microscopic imaging, transgenic animals, specific markers and function blocking mAbs that is beginning to provide a rational conceptual framework. This article provides a critical review of the recent literature, highlighting seminal discoveries that have revealed the fascinating ultrastructure of leucocyte entry sites in lymphatic vessels, as well as generating controversies over the involvement of integrin adhesion, chemotactic and haptotactic mechanisms in DC entry under normal and inflamed conditions. It also discusses the major changes in lymphatic architecture that occur during inflammation and the different modes of leucocyte entry and trafficking within inflamed lymphatic vessels, as well as presenting a timely update on the likely role of hyaluronan and the major lymphatic endothelial hyaluronan receptor LYVE-1 in leucocyte transit. PMID:27808282

  1. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices. To learn more or to help with this cause, visit the Somaly Mam Foundation at www.somaly.org or the U.S. Department of State at www. state.gov.

  2. Food combinations for cholesterol lowering.

    PubMed

    Harland, Janice I

    2012-12-01

    Reducing elevated LDL-cholesterol is a key public health challenge. There is substantial evidence from randomised controlled trials (RCT) that a number of foods and food components can significantly reduce LDL-cholesterol. Data from RCT have been reviewed to determine whether effects are additive when two or more of these components are consumed together. Typically components, such as plant stanols and sterols, soya protein, β-glucans and tree nuts, when consumed individually at their target rate, reduce LDL-cholesterol by 3-9 %. Improved dietary fat quality, achieved by replacing SFA with unsaturated fat, reduces LDL-cholesterol and can increase HDL-cholesterol, further improving blood lipid profile. It appears that the effect of combining these interventions is largely additive; however, compliance with multiple changes may reduce over time. Food combinations used in ten 'portfolio diet' studies have been reviewed. In clinical efficacy studies of about 1 month where all foods were provided, LDL-cholesterol is reduced by 22-30 %, whereas in community-based studies of >6 months' duration, where dietary advice is the basis of the intervention, reduction in LDL-cholesterol is about 15 %. Inclusion of MUFA into 'portfolio diets' increases HDL-cholesterol, in addition to LDL-cholesterol effects. Compliance with some of these dietary changes can be achieved more easily compared with others. By careful food component selection, appropriate to the individual, the effect of including only two components in the diet with good compliance could be a sustainable 10 % reduction in LDL-cholesterol; this is sufficient to make a substantial impact on cholesterol management and reduce the need for pharmaceutical intervention.

  3. Cholesterol induces proliferation of chicken primordial germ cells.

    PubMed

    Chen, Dongyang; Chen, Meijuan; Lu, Zhenping; Yang, Mengmeng; Xie, Long; Zhang, Wenxin; Xu, Huiyan; Lu, Kehuan; Lu, Yangqing

    2016-08-01

    Primordial germ cells (PGCs) are the precursors of sperm and eggs and may serve as suitable cells for use in research in developmental biology and transgenic animals. However, the long-term propagation of PGCs in vitro has so far been plagued by the loss of their germ cell characteristics. This is largely because of the scarcity of knowledge concerning cell division and proliferation in these cells and the poor optimization of the culture medium. The sonic hedgehog (SHH) signaling pathway is involved in proliferation of many types of cells, but little is known about its role in chicken PGCs. The results of the current study indicate that the proliferation of chicken PGCs increases significantly when cholesterol, a molecule that facilitates the trafficking of HH ligands, is supplemented in the culture medium. This effect was attenuated when an SHH antagonist, cyclopamine was added, suggesting the involvement of SHH signaling in this process. The characterization of PGCs treated with cholesterol has shown that these cells express germ-cell-related markers and retain their capability to colonize the embryonic gonad after re-introduction to vasculature of stage-15 HH embryos, indicating that proliferation of PGCs induced by cholesterol does not alter the germ cell characteristics of these cells.

  4. Parallel pipelining

    SciTech Connect

    Joseph, D.D.; Bai, R.; Liao, T.Y.; Huang, A.; Hu, H.H.

    1995-09-01

    In this paper the authors introduce the idea of parallel pipelining for water lubricated transportation of oil (or other viscous material). A parallel system can have major advantages over a single pipe with respect to the cost of maintenance and continuous operation of the system, to the pressure gradients required to restart a stopped system and to the reduction and even elimination of the fouling of pipe walls in continuous operation. The authors show that the action of capillarity in small pipes is more favorable for restart than in large pipes. In a parallel pipeline system, they estimate the number of small pipes needed to deliver the same oil flux as in one larger pipe as N = (R/r){sup {alpha}}, where r and R are the radii of the small and large pipes, respectively, and {alpha} = 4 or 19/7 when the lubricating water flow is laminar or turbulent.

  5. Epigenetic regulation of cholesterol homeostasis

    PubMed Central

    Meaney, Steve

    2014-01-01

    Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g., the Hedgehog system). A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more “traditional” regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review. PMID:25309573

  6. How Is High Blood Cholesterol Treated?

    MedlinePlus

    ... the NHLBI on Twitter. How Is High Blood Cholesterol Treated? High blood cholesterol is treated with lifestyle ... need to follow a heart healthy diet . Lowering Cholesterol Using Therapeutic Lifestyle Changes TLC is a set ...

  7. What Are High Blood Cholesterol and Triglycerides?

    MedlinePlus

    ANSWERS by heart Lifestyle + Risk Reduction Cholesterol What Are High Blood Cholesterol and Triglycerides? Cholesterol travels to the body’s cells through the bloodstream by way of lipoproteins (LDL and ...

  8. Top Five Lifestyle Changes to Reduce Cholesterol

    MedlinePlus

    Top 5 lifestyle changes to improve your cholesterol Lifestyle changes can help reduce cholesterol, keep you off cholesterol-lowering medications or enhance the effect of your medications. Here are five lifestyle ...

  9. Understand Your Risk for High Cholesterol

    MedlinePlus

    ... Aortic Aneurysm More Understand Your Risk for High Cholesterol Updated:Apr 1,2016 LDL (bad) cholesterol is ... content was last reviewed on 04/21/2014. Cholesterol Guidelines: Putting the pieces together Myth vs. Truth – ...

  10. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis

    PubMed Central

    Johnson, Tory A.; Pfeffer, Suzanne R.

    2016-01-01

    Human NPC1L1 protein mediates cholesterol absorption in the intestine and liver and is the target of the drug ezetimibe, which is used to treat hypercholesterolemia. Previous studies concluded that NPC1L1-GFP protein trafficking is regulated by cholesterol binding and that ezetimibe blocks NPC1L1-GFP function by inhibiting its endocytosis. We used cell surface biotinylation to monitor NPC1L1-GFP endocytosis and show that ezetimibe does not alter the rate of NPC1L1-GFP endocytosis in cultured rat hepatocytes grown under normal growth conditions. As expected, NPC1L1-GFP endocytosis depends in part on C-terminal, cytoplasmically oriented sequences, but endocytosis does not require cholesterol binding to NPC1L1’s N-terminal domain. In addition, two small- molecule inhibitors of general (and NPC1L1-GFP) endocytosis failed to inhibit the ezetimibe-sensitive uptake of [3H]cholesterol from taurocholate micelles. These experiments demonstrate that cholesterol uptake by NPC1L1 does not require endocytosis; moreover, ezetimibe interferes with NPC1L1’s cholesterol adsorption activity without blocking NPC1L1 internalization in RH7777 cells. PMID:27075173

  11. Lateral organization of cholesterol molecules in lipid-cholesterol assemblies.

    SciTech Connect

    Singh, Rajiv R. P.; Slepoy, Alexander; Sengupta, Pinaki; Cox, Daniel L.

    2005-05-01

    We present results of an off-lattice simulation of a two-component planar system, as a model for lateral organization of cholesterol molecules in lipid-cholesterol assemblies. We explore the existence of 'superlattice' structures even in fluid systems, in the absence of an underlying translational long-range order, and study their coupling to hexatic or bond-orientational order. We discuss our results in context of geometric superlattice theories and 'condensation complexes' in understanding a variety of experiments in artificial lipid-cholesterol assemblies.

  12. Cholesterol metabolism and colon cancer.

    PubMed

    Broitman, S A; Cerda, S; Wilkinson, J

    1993-01-01

    While epidemiologic and concordant experimental data indicate a direct relationship between dietary fat (and presumably caloric) intake and the development of colon cancer, the effect of dietary cholesterol on this disease is still not clear. However, there appears to be a developing literature concerning an inverse relationship between serum and plasma cholesterol levels, and the risk for colon cancer. Findings that low serum cholesterol levels are apparent as early as ten years prior to the detection of colon cancer implies that sub clinical disease is probably not involved initially in this process. The possibility of low serum cholesterol as a bio-marker was considered in epidemiologic studies which focused upon obese men with lower than normal serum cholesterol levels who were found to be at increased risk to colon cancer. While the relationship between low serum cholesterol and colonic or intestinal cholesterol metabolism is presently not understood, current genetic studies provide a promising though as yet unexplored potential association. Alterations which occur during the developmental progression of colonic cancer include changes in chromosome 5, which also carries two genes vital to the biosynthesis and regulation of systemic and cellular cholesterol metabolism, 3-hydroxy-3-methylglutaryl coenzyme A synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA R). Regulation of cholesterol metabolism in intestinal cells in vivo and in vitro varies from that seen in normal fibroblasts or hepatocytes in terms of exogenous sources of cholesterol and how these sources regulate internal synthesis. Colonic cancer cells have been used to assess small bowel enterocyte cholesterol metabolism, which has been possible because of their ability to differentiate in culture, however information regarding true colonic enterocyte cholesterol metabolism is relatively scarce. Colonic cancer cells have been shown to possess a diminished or nonexistent ability to use

  13. 3 CFR 8621 - Proclamation 8621 of December 22, 2010. National Slavery and Human Trafficking Prevention Month...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Slavery and Human Trafficking Prevention Month, 2011 8621 Proclamation 8621 Presidential Documents Proclamations Proclamation 8621 of December 22, 2010 Proc. 8621 National Slavery and Human Trafficking... Trafficking Prevention Month, we rededicate ourselves to preventing and ending human trafficking, and...

  14. Child Sex Trafficking in America: A Guide for Parents and Guardians

    MedlinePlus

    Child Sex Trafficking in America: A Guide for Parents and Guardians What is Child Sex Trafficking ? Child sex trafficking is one of the most common types of commercial sexual exploitation . Child sex trafficking is a high priority at the National ...

  15. Alterations in membrane trafficking and pathophysiological implications in lysosomal storage disorders.

    PubMed

    Kuech, Eva-Maria; Brogden, Graham; Naim, Hassan Y

    2016-11-01

    Lysosomal storage disorders are a heterogeneous group of more than 50 distinct inborn metabolic diseases affecting about 1 in 5000 to 7000 live births. The diseases often result from mutations followed by functional deficiencies of enzymes or transporters within the acidic environment of the lysosome, which mediate the degradation of a wide subset of substrates, including glycosphingolipids, glycosaminoglycans, cholesterol, glycogen, oligosaccharides, peptides and glycoproteins, or the export of the respective degradation products from the lysosomes. The progressive accumulation of uncleaved substrates occurs in multiple organs and finally causes a broad spectrum of different pathologies including visceral, neurological, skeletal and hematologic manifestations. Besides deficient lysosomal enzymes and transporters other defects may lead to lysosomal storage disorders, including activator defects, membrane defects or defects in modifier proteins. In this review we concentrate on four different lysosomal storage disorders: Niemann-Pick type C, Fabry disease, Gaucher disease and Pompe disease. While the last three are caused by defective lysosomal hydrolases, Niemann-Pick type C is caused by the inability to export LDL-derived cholesterol out of the lysosome. We want to emphasise potential implications of membrane trafficking defects on the pathology of these diseases, as many mutations interfere with correct lysosomal protein trafficking and alter cellular lipid homeostasis. Current therapeutic strategies are summarised, including substrate reduction therapy as well as pharmacological chaperone therapy which directly aim to improve folding and lysosomal transport of misfolded mutant proteins.

  16. Think Again About Cholesterol Survey.

    PubMed

    Catapano, Alberico L; Wiklund, Olov

    2015-12-01

    Cardiovascular disease (CVD) is still the main cause of death in Europe. Elevated plasma cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), is the main causative risk factor for CVD, most prominently associated with coronary heart disease. A widespread disinformation about cholesterol and CVD is one factor underlying a poor compliance to lipid-lowering therapy. To investigate how cholesterol, CVD and cholesterol reduction is perceived in the population, a survey was commissioned by the European Atherosclerosis Society (EAS). Nearly half of people above 25 years of age are most worried about cancer (45%), compared to just over one in four who are worried about heart disease (27%). A majority believe being overweight (72%), blood pressure (70%) and smoking (67%) most affect heart health, far more than note cholesterol (59%) and family history (39%). The majority of adults recognize that high LDL (or "bad") cholesterol should be a health priority for everyone, including those younger than 40 and those who are not overweight. However, 1 in 4 (25%) incorrectly believe that it does not need to be a concern until someone shows signs or symptoms. Although 89% of adults surveyed agreed it is important for people to know whether or not they have high LDL-C, an overwhelming 92% did not know their LDL-C levels or had never had their cholesterol levels tested. A high 63% had never heard of familial hypercholesterolemia: France had the lowest level of awareness (41%) to Denmark with a high 80%, and the association of the disease with high levels of LDL-C is quite poor (only 36%), with Sweden only at 22% versus a high in Spain of 54%. A large part of the people participating in the survey were quite uncertain about the modality of transmission for familial hypercholesterolemia in the family. All in all, this survey highlights the need for more information among citizens for the role of cholesterol in determining CVD.

  17. Regulation of GPCR Trafficking by Ubiquitin

    PubMed Central

    Kennedy, Justine E.; Marchese, Adriano

    2015-01-01

    G protein-coupled receptor (GPCR)-promoted signaling mediates cellular responses to a variety of stimuli involved in diverse physiological processes. In addition, GPCRs are also the largest class of target for many drugs used to treat a variety of diseases. Despite the role of GPCR signaling in health and disease, the molecular mechanisms governing GPCR signaling remain poorly understanding. Classically, GPCR signaling is tightly regulated by GPCR kinases and β-arrestins, which act in a concerted fashion to govern GPCR desensitization and also GPCR trafficking. Ubiquitination has now emerged as an important posttranslational modification that has multiple roles, either directly or indirectly, in governing GPCR trafficking. Recent studies have revealed a mechanistic link between GPCR phosphorylation, β-arrestins, and ubiquitination. Here, we review recent developments in our understanding of how ubiquitin regulates GPCR trafficking within the endocytic pathway. PMID:26055053

  18. Vesicle trafficking and cell surface membrane patchiness.

    PubMed Central

    Tang, Q; Edidin, M

    2001-01-01

    Membrane proteins and lipids often appear to be distributed in patches on the cell surface. These patches are often assumed to be membrane domains, arising from specific molecular associations. However, a computer simulation (Gheber and Edidin, 1999) shows that membrane patchiness may result from a combination of vesicle trafficking and dynamic barriers to lateral mobility. The simulation predicts that the steady-state patches of proteins and lipids seen on the cell surface will decay if vesicle trafficking is inhibited. To test this prediction, we compared the apparent sizes and intensities of patches of class I HLA molecules, integral membrane proteins, before and after inhibiting endocytic vesicle traffic from the cell surface, either by incubation in hypertonic medium or by expression of a dominant-negative mutant dynamin. As predicted by the simulation, the apparent sizes of HLA patches increased, whereas their intensities decreased after endocytosis and vesicle trafficking were inhibited. PMID:11423406

  19. Monocyte trafficking in acute and chronic inflammation.

    PubMed

    Ingersoll, Molly A; Platt, Andrew M; Potteaux, Stephane; Randolph, Gwendalyn J

    2011-10-01

    Environmental signals at the site of inflammation mediate rapid monocyte mobilization and dictate differentiation programs whereby these cells give rise to macrophages or dendritic cells. Monocytes participate in tissue healing, clearance of pathogens and dead cells, and initiation of adaptive immunity. However, recruited monocytes can also contribute to the pathogenesis of infection and chronic inflammatory disease, such as atherosclerosis. Here, we explore monocyte trafficking in the context of acute inflammation, relying predominantly on data from microbial infection models. These mechanisms will be compared to monocyte trafficking during chronic inflammation in experimental models of atherosclerosis. Recent developments suggest that monocyte trafficking shares common themes in diverse inflammatory diseases; however, important differences exist between monocyte migratory pathways in acute and chronic inflammation.

  20. Targeting cancer using cholesterol conjugates

    PubMed Central

    Radwan, Awwad A.; Alanazi, Fares K.

    2013-01-01

    Conjugation of cholesterol moiety to active compounds for either cancer treatment or diagnosis is an attractive approach. Cholesterol derivatives are widely studied as cancer diagnostic agents and as anticancer derivatives either in vitro or in vivo using animal models. In largely growing studies, anticancer agents have been chemically conjugated to cholesterol molecules, to enhance their pharmacokinetic behavior, cellular uptake, target specificity, and safety. To efficiently deliver anticancer agents to the target cells and tissues, many different cholesterol–anticancer conjugates were synthesized and characterized, and their anticancer efficiencies were tested in vitro and in vivo. PMID:24493968

  1. Cholesterol perturbs lipid bilayers nonuniversally.

    PubMed

    Pan, Jianjun; Mills, Thalia T; Tristram-Nagle, Stephanie; Nagle, John F

    2008-05-16

    Cholesterol is well known to modulate the physical properties of biomembranes. Using modern x-ray scattering methods, we have studied the effects of cholesterol on the bending modulus K(C), the thickness D(HH), and the orientational order parameter S(xray) of lipid bilayers. We find that the effects are different for at least three classes of phospholipids characterized by different numbers of saturated hydrocarbon chains. Most strikingly, cholesterol strongly increases K(C) when both chains of the phospholipid are fully saturated but not at all when there are two monounsaturated chains.

  2. Cholesterol Perturbs Lipid Bilayers Nonuniversally

    SciTech Connect

    Pan Jianjun; Mills, Thalia T.; Tristram-Nagle, Stephanie; Nagle, John F.

    2008-05-16

    Cholesterol is well known to modulate the physical properties of biomembranes. Using modern x-ray scattering methods, we have studied the effects of cholesterol on the bending modulus K{sub C}, the thickness D{sub HH}, and the orientational order parameter S{sub xray} of lipid bilayers. We find that the effects are different for at least three classes of phospholipids characterized by different numbers of saturated hydrocarbon chains. Most strikingly, cholesterol strongly increases K{sub C} when both chains of the phospholipid are fully saturated but not at all when there are two monounsaturated chains.

  3. Role of Occupational Therapy in Combating Human Trafficking.

    PubMed

    Gorman, Kathleen W; Hatkevich, Beth Ann

    Human trafficking is a modern-day form of slavery that includes sex trafficking, labor trafficking, and trafficking of children. It is estimated that 35.8 million people are enslaved around the world. Because of the traumatic experiences that victims of human trafficking encounter, the needs of victims are extensive and require the services of several providers, including health care providers, for victims to transform into survivors and thrivers. Currently, the role of occupational therapy is minimal and unexplored. The profession of occupational therapy has the capacity of having a profound role in both providing client-centered care services to victims and survivors of human trafficking and partaking in preventive advocacy efforts to combat human trafficking. Further advocacy efforts are required to promote the profession of occupational therapy in combating human trafficking.

  4. Venezuelan equine encephalitis virus entry mechanism requires late endosome formation and resists cell membrane cholesterol depletion

    SciTech Connect

    Kolokoltsov, Andrey A.; Fleming, Elisa H.; Davey, Robert A. . E-mail: radavey@utmb.edu

    2006-04-10

    Virus envelope proteins determine receptor utilization and host range. The choice of receptor not only permits specific targeting of cells that express it, but also directs the virus into specific endosomal trafficking pathways. Disrupting trafficking can result in loss of virus infectivity due to redirection of virions to non-productive pathways. Identification of the pathway or pathways used by a virus is, thus, important in understanding virus pathogenesis mechanisms and for developing new treatment strategies. Most of our understanding of alphavirus entry has focused on the Old World alphaviruses, such as Sindbis and Semliki Forest virus. In comparison, very little is known about the entry route taken by more pathogenic New World alphaviruses. Here, we use a novel contents mixing assay to identify the cellular requirements for entry of a New World alphavirus, Venezuelan equine encephalitis virus (VEEV). Expression of dominant negative forms of key endosomal trafficking genes shows that VEEV must access clathrin-dependent endocytic vesicles for membrane fusion to occur. Unexpectedly, the exit point is different from Old World alphaviruses that leave from early endosomes. Instead, VEEV also requires functional late endosomes. Furthermore, unlike the Old World viruses, VEEV entry is insensitive to cholesterol sequestration from cell membranes and may reflect a need to access an endocytic compartment that lacks cholesterol. This indicates fundamental differences in the entry route taken by VEEV compared to Old World alphaviruses.

  5. Human telomerase: biogenesis, trafficking, recruitment, and activation.

    PubMed

    Schmidt, Jens C; Cech, Thomas R

    2015-06-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species.

  6. GTPases in intracellular trafficking: an overview.

    PubMed

    Segev, Nava

    2011-02-01

    Small GTPases that belong to the ras sub-families of Rab, Arf, and Rho, and the large GTPase dynamin, regulate intracellular trafficking. This issue of Seminars of Cell and Developmental Biology highlights topics regarding mechanisms by which these GTPases regulate the different steps of vesicular transport: vesicle formation, scission, targeting and fusion. In addition, the emerging roles of GTPases in coordination of individual transport steps as well as coordination of intracellular trafficking with other cellular processes are reviewed. Finally, common structures and mechanisms underlying the function of the ras-like GTPases and the importance of their function to human health and disease are discussed.

  7. Human telomerase: biogenesis, trafficking, recruitment, and activation

    PubMed Central

    Schmidt, Jens C.

    2015-01-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. PMID:26063571

  8. Organ trading, tourism, and trafficking within Europe.

    PubMed

    Pattinson, Shaun D

    2008-03-01

    This article argues for a regulatory and institutional response towards organ trading, tourism and trafficking that differs from extant approaches. European countries have hitherto adopted blanket prohibitions on organ trading (i.e. the buying or selling of human organs). This article advances the view that policy makers have thereby overreacted to legitimate public health concerns and the evils of organ trafficking (i.e. organ trading and tourism involving coercion or deception). It argues for a trial of a very tightly regulated system of organ trading that could eventually lead to a limited system of organ tourism (i.e. organ trading involving more than one jurisdiction).

  9. Peptides having reduced toxicity that stimulate cholesterol efflux

    DOEpatents

    Bielicki, John K.; Johansson, Jan; Danho, Waleed

    2016-08-16

    The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABCA1 that parallels that of full-length apolipoproteins. Further, the peptides of the invention have little or no toxicity when administered at therapeutic and higher doses. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia and inflammation.

  10. Cholesterol Translocation in a Phospholipid Membrane

    NASA Astrophysics Data System (ADS)

    Choubey, Amit; Kalia, Rajiv; Malmstadt, Noah; Nakano, Aiichiro; Vashistha, Priya

    2013-03-01

    Cholesterol (CHOL) molecules play a key role in modulating the rigidity of cell membranes, and controlling intracellular transport and signal transduction. Using all-atom molecular dynamics and the parallel replica approach, we study the process of CHOL interleaflet transport (flip-flop) in a dipalmitoylphosphatidycholine (DPPC)-CHOL bilayer, the effect of this process on mechanical stress across the bilayer, and the role of CHOL in inducing molecular order in the respective bilayer leaflets. The simulations are carried out at physiologically relevant CHOL concentration (30%), temperature 323 K and pressure 1 bar. CHOL flip-flop events are observed with a rate constant of 3 ×104 s-1. Once a flip-flop event is triggered, a CHOL molecule takes an average of 73 nanoseconds to migrate from one bilayer leaflet to the other.

  11. Formation of Cholesterol Bilayer Domains Precedes Formation of Cholesterol Crystals in Cholesterol/Dimyristoylphosphatidylcholine Membranes: EPR and DSC Studies

    PubMed Central

    Mainali, Laxman; Raguz, Marija; Subczynski, Witold K.

    2013-01-01

    Saturation-recovery EPR along with DSC were used to determine the cholesterol content at which pure cholesterol bilayer domains (CBDs) and cholesterol crystals begin to form in dimyristoylphosphatidylcholine (DMPC) membranes. To preserve compositional homogeneity throughout the membrane suspension, lipid multilamellar dispersions were prepared using a rapid solvent exchange method. The cholesterol content increased from 0 to 75 mol%. With spin-labeled cholesterol analogs it was shown that the CBDs begin to form at ~50 mol% cholesterol. It was confirmed by DSC that the cholesterol solubility threshold for DMPC membranes is detected at ~66 mol% cholesterol. At levels above this cholesterol content, monohydrate cholesterol crystals start to form. The major finding is that formation of CBDs precedes formation of cholesterol crystals. The region of the phase diagram for cholesterol contents between 50 and 66 mol% is described as a structured one-phase region in which CBDs have to be supported by the surrounding DMPC bilayer saturated with cholesterol. Thus, the phase boundary located at 66 mol% cholesterol separates the structured one-phase region (liquid-ordered phase of DMPC with CBDs) from the two-phase region where the structured liquid-ordered phase of DMPC coexists with cholesterol crystals. It is likely that CBDs are precursors of monohydrate cholesterol crystals. PMID:23834375

  12. Cholesterol's location in lipid bilayers

    SciTech Connect

    Marquardt, Drew; Kučerka, Norbert; Wassall, Stephen R.; Harroun, Thad A.; Katsaras, John

    2016-04-04

    It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered Lo phase contains rapidly diffusing lipids with their acyl chains in the all trans configuration, similar to gel phase bilayers. Moreover, the Lo phase is commonly associated with cholesterol-enriched lipid rafts, which are thought to serve as platforms for signaling proteins in the plasma membrane. Cholesterol's location in lipid bilayers has been studied extensively, and it has been shown – at least in some bilayers – to align differently from its canonical upright orientation, where its hydroxyl group is in the vicinity of the lipid–water interface. In this study we review recent works describing cholesterol's location in different model membrane systems with emphasis on results obtained from scattering, spectroscopic and molecular dynamics studies.

  13. Cholesterol's location in lipid bilayers

    DOE PAGES

    Marquardt, Drew; Kučerka, Norbert; Wassall, Stephen R.; ...

    2016-04-04

    It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered Lo phase contains rapidly diffusing lipids with their acyl chains in the all trans configuration, similar to gel phase bilayers. Moreover, the Lo phase is commonly associated with cholesterol-enriched lipid rafts, which are thought to serve as platforms for signaling proteins in the plasma membrane. Cholesterol's location in lipid bilayers has been studied extensively, and it has been shown – at least in some bilayers – to align differently from its canonical upright orientation, where its hydroxyl group is in themore » vicinity of the lipid–water interface. In this study we review recent works describing cholesterol's location in different model membrane systems with emphasis on results obtained from scattering, spectroscopic and molecular dynamics studies.« less

  14. Americans' Cholesterol Levels Keep Falling

    MedlinePlus

    ... and 2013-2014, the CDC reported. Dr. David Friedman is chief of heart failure services at Long ... for cholesterol treatment, all seem to be working," Friedman said. The study was published online Nov. 30 ...

  15. Human Trafficking: A Review for Mental Health Professionals

    ERIC Educational Resources Information Center

    Yakushko, Oksana

    2009-01-01

    This article provides a review of current research on human trafficking for mental health practitioners and scholars. In addition to an overview of definitions, causes and processes of trafficking, the article highlights mental health consequences of trafficking along with suggestions for treatment of survivors. Directions for counseling services,…

  16. 78 FR 59317 - Federal Acquisition Regulation; Ending Trafficking in Persons

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ... range of human trafficking-related issues. Commonly raised themes included the following: (1..., and 52 RIN 9000-AM55 Federal Acquisition Regulation; Ending Trafficking in Persons AGENCY: Department... Acquisition Regulation (FAR) to strengthen protections against trafficking in persons in Federal...

  17. Trafficking of Children in Albania: Patterns of Recruitment and Reintegration

    ERIC Educational Resources Information Center

    Gjermeni, Eglantina; Van Hook, Mary P.; Gjipali, Saemira; Xhillari, Lindita; Lungu, Fatjon; Hazizi, Anila

    2008-01-01

    Problem: Many children in Albania and other countries of Eastern Europe are being trafficked as part of the global business of human trafficking. Objectives: The study sought to identify the patterns of child trafficking involving Albanian children, and especially children's views of the role of family issues and the nature of the trafficking…

  18. Child organ trafficking: global reality and inadequate international response.

    PubMed

    Bagheri, Alireza

    2016-06-01

    In organ transplantation, the demand for human organs has grown far faster than the supply of organs. This has opened the door for illegal organ trade and trafficking including from children. Organized crime groups and individual organ brokers exploit the situation and, as a result, black markets are becoming more numerous and organized organ trafficking is expanding worldwide. While underprivileged and vulnerable men and women in developing countries are a major source of trafficked organs, and may themselves be trafficked for the purpose of illegal organ removal and trade, children are at especial risk of exploitation. With the confirmed cases of children being trafficked for their organs, child organ trafficking, which once called a "modern urban legend", is a sad reality in today's world. By presenting a global picture of child organ trafficking, this paper emphasizes that child organ trafficking is no longer a myth but a reality which has to be addressed. It argues that the international efforts against organ trafficking and trafficking in human beings for organ removal have failed to address child organ trafficking adequately. This chapter suggests that more orchestrated international collaboration as well as development of preventive measure and legally binding documents are needed to fight child organ trafficking and to support its victims.

  19. Cholesterol and benign prostate disease.

    PubMed

    Freeman, Michael R; Solomon, Keith R

    2011-01-01

    The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept.

  20. Cholesterol and Benign Prostate Disease

    PubMed Central

    Freeman, Michael R.; Solomon, Keith R.

    2014-01-01

    The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association bet ween BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemi, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept. PMID:21862201

  1. Oxidative stress inhibits caveolin-1 palmitoylation and trafficking in endothelial cells

    NASA Technical Reports Server (NTRS)

    Parat, Marie-Odile; Stachowicz, Rafal Z.; Fox, Paul L.

    2002-01-01

    During normal and pathological conditions, endothelial cells (ECs) are subjected to locally generated reactive oxygen species, produced by themselves or by other vessel wall cells. In excess these molecules cause oxidative injury to the cell but at moderate levels they might modulate intracellular signalling pathways. We have investigated the effect of oxidative stress on the palmitoylation and trafficking of caveolin-1 in bovine aortic ECs. Exogenous H2O2 did not alter the intracellular localization of caveolin-1 in ECs. However, metabolic labelling experiments showed that H2O2 inhibited the trafficking of newly synthesized caveolin-1 to membrane raft domains. Several mechanisms potentially responsible for this inhibition were examined. Impairment of caveolin-1 synthesis by H2O2 was not responsible for diminished trafficking. Similarly, the inhibition was independent of H2O2-induced caveolin-1 phosphorylation as shown by the markedly different concentration dependences. We tested the effect of H2O2 on palmitoylation of caveolin-1 by the incorporation of [3H]palmitic acid. Exposure of ECs to H2O2 markedly inhibited the palmitoylation of caveolin-1. Comparable inhibition was observed after treatment of cells with H2O2 delivered either as a bolus or by continuous delivery with glucose and glucose oxidase. Kinetic studies showed that H2O2 did not alter the rate of caveolin-1 depalmitoylation but instead decreased the 'on-rate' of palmitoylation. Together these results show for the first time the modulation of protein palmitoylation by oxidative stress, and suggest a cellular mechanism by which stress might influence caveolin-1-dependent cell activities such as the concentration of signalling proteins and cholesterol trafficking.

  2. β-COP as a Component of Transport Vesicles for HDL Apolipoprotein-Mediated Cholesterol Exocytosis

    PubMed Central

    Ma, Weilie; Lin, Margarita; Ding, Hang; Lin, Guorong; Zhang, Zhizhen

    2016-01-01

    Objective HDL and its apolipoproteins protect against atherosclerotic disease partly by removing excess cholesterol from macrophage foam cells. But the underlying mechanisms of cholesterol clearance are still not well defined. We investigated roles of vesicle trafficking of coatomer β-COP in delivering cholesterol to the cell surface during apoA-1 and apoE-mediated lipid efflux from fibroblasts and THP-1 macrophages. Methods shRNA knockout, confocal and electron microscopy and biochemical analysis were used to investigate the roles of β-COP in apolipoprotein-mediated cholesterol efflux in fibroblasts and THP-1 macrophages. Results We showed that β-COP knockdown by lentiviral shRNA resulted in reduced apoA-1-mediated cholesterol efflux, while increased cholesterol accumulation and formation of larger vesicles were observed in THP-1 macrophages by laser scanning confocal microscopy. Immunogold electron microscopy showed that β-COP appeared on the membrane protrusion complexes and colocalized with apoA-1 or apoE during cholesterol efflux. This was associated with releasing heterogeneous sizes of small particles into the culture media of THP-1 macrophage. Western blotting also showed that apoA-1 promotes β-COP translocation to the cell membrane and secretion into culture media, in which a total of 17 proteins were identified by proteomics. Moreover, β-COP exclusively associated with human plasma HDL fractions. Conclusion ApoA-1 and apoE promoted transport vesicles consisting of β-COP and other candidate proteins to exocytose cholesterol, forming the protrusion complexes on cell surface, which were then released from the cell membrane as small particles to media. PMID:26986486

  3. Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.

    PubMed

    McCauliff, Leslie A; Xu, Zhi; Li, Ran; Kodukula, Sarala; Ko, Dennis C; Scott, Matthew P; Kahn, Peter C; Storch, Judith

    2015-11-06

    The cholesterol storage disorder Niemann-Pick type C (NPC) disease is caused by defects in either of two late endosomal/lysosomal proteins, NPC1 and NPC2. NPC2 is a 16-kDa soluble protein that binds cholesterol in a 1:1 stoichiometry and can transfer cholesterol between membranes by a mechanism that involves protein-membrane interactions. To examine the structural basis of NPC2 function in cholesterol trafficking, a series of point mutations were generated across the surface of the protein. Several NPC2 mutants exhibited deficient sterol transport properties in a set of fluorescence-based assays. Notably, these mutants were also unable to promote egress of accumulated intracellular cholesterol from npc2(-/-) fibroblasts. The mutations mapped to several regions on the protein surface, suggesting that NPC2 can bind to more than one membrane simultaneously. Indeed, we have previously demonstrated that WT NPC2 promotes vesicle-vesicle interactions. These interactions were abrogated, however, by mutations causing defective sterol transfer properties. Molecular modeling shows that NPC2 is highly plastic, with several intense positively charged regions across the surface that could interact favorably with negatively charged membrane phospholipids. The point mutations generated in this study caused changes in NPC2 surface charge distribution with minimal conformational changes. The plasticity, coupled with membrane flexibility, probably allows for multiple cholesterol transfer routes. Thus, we hypothesize that, in part, NPC2 rapidly traffics cholesterol between closely appositioned membranes within the multilamellar interior of late endosomal/lysosomal proteins, ultimately effecting cholesterol egress from this compartment.

  4. Facts about...Blood Cholesterol. Revised.

    ERIC Educational Resources Information Center

    National Heart, Lung, and Blood Inst. (DHHS/NIH), Bethesda, MD.

    This fact sheet on blood cholesterol examines the connection between cholesterol and heart disease, lists risk factors for heart disease that can and cannot be controlled, points out who can benefit from lowering blood cholesterol, distinguishes between blood and dietary cholesterol, describes low density lipoprotein and high density lipoprotein…

  5. Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies

    PubMed Central

    Kasmas, S.H.; Izar, M.C.; França, C.N.; Ramos, S.C.; Moreira, F.T.; Helfenstein, T.; Moreno, R.A.; Borges, N.C.; Figueiredo-Neto, A.M.; Fonseca, F.A.

    2012-01-01

    Effective statin therapy is associated with a marked reduction of cardiovascular events. However, the explanation for full benefits obtained for LDL cholesterol targets by combined lipid-lowering therapy is controversial. Our study compared the effects of two equally effective lipid-lowering strategies on markers of cholesterol synthesis and absorption. A prospective, open label, randomized, parallel design study, with blinded endpoints, included 116 subjects. We compared the effects of a 12-week treatment with 40 mg rosuvastatin or the combination of 40 mg simvastatin/10 mg ezetimibe on markers of cholesterol absorption (campesterol and β-sitosterol), synthesis (desmosterol), and their ratios to cholesterol. Both therapies similarly decreased total and LDL cholesterol, triglycerides and apolipoprotein B, and increased apolipoprotein A1 (P < 0.05 vs baseline for all). Simvastatin/ezetimibe increased plasma desmosterol (P = 0.012 vs baseline), and decreased campesterol and β-sitosterol (P < 0.0001 vs baseline for both), with higher desmosterol (P = 0.007) and lower campesterol and β-sitosterol compared to rosuvastatin, (P < 0.0001, for both). In addition, rosuvastatin increased the ratios of these markers to cholesterol (P < 0.002 vs baseline for all), whereas simvastatin/ezetimibe significantly decreased the campesterol/cholesterol ratio (P = 0.008 vs baseline) and tripled the desmosterol/cholesterol ratio (P < 0.0001 vs baseline). The campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower, whereas the desmosterol/cholesterol ratio was higher in patients receiving simvastatin/ezetimibe (P < 0.0001 vs rosuvastatin, for all). Pronounced differences in markers of cholesterol absorption and synthesis were observed between two equally effective lipid-lowering strategies. PMID:22801416

  6. T Cell Trafficking through Lymphatic Vessels

    PubMed Central

    Hunter, Morgan C.; Teijeira, Alvaro; Halin, Cornelia

    2016-01-01

    T cell migration within and between peripheral tissues and secondary lymphoid organs is essential for proper functioning of adaptive immunity. While active T cell migration within a tissue is fairly slow, blood vessels and lymphatic vessels (LVs) serve as speedy highways that enable T cells to travel rapidly over long distances. The molecular and cellular mechanisms of T cell migration out of blood vessels have been intensively studied over the past 30 years. By contrast, less is known about T cell trafficking through the lymphatic vasculature. This migratory process occurs in one manner within lymph nodes (LNs), where recirculating T cells continuously exit into efferent lymphatics to return to the blood circulation. In another manner, T cell trafficking through lymphatics also occurs in peripheral tissues, where T cells exit the tissue by means of afferent lymphatics, to migrate to draining LNs and back into blood. In this review, we highlight how the anatomy of the lymphatic vasculature supports T cell trafficking and review current knowledge regarding the molecular and cellular requirements of T cell migration through LVs. Finally, we summarize and discuss recent insights regarding the presumed relevance of T cell trafficking through afferent lymphatics. PMID:28066423

  7. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

    PubMed Central

    Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis C; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond T; Fernández-Hernando, Carlos; Kaplan, Lee M; Bernards, Andre; Gerszten, Robert E; Näär, Anders M

    2016-01-01

    Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders. PMID:26501192

  8. Amperometric determination of serum total cholesterol with nanoparticles of cholesterol esterase and cholesterol oxidase.

    PubMed

    Aggarwal, V; Malik, J; Prashant, A; Jaiwal, P K; Pundir, C S

    2016-05-01

    We describe the preparation of glutaraldehyde cross-linked and functionalized cholesterol esterase nanoparticles (ChENPs) and cholesterol oxidase nanoparticles (ChOxNPs) aggregates and their co-immobilization onto Au electrode for improved amperometric determination of serum total cholesterol. Transmission electron microscope (TEM) images of ChENPs and ChOxNPs showed their spherical shape and average size of 35.40 and 56.97 nm, respectively. Scanning electron microscope (SEM) studies of Au electrode confirmed the co-immobilization of enzyme nanoparticles (ENPs). The biosensor exhibited optimal response at pH 5.5 and 40°C within 5 s when polarized at +0.25 V versus Ag/AgCl. The working/linear range of the biosensor was 10-700 mg/dl for cholesterol. The sensor showed high sensitivity and measured total cholesterol as low as 0.1 mg/dl. The biosensor was evaluated and employed for total cholesterol determination in sera of apparently healthy and diseased persons. The analytical recovery of added cholesterol was 90%, whereas the within-batch and between-batch coefficients of variation (CVs) were less than 2% and less than 3%. There was a good correlation (r = 0.99) between serum cholesterol values as measured by the standard enzymic colorimetric method and the current method. The initial activity of ENPs/working electrode was reduced by 50% during its regular use (200 times) over a period of 60 days when stored dry at 4°C.

  9. Dysregulation of protein trafficking in neurodegeneration.

    PubMed

    Wang, Xin; Huang, Timothy; Bu, Guojun; Xu, Huaxi

    2014-08-25

    Intracellular protein trafficking plays an important role in neuronal function and survival. Protein misfolding is a common theme found in many neurodegenerative diseases, and intracellular trafficking machinery contributes to the pathological accumulation and clearance of misfolded proteins. Although neurodegenerative diseases exhibit distinct pathological features, abnormal endocytic trafficking is apparent in several neurodegenerative diseases, such as Alzheimer's disease (AD), Down syndrome (DS) and Parkinson's disease (PD). In this review, we will focus on protein sorting defects in three major neurodegenerative diseases, including AD, DS and PD. An important pathological feature of AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of β-amyloid (Aβ) peptide aggregates. Multiple lines of evidence demonstrate that over-production/aggregation of Aβ in the brain is a primary cause of AD and attenuation of Aβ generation has become a topic of extreme interest in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavage by β-secretase and the γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα which precludes Aβ generation. DS patients display a strikingly similar pathology to AD patients, including the generation of neuronal amyloid plaques. Moreover, all DS patients develop an AD-like neuropathology by their 40 s. Therefore, understanding the metabolism/processing of APP and how these underlying mechanisms may be pathologically compromised is crucial for future AD and DS therapeutic strategies. Evidence accumulated thus far reveals that synaptic vesicle regulation, endocytic trafficking, and lysosome-mediated autophagy are involved in increased susceptibility to PD. Here we review current knowledge of endosomal trafficking regulation in AD, DS and PD.

  10. Domestic minor sex trafficking: what the PNP needs to know.

    PubMed

    Hornor, Gail

    2015-01-01

    Human trafficking is a major global public health problem and represents a substantial human rights violation. Human trafficking has been receiving attention in both the lay media and professional literature. Human trafficking can include commercial sex, forced labor, child soldiers, and stealing of human organs. One form of human trafficking represents a significant American pediatric health problem: domestic minor sex trafficking (DMST). DMST is the commercial sexual abuse of children by selling, buying, or trading their sexual service. This continuing education article will define DMST and discuss it in terms of prevalence, risk factors, and practice implications for the pediatric nurse practitioner.

  11. Migration as a business: the case of trafficking.

    PubMed

    Salt, J; Stein, J

    1997-01-01

    "A case is made for treating international migration as a global business which has both legitimate and illegitimate sides.... The article focuses on migrant trafficking, the core of the illegitimate business.... Our model conceives of trafficking as an intermediary part of the global migration business facilitating movement of people between origin and destination countries.... The model also suggests how through the existence of common routes and networks of contacts, traffickers increasingly channel migrants, thus determining the geography of movement. We also demonstrate the model with available evidence on trafficking mainly in and across Europe and attempt thereby to show how trafficking operates both theoretically and in practice." (EXCERPT)

  12. Project NO REST: Addressing Human Trafficking in North Carolina.

    PubMed

    Duncan, Dean F

    Project NO REST (North Carolina Organizing and Responding to the Exploitation and Sexual Trafficking of Children) is a 5-year effort funded by the US Children's Bureau to address the trafficking of individuals age 25 years and younger in North Carolina. The project aims to increase awareness of human trafficking affecting children and youth, especially those in the child welfare system; to reduce the number of these youth who are trafficked; and to improve outcomes for those who are trafficked. In the project's first year, nearly 100 stakeholders statewide developed a comprehensive plan to address trafficking. Later, 5 communities were recruited to implement the plan at the local level. Their experiences will be used to develop a toolkit for future anti-trafficking efforts.

  13. Trafficking and contract migrant workers in the Middle East.

    PubMed

    Jureidini, Ray

    2010-01-01

    The paper addresses a number of issues regarding the extent to which trafficking may be applied to migrant domestic workers who enter under the kafala system of sponsorship in the Middle East. Migrant domestic workers are the most numerous of those mentioned in reports on trafficking for labour exploitation in the region. The discussion seeks to determine whether "trafficking" can be ex post facto, rather than ex ante? In other words, can the label of trafficking be attributed only after the worker has arrived in the receiving country and is victimized according to the principles of trafficking protocols? In addition, must there be a proven intent to traffic by agents, or can employers who harm and/or exploit them be considered as traffickers alone? Should the harm done to workers on arrival at their place of work be classified (and assisted) as victims of trafficking, or as exploited workers?

  14. Dietary cholesterol supplementation to a plant-based diet suppresses the complete pathway of cholesterol synthesis and induces bile acid production in Atlantic salmon (Salmo salar L.).

    PubMed

    Kortner, Trond M; Björkhem, Ingemar; Krasnov, Aleksei; Timmerhaus, Gerrit; Krogdahl, Åshild

    2014-06-28

    Plants now supply more than 50 % of protein in Norwegian salmon aquafeeds. The inclusion of plant protein in aquafeeds may be associated with decreased lipid digestibility and cholesterol and bile salt levels, indicating that the replacement of fishmeal with plant protein could result in inadequate supplies of cholesterol in fish. A reduction in feed efficiency, fish growth and pathogen resistance is often observed in parallel to alterations in sterol metabolism. Previous studies have indicated that the negative effects induced by plant components can be attenuated when diets are supplemented with cholesterol. The present study evaluated the effects of dietary cholesterol supplementation (1·5 %) in Atlantic salmon fed a plant-based diet for 77 d. The weights of body, intestines and liver were recorded and blood, tissues, faeces, chyme and bile were sampled for the evaluation of effects on growth, nutrient utilisation and metabolism, and transcriptome and metabolite levels, with particular emphasis on sterol metabolism and organ structure and function. Cholesterol supplementation did not affect the growth or organ weights of Atlantic salmon, but seemed to promote the induction of cholesterol and plant sterol efflux in the intestine while suppressing sterol uptake. Cholesterol biosynthesis decreased correspondingly and conversion into bile acids increased. The marked effect of cholesterol supplementation on bile acid synthesis suggests that dietary cholesterol can be used to increase bile acid synthesis in fish. The present study clearly demonstrated how Atlantic salmon adjusted their metabolic functions in response to the dietary load of cholesterol. It has also expanded our understanding of sterol metabolism and turnover, adding to the existing, rather sparse, knowledge of these processes in fish.

  15. [Accuracy of HDL cholesterol measurements].

    PubMed

    Niedmann, P D; Luthe, H; Wieland, H; Schaper, G; Seidel, D

    1983-02-01

    The widespread use of different methods for the determination of HDL-cholesterol (in Europe: sodium phosphotungstic acid/MgCl2) in connection with enzymatic procedures (in the USA: heparin/MnCl2 followed by the Liebermann-Burchard method) but common reference values makes it necessary to evaluate not only accuracy, specificity, and precision of the precipitation step but also of the subsequent cholesterol determination. A high ratio of serum vs. concentrated precipitation reagent (10:1 V/V) leads to the formation of variable amounts of delta-3.5-cholestadiene. This substance is not recognized by cholesterol oxidase but leads to an 1.6 times overestimation by the Liebermann-Burchard method. Therefore, errors in HDL-cholesterol determination should be considered and differences up to 30% may occur between HDL-cholesterol values determined by the different techniques (heparin/MnCl2 - Liebermann-Burchard and NaPW/MgCl2-CHOD-PAP).

  16. [Determination of HDL-cholesterol].

    PubMed

    Herrmann, W; Schütz, C; Reuter, W

    1983-01-01

    For the clinical practice methods of the determination of HDL-cholesterol made their way which are based on the precipitation of apolipoprotein-B-containing lipoproteins and a determination of cholesterol following. The expensive methods of the ultracentrifugation serve as reference methods. The most-spread precipitation techniques (heparin/MCl2, dextran sulphate/CaCl2 or MgCl2 photungstic acid/MgCl2) are comparatively observed with regard to their effectiveness, practicability and methodical and technical conditions (influence of the concentration of the precipitation reagents, pH-value, temperature, incubation and centrifugation conditions). Results of own investigations as well as data from literature are presented to the problem of the harmonization of the cholesterol determination with the precipitation technique. According to the opinion of the authors for the enzymatic determination of cholesterol by means of the CHOD-PAP-method the phosphotungstic acid precipitation well stood the test, whereas for the chemical determination of cholesterol after Liebermann-Burchard in manual or automatized works the precipitation by means of dextran sulphate/CaCl2 (40 g/l, 2.0 mol/l) is to be recommended. The superabundant precipitations with phosphotungstic acid and dextran sulphate/MgCl2 (20 g/l, 2.0 mol/l) achieve higher results in Liebermann-Burchard's reaction likely on account of interferences.

  17. Cholesterol depletion induces PKA-mediated basolateral-to-apical transcytosis of the scavenger receptor class B type I in MDCK cells

    PubMed Central

    Burgos, Patricia V.; Klattenhoff, Carla; de la Fuente, Erwin; Rigotti, Attilio; González, Alfonso

    2004-01-01

    Cholesterol-based membrane microdomains, or lipid rafts, are believed to play important, yet poorly defined, roles in protein trafficking and signal transduction. In polarized epithelial cells, the current view is that rafts are involved in apical but not in basolateral protein transport from the trans-Golgi network (TGN). We report here that cholesterol is required in a post-TGN mechanism of basolateral regionalization. Permanently transfected Madin-Darby canine kidney cells segregated the caveolae/raft-associated high-density lipoprotein scavenger receptor class B type I (SR-BI) predominantly to the basolateral domain where it was constitutively internalized and recycled basolaterally. Acute cholesterol depletion did not significantly alter SR-BI internalization, implying a cholesterol depletion-insensitive endocytic process but instead induced its transcytosis through a protein kinase A (PKA)- and microtubule-dependent mechanism. Forskolin also elicited SR-BI transcytosis. The basolateral distribution of endogenous epidermal growth factor receptor remained unaffected. Strikingly, cholesterol depletion induced PKA activity without increasing the cAMP levels. Thus, our results are consistent with a scenario in which cholesterol-based rafts promote internalization and basolateral recycling of internalized SR-BI whereas a PKA pool sensitive to cholesterol depletion mediates SR-BI transcytosis. Regulated transcytosis of SR-BI may provide an additional mechanism to control cholesterol homeostasis. These results disclose relationships between cholesterol-based rafts and PKA activity operating in a post-TGN mechanism of regulated apical-to-basolateral cell surface protein distribution. PMID:15007173

  18. Induction of tissue inhibitor of matrix metalloproteinase-2 by cholesterol depletion leads to the conversion of proMMP-2 into active MMP-2 in human dermal fibroblasts

    PubMed Central

    Kim, Sangmin; Oh, Jang-Hee; Lee, Youngae; Lee, Jeongyoon; Cho, Kwang Hyun

    2010-01-01

    Cholesterol is one of major components of cell membrane and plays a role in vesicular trafficking and cellular signaling. We investigated the effects of cholesterol on matrix metalloproteinase-2 (MMP-2) activation in human dermal fibroblasts. We found that tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) expression and active form MMP-2 (64 kD) were dose-dependently increased by methyl-β-cyclodextrin (MβCD), a cholesterol depletion agent. In contrast, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation were suppressed by cholesterol repletion. Then we investigated the regulatory mechanism of TIMP-2 expression by cholesterol depletion. We found that the phosphorylation of JNK as well as ERK was significantly increased by cholesterol depletion. Moreover, cholesterol depletion-induced TIMP-2 expression and MMP-2 activation was significantly decreased by MEK inhibitor U0126, and JNK inhibitor SP600125, respectively. While a low dose of recombinant TIMP-2 (100 ng/ml) increased the level of active MMP-2 (64 kD), the high dose of TIMP-2 (≥ 200 ng/ml) decreased the level of active MMP-2 (64 kD). Taken together, we suggest that the induction of TIMP-2 by cholesterol depletion leads to the conversion of proMMP-2 (72 kD) into active MMP-2 (64 kD) in human dermal fibroblasts. PMID:19887895

  19. Physical health symptoms reported by trafficked women receiving post-trafficking support in Moldova: prevalence, severity and associated factors

    PubMed Central

    2012-01-01

    Background Many trafficked people suffer high levels of physical, sexual and psychological abuse. Yet, there has been limited research on the physical health problems associated with human trafficking or how the health needs of women in post-trafficking support settings vary according to socio-demographic or trafficking characteristics. Methods We analysed the prevalence and severity of 15 health symptoms reported by 120 trafficked women who had returned to Moldova between December 2007 and December 2008 and were registered with the International Organisation for Migration Assistance and Protection Programme. Women had returned to Moldova an average of 5.9 months prior to interview (range 2-12 months). Results Headaches (61.7%), stomach pain (60.9%), memory problems (44.2%), back pain (42.5%), loss of appetite (35%), and tooth pain (35%) were amongst the most commonly reported symptoms amongst both women trafficked for sexual exploitation and women trafficked for labour exploitation. The prevalence of headache and memory problems was strongly associated with duration of exploitation. Conclusions Trafficked women who register for post-trafficking support services after returning to their country of origin are likely to have long-term physical and dental health needs and should be provided with access to comprehensive medical services. Health problems among women who register for post-trafficking support services after returning to their country of origin are not limited to women trafficked for sexual exploitation but are also experienced by victims of labour exploitation. PMID:22834807

  20. Phytosterols esterified with conjugated linoleic acid. In vitro intestinal digestion and interaction on cholesterol bioaccessibility.

    PubMed

    Moran-Valero, Maria I; Martin, Diana; Torrelo, Guzman; Reglero, Guillermo; Torres, Carlos F

    2012-11-14

    Intestinal in vitro digestion of phytosterols esterified with conjugated linoleic acid (PS-CLA) was performed to study (1) the potential bioaccessibility of the released bioactive-lipid products and (2) the interference with cholesterol bioaccessibility. Commercial food-grade PS ester (PS-C) was assayed as reference. Hydrolysis of PS-CLA by digestive enzymes was similar to that of PS-C (51 and 47%, respectively), most lipids products being mainly included in the bioaccessible fraction, namely, the micellar phase (MP). Control assays in the absence of PS esters showed most cholesterol solubilized within the MP, whereas a displacement of total cholesterol was caused from MP after digestion of PS esters (14 and 36% displacement for PS-CLA and PS-C, respectively), cholesterol being partially precipitated. Precipitated cholesterol was linearly related to a parallel precipitation of saturated-chain PS, mainly determined by sitosterol (R² = 0.936). The higher composition in sitosteryl esters of PS-C with respect to PS-CLA might explain their different effects on cholesterol. Therefore, besides being a lipid delivery form of PS similar to other commercial esterified PS, the PS-CLA might have the additional advantage of being a lipid delivery form of CLA. Moreover, PS-CLA might hinder the bioaccessibility of cholesterol. Furthermore, the qualitative/quantitative profile in esterified PS forms might determine the magnitude of cholesterol interaction.

  1. Increased Membrane Cholesterol in Lymphocytes Diverts T-Cells toward an Inflammatory Response

    PubMed Central

    Surls, Jacqueline; Nazarov-Stoica, Cristina; Kehl, Margaret; Olsen, Cara; Casares, Sofia; Brumeanu, Teodor-D.

    2012-01-01

    Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40–50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4+ Foxp3+ T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response. PMID:22723880

  2. Polarizable multipolar electrostatics for cholesterol

    NASA Astrophysics Data System (ADS)

    Fletcher, Timothy L.; Popelier, Paul L. A.

    2016-08-01

    FFLUX is a novel force field under development for biomolecular modelling, and is based on topological atoms and the machine learning method kriging. Successful kriging models have been obtained for realistic electrostatics of amino acids, small peptides, and some carbohydrates but here, for the first time, we construct kriging models for a sizeable ligand of great importance, which is cholesterol. Cholesterol's mean total (internal) electrostatic energy prediction error amounts to 3.9 kJ mol-1, which pleasingly falls below the threshold of 1 kcal mol-1 often cited for accurate biomolecular modelling. We present a detailed analysis of the error distributions.

  3. Effect of ezetimibe on plasma cholesterol levels, cholesterol absorption, and secretion of biliary cholesterol in laboratory opossums with high and low responses to dietary cholesterol.

    PubMed

    Chan, Jeannie; Kushwaha, Rampratap S; Vandeberg, Jane F; Vandeberg, John L

    2008-12-01

    Partially inbred lines of laboratory opossums differ in plasma low-density lipoprotein cholesterol concentration and cholesterol absorption on a high-cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high-cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/(kg d) and treated 6 high- and 6 low-responding opossums with this dose (with equal numbers of controls) for 3 weeks while the opossums consumed a high-cholesterol and low-fat diet. Plasma and low-density lipoprotein cholesterol concentrations decreased significantly (P < .05) in treated but not in untreated high-responding opossums. Plasma cholesterol concentrations increased slightly (P < .05) in untreated low responders but not in treated low responders. The percentage of cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P < .01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P < .05) higher than those in low responders with or without treatment (P < .001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P < .05) lower than those in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Because ezetimibe's target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated

  4. Trafficking of Aminoglycosides Into Endolymph in Vivo

    NASA Astrophysics Data System (ADS)

    Wang, Qi; Steyger, Peter S.

    2009-02-01

    In vitro, aminoglycosides increase the stiffness of cochlear hair cell stereocilia, altering bundle motion and transduction kinetics. Aminoglycosides also permeate the mechanosensitive transduction channel and rapidly initiate cytotoxicity in hair cells. If these effects occur in vivo, aminoglycosides would need to enter endolymph. The most direct route for systemically-administered aminoglycosides to enter endolymph is by trafficking from strial capillaries across the stria vascularis. An as-yet-unidentified active transporter is required to translocate aminoglycosides from the intra-strial space into the cytoplasm of marginal cells. Once in marginal cells, aminoglycosides would passively flow down the electrochemical gradient into endolymph. We present data that support a trans-strial trafficking route of aminoglycosides into endolymph, where they can then interfere with the mechanosensitive hair bundles.

  5. Technosocial Predictive Analytics for Illicit Nuclear Trafficking

    SciTech Connect

    Sanfilippo, Antonio P.; Butner, R. Scott; Cowell, Andrew J.; Dalton, Angela C.; Haack, Jereme N.; Kreyling, Sean J.; Riensche, Roderick M.; White, Amanda M.; Whitney, Paul D.

    2011-03-29

    Illicit nuclear trafficking networks are a national security threat. These networks can directly lead to nuclear proliferation, as state or non-state actors attempt to identify and acquire nuclear weapons-related expertise, technologies, components, and materials. The ability to characterize and anticipate the key nodes, transit routes, and exchange mechanisms associated with these networks is essential to influence, disrupt, interdict or destroy the function of the networks and their processes. The complexities inherent to the characterization and anticipation of illicit nuclear trafficking networks requires that a variety of modeling and knowledge technologies be jointly harnessed to construct an effective analytical and decision making workflow in which specific case studies can be built in reasonable time and with realistic effort. In this paper, we explore a solution to this challenge that integrates evidentiary and dynamic modeling with knowledge management and analytical gaming, and demonstrate its application to a geopolitical region at risk.

  6. Impaired intracellular trafficking defines early Parkinson's disease.

    PubMed

    Hunn, Benjamin H M; Cragg, Stephanie J; Bolam, J Paul; Spillantini, Maria-Grazia; Wade-Martins, Richard

    2015-03-01

    Parkinson's disease (PD) is an insidious and incurable neurodegenerative disease, and represents a significant cost to individuals, carers, and ageing societies. It is defined at post-mortem by the loss of dopamine neurons in the substantia nigra together with the presence of Lewy bodies and Lewy neurites. We examine here the role of α-synuclein and other cellular transport proteins implicated in PD and how their aberrant activity may be compounded by the unique anatomy of the dopaminergic neuron. This review uses multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells, and refined animal models to argue that prodromal PD can be defined as a disease of impaired intracellular trafficking. Dysfunction of the dopaminergic synapse heralds trafficking impairment.

  7. Sex Trafficking: Policies, Programs, and Services.

    PubMed

    Orme, Julie; Ross-Sheriff, Fariyal

    2015-10-01

    Sex trafficking (ST), a contemporary form of female slavery, is a human rights issue of critical concern to social work. The global response to ST has been substantial, and 166 countries have adopted anti-ST legislation. Despite considerable efforts to combat ST, the magnitude is increasing. To date, the majority of anti-ST efforts have focused on criminalization policies that target traffickers or purchasers of sexual services, who are predominantly male; prevention programming and services for predominantly female victims have received less support. Therapeutic services to assist pornography addicts and purchasers of sexual services are also necessary. In this article, authors examine current anti-ST policies, programs, and services, both domestically and globally, and present an innovative paradigm that addresses social inequities and emphasizes prevention programming. They conclude with a discussion of the paradigm's implications for social work policies, practices, and services.

  8. The Strategic Implications of Human Trafficking

    DTIC Science & Technology

    2007-11-02

    within national or across international borders through coercion, force, kidnapping, deception or fraud, for purposes of placing persons in situations ...prominent form of human trade in West Africa. Parents of families living in poverty are susceptible to the supposed financial benefits derived from...orphans is increasing as a result of armed conflicts and HIV/AIDS. Trafficked children are unlikely to receive immunizations to help eliminate childhood

  9. Trafficking of ThermoTRP Channels

    PubMed Central

    Ferrandiz-Huertas, Clotilde; Mathivanan, Sakthikumar; Wolf, Christoph Jakob; Devesa, Isabel; Ferrer-Montiel, Antonio

    2014-01-01

    ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides. PMID:25257900

  10. Ubiquitination and dynactin regulate TMEPAI lysosomal trafficking

    PubMed Central

    Luo, Shenheng; Jing, Lei; Zhao, Tian; Li, Yuyin; Liu, Zhenxing; Diao, Aipo

    2017-01-01

    The transmembrane prostate androgen-induced protein (TMEPAI) has been reported to be elevated in various tumor cells, is localized to the lysosome and promotes lysosome stability. The molecular mechanism of TMEPAI trafficking however to the lysosome is unknown. Here we report that clathrin and CI-M6PR mediate TMEPAI transport from the Golgi directly into the endo-lysosomal pathway. TMEPAI is ubiquitinated at its C-terminal region and ubiquitination modification of TMEPAI is a signal for its lysosomal trafficking. Moreover, TMEPAI binds the ubiquitin binding proteins Hrs and STAM which is required for its lysosomal transport. In addition, TMEPAI interacts with the dynactin pointed-end complex subunits dynactin 5 and dynactin 6. The aa 132–155 domain is essential for specific TMEPAI binding and deletion of this binding site leads to mis-trafficking of TMEPAI to the plasma membrane. These results reveal the pathway and mechanism regulating transport of TMEPAI to the lysosome, which helps to further understand the role of TMEPAI in tumorigenesis. PMID:28218281

  11. Cholesterol autoxidation in phospholipid membrane bilayers

    SciTech Connect

    Sevanian, A.; McLeod, L.L.

    1987-09-01

    Lipid peroxidation in unilamellar liposomes of known cholesterol-phospholipid composition was monitored under conditions of autoxidation or as induced by a superoxide radical generating system, gamma-irradiation or cumene hydroperoxide. Formation of cholesterol oxidation products was indexed to the level of lipid peroxidation. The major cholesterol oxidation products identified were 7-keto-cholesterol, isomeric cholesterol 5,6-epoxides, isomeric 7-hydroperoxides and isomeric 3,7-cholestane diols. Other commonly encountered products included 3,5-cholestadiene-7-one and cholestane-3 beta, 5 alpha, 6 beta-triol. Superoxide-dependent peroxidation required iron and produced a gradual increase in 7-keto-cholesterol and cholesterol epoxides. Cholesterol oxidation was greatest in liposomes containing high proportions of unsaturated phospholipid to cholesterol (4:1 molar ratio), intermediate with low phospholipid to cholesterol ratios (2:1) and least in liposomes prepared with dipalmitoylphosphatidylcholine and cholesterol. This relationship held regardless of the oxidizing conditions used. Cumene hydroperoxide-dependent lipid peroxidation and/or more prolonged oxidations with other oxidizing systems yielded a variety of products where cholesterol-5 beta,6 beta-epoxide, 7-ketocholesterol and the 7-hydroperoxides were most consistently elevated. Oxyradical initiation of lipid peroxidation produced a pattern of cholesterol oxidation products distinguishable from the pattern derived by cumene hydroperoxide-dependent peroxidation.

  12. Sericin reduces serum cholesterol in rats and cholesterol uptake into Caco-2 cells.

    PubMed

    Limpeanchob, Nanteetip; Trisat, Kanittaporn; Duangjai, Acharaporn; Tiyaboonchai, Waree; Pongcharoen, Sutatip; Sutheerawattananonda, Manote

    2010-12-08

    A cholesterol lowering effect of sericin was investigated both in vivo and in vitro. Rats were dosed with cholesterol with and without sericin for 14 days. Non-high-density lipoprotein (HDL) and total serum cholesterols were reduced in rats fed high-cholesterol diet with all three tested doses of sericin (10, 100, and 1000 mg kg(-1) day(-1)). The potential mechanism of actions was determined by measuring the uptake of radiolabeled cholesterol into differentiated Caco-2 cells and cholesterol solubility in mixed lipid micelles. Concentration of sericin as low as 25 and 50 μg/mL inhibited 30% of cholesterol uptake into Caco-2 cells whereas no effect was found at higher concentration. Cholesterol micellar solubility was reduced in the presence of sericin. This study suggests the cholesterol lowering effect of sericin results from its inhibition of cholesterol absorption in intestinal cells and its reduction of cholesterol solubility in lipid micelles.

  13. Community Guide to Cholesterol Resources.

    ERIC Educational Resources Information Center

    National Heart and Lung Inst. (DHHS/NIH), Bethesda, MD.

    This guide is divided into two sections, one for physicians and the other for patients. The physician section lists different resources including continuing medical education opportunities on the medical and scientific aspects of cholesterol and heart disease and on the physician's role in diagnosis and patient management. Additional materials on…

  14. Membrane Cholesterol Modulates Superwarfarin Toxicity

    SciTech Connect

    Marangoni, M. Natalia; Martynowycz, Michael W.; Kuzmenko, Ivan; Braun, David; Polak, Paul E.; Weinberg, Guy; Rubinstein, Israel; Gidalevitz, David; Feinstein, Douglas L.

    2016-04-26

    Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.

  15. Human Trafficking, Mental Illness, and Addiction: Avoiding Diagnostic Overshadowing.

    PubMed

    Stoklosa, Hanni; MacGibbon, Marti; Stoklosa, Joseph

    2017-01-01

    This article reviews an emergency department-based clinical vignette of a trafficked patient with co-occurring pregnancy-related, mental health, and substance use disorder issues. The authors, including a survivor of human trafficking, draw on their backgrounds in addiction care, human trafficking, emergency medicine, and psychiatry to review the literature on relevant general health and mental health consequences of trafficking and propose an approach to the clinical complexities this case presents. In their discussion, the authors explicate the deleterious role of implicit bias and diagnostic overshadowing in trafficked patients with co-occurring addiction and mental illness. Finally, the authors propose a trauma-informed, multidisciplinary response to potentially trafficked patients.

  16. Child human trafficking victims: challenges for the child welfare system.

    PubMed

    Fong, Rowena; Berger Cardoso, Jodi

    2010-08-01

    Since the passing of the Victims of Trafficking and Violence Protection Act in 2000 and its reauthorization by President George Bush in 2008, federal, state and community efforts in identifying and providing services for victims of human trafficking have significantly improved. However, most of the research and resources for trafficking victims have been directed towards adults rather than children. Researchers agree that there is a growing number of sexually exploited and trafficked children in the United States yet few programs emphasize the unique experiences and special needs of this population. This article examines commercial sexual exploitation of children; differentiates the needs and problems between child prostitution and victims of human trafficking; reviews and critiques current treatment practices; and summarizes challenges and successes in working with child victims of human trafficking, offering practice and policy recommendations.

  17. Membrane trafficking in protozoa SNARE proteins, H+-ATPase, actin, and other key players in ciliates.

    PubMed

    Plattner, Helmut

    2010-01-01

    Due to their well-defined pathways of vesicle trafficking and manyfold mutants ciliates have served as good model systems. Further studies required the development of databases, now available for Paramecium and Tetrahymena. A variety of key players have been identified and characterized based on BLAST search, domain analysis, localization, and gene-silencing studies. They include NSF (N-ethylmaleimide sensitive factor), SNAREs (soluble NSF attachment protein [SNAP] receptors), the H(+)-ATPase (V-ATPase) and actin, while Arf (ADP-ribosylation factor) and Rab-type small GTPases, COPs (coatamer proteins) and many others remain to be elucidated. The number of SNAREs, H(+)-ATPase subunits, and actins ever found within one cell type are unexpectedly high and most of the manifold vesicle types seem to be endowed with specific molecular components pertinent to trafficking. As in higher eukaryotes, multifactorial targeting likely occurs. It appears that, in parallel to higher organisms, ciliates have evolved a similar structural and molecular complexity of vesicle trafficking.

  18. Trends in Production, Trafficking and Consumption of Methamphetamine and Cocaine in Mexico

    PubMed Central

    Brouwer, Kimberly C.; Case, Patricia; Ramos, Rebeca; Magis-Rodríguez, Carlos; Bucardo, Jesus; Patterson, Thomas L.; Strathdee, Steffanie A.

    2009-01-01

    Over the past decade, Mexico has experienced a significant increase in trafficking of cocaine and trafficking and production of methamphetamine. An estimated 70% of U.S. cocaine originating in South America passes through the Central America-Mexico corridor. Mexico-based groups are now believed to control 70%–90% of methamphetamine production and distribution in the U.S. Increased availability of these drugs at reduced prices has led to a parallel rise in local drug consumption. Methamphetamine abuse is now the primary reason for seeking drug user treatment in a number of cities, primarily in northwestern Mexico. While cocaine and methamphetamine use have been linked with the sex trade and high risk behaviors such as shooting gallery attendance and unprotected sex in other settings, comparatively little is known about the risk behaviors associated with use of these drugs in Mexico, especially for methamphetamines. We review historical aspects and current trends in cocaine and methamphetamine production, trafficking and consumption in Mexico, with special emphasis on the border cities of Ciudad Juarez and Tijuana. Additionally, we discuss the potential public health consequences of cocaine use and the recent increase in methamphetamine use, especially in regards to the spread of bloodborne and other infections, in an effort to inform appropriate public health interventions. PMID:16603456

  19. High Cholesterol: Medicines to Help You

    MedlinePlus

    ... Consumers Consumer Information by Audience For Women High Cholesterol--Medicines To Help You Share Tweet Linkedin Pin ... side effects for each drug, check Drugs@FDA . Cholesterol Absorption Inhibitors Brand Name Generic Name Zetia Ezetimibe ...

  20. Do You Know Your Cholesterol Levels?

    MedlinePlus

    ... The Health Information Center Do You Know Your Cholesterol Levels? Print-friendly Version (PDF, 6.1 MB) ... Eat Smart Did you know that high blood cholesterol is a serious problem among Latinos? About one ...

  1. What You Need to Know about Cholesterol

    MedlinePlus

    ... 164304.html What You Need to Know About Cholesterol Heart expert explains the difference between good and ... 28, 2017 MONDAY, March 27, 2017 (HealthDay News) -- Cholesterol plays a vital role in your health, so ...

  2. Active membrane cholesterol as a physiological effector.

    PubMed

    Lange, Yvonne; Steck, Theodore L

    2016-09-01

    Sterols associate preferentially with plasma membrane sphingolipids and saturated phospholipids to form stoichiometric complexes. Cholesterol in molar excess of the capacity of these polar bilayer lipids has a high accessibility and fugacity; we call this fraction active cholesterol. This review first considers how active cholesterol serves as an upstream regulator of cellular sterol homeostasis. The mechanism appears to utilize the redistribution of active cholesterol down its diffusional gradient to the endoplasmic reticulum and mitochondria, where it binds multiple effectors and directs their feedback activity. We have also reviewed a broad literature in search of a role for active cholesterol (as opposed to bulk cholesterol or lipid domains such as rafts) in the activity of diverse membrane proteins. Several systems provide such evidence, implicating, in particular, caveolin-1, various kinds of ABC-type cholesterol transporters, solute transporters, receptors and ion channels. We suggest that this larger role for active cholesterol warrants close attention and can be tested easily.

  3. Cholesterol - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Information Translations Cholesterol and Fat Content of Common Foods 一般食品膽固醇及脂肪成份 - 繁體中文 (Chinese - Traditional) Bilingual PDF Chinese Community Health Resource Center Cholesterol ...

  4. United States Federal Guidance on Witness Protection in Human Trafficking

    DTIC Science & Technology

    2015-06-12

    UNITED STATES FEDERAL GUIDANCE ON WITNESS PROTECTION IN HUMAN TRAFFICKING A thesis presented to the Faculty of the U.S. Army...JUN 2015 4. TITLE AND SUBTITLE United States Federal Guidance on Witness Protection in Human Trafficking 5a. CONTRACT NUMBER 5b. GRANT NUMBER...United States needs overarching federal guidance on witness protection for human trafficking victims/witnesses in order to enhance their safety and

  5. The Need to Communicate: Fighting Human Trafficking in Vietnam

    DTIC Science & Technology

    2014-06-01

    trafficking for sexual exploitation, labor exploitation, fraudulent marriages, and adoption. 9 Destination countries include (but are not limited to) those...problem. Scholars have studied human trafficking from multiple angles. Siddharth Kara’s book Sex Trafficking: Inside the Business of Modern Slavery is... Slavery (Columbia University Press, 2008), http://www.jstor.org/stable/10.7312/kara13960. 16 Ibid., 200. 17 Do Anh Tuan and Ma Dang Thi Thanh, Policing

  6. Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats.

    PubMed

    Zhang, Min; Xie, Zongkai; Gao, Weina; Pu, Lingling; Wei, Jingyu; Guo, Changjiang

    2016-03-01

    Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography-based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and

  7. Parallel pivoting combined with parallel reduction

    NASA Technical Reports Server (NTRS)

    Alaghband, Gita

    1987-01-01

    Parallel algorithms for triangularization of large, sparse, and unsymmetric matrices are presented. The method combines the parallel reduction with a new parallel pivoting technique, control over generations of fill-ins and a check for numerical stability, all done in parallel with the work being distributed over the active processes. The parallel technique uses the compatibility relation between pivots to identify parallel pivot candidates and uses the Markowitz number of pivots to minimize fill-in. This technique is not a preordering of the sparse matrix and is applied dynamically as the decomposition proceeds.

  8. Domestic minor sex trafficking in the United States.

    PubMed

    Kotrla, Kimberly

    2010-04-01

    By now, most social workers are familiar with the issue of human trafficking. However, many are likely unfamiliar with research indicating that youths constitute the most vulnerable group in the United States for becoming victims of sex trafficking and that most women in prostitution actually entered as minors. Some experts are now referring to the sex trafficking of U.S. children and youths as "domestic minor sex trafficking," or DMST. This article seeks to acquaint readers with what is currently known regarding the extent of DMST, who is at risk for becoming a victim, and implications for the social work profession in addressing this tragedy.

  9. Tackling Trafficking by Targeting Sex Buyers: Can It Work?

    PubMed

    Niemi, Johanna; Aaltonen, Jussi

    2016-08-23

    The European legal instruments on human trafficking encourage states to tackle the demand for services of trafficked persons, for example, by making the use of services of a trafficked person a criminal offense. In Finland, buying sex from a trafficked person is a criminal offense. This article reports the results of an evaluation of the Finnish law and shows that the implementation has been inefficient. The authors argue that with an amendment of the law, the implementation could be improved but a truly efficient policy would require a total ban of sex purchase along the lines of the Swedish model.

  10. Transfer of cholesterol by the NPC team.

    PubMed

    Vance, Jean E

    2010-08-04

    The mechanisms of intracellular cholesterol transport are largely unknown. In this issue of Cell Metabolism, Wang et al. (2010) identify amino acid residues on the lumenal lysosomal protein Niemann-Pick C2 (NPC2) that are required for intralysosomal transfer of endocytosed cholesterol to membrane-bound NPC1 via a process that avoids movement of hydrophobic cholesterol through the aqueous phase.

  11. Isolation of Cholesterol from an Egg Yolk

    ERIC Educational Resources Information Center

    Taber, Douglass F.; Li, Rui; Anson, Cory M.

    2011-01-01

    A simple procedure for the isolation of the cholesterol, by hydrolysis and extraction followed by column chromatography, is described. The cholesterol can be further purified by complexation with oxalic acid. It can also be oxidized and conjugated to cholestenone. The source of the cholesterol is one egg yolk, which contains about 200 mg of…

  12. Cholesterol Screening: A Practical Guide to Implementation.

    ERIC Educational Resources Information Center

    Kingery, Paul M.

    1995-01-01

    Dry-chemistry cholesterol analysis has made screening feasible in a variety of settings. The article provides practical tips for the implementation of mass cholesterol screening using a portable dry-chemistry analyzer and discusses issues involved in conducting effective cholesterol screening programs from start to finish. (SM)

  13. A sensitive assay for ABCA1-mediated cholesterol efflux using BODIPY -cholesterol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies have shown a negative association between cellular cholesterol efflux and coronary artery disease (CAD). Standard protocol for quantifying cholesterol efflux involves labeling cells with [(3)H]cholesterol and measuring release of the labeled sterol. Using [(3)H]cholesterol is not ideal for...

  14. Orientation of fluorinated cholesterol in lipid bilayers analyzed by 19F tensor calculation and solid-state NMR.

    PubMed

    Matsumori, Nobuaki; Kasai, Yusuke; Oishi, Tohru; Murata, Michio; Nomura, Kaoru

    2008-04-09

    6-F-cholesterol was reported to exhibit biological and interfacial properties similar to unmodified cholesterol. We have also found that 6-F-cholesterol mimicked the cholesterol activity observed in the systems of amphotericin B and lipid rafts. However, to use 6-F-cholesterol as a molecular probe to explore molecular recognition in membranes, it is indispensable to have detailed knowledge of the dynamic and orientation properties of the molecule in membrane environments. In this paper, we present the molecular orientation of 6-F-cholesterol (30 mol %) in dimyristoylphosphatidylcholine (DMPC) bilayers revealed by combined use of 19F chemical shift anisotropy (CSA), 2H NMR, and C-F rotational echo double resonance (REDOR) experiments. The axis of rotation of 6-F-cholesterol was shown to be in a similar direction to that of cholesterol in DMPC bilayers, which is almost parallel to the long axis of the molecular frame. The molecular order parameter of 6-F-cholesterol was determined to be ca. 0.85, which is within the range of reported values of cholesterol. These findings suggest that the dynamic properties of 6-F-cholesterol in DMPC are quite similar to those of unmodified cholesterol; therefore, the introduction of a fluorine atom at C6 has virtually no effect on cholesterol dynamics in membranes. In addition, this study demonstrates the practical utility of theoretical calculations for determining the 19F CSA principal axes, which would be extremely difficult to obtain experimentally. The combined use of quantum calculations and solid-state 19F NMR will make it possible to apply the orientation information of 19F CSA tensors to membrane systems.

  15. Serum lipids, lipoprotein composition and liver cholesterol in genetically obese Zucker rats fed semipurified diets containing either casein or soy protein.

    PubMed

    Terpstra, A H; van Tintelen, G; West, C E

    1983-01-01

    The effect of semipurified diets containing either casein or soy protein on serum lipids, lipoprotein composition and liver cholesterol was studied in genetically obese Zucker rats. The ingestion of a cholesterol-enriched semipurified diet containing casein resulted in elevated levels of serum cholesterol and phospholipids compared to the feeding of a soy protein diet. No differences in serum triglycerides were observed. Differences in serum cholesterol and phospholipids were mainly reflected in the very low density lipoproteins and low density lipoproteins and to a minor extent in the high density lipoproteins. Liver cholesterol paralleled the levels of cholesterol in the serum, the rats fed casein exhibited markedly higher levels of liver cholesterol than those fed soy protein. Furthermore, the rats fed casein also had enlarged livers. Thus, this study clearly shows the differential cholesterolemic effect of dietary casein and soy protein in genetically obese Zucker rats.

  16. Mitochondrial cholesterol accumulation in alcoholic liver disease: Role of ASMase and endoplasmic reticulum stress.

    PubMed

    Marí, Montserrat; Morales, Albert; Colell, Anna; García-Ruiz, Carmen; Fernández-Checa, Jose C

    2014-01-01

    Alcoholic liver disease (ALD) is a major cause of chronic liver disease and a growing health concern in theworld. While the pathogenesis of ALD is poorly characterized key players identified in experimental models and patients, such as perturbations in mitochondrial structure and function, selective loss of antioxidant defense and susceptibility to inflammatory cytokines, contribute to ALD progression. Both oxidative stress and mitochondrial dysfunction compromise essential cellular functions and energy generation and hence are important pathogenic mechanisms of ALD. An important process mediating the mitochondrial disruption induced by alcohol intake is the trafficking of cholesterol to mitochondria, mediated by acid sphingomyelinase-induced endoplasmic reticulum stress, which contributes to increased cholesterol synthesis and StARD1upregulation. Mitochondrial cholesterol accumulation not only sensitizes to oxidative stress but it can contribute to the metabolic reprogramming in ALD, manifested by activation of the hypoxia inducible transcription factor 1 and stimulation of glycolysis and lactate secretion. Thus, a better understanding of the mechanisms underlying alcohol-mediated mitochondrial impairment and oxidative stress may lead to the identification of novel treatments for ALD. The present review briefly summarizes current knowledge on the cellular and molecular mechanisms contributing to alcohol-induced mitochondrial dysfunction and cholesterol accumulation and provides insights for potential therapeutic targets in ALD.

  17. Host Cell P-glycoprotein Is Essential for Cholesterol Uptake and Replication of Toxoplasma gondii*

    PubMed Central

    Bottova, Iveta; Hehl, Adrian B.; Štefanić, Saša; Fabriàs, Gemma; Casas, Josefina; Schraner, Elisabeth; Pieters, Jean; Sonda, Sabrina

    2009-01-01

    P-glycoprotein (P-gp) is a membrane-bound efflux pump that actively exports a wide range of compounds from the cell and is associated with the phenomenon of multidrug resistance. However, the role of P-gp in normal physiological processes remains elusive. Using P-gp-deficient fibroblasts, we showed that P-gp was critical for the replication of the intracellular parasite Toxoplasma gondii but was not involved in invasion of host cells by the parasite. Importantly, we found that the protein participated in the transport of host-derived cholesterol to the intracellular parasite. T. gondii replication in P-gp-deficient host cells not only resulted in reduced cholesterol content in the parasite but also altered its sphingolipid metabolism. In addition, we found that different levels of P-gp expression modified the cholesterol metabolism in uninfected fibroblasts. Collectively our findings reveal a key and previously undocumented role of P-gp in host-parasite interaction and suggest a physiological role for P-gp in cholesterol trafficking in mammalian cells. PMID:19389707

  18. Metals and cholesterol: two sides of the same coin in Alzheimer’s disease pathology

    PubMed Central

    Wong, Bruce X.; Hung, Ya Hui; Bush, Ashley I.; Duce, James A.

    2014-01-01

    Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of β-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed. PMID:24860500

  19. D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage

    NASA Astrophysics Data System (ADS)

    Alfonso-García, Alba; Pfisterer, Simon G.; Riezman, Howard; Ikonen, Elina; Potma, Eric O.

    2016-06-01

    We generated a highly deuterated cholesterol analog (D38-cholesterol) and demonstrated its use for selective vibrational imaging of cholesterol storage in mammalian cells. D38-cholesterol produces detectable signals in stimulated Raman scattering (SRS) imaging, is rapidly taken up by cells, and is efficiently metabolized by acyl-CoA cholesterol acyltransferase to form cholesteryl esters. Using hyperspectral SRS imaging of D38-cholesterol, we visualized cholesterol storage in lipid droplets. We found that some lipid droplets accumulated preferentially unesterified D38-cholesterol, whereas others stored D38-cholesteryl esters. In steroidogenic cells, D38-cholesteryl esters and triacylglycerols were partitioned into distinct sets of lipid droplets. Thus, hyperspectral SRS imaging of D38-cholesterol demonstrates a heterogeneous incorporation of neutral lipid species, i.e., free cholesterol, cholesteryl esters, and triacylglycerols, between individual lipid droplets in a cell.

  20. D38-cholesterol as a Raman active probe for imaging intracellular cholesterol storage

    PubMed Central

    Alfonso-García, Alba; Pfisterer, Simon G.; Riezman, Howard; Ikonen, Elina; Potma, Eric O.

    2015-01-01

    Abstract. We generated a highly deuterated cholesterol analog (D38-cholesterol) and demonstrated its use for selective vibrational imaging of cholesterol storage in mammalian cells. D38-cholesterol produces detectable signals in stimulated Raman scattering (SRS) imaging, is rapidly taken up by cells, and is efficiently metabolized by acyl-CoA cholesterol acyltransferase to form cholesteryl esters. Using hyperspectral SRS imaging of D38-cholesterol, we visualized cholesterol storage in lipid droplets. We found that some lipid droplets accumulated preferentially unesterified D38-cholesterol, whereas others stored D38-cholesteryl esters. In steroidogenic cells, D38-cholesteryl esters and triacylglycerols were partitioned into distinct sets of lipid droplets. Thus, hyperspectral SRS imaging of D38-cholesterol demonstrates a heterogeneous incorporation of neutral lipid species, i.e., free cholesterol, cholesteryl esters, and triacylglycerols, between individual lipid droplets in a cell. PMID:26719944

  1. Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

    NASA Astrophysics Data System (ADS)

    Mandal, Pritam; Noutsi, Pakiza; Chaieb, Sahraoui

    2016-06-01

    Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells’ behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MβCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MβCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low.

  2. Dietary cholesterol and plasma lipoprotein profiles: Randomized controlled trials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early work suggested that dietary cholesterol increased plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk, dietary guidelines have consistently recommended limiting food sources of cholesterol....

  3. 3 CFR 8772 - Proclamation 8772 of December 30, 2011. National Slavery and Human Trafficking Prevention Month...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Slavery and Human Trafficking Prevention Month, 2012 8772 Proclamation 8772 Presidential Documents Proclamations Proclamation 8772 of December 30, 2011 Proc. 8772 National Slavery and Human Trafficking... people, organizations, and government entities that are working to combat human trafficking; and...

  4. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President... economy of the United States constituted by the actions of significant narcotics traffickers centered...

  5. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President declared a national emergency with respect to significant narcotics traffickers centered in...

  6. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President... economy of the United States constituted by the actions of significant narcotics traffickers centered...

  7. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President... economy of the United States constituted by the actions of significant narcotics traffickers centered...

  8. Assisting victims of human trafficking: strategies to facilitate identification, exit from trafficking, and the restoration of wellness.

    PubMed

    Hodge, David R

    2014-04-01

    Human trafficking is a pressing social justice concern. Social work is uniquely situated to address this problem. However, despite the profession's commitment to social justice, the scholarship to equip social workers to address this issue has been largely absent from professional discourse. To address this gap, this article helps social work practitioners to assist victims of human trafficking. After orienting readers to the scope and process of human trafficking, the topics of victim identification, exit from trafficking, and the restoration of psychological wellness are discussed. By equipping themselves in these three areas, practitioners can advance social justice on behalf of some of the most exploited people in the world.

  9. Fish protein hydrolysates affect cholesterol metabolism in rats fed non-cholesterol and high-cholesterol diets.

    PubMed

    Hosomi, Ryota; Fukunaga, Kenji; Arai, Hirofumi; Kanda, Seiji; Nishiyama, Toshimasa; Yoshida, Munehiro

    2012-03-01

    Fish consumption is well known to provide health benefits in both experimental animals and human subjects. Numerous studies have demonstrated the beneficial effects of various protein hydrolysates on lipid metabolism. In this context, this study examined the effect of fish protein hydrolysates (FPH) on cholesterol metabolism compared with the effect of casein. FPHs were prepared from Alaska pollock meat using papain as a protease. Male Wistar rats were divided into the following four dietary groups of seven rats each: either casein (20%) or FPH (10%) + casein (10%), with or without 0.5% cholesterol and 0.1% sodium cholate. Serum and liver lipid levels, fecal cholesterol and bile acid excretions, and the hepatic expression of genes encoding proteins involved in cholesterol homeostasis were examined. In rats fed the FPH diets compared with casein diets with or without cholesterol and sodium cholate, the indexes of cholesterol metabolism-namely, serum cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels-were significantly lower, whereas fecal cholesterol and bile acid excretions were higher. Rats fed the FPH diets compared with casein with cholesterol exhibited a lower liver cholesterol level via an increased liver cholesterol 7α-hydroxylase (CYP7A1) expression level. This study demonstrates that the intake of FPH has hypocholesterolemic effects through the enhancement of fecal cholesterol and bile acid excretions and CYP7A1 expression levels. Therefore, fish peptides prepared by papain digestion might provide health benefits by decreasing the cholesterol content in the blood, which would contribute to the prevention of circulatory system diseases such as arteriosclerosis.

  10. Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking

    PubMed Central

    Rohrbough, Jeffrey; Rushton, Emma; Palanker, Laura; Woodruff, Elvin; Matthies, Heinrich J. G.; Acharya, Usha; Acharya, Jairaj K.; Broadie, Kendal

    2009-01-01

    A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C5-ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50–70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50–70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission. PMID:15356190

  11. Ganglioside Regulation of AMPA Receptor Trafficking

    PubMed Central

    Prendergast, Jillian; Umanah, George K.E.; Yoo, Seung-Wan; Lagerlöf, Olof; Motari, Mary G.; Cole, Robert N.; Huganir, Richard L.; Dawson, Ted M.; Dawson, Valina L.

    2014-01-01

    Gangliosides are major cell-surface determinants on all vertebrate neurons. Human congenital disorders of ganglioside biosynthesis invariably result in intellectual disability and are often associated with intractable seizures. To probe the mechanisms of ganglioside functions, affinity-captured ganglioside-binding proteins from rat cerebellar granule neurons were identified by quantitative proteomic mass spectrometry. Of the six proteins that bound selectively to the major brain ganglioside GT1b (GT1b:GM1 > 4; p < 10−4), three regulate neurotransmitter receptor trafficking: Thorase (ATPase family AAA domain-containing protein 1), soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (γ-SNAP), and the transmembrane protein Nicalin. Thorase facilitates endocytosis of GluR2 subunit-containing AMPA-type glutamate receptors (AMPARs) in an ATPase-dependent manner; its deletion in mice results in learning and memory deficits (J. Zhang et al., 2011b). GluR2-containing AMPARs did not bind GT1b, but bound specifically to another ganglioside, GM1. Addition of noncleavable ATP (ATPγS) significantly disrupted ganglioside binding, whereas it enhanced AMPAR association with Thorase, NSF, and Nicalin. Mutant mice lacking GT1b expressed markedly higher brain Thorase, whereas Thorase-null mice expressed higher GT1b. Treatment of cultured hippocampal neurons with sialidase, which cleaves GT1b (and other sialoglycans), resulted in a significant reduction in the size of surface GluR2 puncta. These data support a model in which GM1-bound GluR2-containing AMPARs are functionally segregated from GT1b-bound AMPAR-trafficking complexes. Release of ganglioside binding may enhance GluR2-containing AMPAR association with its trafficking complexes, increasing endocytosis. Disrupting ganglioside biosynthesis may result in reduced synaptic expression of GluR2-contianing AMPARs resulting in intellectual deficits and seizure susceptibility in mice and humans. PMID:25253868

  12. Ganglioside regulation of AMPA receptor trafficking.

    PubMed

    Prendergast, Jillian; Umanah, George K E; Yoo, Seung-Wan; Lagerlöf, Olof; Motari, Mary G; Cole, Robert N; Huganir, Richard L; Dawson, Ted M; Dawson, Valina L; Schnaar, Ronald L

    2014-09-24

    Gangliosides are major cell-surface determinants on all vertebrate neurons. Human congenital disorders of ganglioside biosynthesis invariably result in intellectual disability and are often associated with intractable seizures. To probe the mechanisms of ganglioside functions, affinity-captured ganglioside-binding proteins from rat cerebellar granule neurons were identified by quantitative proteomic mass spectrometry. Of the six proteins that bound selectively to the major brain ganglioside GT1b (GT1b:GM1 > 4; p < 10(-4)), three regulate neurotransmitter receptor trafficking: Thorase (ATPase family AAA domain-containing protein 1), soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (γ-SNAP), and the transmembrane protein Nicalin. Thorase facilitates endocytosis of GluR2 subunit-containing AMPA-type glutamate receptors (AMPARs) in an ATPase-dependent manner; its deletion in mice results in learning and memory deficits (J. Zhang et al., 2011b). GluR2-containing AMPARs did not bind GT1b, but bound specifically to another ganglioside, GM1. Addition of noncleavable ATP (ATPγS) significantly disrupted ganglioside binding, whereas it enhanced AMPAR association with Thorase, NSF, and Nicalin. Mutant mice lacking GT1b expressed markedly higher brain Thorase, whereas Thorase-null mice expressed higher GT1b. Treatment of cultured hippocampal neurons with sialidase, which cleaves GT1b (and other sialoglycans), resulted in a significant reduction in the size of surface GluR2 puncta. These data support a model in which GM1-bound GluR2-containing AMPARs are functionally segregated from GT1b-bound AMPAR-trafficking complexes. Release of ganglioside binding may enhance GluR2-containing AMPAR association with its trafficking complexes, increasing endocytosis. Disrupting ganglioside biosynthesis may result in reduced synaptic expression of GluR2-contianing AMPARs resulting in intellectual deficits and seizure susceptibility in mice and humans.

  13. Ras trafficking, localization and compartmentalized signalling.

    PubMed

    Prior, Ian A; Hancock, John F

    2012-04-01

    Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Three closely related isoforms, HRAS, KRAS and NRAS, are expressed in all cells and have overlapping but distinctive functions. Recent work has revealed how differences between the Ras isoforms in their trafficking, localization and protein-membrane orientation enable signalling specificity to be determined. We review the various strategies used to characterize compartmentalized Ras localization and signalling. Localization is an important contextual modifier of signalling networks and insights from the Ras system are of widespread relevance for researchers interested in signalling initiated from membranes.

  14. Vesicular trafficking and salinity responses in plants.

    PubMed

    Baral, Anirban; Shruthi, K S; Mathew, M K

    2015-09-01

    Research spanning three decades has demonstrated that vesicles pinch off from the plasma membrane and traffic through the cytoplasm of plant cells, much as previously reported in animal cells. Although the well-conserved clathrin-mediated mechanism of endocytosis has been well characterized, relatively little is known about clathrin-independent pathways in plants. Modulation of endocytosis by both physical stimuli and chemical ligands has been reported in plants. Here, we review the effect of salinity-one of the most deleterious environmental assaults-on endocytosis and intracellular trafficking.

  15. A comparative study on fluorescent cholesterol analogs as versatile cellular reporters.

    PubMed

    Sezgin, Erdinc; Can, Fatma Betul; Schneider, Falk; Clausen, Mathias P; Galiani, Silvia; Stanly, Tess A; Waithe, Dominic; Colaco, Alexandria; Honigmann, Alf; Wüstner, Daniel; Platt, Frances; Eggeling, Christian

    2016-02-01

    Cholesterol (Chol) is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of Chol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently labeled Chol analogs. Unfortunately, the introduction of the label may influence the characteristics of the analog, such as its localization, interaction, and trafficking in cells; hence, it is important to get knowledge of such bias. In this report, we compared different fluorescent lipid analogs for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase-separated giant unilamellar vesicles and giant plasma membrane vesicles; 2) cellular trafficking, specifically subcellular localization in Niemann-Pick type C disease cells; and 3) applicability in fluorescence correlation spectroscopy (FCS)-based and super-resolution stimulated emission depletion-FCS-based measurements of membrane diffusion dynamics. The analogs exhibited strong differences, with some indicating positive performance in the membrane-based experiments and others in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent Chol analogs in visualizing cellular Chol dynamics.

  16. A comparative study on fluorescent cholesterol analogs as versatile cellular reporters[S

    PubMed Central

    Sezgin, Erdinc; Can, Fatma Betul; Schneider, Falk; Clausen, Mathias P.; Galiani, Silvia; Stanly, Tess A.; Waithe, Dominic; Colaco, Alexandria; Honigmann, Alf; Wüstner, Daniel; Platt, Frances; Eggeling, Christian

    2016-01-01

    Cholesterol (Chol) is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of Chol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently labeled Chol analogs. Unfortunately, the introduction of the label may influence the characteristics of the analog, such as its localization, interaction, and trafficking in cells; hence, it is important to get knowledge of such bias. In this report, we compared different fluorescent lipid analogs for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase-separated giant unilamellar vesicles and giant plasma membrane vesicles; 2) cellular trafficking, specifically subcellular localization in Niemann-Pick type C disease cells; and 3) applicability in fluorescence correlation spectroscopy (FCS)-based and super-resolution stimulated emission depletion-FCS-based measurements of membrane diffusion dynamics. The analogs exhibited strong differences, with some indicating positive performance in the membrane-based experiments and others in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent Chol analogs in visualizing cellular Chol dynamics. PMID:26701325

  17. Evaluating computational models of cholesterol metabolism.

    PubMed

    Paalvast, Yared; Kuivenhoven, Jan Albert; Groen, Albert K

    2015-10-01

    Regulation of cholesterol homeostasis has been studied extensively during the last decades. Many of the metabolic pathways involved have been discovered. Yet important gaps in our knowledge remain. For example, knowledge on intracellular cholesterol traffic and its relation to the regulation of cholesterol synthesis and plasma cholesterol levels is incomplete. One way of addressing the remaining questions is by making use of computational models. Here, we critically evaluate existing computational models of cholesterol metabolism making use of ordinary differential equations and addressed whether they used assumptions and make predictions in line with current knowledge on cholesterol homeostasis. Having studied the results described by the authors, we have also tested their models. This was done primarily by testing the effect of statin treatment in each model. Ten out of eleven models tested have made assumptions in line with current knowledge of cholesterol metabolism. Three out of the ten remaining models made correct predictions, i.e. predicting a decrease in plasma total and LDL cholesterol or increased uptake of LDL upon treatment upon the use of statins. In conclusion, few models on cholesterol metabolism are able to pass a functional test. Apparently most models have not undergone the critical iterative systems biology cycle of validation. We expect modeling of cholesterol metabolism to go through many more model topologies and iterative cycles and welcome the increased understanding of cholesterol metabolism these are likely to bring.

  18. Piperine prevents cholesterol gallstones formation in mice.

    PubMed

    Song, Xiu-Yun; Xu, Shuang; Hu, Jin-Feng; Tang, Jia; Chu, Shi-Feng; Liu, Hang; Han, Ning; Li, Jing-Wei; Zhang, Dong-Ming; Li, Yue-Ting; Chen, Nai-Hong

    2015-03-15

    Biliary cholesterol may contribute to the formation of cholesterol gallstones, and regulation of these levels could be a useful therapeutic strategy for gallstones disease. Piperine (PA) is a potential cholesterol lowering agent. In this study, we assessed the effect and mechanism of PA in preventing cholesterol gallstones formation induced by feeding lithogenic diet containing high cholesterol levels to mice. C57BL/6 inbred mice were fed lithogenic or chow diets for 10 weeks, with or without PA (15, 30 and 60 mg/kg) or ursodeoxycholic acid (UDCA, 60 mg/kg) administration. Cholesterol, phospholipids and crystals in bile, the lipid in serum, pathological changes and proteins expression in liver were analyzed. The results showed that PA could decrease the cholesterol potency and crystals in bile, reduce total cholesterol (TC), triglycerides (TG) and increase high-density lipoprotein/low-density lipoprotein (HDL/LDL) levels in serum. Furthermore, PA treatment reduced liver lipid peroxidation and protected hepatobiliary cells from liver injury by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD). In addition, PA inhibited the expression of ATP-binding cassette transporters G5/8 (ABCG5/8) and liver X receptor (LXR) in liver, and reduced cholesterol transport from the hepatocytes to the gallbladder. It may be the mechanism of PA in preventing cholesterol gallstones formation. PA as a potential drug for prevention cholesterol gallstones merits further investigation.

  19. Cholesterol metabolism and homeostasis in the brain.

    PubMed

    Zhang, Juan; Liu, Qiang

    2015-04-01

    Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.

  20. The ATP-binding cassette transporter-2 (ABCA2) regulates cholesterol homeostasis and low-density lipoprotein receptor metabolism in N2a neuroblastoma cells.

    PubMed

    Davis, Warren

    2011-12-01

    The ATP-binding cassette transporter-2 (ABCA2) has been identified as a possible regulator of lipid metabolism. ABCA2 is most highly expressed in the brain but its effects on cholesterol homeostasis in neuronal-type cells have not been characterized. It is important to study the role of ABCA2 in regulating cholesterol homeostasis in neuronal-type cells because ABCA2 has been identified as a possible genetic risk factor for Alzheimer's disease. In this study, the effects of ABCA2 expression on cholesterol homeostasis were examined in mouse N2a neuroblastoma cells. ABCA2 reduced total, free- and esterified cholesterol levels as well as membrane cholesterol but did not perturb cholesterol distribution in organelle or lipid raft compartments. ABCA2 did not modulate de novo cholesterol biosynthesis from acetate. Cholesterol trafficking to the plasma membrane was not affected by ABCA2 but efflux to the physiological acceptor ApoE3 and mobilization of plasma membrane cholesterol to the endoplasmic reticulum for esterification were reduced by ABCA2. ABCA2 reduced esterification of serum and low-density lipoprotein-derived cholesterol but not 25-hydroxycholesterol. ABCA2 decreased low-density lipoprotein receptor (LDLR) mRNA and protein levels and increased its turnover rate. The surface expression of LDLR as well as the uptake of fluroresecent DiI-LDL was also reduced by ABCA2. Reduction of endogenous ABCA2 expression by RNAi treatment of N2a cells and rat primary cortical neurons produced the opposite effects of over-expression of ABCA2, increasing LDLR protein levels. This report identifies ABCA2 as a key regulator of cholesterol homeostasis and LDLR metabolism in neuronal cells.

  1. Special parallel processing workshop

    SciTech Connect

    1994-12-01

    This report contains viewgraphs from the Special Parallel Processing Workshop. These viewgraphs deal with topics such as parallel processing performance, message passing, queue structure, and other basic concept detailing with parallel processing.

  2. PKCβ: Expanding role in hepatic adaptation of cholesterol homeostasis to dietary fat/cholesterol.

    PubMed

    Mehta, Devina; Mehta, Kamal D

    2017-03-01

    Cholesterol homeostasis relies on an intricate network of cellular processes whose deregulation in response to Western type high-fat/cholesterol diets can lead to several life-threatening pathologies. Significant advances have been made in resolving the molecular identity and regulatory function of transcription factors sensitive to fat, cholesterol, or bile acids, but whether body senses the presence of both fat and cholesterol simultaneously is not known. Assessing the impact of a high-fat/cholesterol load, rather than an individual component alone, on cholesterol homeostasis is more physiologically relevant because Western diets deliver both fat and cholesterol at the same time. Moreover, dietary fat and dietary cholesterol are reported to act synergistically to impair liver cholesterol homeostasis. A key insight into the role of protein kinase C-β (PKCβ) in hepatic adaptation to high-fat/cholesterol diets was gained recently through the use of knockout mice. The emerging evidence indicates that PKCβ is an important regulator of cholesterol homeostasis that ensures normal adaptation to high-fat/cholesterol intake. Consistent with this function, high-fat/cholesterol diets induce PKCβ expression and signaling in the intestine and liver, while systemic PKCβ deficiency promotes accumulation of cholesterol in the liver and bile. PKCβ disruption results in profound dysregulation of hepatic cholesterol and bile homeostasis and imparts sensitivity to cholesterol gallstone formation. The available results support involvement of a two-pronged mechanism by which intestine and liver PKCβ signaling converge on liver ERK1/2 to dictate diet-induced cholesterol and bile acid homeostasis. Collectively, PKCβ is an integrator of dietary fat/cholesterol signal and mediates changes to cholesterol homeostasis.

  3. Regulation of biliary cholesterol secretion in the rat. Role of hepatic cholesterol esterification.

    PubMed Central

    Nervi, F; Bronfman, M; Allalón, W; Depiereux, E; Del Pozo, R

    1984-01-01

    Although the significance of the enterohepatic circulation of bile salts in the solubilization and biliary excretion of cholesterol is well established, little is known about the intrahepatic determinants of biliary cholesterol output. Studies were undertaken to elucidate some of these determinants in the rat. Feeding 1% diosgenin for 1 wk increased biliary cholesterol output and saturation by 400%. Bile flow, biliary bile salt, phospholipid and protein outputs remained in the normal range. When ethynyl estradiol (EE) was injected into these animals, biliary cholesterol output decreased to almost normal levels under circumstances of minor changes in the rates of biliary bile salt and phospholipid outputs. Similarly, when chylomicron cholesterol was intravenously injected into diosgenin-fed animals, biliary cholesterol output significantly decreased as a function of the dose of chylomicron cholesterol administered. Relative rates of hepatic cholesterol synthesis and esterification were measured in isolated hepatocytes. Although hepatic cholesterogenesis increased 300% in diosgenin-fed animals, the contribution of newly synthesized cholesterol to total biliary cholesterol output was only 19 +/- 9%, compared with 12 +/- 6% in control and 15 +/- 5% in diosgenin-fed and EE-injected rats. The rate of oleate incorporation into hepatocytic cholesterol esters was 30% inhibited in diosgenin-fed rats. When EE was injected into these animals, the rate of cholesterol esterification increased to almost 300%. To investigate further the interrelationship between hepatic cholesterol esterification and biliary cholesterol output, we studied 21 diosgenin-fed rats. Six of them received in addition EE and 10 received chylomicron cholesterol. The relationships between biliary cholesterol output as a function of both microsomal acyl-CoA:cholesterol acyltransferase (ACAT) activity and hepatic cholesterol ester concentration were significantly correlated in a reciprocal manner. From these

  4. Teaching about Trafficking: Opportunities and Challenges for Critical Engagement

    ERIC Educational Resources Information Center

    Dragiewicz, Molly

    2008-01-01

    The author came to know about trafficking by accident, when she was hired as a research assistant at The Protection Project (TPP) in 1999. As a feminist teacher, the author was very aware of the divisions among feminists on the subject of trafficking, and was interested in communicating these differences to students who were not well versed in the…

  5. Domestic Minor Sex Trafficking in the United States

    ERIC Educational Resources Information Center

    Kotrla, Kimberly

    2010-01-01

    By now, most social workers are familiar with the issue of human trafficking. However, many are likely unfamiliar with research indicating that youths constitute the most vulnerable group in the United States for becoming victims of sex trafficking and that most women in prostitution actually entered as minors. Some experts are now referring to…

  6. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.312 Specially designated narcotics trafficker. The term...

  7. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.312 Specially designated narcotics trafficker. The term...

  8. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.312 Specially designated narcotics trafficker. The term...

  9. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.312 Specially designated narcotics trafficker. The term...

  10. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.312 Specially designated narcotics trafficker. The term...

  11. Adolescent Black Males' Drug Trafficking and Addiction: Three Theoretical Perspectives.

    ERIC Educational Resources Information Center

    Moore, Sharon E.

    1995-01-01

    Explains the incidence and nature of drug trafficking and chemical dependency among adolescent black males. The paper also discusses the social science theories of Emile Durkheim, Karl Marx, and Molefi Asante to better understand the behaviors, and the consequences of those behaviors, of young black males who participate in drug trafficking. (GR)

  12. 78 FR 59950 - Advisory Council on Wildlife Trafficking

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-30

    ... Fish and Wildlife Service Advisory Council on Wildlife Trafficking AGENCY: Fish and Wildlife Service, Interior. ACTION: Notice of meeting. SUMMARY: We, the U.S. Fish and Wildlife Service (Service), announce a public meeting of the Advisory Council on Wildlife Trafficking (Council). DATES: The meeting will be...

  13. Evaluation of DOD Contracts Regarding Combating Trafficking in Persons

    DTIC Science & Technology

    2010-01-15

    involving sexual slavery, human trafficking, and debt bondage attracted media attention and motivated Congressional action. Prior to 2000, instances of... sexual slavery, sex with minors, and human trafficking involving U.S. contractors in Bosnia and Herzegovina led to administrative and criminal

  14. Protein kinesis: The dynamics of protein trafficking and stability

    SciTech Connect

    1995-12-31

    The purpose of this conference is to provide a multidisciplinary forum for exchange of state-of-the-art information on protein kinesis. This volume contains abstracts of papers in the following areas: protein folding and modification in the endoplasmic reticulum; protein trafficking; protein translocation and folding; protein degradation; polarity; nuclear trafficking; membrane dynamics; and protein import into organelles.

  15. Falling through the Gaps: Safeguarding Children Trafficked into the UK

    ERIC Educational Resources Information Center

    Bokhari, Farrah

    2008-01-01

    An overview of child trafficking in the UK explores the nature and methods of this abuse, as well as the treatment and protection afforded to these particularly vulnerable children. It highlights the shortcomings and inconsistent standards of local authorities, the lack of specialist protection and the uncertainty of a trafficked child's…

  16. Aggression in Sexually Abused Trafficked Girls and Efficacy of Intervention

    ERIC Educational Resources Information Center

    Deb, Sibnath; Mukherjee, Aparna; Mathews, Ben

    2011-01-01

    The broad objective of this study was to understand the incidence and severity of aggression among sexually abused girls who were trafficked and who were then further used for commercial sexual exploitation (referred to subsequently as sexually abused trafficked girls). In addition, the impact of counseling for minimizing aggression in these girls…

  17. 48 CFR 52.222-50 - Combating Trafficking in Persons.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... Commercial sex act means any sex act on account of which anything of value is given to or received by any... the value of those services as reasonably assessed is not applied toward the liquidation of the debt... trafficking in persons means— (1) Sex trafficking in which a commercial sex act is induced by force, fraud,...

  18. Regulated trafficking of the CFTR chloride channel.

    PubMed

    Kleizen, B; Braakman, I; de Jonge, H R

    2000-08-01

    The cystic fibrosis transmembrane conductance regulator (CFTR), the ABC transporter encoded by the cystic fibrosis gene, is localized in the apical membrane of epithelial cells where it functions as a cyclic AMP-regulated chloride channel and as a regulator of other ion channels and transporters. Whereas a key role of cAMP-dependent phosphorylation in CFTR-channel gating has been firmly established, more recent studies have provided clear evidence for the existence of a second level of cAMP regulation, i.e. the exocytotic recruitment of CFFR to the plasma membrane and its endocytotic retrieval. Regulated trafficking of the CFTR Cl- channel has sofar been demonstrated only in a subset of CFTR-expressing cell types. However, with the introduction of more sensitive methods to measure CFTR cycling and submembrane localization, it might turn out to be a more general phenomenon that could contribute importantly to both the regulation of CFTR-mediated chloride transport itself and to the regulation of other transporters and CFTR-modulated cellular functions. This review aims to summarize the present state of knowledge regarding polarized and regulated CFTR trafficking and endosomal recycling in epithelial cells, to discuss present gaps in our understanding of these processes at the cellular and molecular level, and to consider its possible implications for cystic fibrosis.

  19. Trafficking of Estrella lausannensis in human macrophages.

    PubMed

    Rusconi, Brigida; Kebbi-Beghdadi, Carole; Greub, Gilbert

    2015-07-01

    Estrella lausannensis is a new member of the Chlamydiales order. Like other Chlamydia-related bacteria, it is able to replicate in amoebae and in fish cell lines. A preliminary study investigating the pathogenic potential of Chlamydia-related bacteria found a correlation between antibody response to E. lausannensis and pneumonia in children. To further investigate the pathogenic potential of E. lausannensis, we determined its ability to grow in human macrophages and its intracellular trafficking. The replication in macrophages resulted in viable E. lausannensis; however, it caused a significant cytopathic effect. The intracellular trafficking of E. lausannensis was analyzed by determining the interaction of the Estrella-containing inclusions with various endocytic markers as well as host organelles. The E. lausannensis inclusion escaped the endocytic pathway rapidly avoiding maturation into phagolysosomes by preventing both EEA-1 and LAMP-1 accumulation. Compared to Waddlia chondrophila, another Chlamydia-related bacteria, the recruitment of mitochondria and endoplasmic reticulum was minimal for E. lausannensis inclusions. Estrella lausannensis appears to use a distinct source of nutrients and energy compared to other members of the Chlamydiales order. In conclusion, we hypothesize that E. lausannensis has a restricted growth in human macrophages, due to its reduced capacity to control programmed cell death.

  20. Synaptic Control of Secretory Trafficking in Dendrites

    PubMed Central

    Hanus, Cyril; Kochen, Lisa; Dieck, Susanne tom; Racine, Victor; Sibarita, Jean-Baptiste; Schuman, Erin M.; Ehlers, Michael D.

    2016-01-01

    Summary Localized signaling in neuronal dendrites requires tight spatial control of membrane composition. Upon initial synthesis, nascent secretory cargo in dendrites exits the endoplasmic reticulum (ER) from local zones of ER complexity that are spatially coupled to post-ER compartments. Although newly synthesized membrane proteins can be processed locally, the mechanisms that control the spatial range of secretory cargo transport in dendritic segments are unknown. Here, we monitored the dynamics of nascent membrane proteins in dendritic post-ER compartments under regimes of low or increased neuronal activity. In response to activity blockade, post-ER carriers are highly mobile and are transported over long distances. Conversely, increasing synaptic activity dramatically restricts the spatial scale of post-ER trafficking along dendrites. This activity-induced confinement of secretory cargo requires site-specific phosphorylation of the kinesin motor KIF17 by Ca2+/calmodulin-dependent protein kinases (CaMK). Thus, the length scales of early secretory trafficking in dendrites are tuned by activity-dependent regulation of microtubule-dependent transport. PMID:24931613

  1. Trafficking to the primary cilium membrane

    PubMed Central

    Mukhopadhyay, Saikat; Badgandi, Hemant B.; Hwang, Sun-hee; Somatilaka, Bandarigoda; Shimada, Issei S.; Pal, Kasturi

    2017-01-01

    The primary cilium has been found to be associated with a number of cellular signaling pathways, such as vertebrate hedgehog signaling, and implicated in the pathogenesis of diseases affecting multiple organs, including the neural tube, kidney, and brain. The primary cilium is the site where a subset of the cell's membrane proteins is enriched. However, pathways that target and concentrate membrane proteins in cilia are not well understood. Processes determining the level of proteins in the ciliary membrane include entry into the compartment, removal, and retention by diffusion barriers such as the transition zone. Proteins that are concentrated in the ciliary membrane are also localized to other cellular sites. Thus it is critical to determine the particular role for ciliary compartmentalization in sensory reception and signaling pathways. Here we provide a brief overview of our current understanding of compartmentalization of proteins in the ciliary membrane and the dynamics of trafficking into and out of the cilium. We also discuss major unanswered questions regarding the role that defects in ciliary compartmentalization might play in disease pathogenesis. Understanding the trafficking mechanisms that underlie the role of ciliary compartmentalization in signaling might provide unique approaches for intervention in progressive ciliopathies. PMID:28082521

  2. Rho-GTPase-regulated vesicle trafficking in plant cell polarity.

    PubMed

    Chen, Xu; Friml, Jiří

    2014-02-01

    ROPs (Rho of plants) belong to a large family of plant-specific Rho-like small GTPases that function as essential molecular switches to control diverse cellular processes including cytoskeleton organization, cell polarization, cytokinesis, cell differentiation and vesicle trafficking. Although the machineries of vesicle trafficking and cell polarity in plants have been individually well addressed, how ROPs co-ordinate those processes is still largely unclear. Recent progress has been made towards an understanding of the co-ordination of ROP signalling and trafficking of PIN (PINFORMED) transporters for the plant hormone auxin in both root and leaf pavement cells. PIN transporters constantly shuttle between the endosomal compartments and the polar plasma membrane domains, therefore the modulation of PIN-dependent auxin transport between cells is a main developmental output of ROP-regulated vesicle trafficking. The present review focuses on these cellular mechanisms, especially the integration of ROP-based vesicle trafficking and plant cell polarity.

  3. Psychological Coercion in Human Trafficking: An Application of Biderman's Framework.

    PubMed

    Baldwin, Susie B; Fehrenbacher, Anne E; Eisenman, David P

    2015-09-01

    This study examined coercive conditions experienced by trafficked persons in the context of Biderman's theory of coercion. We conducted semi-structured interviews with 12 adult women trafficked into Los Angeles County, from 10 countries, for domestic work and/or sex work. Participants described health problems they experienced in relation to their trafficking experience and their perceptions of conditions that caused health problems. Utilizing a framework analysis approach, we analyzed themes using Biderman's framework. Participants reported experiencing the range of nonphysical coercive tactics outlined by Biderman, including isolation, monopolization of perception, induced debility or exhaustion, threats, occasional indulgences, demonstration of omnipotence, degradation, and enforcement of trivial demands. Our analysis demonstrates how these coercion tactics reinforced the submission of trafficked persons to their traffickers even in the absence of physical force or restraints. Such psychological abuse creates extreme stress that can lead to acute and chronic, physical and mental health problems.

  4. Human trafficking: the role of the health care provider.

    PubMed

    Dovydaitis, Tiffany

    2010-01-01

    Human trafficking is a major public health problem, both domestically and internationally. Health care providers are often the only professionals to interact with trafficking victims who are still in captivity. The expert assessment and interview skills of providers contribute to their readiness to identify victims of trafficking. The purpose of this article is to provide clinicians with knowledge on trafficking and give specific tools that they may use to assist victims in the clinical setting. Definitions, statistics, and common health care problems of trafficking victims are reviewed. The role of the health care provider is outlined through a case study and clinical practice tools are provided. Suggestions for future research are also briefly addressed.

  5. Entrapment and Enmeshment Schemes Used by Sex Traffickers.

    PubMed

    Reid, Joan A

    2016-09-01

    Emerging research suggests that sex traffickers/pimps control the majority of trafficked girls in the United States. The youthfulness of these victims and their lack of psychosocial maturity severely diminish their ability to detect exploitative motives or withstand manipulation of traffickers. A review of 43 cases of sexually exploited girls involving non-relative traffickers and 10 semi-structured interviews with social service providers revealed numerous scripts and schemes used by sex traffickers to entrap and entangle victims including boyfriend/lover scripts, ruses involving debt bondage, friendship or faux-family scripts, threats of forced abortion or to take away children, and coerced co-offending. These findings inform potential prevention efforts and highlight the need for multi-systemic, victim-centered approaches to intervention.

  6. New Insights into How Trafficking Regulates T Cell Receptor Signaling

    PubMed Central

    Lou, Jieqiong; Rossy, Jérémie; Deng, Qiji; Pageon, Sophie V.; Gaus, Katharina

    2016-01-01

    There is emerging evidence that exocytosis plays an important role in regulating T cell receptor (TCR) signaling. The trafficking molecules involved in lytic granule (LG) secretion in cytotoxic T lymphocytes (CTL) have been well-studied due to the immune disorder known as familial hemophagocytic lymphohistiocytosis (FHLH). However, the knowledge of trafficking machineries regulating the exocytosis of receptors and signaling molecules remains quite limited. In this review, we summarize the reported trafficking molecules involved in the transport of the TCR and downstream signaling molecules to the cell surface. By combining this information with the known knowledge of LG exocytosis and general exocytic trafficking machinery, we attempt to draw a more complete picture of how the TCR signaling network and exocytic trafficking matrix are interconnected to facilitate T cell activation. This also highlights how membrane compartmentalization facilitates the spatiotemporal organization of cellular responses that are essential for immune functions. PMID:27508206

  7. The role of the nurse in combating human trafficking.

    PubMed

    Sabella, Donna

    2011-02-01

    Human trafficking, also called modern slavery, happens worldwide--and the United States is no exception. Within our borders, thousands of foreign nationals and U.S. citizens, many of them children, are forced or coerced into sex work or various forms of labor every year. Nurses and other health care providers who encounter victims of trafficking often don't realize it, and opportunities to intervene are lost. Although no one sign can demonstrate with certainty when someone is being trafficked, there are several indicators that clinicians should know. This article provides an overview of human trafficking, describes how to recognize signs that a person is being trafficked and how to safely intervene, and offers an extensive resource list.

  8. Cholesterol

    MedlinePlus

    ... Diet Plans Nutrients and Nutritional Info Sugar and Sugar Substitutes Exercise and Fitness Exercise Basics Sports Safety Injury Rehabilitation ... Diet Plans Nutrients and Nutritional Info Sugar and Sugar Substitutes Exercise and Fitness Exercise Basics Sports Safety Injury Rehabilitation ...

  9. igr Genes and Mycobacterium tuberculosis cholesterol metabolism.

    PubMed

    Chang, Jennifer C; Miner, Maurine D; Pandey, Amit K; Gill, Wendy P; Harik, Nada S; Sassetti, Christopher M; Sherman, David R

    2009-08-01

    Recently, cholesterol was identified as a physiologically important nutrient for Mycobacterium tuberculosis survival in chronically infected mice. However, it remained unclear precisely when cholesterol is available to the bacterium and what additional bacterial functions are required for its metabolism. Here, we show that the igr locus, which we previously found to be essential for intracellular growth and virulence of M. tuberculosis, is required for cholesterol metabolism. While igr-deficient strains grow identically to the wild type in the presence of short- and long-chain fatty acids, the growth of these bacteria is completely inhibited in the presence of cholesterol. Interestingly, this mutant is still able to respire under cholesterol-dependent growth inhibition, suggesting that the bacteria can metabolize other carbon sources during cholesterol toxicity. Consistent with this hypothesis, we found that the growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as mutation of the mce4 sterol uptake system partially suppresses this effect. In addition, the Delta igr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout infection.

  10. Cholesterol, the central lipid of mammalian cells

    PubMed Central

    Maxfield, Frederick R.; van Meer, Gerrit

    2010-01-01

    Summary of recent advances Despite its importance for mammalian cell biology and human health, there are many basic aspects of cholesterol homeostasis that are not well understood. Even for the well-characterized delivery of cholesterol to cells via lipoproteins, a novel regulatory mechanism has been discovered recently, involving a serum protein called PCSK9, which profoundly affects lipoproteins and their receptors. Cells can export cholesterol by processes that require the activity of ABC transporters, but the molecular mechanisms for cholesterol transport remain unclear. Cholesterol levels in different organelles vary by 5–10 fold, and the mechanisms for maintaining these differences are now partially understood. Several proteins have been proposed to play a role in the inter-organelle movement of cholesterol, but many aspects of the mechanisms for regulating intracellular transport and distribution of cholesterol remain to be worked out. The endoplasmic reticulum is the main organelle responsible for regulation of cholesterol synthesis, and careful measurements have shown that the proteins responsible for sterol sensing respond over a very narrow range of cholesterol concentrations to provide very precise, switch-like control over cholesterol synthesis. PMID:20627678

  11. Illicit trafficking of radiological & nuclear materials : modeling and analysis of trafficking trends and risks.

    SciTech Connect

    York, David L.; Love, Tracia L.; Rochau, Gary Eugene

    2005-01-01

    Concerns over the illicit trafficking of radiological and nuclear materials were focused originally on the lack of security and accountability of such material throughout the former Soviet states. This is primarily attributed to the frequency of events that have occurred involving the theft and trafficking of critical material components that could be used to construct a Radiological Dispersal Device (RDD) or even a rudimentary nuclear device. However, with the continued expansion of nuclear technology and the deployment of a global nuclear fuel cycle these materials have become increasingly prevalent, affording a more diverse inventory of dangerous materials and dual-use items. To further complicate the matter, the list of nuclear consumers has grown to include: (1) Nation-states that have gone beyond the IAEA agreed framework and additional protocols concerning multiple nuclear fuel cycles and processes that reuse the fuel through reprocessing to exploit technologies previously confined to the more industrialized world; (2) Terrorist organizations seeking to acquire nuclear and radiological material due to the potential devastation and psychological effect of their use; (3) Organized crime, which has discovered a lucrative market in trafficking of illicit material to international actors and/or countries; and (4) Amateur smugglers trying to feed their families in a post-Soviet era. An initial look at trafficking trends of this type seems scattered and erratic, localized primarily to a select group of countries. This is not necessarily the case. The success with which other contraband has been smuggled throughout the world suggests that nuclear trafficking may be carried out with relative ease along the same routes by the same criminals or criminal organizations. Because of the inordinately high threat posed by terrorist or extremist groups acquiring the ingredients for unconventional weapons, it is necessary that illicit trafficking of these materials be better

  12. Reduction of blood serum cholesterol

    NASA Technical Reports Server (NTRS)

    Winitz, M. (Inventor)

    1974-01-01

    By feeding a human subject as the sole source of sustenance a defined diet wherein the carbohydrate consists substantially entirely of glucose, maltose or a polysaccharide of glucose, the blood serum cholesterol level of the human subject is substantially reduced. If 25 percent of the carbohydrate is subsequently supplied in the form of sucrose, an immediate increase from the reduced level is observed. The remainder of the defined diet normally includes a source of amino acids, such as protein or a protein hydrolysate, vitamins, minerals and a source of essential fatty acid.

  13. Effects of cholesterol on plasma membrane lipid order in MCF-7 cells by two-photon microscopy

    NASA Astrophysics Data System (ADS)

    Zeng, Yixiu; Chen, Jianling; Yang, Hongqin; Wang, Yuhua; Li, Hui; Xie, Shusen

    2014-09-01

    Lipid rafts are cholesterol- and glycosphingolipids- enriched microdomains on plasma membrane surface of mammal cells, involved in a variety of cellular processes. Depleting cholesterol from the plasma membrane by drugs influences the trafficking of lipid raft markers. Optical imaging techniques are powerful tools to study lipid rafts in live cells due to its noninvasive feature. In this study, breast cancer cells MCF-7 were treated with different concentrations of MβCD to deplete cholesterol and an environmentally sensitive fluorescence probe, Laurdan was loaded to image lipid order by two-photon microscopy. The generalized polarization (GP) values were calculated to distinguish the lipid order and disorder phase. GP images and GP distributions of native and cholesterol-depleted MCF-7 cells were obtained. Our results suggest that even at low concentration (0.5 mM) of MβCD, the morphology of the MCF-7 cells changes. Small high GP areas (lipid order phase) decrease more rapidly than low GP areas (lipid disorder phase), indicating that lipid raft structure was altered more severely than nonraft domains. The data demonstrates that cholesterol dramatically affect raft coverage and plasma membrane fluidity in living cells.

  14. Parallel rendering techniques for massively parallel visualization

    SciTech Connect

    Hansen, C.; Krogh, M.; Painter, J.

    1995-07-01

    As the resolution of simulation models increases, scientific visualization algorithms which take advantage of the large memory. and parallelism of Massively Parallel Processors (MPPs) are becoming increasingly important. For large applications rendering on the MPP tends to be preferable to rendering on a graphics workstation due to the MPP`s abundant resources: memory, disk, and numerous processors. The challenge becomes developing algorithms that can exploit these resources while minimizing overhead, typically communication costs. This paper will describe recent efforts in parallel rendering for polygonal primitives as well as parallel volumetric techniques. This paper presents rendering algorithms, developed for massively parallel processors (MPPs), for polygonal, spheres, and volumetric data. The polygon algorithm uses a data parallel approach whereas the sphere and volume render use a MIMD approach. Implementations for these algorithms are presented for the Thinking Ma.chines Corporation CM-5 MPP.

  15. Hyperinsulinemia and skeletal muscle fatty acid trafficking

    PubMed Central

    Kanaley, Jill A.; Shadid, Samyah; Sheehan, Michael T.; Guo, ZengKui

    2013-01-01

    We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U-13C]palmitate (0400–0900 h) and [U-13C]oleate (0800–1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass−1·min−1) clamp (0800–1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-13C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ∼1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin. PMID:23820622

  16. Imbalanced cholesterol metabolism in Alzheimer's disease.

    PubMed

    Xue-shan, Zhao; Juan, Peng; Qi, Wu; Zhong, Ren; Li-hong, Pan; Zhi-han, Tang; Zhi-sheng, Jiang; Gui-xue, Wang; Lu-shan, Liu

    2016-05-01

    Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.

  17. Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

    PubMed Central

    López, Cesar A.; de Vries, Alex H.; Marrink, Siewert J.

    2011-01-01

    The depletion of cholesterol from membranes, mediated by β-cyclodextrin (β-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from a pure cholesterol monolayer, at atomic resolution. Our results show that efficient cholesterol extraction depends on the structural distribution of the CDs on the surface of the monolayer. With a suitably oriented dimer, cholesterol is extracted spontaneously on a nanosecond time scale. Additional free energy calculations reveal that the CDs have a strong affinity to bind to the membrane surface, and, by doing so, destabilize the local packing of cholesterol molecules making their extraction favorable. Our results have implications for the interpretation of experimental measurements, and may help in the rational design of efficient CD based nano-carriers. PMID:21455285

  18. microRNAs and cholesterol metabolism

    PubMed Central

    Moore, Kathryn J.; Rayner, Katey J.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2010-01-01

    Cholesterol metabolism is tightly regulated at the cellular level. In addition to classic transcriptional regulation of cholesterol metabolism (e.g., by SREBP and LXR), members of a class of non-coding RNAs termed microRNAs (miRNAs) have recently been identified to be potent post-transcriptional regulators of lipid metabolism genes, including cholesterol homeostasis. We and others have recently shown that miR-33 regulates cholesterol efflux and HDL biogenesis by downregulating the expression of the ABC transporters, ABCA1 and ABCG1. In addition to miR-33, miR-122 and miR-370 have been shown to play important roles in regulating cholesterol and fatty acid metabolism. These new data suggest important roles of microRNAs in the epigenetic regulation of cholesterol metabolism and have opened new avenues for the treatment of dyslipidemias. PMID:20880716

  19. Cholesterol Oxidation in Fish and Fish Products.

    PubMed

    Dantas, Natalie Marinho; Sampaio, Geni Rodrigues; Ferreira, Fernanda Silva; Labre, Tatiana da Silva; Torres, Elizabeth Aparecida Ferraz da Silva; Saldanha, Tatiana

    2015-12-01

    Fish and fish products are important from a nutritional point of view due to the presence of high biological value proteins and the high content of polyunsaturated fatty acids, especially those of the n-3 series, and above all eicosapentaenoic acid and docosahexaenoic acid. However, these important food products also contain significant amounts of cholesterol. Although cholesterol participates in essential functions in the human body, it is unstable, especially in the presence of light, oxygen, radiation, and high temperatures that can cause the formation of cholesterol oxidation products or cholesterol oxides, which are prejudicial to human health. Fish processing involves high and low temperatures, as well as other methods for microbiological control, which increases shelf life and consequently added value; however, such processes favor the formation of cholesterol oxidation products. This review brings together data on the formation of cholesterol oxides during the preparation and processing of fish into food products which are recognized and recommended for their nutritional properties.

  20. [Diagnostic importance of HDL cholesterol determination].

    PubMed

    Reissner, J; Herrmann, W

    1990-01-01

    The present paper describes the sensitivity to quantification of changes of HDL-cholesterol in serum by two different precipitation and analytical techniques during the treatment of patients. After the precipitation of VLDL and LDL by phosphotungstic acid/magnesium chloride the chemical determination of HDL-cholesterol in serum with the Liebermann-Burchard reaction yields different results in comparison to enzymatic HDL-cholesterol determined in serum supernatant after the precipitation by polyethylene glycol 20.000. Correlation analyses of apolipoprotein A-I with enzymatic HDL-, HDL2-, HDL3-cholesterol or electrophoretic alpha-cholesterol demonstrate that the therapeutically induced changes (by training and diet) of lipid composition are more correctly reflected by the enzymatic determination of HDL-cholesterol after serum precipitation by polyethylene glycol.

  1. Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome (SLOS)

    PubMed Central

    Chan, Yen-Ming; Merkens, Louise S.; Connor, William E.; Roullet, Jean-Baptiste; Penfield, Jennifer A.; Jordan, Julia M.; Steiner, Robert D.; Jones, Peter J.H.

    2009-01-01

    Deficient cholesterol and/or excessive 7-dehydrocholesterol (7-DHC) may be responsible for the pathology of Smith-Lemli-Opitz syndrome (SLOS). Both high cholesterol diets given to ameliorate cholesterol deficiency while decreasing 7-DHC, and cholesterol-enriched diets plus simvastatin to further decrease sterol synthesis, have been used as potential therapies. However, the effect of dietary cholesterol and simvastatin on cholesterol synthesis in SLOS has not been reported. Twelve SLOS subjects enrolled in the study: Nine had received a high cholesterol diet (HI) for 3 years, and three were studied after 4 weeks on a low cholesterol diet (LO). Cholesterol fractional synthesis rate (FSR) was measured after oral administration of deuterium oxide, using gas-chromatography-isotope ratio mass spectrometry. FSR was lower in HI compared with LO (HI: 1.46±0.62%/d; LO: 4.77±0.95%/d; P<0.001). Three HI subjects were re-tested after 0.8 years taking simvastatin (HI+ST). Simvastatin tended to reduce FSR and significantly decreased (P<0.01) plasma 7-DHC compared to cholesterol supplementation alone. The study demonstrates the utility of the deuterium incorporation method to understand the effect of therapeutic interventions in SLOS. The data suggest that dietary cholesterol supplementation reduces cholesterol synthesis in SLOS and further support the rationale for the combined treatment of SLOS with a cholesterol-enriched diet and simvastatin. PMID:19430384

  2. Metabolism of adrenal cholesterol in man

    PubMed Central

    Borkowski, Abraham; Delcroix, Claude; Levin, Sam

    1972-01-01

    The kinetics of plasma and adrenal cholesteral equilibration were analyzed in patients undergoing bilateral adrenalectomy for generalized mammary carcinoma. A biological model is proposed to help in the understanding of adrenal cholesterol physiology. It comprises two intracellular compartments: (1) A compartment of free adrenal cholesterol which is small (of the order of 17 mg) but turns over very fast; it is renewed approximately 8 times per day: 3 times by the inflow of free plasma cholesterol, and 5 times by the hydrolysis of esterified adrenal cholesterol, the contribution of adrenal cholesterol synthesis appearing to be relatively small. (2) A compartment of esterified adrenal cholesterol which is 20 times larger; it is constantly renewed by in situ esterification and hydrolysis with a daily fractional turnover rate of the order of 0.25. The direct and selective accumulation of plasma cholesteryl esters is practically absent. Only free adrenal cholesterol returns to plasma, mostly after conversion into steroid “hormones.” However small the synthesis of adrenal cholesterol may be, it seems more important in the zona “reticularis.” On the other hand, the inflow of plasma cholesterol and the turnover of the free adrenal compartment tend to be faster in the zona “fasciculata.” The equilibration of plasma and adrenal cholesterol can proceed unmodified under conditions of ACTH suppression. In one patient with Cushing's disease the size of the two adrenal compartments was clearly increased but their equilibration with plasma cholesterol proceeded normally. In another patient the kinetics of hydrocortisone corresponded to those of free adrenal cholesterol in the control studies. PMID:4338119

  3. Liquid disordered-liquid ordered phase coexistence in bicelles containing unsaturated lipids and cholesterol.

    PubMed

    Schmidt, Miranda L; Davis, James H

    2016-04-01

    Magnetically orienting bicelles are often made by combining the long chain phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) with the short chain phospholipid 1,2-dicaproyl-sn-glycero-3-phosphocholine (DCPC) in buffer. These bicelles orient with their bilayer normals perpendicular to the external magnetic field. We have examined the phase behaviour of DMPC/DCPC bicelles and the effects of cholesterol and the unsaturated phospholipid 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine (DPoPC) as a function of temperature using static solid state (2)H nuclear magnetic resonance spectroscopy. As expected, cholesterol has an ordering effect on the long phospholipid chains and this is reflected in the phase behaviour of the bicelle mixtures. Liquid disordered-liquid ordered, fluid-fluid phase coexistence is observed in DMPC/cholesterol/DCPC bicelles with cholesterol mole fractions of 0.13 and higher. DPoPC/DMPC/cholesterol/DCPC bicelles also exhibit two fluid phase coexistence over a broad range of temperatures and compositions. Bicelles can provide a useful medium in which to study membrane bound peptides and proteins. The orientation parallel to the magnetic field is favourable for studying membrane peptides/proteins because information about the orientation of relevant molecular bonds or internuclear vectors can be obtained directly from the resulting (2)H spectra. Lanthanide ions can be used to flip the bicelles to have their bilayer normals parallel to the external magnetic field. Yb(3+) was used to flip the DPoPC/DMPC/cholesterol/DCPC bicelles while Eu(3+) was found to be ineffective at flipping bicelles containing cholesterol in the present work.

  4. Chinese narcotics trafficking: a preliminary report.

    PubMed

    Huang, Kaicheng; Liu, Jianhong; Zhao, Ruohui; Zhao, Guoling; Friday, Paul C

    2012-02-01

    Questions of existence of the "China Route" for drug smuggling and trafficking have been important in the literature. The profile of the offenders, particularly whether they are primarily members of traditional criminal organization, is a hotly debated issue. Much qualitative evidence has been collected and it provides important insights into these questions. However, little quantitative data has ever been collected and analyzed to provide a broader picture of these issues. The present study involves the systematical collection of data from court sentencing files from seven high courts whose jurisdictions cover the China Route. The findings provide valuable information that sheds light on the debated questions. Some evidence consistent with the China Route arguments is found. No evidence supports the idea that traditional organized criminal syndicates are behind most offenses. Logistic regression results reveal interesting associations between offender characteristics and types of offenses.

  5. Dynamics of exosome internalization and trafficking.

    PubMed

    Tian, Tian; Zhu, Yan-Liang; Hu, Fei-Hu; Wang, Yuan-Yuan; Huang, Ning-Ping; Xiao, Zhong-Dang

    2013-07-01

    Cells release exosomes into extracellular medium. Although the important roles of exosomes in many physiological and pathological processes are being revealed, the mechanism of exosome-cell interaction remains unclear. In this article, employing real-time fluorescence microscopy, the motion of exosomes on the plasma membrane or in the cytoplasm of recipient PC12 cells was observed directly. In addition, several motion modes of exosomes were revealed by single particle tracking (SPT). The changes between motion modes were also detected, presenting the dynamic courses of exosome attachment onto plasma membrane and exosome uptake. Octadecyl rhodamine B chloride (R18) was found to be useful to distinguish endocytosis from fusion during exosome uptake. Colocalization with organelle markers showed exosomes were sorted to acidic vesicles after internalization. The results provide new sight into the exosome-cell interaction mode and the intercellular trafficking of exosomes. This study will help to understand the roles of exosomes at cell level.

  6. Dendritic trafficking for neuronal growth and plasticity.

    PubMed

    Ehlers, Michael D

    2013-12-01

    Among the largest cells in the body, neurons possess an immense surface area and intricate geometry that poses many unique cell biological challenges. This morphological complexity is critical for neural circuit formation and enables neurons to compartmentalize cell-cell communication and local intracellular signalling to a degree that surpasses other cell types. The adaptive plastic properties of neurons, synapses and circuits have been classically studied by measurement of electrophysiological properties, ionic conductances and excitability. Over the last 15 years, the field of synaptic and neural electrophysiology has collided with neuronal cell biology to produce a more integrated understanding of how these remarkable highly differentiated cells utilize common eukaryotic cellular machinery to decode, integrate and propagate signals in the nervous system. The present article gives a very brief and personal overview of the organelles and trafficking machinery of neuronal dendrites and their role in dendritic and synaptic plasticity.

  7. Inhibitors of the cellular trafficking of ricin.

    PubMed

    Barbier, Julien; Bouclier, Céline; Johannes, Ludger; Gillet, Daniel

    2012-01-01

    Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic screens for small molecules acting on the intracellular targets required for entry of ricin into cells. These screens have identified inhibitory compounds that can protect cells, and sometimes even animals against ricin. We review these newly discovered cellular inhibitors of ricin intoxication, discuss the advantages and drawbacks of chemical-genetics approaches, and address the issues to be resolved so that the therapeutic development of these small-molecule compounds can progress.

  8. Ricin trafficking in plant and mammalian cells.

    PubMed

    Lord, J Michael; Spooner, Robert A

    2011-07-01

    Ricin is a heterodimeric plant protein that is potently toxic to mammalian and many other eukaryotic cells. It is synthesized and stored in the endosperm cells of maturing Ricinus communis seeds (castor beans). The ricin family has two major members, both, lectins, collectively known as Ricinus communis agglutinin ll (ricin) and Ricinus communis agglutinin l (RCA). These proteins are stored in vacuoles within the endosperm cells of mature Ricinus seeds and they are rapidly broken down by hydrolysis during the early stages of post-germinative growth. Both ricin and RCA traffic within the plant cell from their site of synthesis to the storage vacuoles, and when they intoxicate mammalian cells they traffic from outside the cell to their site of action. In this review we will consider both of these trafficking routes.

  9. Plant Vascular Biology 2013: vascular trafficking.

    PubMed

    Ursache, Robertas; Heo, Jung-Ok; Helariutta, Ykä

    2014-04-01

    About 200 researchers from around the world attended the Third International Conference on Plant Vascular Biology (PVB 2013) held in July 2013 at the Rantapuisto Conference Center, in Helsinki, Finland (http://www.pvb2013.org). The plant vascular system, which connects every organ in the mature plant, continues to attract the interest of researchers representing a wide range of disciplines, including development, physiology, systems biology, and computational biology. At the meeting, participants discussed the latest research advances in vascular development, long- and short-distance vascular transport and long-distance signalling in plant defence, in addition to providing a context for how these studies intersect with each other. The meeting provided an opportunity for researchers working across a broad range of fields to share ideas and to discuss future directions in the expanding field of vascular biology. In this report, the latest advances in understanding the mechanism of vascular trafficking presented at the meeting have been summarized.

  10. Macrophage-mediated cholesterol handling in atherosclerosis.

    PubMed

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

    2016-01-01

    Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.

  11. Dietary plant sterols and cholesterol metabolism.

    PubMed

    Ellegård, Lars H; Andersson, Susan W; Normén, A Lena; Andersson, Henrik A

    2007-01-01

    Plant sterols, naturally occurring in foods of plant origin, reduce cholesterol absorption. Experimental studies show plant sterols to be an important part of the serum-cholesterol lowering effect of certain diets and dietary components. Epidemiological data show that individuals with higher intakes of plant sterols from their habitual diets have lower serum-cholesterol levels. To date, the role of naturally occurring plant sterols for lowering serum cholesterol has probably been underestimated. The consumption of dietary plant sterols should be a part of dietary advice to patients with hypercholesterolemia and the general public for the prevention and management of coronary heart disease.

  12. Impact of cholesterol on disease progression.

    PubMed

    Lin, Chun-Jung; Lai, Cheng-Kuo; Kao, Min-Chuan; Wu, Lii-Tzu; Lo, U-Ging; Lin, Li-Chiung; Chen, Yu-An; Lin, Ho; Hsieh, Jer-Tsong; Lai, Chih-Ho; Lin, Chia-Der

    2015-06-01

    Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios.

  13. Cholesterol and late-life cognitive decline.

    PubMed

    van Vliet, Peter

    2012-01-01

    High cholesterol levels are a major risk factor for cardiovascular disease, but their role in dementia and cognitive decline is less clear. This review highlights current knowledge on the role of cholesterol in late-life cognitive function, cognitive decline, and dementia. When measured in midlife, high cholesterol levels associate with an increased risk of late-life dementia and cognitive decline. However, when measured in late-life, high cholesterol levels show no association with cognitive function, or even show an inverse relation. Although statin treatment has been shown to associate with a lower risk of dementia and cognitive decline in observational studies, randomized controlled trials show no beneficial effect of statin treatment on late-life cognitive function. Lowering cholesterol levels may impair brain function, since cholesterol is essential for synapse formation and maturation and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. However, membrane cholesterol also plays a role in the formation and aggregation of amyloid-β. Factors that influence cholesterol metabolism, such as dietary intake, are shown to play a role in late-life cognitive function and the risk of dementia. In conclusion, cholesterol associates with late-life cognitive function, but the association is strongly age-dependent. There is no evidence that treatment with statins in late-life has a beneficial effect on cognitive function.

  14. Cholesterol modulates Orai1 channel function

    PubMed Central

    Derler, Isabella; Jardin, Isaac; Stathopulos, Peter B.; Muik, Martin; Fahrner, Marc; Zayats, Vasilina; Pandey, Saurabh K.; Poteser, Michael; Lackner, Barbara; Absolonova, Marketa; Schindl, Rainer; Groschner, Klaus; Ettrich, Rüdiger; Ikura, Mitsu; Romanin, Christoph

    2017-01-01

    STIM1 (stromal interaction molecule 1) and Orai proteins are the essential components of Ca2+ release–activated Ca2+ (CRAC) channels. We focused on the role of cholesterol in the regulation of STIM1-mediated Orai1 currents. Chemically induced cholesterol depletion enhanced store-operated Ca2+ entry (SOCE) and Orai1 currents. Furthermore, cholesterol depletion in mucosal-type mast cells augmented endogenous CRAC currents, which were associated with increased degranulation, a process that requires calcium influx. Single point mutations in the Orai1 amino terminus that would be expected to abolish cholesterol binding enhanced SOCE to a similar extent as did cholesterol depletion. The increase in Orai1 activity in cell expressing these cholesterol-binding–deficient mutants occurred without affecting the amount in the plasma membrane or the coupling of STIM1 to Orai1. We detected cholesterol binding to an Orai1 amino-terminal fragment in vitro and to full-length Orai1 in cells. Thus, our data showed that Orai1 senses the amount of cholesterol in the plasma membrane and that the interaction of Orai1 with cholesterol inhibits its activity, thereby limiting SOCE. PMID:26814231

  15. Superresolution imaging of viral protein trafficking

    PubMed Central

    Salka, Kyle; Bhuvanendran, Shivaprasad; Yang, David

    2015-01-01

    The endoplasmic reticulum (ER) membrane is closely apposed to the outer mitochondrial membrane (OMM), which facilitates communication between these organelles. These contacts, known as mitochondria-associated membranes (MAM), facilitate calcium signaling, lipid transfer, as well as antiviral and stress responses. How cellular proteins traffic to the MAM, are distributed therein, and interact with ER and mitochondrial proteins are subject of great interest. The human cytomegalovirus UL37 exon 1 protein or viral mitochondria-localized inhibitor of apoptosis (vMIA) is crucial for viral growth. Upon synthesis at the ER, vMIA traffics to the MAM and OMM, where it reprograms the organization and function of these compartments. vMIA significantly changes the abundance of cellular proteins at the MAM and OMM, including proteins that regulate calcium homeostasis and cell death. Through the use of superresolution imaging, we have shown that vMIA is distributed at the OMM in nanometer scale clusters. This is similar to the clusters reported for the mitochondrial calcium channel, VDAC, as well as electron transport chain, translocase of the OMM complex, and mitochondrial inner membrane organizing system components. Thus, aside from addressing how vMIA targets the MAM and regulates survival of infected cells, biochemical studies and superresolution imaging of vMIA offer insights into the formation, organization, and functioning of MAM. Here, we discuss these insights into trafficking, function, and organization of vMIA at the MAM and OMM and discuss how the use of superresolution imaging is contributing to the study of the formation and trafficking of viruses. PMID:25724304

  16. Membrane orientation and lateral diffusion of BODIPY-cholesterol as a function of probe structure.

    PubMed

    Solanko, Lukasz M; Honigmann, Alf; Midtiby, Henrik Skov; Lund, Frederik W; Brewer, Jonathan R; Dekaris, Vjekoslav; Bittman, Robert; Eggeling, Christian; Wüstner, Daniel

    2013-11-05

    Cholesterol tagged with the BODIPY fluorophore via the central difluoroboron moiety of the dye (B-Chol) is a promising probe for studying intracellular cholesterol dynamics. We synthesized a new BODIPY-cholesterol probe (B-P-Chol) with the fluorophore attached via one of its pyrrole rings to carbon-24 of cholesterol (B-P-Chol). Using two-photon fluorescence polarimetry in giant unilamellar vesicles and in the plasma membrane (PM) of living intact and actin-disrupted cells, we show that the BODIPY-groups in B-Chol and B-P-Chol are oriented perpendicular and almost parallel to the bilayer normal, respectively. B-Chol is in all three membrane systems much stronger oriented than B-P-Chol. Interestingly, we found that the lateral diffusion in the PM was two times slower for B-Chol than for B-P-Chol, although we found no difference in lateral diffusion in model membranes. Stimulated emission depletion microscopy, performed for the first time, to our knowledge, with fluorescent sterols, revealed that the difference in lateral diffusion of the BODIPY-cholesterol probes was not caused by anomalous subdiffusion, because diffusion of both analogs in the PM was free but not hindered. Our combined measurements show that the position and orientation of the BODIPY moiety in cholesterol analogs have a severe influence on lateral diffusion specifically in the PM of living cells.

  17. Crystalline domain structure and cholesterol crystal nucleation in single hydrated DPPC:cholesterol:POPC bilayers.

    PubMed

    Ziblat, Roy; Leiserowitz, Leslie; Addadi, Lia

    2010-07-21

    Grazing incidence X-ray diffraction measurements were performed on single hydrated bilayers and monolayers of DPPC:Cholesterol:POPC at varying concentrations. There are substantial differences in the phase and structure behavior of the crystalline domains formed within the bilayers relative to the corresponding monolayers, due to interactions between the opposing leaflets. Depending on the lipid composition, these interactions led to phase separation, changes in molecular tilt angle, or formation of cholesterol crystals. In monolayers, DPPC and cholesterol form a single crystalline phase at all compositions studied. In bilayers, a second crystalline phase appears when cholesterol levels are increased: domains of cholesterol and DPPC form monolayer thick crystals where each of the lipid leaflets diffracts independently, whereas excess cholesterol forms cholesterol bilayer thick crystals at a DPPC:Chol ratio < 46:54 +/- 2 mol %. The nucleation of the cholesterol crystals occurs at concentrations relevant to the actual cell plasma membrane composition.

  18. Aggression in sexually abused trafficked girls and efficacy of intervention.

    PubMed

    Deb, Sibnath; Mukherjee, Aparna; Mathews, Ben

    2011-03-01

    The broad objective of this study was to understand the incidence and severity of aggression among sexually abused girls who were trafficked and who were then further used for commercial sexual exploitation (referred to subsequently as sexually abused trafficked girls). In addition, the impact of counseling for minimizing aggression in these girls was investigated. A group of 120 sexually abused trafficked Indian girls and a group of 120 nonsexually abused Indian girls, aged 13 to 18, participated in the study. The sexually abused trafficked girls were purposively selected from four shelters located in and around Kolkata, India. The nonsexually abused girls were selected randomly from four schools situated near the shelters, and these girls were matched by age with the sexually abused trafficked girls. Data were collected using a Background Information Schedule and a standardized psychological test, that is, The Aggression Scale. Results revealed that 16.7% of the girls were first sexually abused between 6 and 9 years of age, 37.5% between 10 and 13 years of age, and 45.8% between 14 and 17 years of age. Findings further revealed that 4.2% of the sexually abused trafficked girls demonstrated saturated aggression, and 26.7% were highly aggressive, that is, extremely frustrated and rebellious. Across age groups, the sexually abused trafficked girls suffered from more aggression (p < .05), compared with the nonvictimized girls. Psychological interventions, such as individual and group counseling, were found to have a positive impact on the sexually abused trafficked girls. These findings should motivate counselors to deal with sexually abused children. It is also hoped that authorities in welfare homes will understand the importance of counseling for sexually abused trafficked children, and will appoint more counselors for this purpose.

  19. Human Trafficking of Children in the United States: A Fact Sheet

    ERIC Educational Resources Information Center

    US Department of Education, 2007

    2007-01-01

    This fact sheet presents questions and answers related to the human trafficking of children in the United States. It describes human trafficking and its extent in the United States, how human traffickers target children for coerced labor and sex exploitation, how to identify victims of human trafficking, how to report a suspected incidence of…

  20. Human Trafficking of Children in the United States: A Fact Sheet for Schools

    ERIC Educational Resources Information Center

    Office of Safe and Healthy Students, US Department of Education, 2013

    2013-01-01

    Human trafficking is a serious federal crime with penalties of up to imprisonment for life. Federal law defines "severe forms of trafficking in persons." In short, human trafficking is a form of modern slavery. Those who recruit minors into commercial sexual exploitation (or prostitution) violate federal anti-trafficking laws, even if there is no…

  1. 77 FR 74045 - Request for Information for the 2013 Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-12

    ... smuggling, visa fraud, or child abuse, unless such conduct occurs in the context of human trafficking... traffickers to justice are the ultimate goals of the report and of the U.S Government's anti-human trafficking... Activities to Combat Human Trafficking (``AG Report'') mandated by section 105 of the TVPA (22 U.S.C....

  2. 75 FR 11982 - Request for Information for the 2010 Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-12

    ... conduct occurs in the context of human trafficking. Confidentiality: Please provide the name, phone number... report and of the U.S government's anti-human trafficking policy. The Department prepares the TIP Report... Combat Human Trafficking (``AG Report''), mandated by the Trafficking TVPA, 22 U.S.C. 7103(d)(7). The...

  3. Neonatal dietary cholesterol and alleles of cholesterol 7-alpha hydroxylase affect piglet cerebrum weight, cholesterol concentration, and behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This experiment was designed to test the effect of polymorphism in the cholesterol 7-alpha hydroxylase (CYP7) gene locus, and dietary cholesterol (C) on cerebrum C in neonatal pigs fed sow's milk formulas. Thirty-six pigs (18 male and 18 female) genetically selected for high (HG), or low (LG) plasma...

  4. ACAT inhibitors: the search for novel cholesterol lowering agents.

    PubMed

    Pal, Palash; Gandhi, Hardik; Giridhar, Rajani; Yadav, Mange Ram

    2013-06-01

    Increased level of serum cholesterol (hyperlipidemia) is the most significant risk factor for the development of atherosclerosis. Cholesterol levels are affected by factors such as rate of endogenous cholesterol synthesis, biliary cholesterol excretion and dietary cholesterol absorption. Acyl CoA: Cholesterol O-acyl transferases (ACAT) are a small family of enzymes that catalyze cholesterol esterification and cholesterol absorption in intestinal mucosal cells and maintain the cholesterol homeostasis in the blood. Inhibition of the ACAT enzymes is one of the attractive targets to treat hyperlipidemia. Literature survey shows that structurally diverse compounds possess ACAT inhibitory properties. In this review, a comprehensive presentation of the literature on diverse ACAT inhibitors has been given.

  5. The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain.

    PubMed

    Sims-Robinson, Catrina; Bakeman, Anna; Rosko, Andrew; Glasser, Rebecca; Feldman, Eva L

    2016-05-01

    Abnormalities in lysosomal function have been reported in diabetes, aging, and age-related degenerative diseases. These lysosomal abnormalities are an early manifestation of neurodegenerative diseases and often precede the onset of clinical symptoms such as learning and memory deficits; however, the mechanism underlying lysosomal dysfunction is not known. In the current study, we investigated the mechanism underlying lysosomal dysfunction in the cortex and hippocampi, key structures involved in learning and memory, of a type 2 diabetes (T2D) mouse model, the leptin receptor deficient db/db mouse. We demonstrate for the first time that diabetes leads to destabilization of lysosomes as well as alterations in the protein expression, activity, and/or trafficking of two lysosomal enzymes, hexosaminidase A and cathepsin D, in the hippocampus of db/db mice. Pioglitazone, a thiazolidinedione (TZD) commonly used in the treatment of diabetes due to its ability to improve insulin sensitivity and reverse hyperglycemia, was ineffective in reversing the diabetes-induced changes on lysosomal enzymes. Our previous work revealed that pioglitazone does not reverse hypercholesterolemia; thus, we investigated whether cholesterol plays a role in diabetes-induced lysosomal changes. In vitro, cholesterol promoted the destabilization of lysosomes, suggesting that lysosomal-related changes associated with diabetes are due to elevated levels of cholesterol. Since lysosome dysfunction precedes neurodegeneration, cognitive deficits, and Alzheimer's disease neuropathology, our results may provide a potential mechanism that links diabetes with complications of the central nervous system.

  6. 21 CFR 862.1175 - Cholesterol (total) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cholesterol (total) test system. 862.1175 Section... Systems § 862.1175 Cholesterol (total) test system. (a) Identification. A cholesterol (total) test system is a device intended to measure cholesterol in plasma and serum. Cholesterol measurements are used...

  7. Human trafficking and health: a cross-sectional survey of NHS professionals’ contact with victims of human trafficking

    PubMed Central

    Ross, Claire; Dimitrova, Stoyanka; Howard, Louise M; Dewey, Michael; Zimmerman, Cathy; Oram, Siân

    2015-01-01

    Objectives (1) To estimate the proportion of National Health Service (NHS) professionals who have come into contact with trafficked people and (2) to measure NHS professionals’ knowledge and confidence to respond to human trafficking. Design A cross-sectional survey. Setting Face-to-face mandatory child protection and/or vulnerable adults training sessions at 10 secondary healthcare provider organisations in England, and meetings of the UK College of Emergency Medicine. Participants 782/892 (84.4%) NHS professionals participated, including from emergency medicine, maternity, mental health, paediatrics and other clinical disciplines. Measures Self-completed questionnaire developed by an expert panel. Questionnaire asks about prior training and contact with potential victims of trafficking, perceived and actual human trafficking knowledge, confidence in responding to human trafficking, and interest in future human trafficking training. Results 13% participants reported previous contact with a patient they knew or suspected of having been trafficked; among maternity services professionals this was 20.4%. However, 86.8% (n=679) reported lacking knowledge of what questions to ask to identify potential victims and 78.3% (n=613) reported that they had insufficient training to assist trafficked people. 71% (n=556), 67.5% (n=528) and 53.4% (n=418) lacked confidence in making appropriate referrals for men, women and children, respectively, who had been trafficked. 95.3% (n=746) of respondents were unaware of the scale of human trafficking in the UK, and 76.5% (n=598) were unaware that calling the police could put patients in more danger. Psychometric analysis showed that subscales measuring perceived knowledge, actual knowledge and confidence to respond to human trafficking demonstrated good internal consistency (Cronbach's αs 0.93, 0.63 and 0.64, respectively) and internal correlations. Conclusions NHS professionals working in secondary care are in contact with potential

  8. Cholesterol Level: Can It Be Too Low?

    MedlinePlus

    ... low? Can your total cholesterol level be too low? Answers from Francisco Lopez-Jimenez, M.D. A high blood cholesterol level increases your ... better, but in rare cases having a very low level of low-density lipoprotein (LDL, or "bad") ...

  9. Role of cholesterol in Mycobacterium tuberculosis infection.

    PubMed

    Miner, Maurine D; Chang, Jennifer C; Pandey, Amit K; Sassetti, Christopher M; Sherman, David R

    2009-06-01

    Mycobacterium tuberculosis (MTB) acquisition and utilization of nutrients within the host cell is poorly understood, although it has been hypothesized that host lipids probably play an important role in MTB survival. Cholesterol has recently been identified as an important lipid for mycobacterial infection. The mce4 transport system is required for cholesterol import into bacterial cells, and deletion of mce4 locus resulted in severe attenuation in a chronic mouse model of infection. However, it has remained unclear what additional bacterial functions were required for utilization of this sterol. We have found that the igr locus, which was previously found essential for intracellular growth and virulence of MTB, is required for cholesterol metabolism: igr-deficient bacteria cannot grow using cholesterol as a primary carbon source. The growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as the delta igr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout the course of infection, and that degradation of this sterol is crucial for bacterial persistence.

  10. Cholesterol: An Achilles' Heel for Glioblastoma?

    PubMed

    An, Zhenyi; Weiss, William A

    2016-11-14

    In this issue of Cancer Cell, Villa et al. report that survival of glioblastoma cells is dependent on uptake of cholesterol. A synthetic agonist of the Liver X receptor depleted cholesterol in GBM cells, slowing growth of GBM xenografts.

  11. Recognizing victims of human trafficking in the pediatric emergency department.

    PubMed

    Becker, Heather J; Bechtel, Kirsten

    2015-02-01

    Human trafficking is a form of modern-day slavery that is rapidly expanding in the United States and throughout the world. It is a crime under both the United States and international law. The child and adult victims of human trafficking are denied their basic human rights and subjected to unspeakable physical and emotional harm. Traffickers exert complete control over their victims and are proficient at hiding their condition from authorities. Healthcare practitioners may be the only professionals who come into contact with victims if they present for medical care. This article will describe human trafficking and its potential victims, as well as guide medical management and access to services that will ensure their safety and restore their freedom.

  12. Kainate receptor trafficking: physiological roles and molecular mechanisms.

    PubMed

    Isaac, John T R; Mellor, Jack; Hurtado, David; Roche, Katherine W

    2004-12-01

    Recently, there has been intense interest in the mechanisms regulating the trafficking and synaptic targeting of kainate receptors in neurons. This topic is still in its infancy when compared with studies of trafficking of other ionotropic glutamate receptors; however, it is already clear that mechanisms exist for subunit- and splice variant-specific trafficking of kainate receptors. There is also enormous diversity of kainate receptor targeting, with the best-studied neurons in this regard being hippocampal CA3 pyramidal neurons and CA1 GABAergic interneurons. This review summarizes the current state of knowledge on this topic, focusing on the molecular mechanisms of kainate receptor trafficking and the potential for these mechanisms to regulate neuronal kainate receptor function.

  13. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.

    PubMed

    Zhou, Xiaolai; Sun, Lirong; Bastos de Oliveira, Francisco; Qi, Xiaoyang; Brown, William J; Smolka, Marcus B; Sun, Ying; Hu, Fenghua

    2015-09-14

    Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1. PSAP deficiency in mice leads to severe PGRN trafficking defects and a drastic increase in serum PGRN levels. We further showed that this PSAP pathway is independent of, but complementary to, the previously identified PGRN lysosomal trafficking mediated by sortilin. Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.

  14. The Medical Response to Sex Trafficking of Minors in Wisconsin.

    PubMed

    Rabbitt, Angela

    2015-04-01

    Medical professionals are in a unique position to identify and assist pediatric victims of sex trafficking, who experience a high prevalence of physical, mental, and sexual health problems. However, providers report a need for education and guidelines for medical care of this population. A literature review was conducted on the nature and scope of pediatric sex trafficking in Wisconsin, the medical and mental health needs of victims, and existing guidelines for medical management. Few existing medical guidelines for the care of trafficking victims are specific to pediatrics or include specific recommendations for the forensic medical evaluation. Because of legislation and resources specific to Wisconsin, national guidelines may not apply locally. Based on the literature review, as well as input from community partners and medical professionals who frequently provide services to victims, guidelines for the medical care of pediatric sex trafficking victims in Wisconsin were developed. Additional community barriers that may prevent an effective medical response also are discussed.

  15. Global initiatives to tackle organ trafficking and transplant tourism.

    PubMed

    Bagheri, Alireza; Delmonico, Francis L

    2013-11-01

    The increasing gap between organ supply and demand has opened the door for illegal organ sale, trafficking of human organs, tissues and cells, as well as transplant tourism. Currently, underprivileged and vulnerable populations in resource-poor countries are a major source of organs for rich patient-tourists who can afford to purchase organs at home or abroad. This paper presents a summary of international initiatives, such as World Health Organization's Principle Guidelines, The Declaration of Istanbul, Asian Task Force Recommendations, as well as UNESCO's and the United Nation's initiatives against trafficking of human organs, tissues, cells, and transplant tourism. Beyond the summary, it calls for more practical measures to be taken to implement the existing guidelines and recommendations, in order to prevent exploitation of the poor as organ providers. The paper suggests that an international legally binding agreement in criminalizing organ trafficking would be a step forward to bring a change in the global picture of organ trafficking and transplant tourism.

  16. Three-dimensional imaging of nucleolin trafficking in normal cells, transfectants, and heterokaryons

    NASA Astrophysics Data System (ADS)

    Ballou, Byron T.; Fisher, Gregory W.; Deng, Jau-Shyong; Hakala, Thomas R.; Srivastava, Meera; Farkas, Daniel L.

    1996-04-01

    The study of intracellular trafficking using labeled molecules has been aided by the development of the cyanine fluorochromes, which are easily coupled, very soluble, resist photobleaching, and fluoresce at far-red wavelengths where background fluorescence is minimal. We have used Cy3-, Cy5-, and Cy5.5-labeled antibodies, antigen-binding fragments, and specifically binding single-stranded oligonucleotides to follow expression and trafficking of nucleolin, the most abundant protein of the nucleolus. Nucleolin shuttles between the nucleolus and the cytoplasm, and is also expressed on the cell surface, allowing us to test our techniques at all three cellular sites. Differentially cyanine-labeled non-specific antibodies were used to control for non-specific binding. Similarly, the differentially labeled non-binding strand of the cloned oligonucleotide served as a control. The multimode microscope allowed us to follow both rapid and slow redistributions of labeled ligands in the same study. We also performed 3-D reconstructions of nucleolin distribution in cells using rapid acquisition and deconvolution. Microinjection of labeled ligands was used to follow intracellular distribution, while incubation of whole cells with antibody and antigen-binding fragments was used to study uptake. To unambiguously define trafficking, and eliminate the possibility of interference by cross-reactive proteins, we transfected mouse renal cell carcinoma cells that express cell surface nucleolin with human nucleolin. We used microinjection and cell surface staining with Cy3- or Cy5- labeled monoclonal antibody D3 (specific for human nucleolin) to assess the cellular distribution of the human protein. Several clones expressed human nucleolin on their surfaces and showed high levels of transport of the human protein into the mouse nucleus and nucleolus. This distribution roughly parallels that of mouse nucleolin as determined by labeled polyclonal antibody. We have used these engineered

  17. Prosopis farcta beans increase HDL cholesterol and decrease LDL cholesterol in ostriches (Struthio camelus).

    PubMed

    Omidi, Arash; Ansari nik, Hossein; Ghazaghi, Mahmood

    2013-02-01

    Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.

  18. Cholesterol-lowering effect of plant sterols.

    PubMed

    AbuMweis, Suhad S; Jones, Peter J H

    2008-12-01

    Plant sterols are plant components that have a chemical structure similar to cholesterol except for the addition of an extra methyl or ethyl group; however, plant sterol absorption in humans is considerably less than that of cholesterol. In fact, plant sterols reduce cholesterol absorption and thus reduce circulating levels of cholesterol. Earlier studies that have tested the efficacy of plant sterols as cholesterol-lowering agents incorporated plant sterols into fat spreads. Later on, plant sterols were added to other food matrices, including juices, nonfat beverages, milk and yogurt, cheese, meat, croissants and muffins, and cereal and chocolate bars. The beneficial physiologic effects of plant sterols could be further enhanced by combining them with other beneficial substances, such as olive and fish oils, fibers, and soy proteins, or with exercise. The addition of plant sterols to the diet is suggested by health experts as a safe and effective way to reduce the risk of coronary heart disease.

  19. Cholesterol granulomas in three meerkats (Suricata suricatta).

    PubMed

    Sladky, K K; Dalldorf, F G; Steinberg, H; Wright, J F; Loomis, M R

    2000-11-01

    Cholesterol granulomas are uncommon pathologic lesions in animals, although they are important intracranial tumors in humans. This report describes cholesterol granulomas associated with multiple organ systems of three captive meerkats. In the most severe case, meerkat No. 1, the pathologic behavior of the cholesterol granuloma was unique in that it appeared to locally invade the cerebrum and calvarium, possibly contributing to neurological deficits observed antemortem. A review of other meerkat necropsies revealed incidental, asymptomatic cholesterol granulomas in organs of two other individuals, meerkat Nos. 2 and 3. Histologically, all lesions were composed of cholesterol clefts admixed with large, foamy macrophages containing hemosiderin, multinucleated giant cells, lymphocytes, plasma cells, and foci of mineralization. Hypercholesterolemia was documented in two of the three meerkats.

  20. Sex trafficking of minors in metropolitan, micropolitan, and rural communities.

    PubMed

    Cole, Jennifer; Sprang, Ginny

    2015-02-01

    The purpose of the study was to examine professionals' awareness, knowledge, and experiences working with youth victims of sex trafficking in metropolitan and non-metropolitan communities. Professionals who worked with at-risk youth and/or crime victims were recruited from all counties in a southern, rural state in the U.S. to complete a telephone survey. Surveys included closed and open-ended questions, which were theme coded. Professionals' (n=289) were classified into one of four categories based on the counties in which they worked: metropolitan, micropolitan, rural, and all three community types. Although there were many similarities found in trafficking situations across the different types of communities, some expected differences were found. First, as expected, more professionals in metropolitan communities perceived CSEC as being a fairly or very serious problem in the state overall. Consistent with other studies, more professionals in metropolitan communities had received training on human trafficking and reported they were familiar with the state and federal laws on human trafficking (Newton et al., 2008). Significantly more professionals in metropolitan (54.7%) communities reported they had worked with a suspected or definite victim of STM compared to professionals in micropolitan communities (29.8%). There were few differences in victim characteristics, vulnerability factors, and trafficking situations (e.g., relationship to trafficker, traffickers' techniques for controlling victims, transportation, and Internet-facilitation of trafficking) across the community types. There is a continued need for awareness building of STM and training, particularly in non-metropolitan communities, as well as adoption of screening tools, integration of trauma-informed care, and identification of best practices.

  1. Drug Trafficking Organizations and Local Economic Activity in Mexico

    PubMed Central

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000–2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations. PMID:26348041

  2. Human Trafficking in Southeast Asia: Causes and Policy Implications

    DTIC Science & Technology

    2009-06-01

    targeted victims arise from strikingly different circumstances. Sex trafficking has been particularly driven by the low level of rights afforded to women ...solely a concern that women are being sexually exploited, but also that their lack of general rights leads to their exploitation within the overall...labor market as well. In early research regarding human trafficking, the lack of rights that were afforded to women was highlighted as a primary

  3. Drug Trafficking Organizations and Local Economic Activity in Mexico.

    PubMed

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000-2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations.

  4. Trafficking in Persons: The U.S. and International Response

    DTIC Science & Technology

    2006-07-07

    CRS Report RL33200, Trafficking in Persons in Latin America and the Caribbean, by Clare M. Ribando. 15 Casa Alianza/ Covenant House Latin America, “Casa...assistance programs under this act; ! Amended the Immigration and Nationality Act to allow the Attorney General to grant up to 5000 non-immigrant...attempt to kill. The Bush Administration, as well Congress, continued the anti-trafficking effort with strong bipartisan support. Attorney General

  5. Parallel flow diffusion battery

    DOEpatents

    Yeh, Hsu-Chi; Cheng, Yung-Sung

    1984-08-07

    A parallel flow diffusion battery for determining the mass distribution of an aerosol has a plurality of diffusion cells mounted in parallel to an aerosol stream, each diffusion cell including a stack of mesh wire screens of different density.

  6. Parallel flow diffusion battery

    DOEpatents

    Yeh, H.C.; Cheng, Y.S.

    1984-01-01

    A parallel flow diffusion battery for determining the mass distribution of an aerosol has a plurality of diffusion cells mounted in parallel to an aerosol stream, each diffusion cell including a stack of mesh wire screens of different density.

  7. Fish protein decreases serum cholesterol in rats by inhibition of cholesterol and bile acid absorption.

    PubMed

    Hosomi, Ryota; Fukunaga, Kenji; Arai, Hirofumi; Kanda, Seiji; Nishiyama, Toshimasa; Yoshida, Munehiro

    2011-05-01

    Fish protein has been shown to decrease serum cholesterol content by inhibiting absorption of cholesterol and bile acid in laboratory animals, though the mechanism underlying this effect is not yet fully understood. The purpose of this study was to elucidate the mechanism underlying the inhibition of cholesterol and bile acid absorption following fish protein intake. Male Wistar rats were divided into 2 dietary groups of 7 rats each, 1 group receiving a diet consisting of 20% casein and the other receiving a diet consisting of 10% casein and 10% fish protein. Both experimental diets also contained 0.5% cholesterol and 0.1% sodium cholate. After the rats had been on their respective diets for 4 wk, their serum and liver cholesterol contents and fecal cholesterol, bile acid, and nitrogen excretion contents were measured. Fish protein consumption decreased serum and liver cholesterol content and increased fecal cholesterol and bile acid excretion and simultaneously increased fecal nitrogen excretion. In addition, fish protein hydrolyzate prepared by in vitro digestion had lower micellar solubility of cholesterol and higher binding capacity for bile acids compared with casein hydrolyzate. These results suggest that the hypocholesterolemic effect of fish protein is mediated by increased fecal cholesterol and bile acid excretion, which is due to the digestion products of fish protein having reduced micellar solubility of cholesterol and increased bile acid binding capacity.

  8. Cellular membrane trafficking of mesoporous silica nanoparticles

    SciTech Connect

    Fang, I-Ju

    2012-01-01

    This dissertation mainly focuses on the investigation of the cellular membrane trafficking of mesoporous silica nanoparticles. We are interested in the study of endocytosis and exocytosis behaviors of mesoporous silica nanoparticles with desired surface functionality. The relationship between mesoporous silica nanoparticles and membrane trafficking of cells, either cancerous cells or normal cells was examined. Since mesoporous silica nanoparticles were applied in many drug delivery cases, the endocytotic efficiency of mesoporous silica nanoparticles needs to be investigated in more details in order to design the cellular drug delivery system in the controlled way. It is well known that cells can engulf some molecules outside of the cells through a receptor-ligand associated endocytosis. We are interested to determine if those biomolecules binding to cell surface receptors can be utilized on mesoporous silica nanoparticle materials to improve the uptake efficiency or govern the mechanism of endocytosis of mesoporous silica nanoparticles. Arginine-glycine-aspartate (RGD) is a small peptide recognized by cell integrin receptors and it was reported that avidin internalization was highly promoted by tumor lectin. Both RGD and avidin were linked to the surface of mesoporous silica nanoparticle materials to investigate the effect of receptor-associated biomolecule on cellular endocytosis efficiency. The effect of ligand types, ligand conformation and ligand density were discussed in Chapter 2 and 3. Furthermore, the exocytosis of mesoporous silica nanoparticles is very attractive for biological applications. The cellular protein sequestration study of mesoporous silica nanoparticles was examined for further information of the intracellular pathway of endocytosed mesoporous silica nanoparticle materials. The surface functionality of mesoporous silica nanoparticle materials demonstrated selectivity among the materials and cancer and normal cell lines. We aimed to determine

  9. Parallel processing ITS

    SciTech Connect

    Fan, W.C.; Halbleib, J.A. Sr.

    1996-09-01

    This report provides a users` guide for parallel processing ITS on a UNIX workstation network, a shared-memory multiprocessor or a massively-parallel processor. The parallelized version of ITS is based on a master/slave model with message passing. Parallel issues such as random number generation, load balancing, and communication software are briefly discussed. Timing results for example problems are presented for demonstration purposes.

  10. National Human Trafficking Initiatives: Dimensions of Policy Diffusion.

    PubMed

    Yoo, Eun-Hye; Boyle, Elizabeth Heger

    2015-01-01

    The implementation of criminal law involves formal law enforcement, education and public outreach aimed at preventing criminal activity, and providing services for victims. Historically, quantitative research on global trends has tended to focus on a single policy dimension, potentially masking the unique factors that affect the diffusion of each policy dimension independently. Using an ordered-probit model to analyze new human trafficking policy data on national prosecution, prevention, and victim-protection efforts, we find that global ties and domestic interest groups matter more in areas where international law is less defined. While prosecution, officially mandated by the Trafficking Protocol, was relatively impervious to global ties and domestic interest groups, both trafficking prevention and victim protection were associated with these factors. Our findings also suggest that fear of repercussions is not a major driver of state actions to combat trafficking-neither ratification of the Trafficking Protocol nor levels of United States aid were associated with greater implementation of anti-trafficking measures.

  11. Research in parallel computing

    NASA Technical Reports Server (NTRS)

    Ortega, James M.; Henderson, Charles

    1994-01-01

    This report summarizes work on parallel computations for NASA Grant NAG-1-1529 for the period 1 Jan. - 30 June 1994. Short summaries on highly parallel preconditioners, target-specific parallel reductions, and simulation of delta-cache protocols are provided.

  12. Parallel simulation today

    NASA Technical Reports Server (NTRS)

    Nicol, David; Fujimoto, Richard

    1992-01-01

    This paper surveys topics that presently define the state of the art in parallel simulation. Included in the tutorial are discussions on new protocols, mathematical performance analysis, time parallelism, hardware support for parallel simulation, load balancing algorithms, and dynamic memory management for optimistic synchronization.

  13. Sterol carrier protein-2 alters high density lipoprotein-mediated cholesterol efflux.

    PubMed

    Atshaves, B P; Starodub, O; McIntosh, A; Petrescu, A; Roths, J B; Kier, A B; Schroeder, F

    2000-11-24

    Although sterol carrier protein-2 (SCP-2) participates in the uptake and intracellular trafficking of cholesterol, its effect on "reverse cholesterol transport" has not been explored. As shown herein, SCP-2 expression inhibited high density lipoprotein (HDL)-mediated efflux of [(3)H]cholesterol and fluorescent 22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3b-ol (NBD-cholesterol) up to 61 and 157%, respectively. Confocal microscopy of living cells allowed kinetic analysis of two intracellular pools of HDL-mediated NBD-cholesterol efflux: the highly fluorescent lipid droplet pool and the less fluorescent pool outside the lipid droplets, designated the cytoplasmic compartment. Both the whole cell and the cytoplasmic compartment exhibited two similar kinetic pools, the half-times of which were consistent with protein (t(b)(12) near 1 min) and vesicular (t(d)(12) = 10-20 min) mediated sterol transfer. Although SCP-2 expression did not alter cytoplasmic sterol pool sizes, the rapid t(b)(12) decreased 36%, while the slower t(d)(12) increased 113%. Lipid droplets also exhibited two kinetic pools of NBD-cholesterol efflux but with half-times over 200% shorter than those of the cytoplasmic compartment. The lipid droplet slower effluxing pool size and t(d)(12) were increased 48% and 115%, respectively, in SCP-2-expressing cells. Concomitantly, the level of the lipid droplet-specific adipose differentiation-related protein decreased 70%. Overall, HDL-mediated sterol efflux from L-cell fibroblasts reflected that of the cytoplasmic rather than lipid droplet compartment. SCP-2 differentially modulated sterol efflux from the two cytoplasmic pools. However, net efflux was determined primarily by inhibition of the slowly effluxing pool rather than by acceleration of the rapid protein-mediated pool. Finally, SCP-2 expression also inhibited sterol efflux from lipid droplets, an effect related to decreased adipose differentiation-related protein, a lipid

  14. Major Risk Factors for Heart Disease: High Blood Cholesterol

    MedlinePlus

    ... Major Risk Factors for Heart Disease High Blood Cholesterol High blood cholesterol is another major risk factor for heart disease ... can do something about. The higher your blood cholesterol level, the greater your risk for developing heart ...

  15. Cholesterol: Top Five Foods to Lower Your Numbers

    MedlinePlus

    Cholesterol: Top foods to improve your numbers Diet can play an important role in lowering your cholesterol. Here are the top foods to lower your cholesterol and protect your heart. By Mayo Clinic Staff ...

  16. High Blood Cholesterol: What You Need to Know

    MedlinePlus

    ... Audiences Contact The Health Information Center High Blood Cholesterol: What You Need To Know Table of Contents ... Lifestyle Changes (TLC) Drug Treatment Resources Why Is Cholesterol Important? Your blood cholesterol level has a lot ...

  17. Cholesterol-Lowering Supplements: Lower Your Numbers without Prescription Medication

    MedlinePlus

    ... cholesterol and LDL cholesterol May cause nausea, indigestion, gas, diarrhea or constipation; may be ineffective if you take ezetimibe (Zetia), a prescription cholesterol medication Soy protein as a substitute for other high-fat protein sources May reduce ...

  18. Analysis of occludin trafficking, demonstrating continuous endocytosis, degradation, recycling and biosynthetic secretory trafficking.

    PubMed

    Fletcher, Sarah J; Iqbal, Mudassar; Jabbari, Sara; Stekel, Dov; Rappoport, Joshua Z

    2014-01-01

    Tight junctions (TJs) link adjacent cells and are critical for maintenance of apical-basolateral polarity in epithelial monolayers. The TJ protein occludin functions in disparate processes, including wound healing and Hepatitis C Virus infection. Little is known about steady-state occludin trafficking into and out of the plasma membrane. Therefore, we determined the mechanisms responsible for occludin turnover in confluent Madin-Darby canine kidney (MDCK) epithelial monolayers. Using various biotin-based trafficking assays we observed continuous and rapid endocytosis of plasma membrane localised occludin (the majority internalised within 30 minutes). By 120 minutes a significant reduction in internalised occludin was observed. Inhibition of lysosomal function attenuated the reduction in occludin signal post-endocytosis and promoted co-localisation with the late endocytic system. Using a similar method we demonstrated that ∼20% of internalised occludin was transported back to the cell surface. Consistent with these findings, significant co-localisation between internalised occludin and recycling endosomal compartments was observed. We then quantified the extent to which occludin synthesis and transport to the plasma membrane contributes to plasma membrane occludin homeostasis, identifying inhibition of protein synthesis led to decreased plasma membrane localised occludin. Significant co-localisation between occludin and the biosynthetic secretory pathway was demonstrated. Thus, under steady-state conditions occludin undergoes turnover via a continuous cycle of endocytosis, recycling and degradation, with degradation compensated for by biosynthetic exocytic trafficking. We developed a mathematical model to describe the endocytosis, recycling and degradation of occludin, utilising experimental data to provide quantitative estimates for the rates of these processes.

  19. Dietary cholesterol and the origin of cholesterol in the brain of developing rats.

    PubMed

    Edmond, J; Korsak, R A; Morrow, J W; Torok-Both, G; Catlin, D H

    1991-09-01

    Milk substitutes containing cholesterol at concentrations lower, equal to or greater than the concentrations found in natural rat milk were fed to artificially reared rat pups from 5 d until 15 or 16 d after birth. Pups reared by their mother served as controls. In one experiment, D7-cholesterol was fed in the milk at four different concentrations. The purpose of the study was to determine whether cholesterol in milk influenced growth and the sterol composition of brain over the period of its most rapid accumulation in this organ. We found that body and brain weights were not different, irrespective of the concentration of cholesterol in the milk substitutes. High concentrations of cholesterol in milk caused a significant increase in cholesterol in liver and plasma, whereas the concentration of cholesterol in brain was not different from the concentration in the brain of controls. The amounts of D7-cholesterol in lung and liver, and in plasma and RBC that pass the brain, were consistent with the concentration fed in the milk and approached 70% of the total content of cholesterol in these organs at the highest concentration fed. Brain, by contrast, contained very small amounts of D7-cholesterol, which could readily be attributed to D7-cholesterol associated with the vascular system of the blood-brain barrier. We found that the sterol composition of brain is not influenced by the concentration of cholesterol in milk and that cholesterol exogenous to brain, even in a hypercholesterolemic condition, does not gain entry to the brain. We conclude that the brain biosynthesizes de novo all the cholesterol it requires.

  20. Telomerase trafficking and assembly in Xenopus oocytes

    PubMed Central

    Li, Zhu-Hong; Tomlinson, Rebecca L.; Terns, Rebecca M.; Terns, Michael P.

    2010-01-01

    The core components of telomerase are telomerase RNA (TR) and telomerase reverse transcriptase (TERT). In vertebrate cells, TR and TERT have been reported to associate with intranuclear structures, including Cajal bodies and nucleoli as well as telomeres. Here, we examined the time course of both TR localization and assembly of TR with TERT in Xenopus oocytes. The major trafficking pathway for microinjected TR is through Cajal bodies into the nucleoplasm, with a fraction of TR found in nucleoli at later time points. Telomerase assembly precedes nucleolar localization of TR, and TR mutants that do not localize to nucleoli form active enzyme, indicating that localization of TR to nucleoli is not required for assembly with TERT. Assembly of telomerase coincides with Cajal-body localization; however, assembly is also unaffected by a CAB-box mutation (which significantly reduces association with Cajal bodies), suggesting that Cajal-body localization is not important for assembly. Our results suggest that assembly of TR with TERT occurs in the nucleoplasm. Unexpectedly, however, our experiments reveal that disruption of the CAB box does not eliminate early targeting to Cajal bodies, indicating that a role for Cajal bodies in telomerase assembly cannot be excluded on the basis of existing knowledge. PMID:20592184

  1. Cortical HCN channels: function, trafficking and plasticity

    PubMed Central

    Shah, Mala M

    2014-01-01

    The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated potassium ion channels. They are, however, activated by hyperpolarizing potentials and are permeable to cations. Four HCN subunits have been cloned, of which HCN1 and HCN2 subunits are predominantly expressed in the cortex. These subunits are principally located in pyramidal cell dendrites, although they are also found at lower concentrations in the somata of pyramidal neurons as well as other neuron subtypes. HCN channels are actively trafficked to dendrites by binding to the chaperone protein TRIP8b. Somato-dendritic HCN channels in pyramidal neurons modulate spike firing and synaptic potential integration by influencing the membrane resistance and resting membrane potential. Intriguingly, HCN channels are present in certain cortical axons and synaptic terminals too. Here, they regulate synaptic transmission but the underlying mechanisms appear to vary considerably amongst different synaptic terminals. In conclusion, HCN channels are expressed in multiple neuronal subcellular compartments in the cortex, where they have a diverse and complex effect on neuronal excitability. PMID:24756635

  2. Opioid receptor trafficking and interaction in nociceptors

    PubMed Central

    Zhang, X; Bao, L; Li, S

    2015-01-01

    Opiate analgesics such as morphine are often used for pain therapy. However, antinociceptive tolerance and dependence may develop with long-term use of these drugs. It was found that μ-opioid receptors can interact with δ-opioid receptors, and morphine antinociceptive tolerance can be reduced by blocking δ-opioid receptors. Recent studies have shown that μ- and δ-opioid receptors are co-expressed in a considerable number of small neurons in the dorsal root ganglion. The interaction of μ-opioid receptors with δ-opioid receptors in the nociceptive afferents is facilitated by the stimulus-induced cell-surface expression of δ-opioid receptors, and contributes to morphine tolerance. Further analysis of the molecular, cellular and neural circuit mechanisms that regulate the trafficking and interaction of opioid receptors and related signalling molecules in the pain pathway would help to elucidate the mechanism of opiate analgesia and improve pain therapy. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24611685

  3. Molecular trafficking in tissue engineered cartilage constructs

    NASA Astrophysics Data System (ADS)

    de Rosa, Enrica

    2005-03-01

    Tissue processing in vitro requires an effective trafficking of biologically active agents within three-dimensional constructs for induction of appropriate and enhanced cellular growth, biosynthesis and tissue remodeling. Moreover, nutrients and waste products need to move freely through the cellular constructs to minimize the presence of regions with necrotic and/or apoptotic cells. In tissue-engineered cartilage, for example, during the time of culture, cells seeded within the three-dimensional constructs lay-down their own extracellular matrix and this may lead to a heterogeneous distribution of transport properties both in time and space. In this work the diffusion coefficient of BSA and 500kDa dextran has been measured with FRAP thecnique in agarose gel chondrocytes constructs at different position and time during the culture. The diffusion coefficient of both molecular probes within the developing tissue well correlated with the ECM production and assembly. Moreover the comparision between BSA and dextran transport parameters revealed a selective hindrance effect of the neo tissue on high interacting molecules.

  4. Parallel algorithm development

    SciTech Connect

    Adams, T.F.

    1996-06-01

    Rapid changes in parallel computing technology are causing significant changes in the strategies being used for parallel algorithm development. One approach is simply to write computer code in a standard language like FORTRAN 77 or with the expectation that the compiler will produce executable code that will run in parallel. The alternatives are: (1) to build explicit message passing directly into the source code; or (2) to write source code without explicit reference to message passing or parallelism, but use a general communications library to provide efficient parallel execution. Application of these strategies is illustrated with examples of codes currently under development.

  5. Physiological and pathological implications of cholesterol.

    PubMed

    Cortes, Victor A; Busso, Dolores; Maiz, Alberto; Arteaga, Antonio; Nervi, Flavio; Rigotti, Attilio

    2014-01-01

    Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.

  6. Cholesterol Asymmetry in Synaptic Plasma Membranes

    PubMed Central

    Wood, W. Gibson; Igbavboa, Urule; Müller, Walter E.; Eckert, Gunter P.

    2010-01-01

    Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditions in vivo: 1) chronic ethanol consumption; 2) statins; 3) aging; and 4) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low-density-lipoprotein receptor, sterol carrier protein-2, fatty acid binding proteins, polyunsaturated fatty acids, p-glycoprotein and caveolin-1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function. PMID:21214553

  7. Parallel Atomistic Simulations

    SciTech Connect

    HEFFELFINGER,GRANT S.

    2000-01-18

    Algorithms developed to enable the use of atomistic molecular simulation methods with parallel computers are reviewed. Methods appropriate for bonded as well as non-bonded (and charged) interactions are included. While strategies for obtaining parallel molecular simulations have been developed for the full variety of atomistic simulation methods, molecular dynamics and Monte Carlo have received the most attention. Three main types of parallel molecular dynamics simulations have been developed, the replicated data decomposition, the spatial decomposition, and the force decomposition. For Monte Carlo simulations, parallel algorithms have been developed which can be divided into two categories, those which require a modified Markov chain and those which do not. Parallel algorithms developed for other simulation methods such as Gibbs ensemble Monte Carlo, grand canonical molecular dynamics, and Monte Carlo methods for protein structure determination are also reviewed and issues such as how to measure parallel efficiency, especially in the case of parallel Monte Carlo algorithms with modified Markov chains are discussed.

  8. Proteins and cholesterol-rich domains.

    PubMed

    Epand, Richard M

    2008-01-01

    Biological membranes are composed of many molecular species of lipids and proteins. These molecules do not mix ideally. In the plane of the membrane components are segregated into domains that are enriched in certain lipids and proteins. Cholesterol is a membrane lipid that is not uniformly distributed in the membrane. Proteins play an important role in determining cholesterol distribution. Certain types of protein lipidation are known to cause the lipoprotein to sequester with cholesterol and to stabilize cholesterol-rich domains. However, proteins that are excluded from such domains also contribute to the redistribution of cholesterol. One of the motifs that favor interaction with cholesterol is the CRAC motif. The role of the CRAC motif of the gp41 fusogenic protein of HIV is discussed. The distribution of the multianionic lipid, phosphatidylinositol(4,5)bis-phosphate (PtnIns(4,5)P2), is also not uniform in cell membranes. This lipid has several functions in the cell, including a morphological role in determining the sites of attachment of the actin cytoskeleton to the plasma membrane. PtnIns(4,5)P2 is sequestered by proteins having clusters of cationic residues in their sequence. Certain proteins containing cationic clusters also contain moieties such as myristoylation or a CRAC segment that would also endow them with the ability to sequester to a cholesterol-rich domain. These proteins interact with PtnIns(4,5)P2 in a cholesterol-dependent manner forming domains that are enriched in both cholesterol and in PtnIns(4,5)P2 but can also be distinct from liquid-ordered raft-like domains.

  9. Cellular Cholesterol Transport Proteins in Diabetic Nephropathy

    PubMed Central

    Tsun, Joseph G. S.; Yung, Susan; Chau, Mel K. M.; Shiu, Sammy W. M.; Chan, Tak Mao; Tan, Kathryn C. B.

    2014-01-01

    Background Lipid accumulation has been shown to accelerate renal injury, and the intracellular accumulation of lipids may be caused by alterations in synthesis as well as lipid uptake and efflux. We have investigated the role of cellular cholesterol transport proteins including adenosine triphosphate binding cassette transporter A1 (ABCA1), G1 (ABCG1) and scavenger receptor class B type I (SR-BI) in diabetic nephropathy. Methods Protein expression and the ability to mediate cholesterol efflux of ABCA1, ABCG1 and SR-BI was determined in human renal mesangial cells and proximal tubular epithelial cells cultured under normal or high glucose conditions. Renal expression of these cholesterol transporters was examined in a murine model of streptozotocin-induced type 1 diabetes. Results ABCA1, ABCG1 and SR-BI were expressed in both human renal mesangial cells and proximal tubular epithelial cells, and mediated cholesterol efflux to apolipoprotein AI and HDL. In vitro, hyperglycemia reduced the expression and the ability to mediate cholesterol efflux of all three cholesterol transporters (p<0.05). In vivo studies showed that intra-renal accumulation of lipids was increased in diabetic mice, particularly in mice with nephropathy. This was associated with a significant reduction in the expression of ABCA1, ABCG1 and SR-BI in the kidneys. These changes were already seen in diabetic mice without nephropathy and preceded the development of nephropathy. Diabetic mice with nephropathy had the lowest level of these cholesterol transporters. Conclusion Inducing diabetes with streptozotocin significantly reduced renal expression of ABCA1, ABCG1 and SR-BI. Defects in cholesterol export pathway in renal cells could therefore promote cholesterol accumulation and might contribute to the development of diabetic nephropathy. PMID:25181357

  10. The Anatomy of Human Trafficking: Learning About the Blues: A Healthcare Provider's Guide.

    PubMed

    Stevens, Meriam; Berishaj, Kelly

    2016-01-01

    Human trafficking is a major global public health concern. It is a grave crime that violates human rights. Contrary to healthcare providers' perceptions, victims of human trafficking come in contact with the healthcare system while being trafficked, with the emergency department being the most frequented setting for medical treatment. In this article, we explore the anatomy of human trafficking, including the scope of the problem, definitions, and types and elements of human trafficking. The roles of clinicians, particularly emergency department nurses and advanced practice nurses, in screening and identifying those at risk are examined. Clinical practice tools and guidelines that may be used by clinicians to guide the treatment of human trafficking victims are reviewed. Finally, current strategies and resources that address human trafficking are presented. For the purpose of this article, the terms "human trafficking" or "trafficking" will be used throughout.

  11. Simultaneous labeling of lipoprotein intracellular trafficking in pigeon monocyte-derived macrophages.

    PubMed Central

    Jones, N. L.

    1997-01-01

    Macrophage foam cell formation resulting from the accumulation of cholesterol and cholesterol esters derived from plasma lipoproteins is important for progression of atherosclerosis. Hypothetically, intracellular processing of lipoproteins that stimulate foam cell formation differs from processing of lipoproteins that do not. To test this, we examined simultaneous subcellular trafficking of lipoproteins in pigeon monocyte-derived macrophages. Pigeon beta-very-low-density lipoprotein (beta-VLDL), low-density lipoprotein (LDL), and acetylated low-density lipoprotein (Ac-LDL), differentially labeled with colloidal gold, were added in pairs to cells at 4 degrees C for 2 hours before uptake at 18 degrees C, 22 degrees C, or 37 degrees C for either 30 minutes or 2 hours. The colloidal gold distribution and percent co-labeling as observed by transmission electron microscopy were determined for organelles of the endocytic pathway. Incubations at 18 degrees C and 22 degrees C blocked lipoprotein trafficking to lysosomes. Incubation at 18 degrees C increased the percent distribution of lipoproteins in the endocytic pathway up to the early cisternal endosomes. Incubations at 22 degrees C resulted in a greater distribution of lipoproteins in the spherical late endosomes and late endosomal-prelysosomal tubular reticular compartment. The distribution in the endocytic pathway was a factor of time and temperature rather than lipoprotein type. The percentage of co-labeling of organelles for the three pairs of lipoproteins examined, Ac-LDL plus beta-VLDL, LDL plus beta-VLDL, and LDL plus Ac-LDL, was similar. Fewer noncoated and clathrin-coated pits and vesicles were co-labeled (average of 6%, maximum of 17%) than the rest of the endocytic pathway, early cisternal endosomes, spherical late endosomes, late endosomal-prelysosomal tubuloreticular compartment, and spherical lysosomes (average of 36%, maximum of 47%). The 36% of co-labeled later endocytic organelles contained an average

  12. Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

    PubMed Central

    Mandal, Pritam; Noutsi, Pakiza; Chaieb, Sahraoui

    2016-01-01

    Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells’ behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MβCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MβCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low. PMID:27245215

  13. Effect of dietary cholesterol and fat on cell cholesterol transfer to postprandial plasma in hyperlipidemic men.

    PubMed

    Sutherland, Wayne H F; de Jong, Sylvia A; Walker, Robert J

    2007-10-01

    Postprandial chylomicrons are potent ultimate acceptors of cell membrane cholesterol and are believed to accelerate reverse cholesterol transport (RCT). We compared the effects of meals rich in polyunsaturated fat (PUFA) and either high (605 mg) or low (151 mg) in cholesterol and a meal rich in dairy fat (DF) in the form of cream on net in vitro transport of red blood cell (RBC) membrane cholesterol to 4 and 6 h postprandial plasma in eight normotriglyceridemic (NTG-H) and eight hypertriglyceridemic (HTG-H) men with mild to moderate hypercholesterolemia. In HTG-H men, cell cholesterol accumulation in 6-h postprandial plasma was significantly (P = 0.02) less after the PUFA-HC meal compared with the other meals. The significant (P < 0.001) increase in cell plus endogenous cholesterol accumulation in the triglyceride-rich lipoprotein (TRL) fraction of 4 h postprandial plasma incubated with RBC was significantly (P = 0.007) higher after the PUFA-HC meal compared with DF meal in HTG-H men. In NTG-H men, cholesterol accumulation in plasma and plasma lipoproteins in the presence and absence of RBC was not significantly affected by the type of meal ingested. These data suggest that addition of large amounts of cholesterol to a PUFA meal may impair diffusion-mediated transport of cell membrane cholesterol to postprandial plasma and that replacing DF with PUFA in a meal increases postprandial lipemia and may potentially increase cholesterol accumulation in atherogenic postprandial TRL in HTG-H men.

  14. Relative activity of cholesterol in OPPC/cholesterol/sphingomyelin mixtures measured with an acoustic sensor.

    PubMed

    Melzak, Kathryn A; Gizeli, Electra

    2009-03-01

    Acoustic devices are sensitive to the mole fraction of cholesterol present in liposomes adsorbed to the device surface as a result of the different mechanical properties of the liposomes. This fact was exploited to develop an acoustic assay to determine the relative affinity of cholesterol for different lipid mixtures. In the assay described here, the initial rate of beta-cyclodextrin-induced removal of cholesterol was measured for liposomes having a range of compositions. The initial rate of cholesterol removal was found to be directly proportional to the concentration of beta-cyclodextrin (betaCD) present over the range of 0-7.5 mg/ml (0-6.6 mM), consistent with other assays measuring the betaCD-accelerated transfer of cholesterol between liposomes. The affinity of cholesterol for 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphocholine (OPPC) liposomes with a sphingomyelin mole fraction, chi(SPM), of 0.2 was found to be 1.4x higher than that for pure OPPC liposomes. For liposomes composed only of OPPC and cholesterol in varying ratios, the initial rate of cholesterol removal was determined as a function of cholesterol mole fraction (chi(C)). The initial rate of removal showed an increase at chi(C) = 0.13, consistent with phase diagrams showing the start of liquid ordered domain formation, but no such increase at chi(C) = 0.25, in contrast to the predictions of the umbrella model for OPPC/cholesterol interactions.

  15. Effect of cholesterol on structural and dynamic properties of tripalmitoyl glyceride. A high-pressure infrared spectroscopic study.

    PubMed

    Wong, P T; Chagwedera, T E; Mantsch, H H

    1989-11-01

    The infrared spectra of tripalmitoyl glyceride confirm the tuning fork configuration previously attributed to trilauroyl glyceride (Small, D. M. 1986. Handbook of Lipid Research. Vol. 4). The acyl chains in solid tripalmitoyl glycerol, either within each molecule or between neighboring molecules, are oriented parallel to each other with the sn-3 acyl chains extended toward the opposite direction of the sn-1 and sn-2 chains. The presence of cholesterol increases the orientational disorder of the tripalmitoyl glyceride molecules in terms of increased reorientational fluctuations and twisting/torsion motions of the acyl chains. In the solid mixture, cholesterol is embedded in the tripalmitoyl glyceride lattice which results in a reorientation of the acyl chains within each molecule from a parallel packing to a nonparallel packing. No evidence was found for hydrogen bond formation between the OH group of cholesterol and any of the three C = O groups of tripalmitoyl glyceride.

  16. Human trafficking and health: a conceptual model to inform policy, intervention and research.

    PubMed

    Zimmerman, Cathy; Hossain, Mazeda; Watts, Charlotte

    2011-07-01

    Human trafficking is an international crime renowned for extreme forms of violence against women, men and children. Although trafficking-related violence has been well-documented, the health of trafficked persons has been a largely neglected topic. For people who are trafficked, health risks and consequences may begin before they are recruited into the trafficking process, continue throughout the period of exploitation and persist even after individuals are released. Policy-making, service provision and research often focus narrowly on criminal violations that occur during the period of exploitation, regularly overlooking the health implications of trafficking. Similarly, the public health sector has not yet incorporated human trafficking as a health concern. We present a conceptual model that highlights the migratory and exploitative nature of a multi-staged trafficking process, which includes: 'recruitment', travel-transit', 'exploitation' and 'integration' or 'reintegration', and for some trafficked persons, 'detention' and 're-trafficking' stages. Trafficked persons may suffer from physical, sexual and psychological harm, occupational hazards, legal restrictions and difficulties associated with being marginalised or stigmatised. Researchers and decision-makers will benefit from a theoretical approach that conceptualizes trafficking and health as a multi-staged process of cumulative harm. To address a health risk such as trafficking, which spans geographical boundaries and involves multiple sectors, including immigration and law enforcement, labour, social and health services, interventions must be coordinated between nations and across sectors to promote the protection and recovery of people who are trafficked.

  17. Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway.

    PubMed

    Ma, Guoqiang; Li, Shuang; Han, Yuhong; Li, Shuangxi; Yue, Tao; Wang, Bing; Jiang, Jin

    2016-11-21

    Hedgehog (Hh) signaling plays a central role in development and diseases. Hh activates its signal transducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifications remains unexplored. Here we show that sumoylation acts in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling. We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1. Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-surface accumulation and elevated Hh pathway activity. We also provide evidence that Shh stimulates sumoylation of mammalian Smo (mSmo) and that sumoylation promotes ciliary localization of mSmo and Shh pathway activity. Our findings reveal a conserved mechanism whereby the SUMO pathway promotes Hh signaling by regulating Smo subcellular localization and shed light on how sumoylation regulates membrane protein trafficking.

  18. Dietary Phospholipids and Intestinal Cholesterol Absorption

    PubMed Central

    Cohn, Jeffrey S.; Kamili, Alvin; Wat, Elaine; Chung, Rosanna W. S.; Tandy, Sally

    2010-01-01

    Experiments carried out with cultured cells and in experimental animals have consistently shown that phospholipids (PLs) can inhibit intestinal cholesterol absorption. Limited evidence from clinical studies suggests that dietary PL supplementation has a similar effect in man. A number of biological mechanisms have been proposed in order to explain how PL in the gut lumen is able to affect cholesterol uptake by the gut mucosa. Further research is however required to establish whether the ability of PLs to inhibit cholesterol absorption is of therapeutic benefit. PMID:22254012

  19. Acyl-coenzyme A:cholesterol acyltransferases

    PubMed Central

    Chang, Ta-Yuan; Li, Bo-Liang; Chang, Catherine C. Y.; Urano, Yasuomi

    2009-01-01

    The enzymes acyl-coenzyme A (CoA):cholesterol acyltransferases (ACATs) are membrane-bound proteins that utilize long-chain fatty acyl-CoA and cholesterol as substrates to form cholesteryl esters. In mammals, two isoenzymes, ACAT1 and ACAT2, encoded by two different genes, exist. ACATs play important roles in cellular cholesterol homeostasis in various tissues. This chapter summarizes the current knowledge on ACAT-related research in two areas: 1) ACAT genes and proteins and 2) ACAT enzymes as drug targets for atherosclerosis and for Alzheimer's disease. PMID:19141679

  20. Genetic therapies to lower cholesterol.

    PubMed

    Khoo, Bernard

    2015-01-01

    This review surveys the state-of-the-art in genetic therapies for familial hypercholesterolaemia (FH), caused most commonly by mutations in the LDL receptor (LDLR) gene. FH manifests as highly elevated low density lipoprotein (LDL) cholesterol levels and consequently accelerated atherosclerosis. Modern pharmacological therapies for FH are insufficiently efficacious to prevent premature cardiovascular disease, can cause significant adverse effects and can be expensive. Genetic therapies for FH have been mooted since the mid 1990s but gene replacement strategies using viral vectors have so far been unsuccessful. Other strategies involve knocking down the expression of Apolipoprotein B100 (APOB100) and the protease PCSK9 which designates LDLR for degradation. The antisense oligonucleotide mipomersen, which knocks down APOB100, is currently marketed (with restrictions) in the USA, but is not approved in Europe due to its adverse effects. To address this problem, we have devised a novel therapeutic concept, APO-skip, which is based on modulation of APOB splicing, and which has the potential to deliver a cost-effective, efficacious and safe therapy for FH.

  1. Differential subcellular localization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders.

    PubMed

    McGlynn, Robert; Dobrenis, Kostantin; Walkley, Steven U

    2004-12-20

    The mucopolysaccharidoses (MPSs) are a complex family of lysosomal storage disorders characterized by failure to degrade heparan sulfate (HS) and/or other types of glycosaminoglycans (GAGs) secondary to the absence of specific lysosomal enzymes. An accompanying storage of glycosphingolipids (GSLs), most notably GM2 and GM3 gangliosides, has also been documented to occur in many types of MPS disease and is believed to be caused by secondary inhibition of GSL-degradative enzymes by intracellular GAG accumulation. We have documented the presence of secondary ganglioside accumulation in mouse models of several MPS disorders (types I, IIIA, IIIB, and VII) and report that this storage is accompanied by sequestration of free cholesterol in a manner similar to that observed in primary gangliosidoses. Using confocal microscopy, we evaluated the cellular distribution of cholesterol, GM2 and GM3 gangliosides, and HS in brains of mice with MPS IIIA disease. Unexpectedly, we found that although both gangliosides often accumulated in the same neurons, they were consistently located in separate populations of cytoplasmic vesicles. Additionally, GM3 ganglioside only partially co-localized with the primary storage material (HS), and cholesterol likewise only partially co-localized with the GM2 and GM3 gangliosides. These findings raise significant questions about the mechanism(s) responsible for secondary accumulation of storage materials in MPS disease. Furthermore, given that GSLs and cholesterol are constituents of membrane rafts believed critical in signal transduction events in neurons, their co-sequestration in individual neurons suggests the presence of defects in the composition, trafficking, and/or recycling of raft components and thus possible new mechanisms to explain neuronal dysfunction in MPS disorders.

  2. Human trafficking: Role of oral health care providers.

    PubMed

    Nuzzolese, E

    2014-11-30

    Trafficking in human beings is a modern form of slavery and is a well-known phenomenon throughout the European Union and beyond. After drug dealing and the weapons industry, human trafficking is the second largest criminal activity in the world today and it is a growing crime. The aim of governmental and non-governmental agencies, which are either directly or indirectly involved in combating trafficking in human beings, is the identification and referral of victims of trafficking and also to encourage self-referrals. Identification is the most important step to provide protection and assistance to victims of trafficking. Victims often have a variety of physical and mental health needs, including psychological trauma, injuries from violence, head and neck trauma, sexually transmitted infections and other gynaecological problems, dental/oral problems and have poor nutrition. The author's experience in the field of community dentistry in presented within. Volunteer dental services are offered to non-European Union patients held in a centre for asylum seekers in Bari (Italy). Dental professionals can, in fact, contribute to the identification, assistance and protection of trafficked persons, as well as offering forensic services to assist the police investigation in order to identify crimes and find the criminal organizations behind them. As for domestic violence and child abuse cases, there are ethical concerns involved in the identification and protection of the trafficked persons, as well as the need for interdisciplinary work and awareness. Adequate training in behavioural science and intercultural learning is paramount in order to avoid misunderstandings and increase sensitivity.

  3. Rapid turn-over of plasma membrane sphingomyelin and cholesterol in baby hamster kidney cells after exposure to sphingomyelinase.

    PubMed

    Slotte, J P; Härmälä, A S; Jansson, C; Pörn, M I

    1990-12-14

    Plasma membrane sphingomyelin in baby hamster kidney (BHK-21) cells was hydrolyzed with sphingomyelinase (Staphylococcus aureus) and the effects on membrane cholesterol translocation and the properties of membrane bound adenylate cyclase and Na+/K(+)-ATPase were determined. Exposure of confluent BHK-21 cells to 0.1 U/ml of sphingomyelinase led to the degradation (at 37 degrees C) of about 60% of cell sphingomyelin. No simultaneous hydrolysis of phosphatidylcholine occurred. The hydrolysis of sphingomyelin subsequently led to the translocation (within 40 min) of about 50-60% of cell [3H]cholesterol from a cholesterol oxidase susceptible pool to an oxidase resistant compartment. The translocation of [3H]cholesterol from the cell surface to intracellular membranes was accompanied by a paralleled increase in [3H]cholesterol ester formation. When cells were first exposed to sphingomyelinase (to degrade sphingomyelin) and then incubated without the enzyme in serum-free media, the mass of cell sphingomyelin decreased initially (by 60%), but then began to increase and reached control levels within 3-4 h. The rapid re-synthesis of sphingomyelin was accompanied by an equally rapid normalization of cell [3H]cholesterol distribution. The re-formation of cell sphingomyelin also led to a decreased content of cellular [3H]cholesterol esters, indicating that unesterified [3H]cholesterol was pulled out of the cholesterol ester cycle and transported to the cell surface. Exposure of BHK-21 cells to sphingomyelinase further led to a dramatically decreased activity of ouabain-sensitive Na+/K(+)-ATPase, whereas forskolin-stimulated adenylate cyclase activity was not affected. The activity of Na+/K(+)-ATPase returned to normal in parallel with the normalization of cell sphingomyelin mass and cholesterol distribution. We conclude that sphingomyelin has profound effects on the steady-state distribution of cell cholesterol, and that manipulations of cell sphingomyelin levels directly and

  4. Educating Health Care Professionals on Human Trafficking

    PubMed Central

    Grace, Aimee M.; Lippert, Suzanne; Collins, Kristin; Pineda, Noelle; Tolani, Alisha; Walker, Rebecca; Jeong, Monica; Trounce, Milana Boukhman; Graham-Lamberts, Caroline; Bersamin, Melina; Martinez, Det. Jeremy; Dotzler, Det. Jennifer; Vanek, Lt John; Storfer-Isser, Amy; Chamberlain, Lisa J.; Horwitz, Sarah M.

    2015-01-01

    Background The US Department of State estimates that there are between 4 and 27 million individuals worldwide in some form of modern slavery. Recent studies have demonstrated that 28% to 50% of trafficking victims in the United States encountered health care professionals while in captivity, but were not identified and recognized. This study aimed to determine whether an educational presentation increased emergency department (ED) providers' recognition of human trafficking (HT) victims and knowledge of resources to manage cases of HT. Methods The 20 largest San Francisco Bay Area EDs were randomized into intervention (10 EDs) or delayed intervention comparison groups (10 EDs) to receive a standardized educational presentation containing the following: background about HT, relevance of HT to health care, clinical signs in potential victims, and referral options for potential victims. Participants in the delayed intervention group completed a pretest in the period the immediate intervention group received the educational presentation, and all participants were assessed immediately before (pretest) and after (posttest) the intervention. The intervention effect was tested by comparing the pre–post change in the intervention group to the change in 2 pretests in the delayed intervention group adjusted for the effect of clustering within EDs. The 4 primary outcomes were importance of knowledge of HT to the participant's profession (5-point Likert scale), self-rated knowledge of HT (5-point Likert scale), knowledge of who to call for potential HT victims (yes/no), and suspecting that a patient was a victim of HT (yes/no). Findings There were 258 study participants from 14 EDs; 141 from 8 EDs in the intervention group and 117 from 7 EDs in the delayed intervention comparison group, of which 20 served as the delayed intervention comparison group. Participants in the intervention group reported greater increases in their level of knowledge about HT versus those in the

  5. The role of cholesterol absorption and hepatic cholesterol content in high and low responses to dietary cholesterol and fat in pedigreed baboons (Papio species).

    PubMed

    Kushwaha, R S; Rice, K S; Lewis, D S; McGill, H C; Carey, K D

    1993-06-01

    Selective breeding has produced baboon families with low and high plasma cholesterol responses to dietary cholesterol and fat. We used 12 high- and 12 low-responding (mainly in low-density lipoprotein [LDL] cholesterol) pedigreed baboons to determine whether cholesterol absorption and hepatic cholesterol concentration are associated with these responses. We measured cholesterol absorption first on the chow diet, which was low in cholesterol and fat, and after 3 and 13 weeks on the challenge diets, which contained 0.45 mg cholesterol/kcal and 40% of calories as either coconut oil or corn oil. Plasma, lipoprotein, and hepatic cholesterol concentrations were measured 1 week after cholesterol absorption measurements. High-responding baboons had higher percentage cholesterol absorption than low-responding baboons on both chow and challenge diets, regardless of the type of dietary fat. Both high and low responders had higher percentage cholesterol absorption with corn oil than with coconut oil. High responders also had higher hepatic cholesterol concentrations than low responders on chow and after consuming the challenge diets for 4 weeks. After consuming the challenge diets for 14 weeks, low responders fed coconut oil had hepatic cholesterol levels equal to those of high responders, while low responders fed corn oil continued to have low hepatic cholesterol levels. Thus, percentage cholesterol absorption is consistently higher in high-responding baboons regardless of diet, but hepatic cholesterol concentration varies with duration of challenge and type of fat. The results suggest that both cholesterol absorption and hepatic cholesterol concentration regulate cholesterolemic responses to diet, but by different mechanisms.

  6. Human Trafficking in Areas of Conflict: Health Care Professionals' Duty to Act.

    PubMed

    Bloem, Christina; Morris, Rikki E; Chisolm-Straker, Makini

    2017-01-01

    Given the significant global burden of human trafficking, the ability of clinicians to identify and provide treatment for trafficked persons is critical. Particularly in conflict settings, health care facilities often serve as the first and sometimes only point of contact for trafficked persons. As such, medical practitioners have a unique opportunity and an ethical imperative to intervene, even in nonclinical roles. With proper training, medical practitioners can assist trafficked persons by documenting human trafficking cases, thereby placing pressure on key stakeholders to enforce legal protections, and by providing adequate services to those trafficked.

  7. Structures of yeast vesicle trafficking proteins.

    PubMed Central

    Tishgarten, T.; Yin, F. F.; Faucher, K. M.; Dluhy, R. A.; Grant, T. R.; Fischer von Mollard, G.; Stevens, T. H.; Lipscomb, L. A.

    1999-01-01

    In protein transport between organelles, interactions of v- and t-SNARE proteins are required for fusion of protein-containing vesicles with appropriate target compartments. Mammalian SNARE proteins have been observed to interact with NSF and SNAP, and yeast SNAREs with yeast homologues of NSF and SNAP proteins. This observation led to the hypothesis that, despite low sequence homology, SNARE proteins are structurally similar among eukaryotes. SNARE proteins can be classified into two groups depending on whether they interact with SNARE binding partners via conserved glutamine (Q-SNAREs) or arginine (R-SNAREs). Much of the published structural data available is for SNAREs involved in exocytosis (either in yeast or synaptic vesicles). This paper describes circular dichroism, Fourier transform infrared spectroscopy, and dynamic light scattering data for a set of yeast v- and t-SNARE proteins, Vti1p and Pep12p, that are Q-SNAREs involved in intracellular trafficking. Our results suggest that the secondary structure of Vti1p is highly alpha-helical and that Vti1p forms multimers under a variety of solution conditions. In these respects, Vti1p appears to be distinct from R-SNARE proteins characterized previously. The alpha-helicity of Vti1p is similar to that of Q-SNARE proteins characterized previously. Pep12p, a Q-SNARE, is highly alpha-helical. It is distinct from other Q-SNAREs in that it forms dimers under many of the solution conditions tested in our experiments. The results presented in this paper are among the first to suggest heterogeneity in the functioning of SNARE complexes. PMID:10595551

  8. Accumulation of cholesterol and increased demand for zinc in serum-deprived RPE cells

    PubMed Central

    Mishra, Sanghamitra; Peterson, Katherine; Yin, Lili; Berger, Alan; Fan, Jianguo

    2016-01-01

    Purpose Having observed that confluent ARPE-19 cells (derived from human RPE) survive well in high-glucose serum-free medium (SFM) without further feeding for several days, we investigated the expression profile of RPE cells under the same conditions. Methods Expression profiles were examined with microarray and quantitative PCR (qPCR) analyses, followed by western blot analysis of key regulated proteins. The effects of low-density lipoprotein (LDL) and zinc supplementation were examined with qPCR. Immunofluorescence was used to localize the LDL receptor and to examine LDL uptake. Cellular cholesterol levels were measured with filipin binding. Expression patterns in primary fetal RPE cells were compared using qPCR. Results Microarray analyses of gene expression in ARPE-19, confirmed with qPCR, showed upregulation of lipid and cholesterol biosynthesis pathways in SFM. At the protein level, the cholesterol synthesis control factor SRBEF2 was activated, and other key lipid synthesis proteins increased. Supplementation of SFM with LDL reversed the upregulation of lipid and cholesterol synthesis genes, but not of cholesterol transport genes. The LDL receptor relocated to the plasma membrane, and LDL uptake was activated by day 5–7 in SFM, suggesting increased demand for cholesterol. Confluent ARPE-19 cells in SFM accumulated intracellular cholesterol, compared with cells supplemented with serum, over 7 days. Over the same time course in SFM, the expression of metallothioneins decreased while the major zinc transporter was upregulated, consistent with a parallel increase in demand for zinc. Supplementation with zinc reversed expression changes for metallothionein genes, but not for other zinc-related genes. Similar patterns of regulation were also seen in primary fetal human RPE cells in SFM. Conclusions ARPE-19 cells respond to serum deprivation and starvation with upregulation of the lipid and cholesterol pathways, accumulation of intracellular cholesterol, and

  9. [Cholesterol and atherosclerosis. Historical considerations and treatment].

    PubMed

    Zárate, Arturo; Manuel-Apolinar, Leticia; Basurto, Lourdes; De la Chesnaye, Elsa; Saldívar, Iván

    2016-01-01

    Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming «cholesterol»; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.

  10. HDL Function, Dysfunction, and Reverse Cholesterol Transport

    PubMed Central

    Fisher, Edward A.; Feig, Jonathan E.; Hewing, Bernd; Hazen, Stanley L.; Smith, Jonathan D.

    2012-01-01

    Although high HDL-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. Raising HDL levels in animal models by infusion or over expression of apolipoprotein A-I has shown clear vascular improvements, such as delayed atherosclerotic lesion progression and accelerated lesion regression, along with increased reverse cholesterol transport. Inflammation and other factors, such as myeloperoxidase mediated oxidation, can impair HDL production and HDL function, in regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. Thus, tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels. PMID:23152494

  11. Parallel digital forensics infrastructure.

    SciTech Connect

    Liebrock, Lorie M.; Duggan, David Patrick

    2009-10-01

    This report documents the architecture and implementation of a Parallel Digital Forensics infrastructure. This infrastructure is necessary for supporting the design, implementation, and testing of new classes of parallel digital forensics tools. Digital Forensics has become extremely difficult with data sets of one terabyte and larger. The only way to overcome the processing time of these large sets is to identify and develop new parallel algorithms for performing the analysis. To support algorithm research, a flexible base infrastructure is required. A candidate architecture for this base infrastructure was designed, instantiated, and tested by this project, in collaboration with New Mexico Tech. Previous infrastructures were not designed and built specifically for the development and testing of parallel algorithms. With the size of forensics data sets only expected to increase significantly, this type of infrastructure support is necessary for continued research in parallel digital forensics. This report documents the implementation of the parallel digital forensics (PDF) infrastructure architecture and implementation.

  12. National Human Trafficking Initiatives: Dimensions of Policy Diffusion1

    PubMed Central

    Yoo, Eun-hye; Boyle, Elizabeth Heger

    2014-01-01

    The implementation of criminal law involves formal law enforcement, education and public outreach aimed at preventing criminal activity, and providing services for victims. Historically, quantitative research on global trends has tended to focus on a single policy dimension, potentially masking the unique factors that affect the diffusion of each policy dimension independently. Using an ordered-probit model to analyze new human trafficking policy data on national prosecution, prevention, and victim-protection efforts, we find that global ties and domestic interest groups matter more in areas where international law is less defined. While prosecution, officially mandated by the Trafficking Protocol, was relatively impervious to global ties and domestic interest groups, both trafficking prevention and victim protection were associated with these factors. Our findings also suggest that fear of repercussions is not a major driver of state actions to combat trafficking—neither ratification of the Trafficking Protocol nor levels of United States aid were associated with greater implementation of anti-trafficking measures. PMID:26538806

  13. 3 CFR 8471 - Proclamation 8471 of January 4, 2010. National Slavery and Human Trafficking Prevention Month, 2010

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Slavery and Human Trafficking Prevention Month, 2010 8471 Proclamation 8471 Presidential Documents Proclamations Proclamation 8471 of January 4, 2010 Proc. 8471 National Slavery and Human Trafficking Prevention... the United States. During National Slavery and Human Trafficking Prevention Month, we acknowledge...

  14. Introduction to Parallel Computing

    DTIC Science & Technology

    1992-05-01

    Topology C, Ada, C++, Data-parallel FORTRAN, 2D mesh of node boards, each node FORTRAN-90 (late 1992) board has 1 application processor Devopment Tools ...parallel machines become the wave of the present, tools are increasingly needed to assist programmers in creating parallel tasks and coordinating...their activities. Linda was designed to be such a tool . Linda was designed with three important goals in mind: to be portable, efficient, and easy to use

  15. Parallel Wolff Cluster Algorithms

    NASA Astrophysics Data System (ADS)

    Bae, S.; Ko, S. H.; Coddington, P. D.

    The Wolff single-cluster algorithm is the most efficient method known for Monte Carlo simulation of many spin models. Due to the irregular size, shape and position of the Wolff clusters, this method does not easily lend itself to efficient parallel implementation, so that simulations using this method have thus far been confined to workstations and vector machines. Here we present two parallel implementations of this algorithm, and show that one gives fairly good performance on a MIMD parallel computer.

  16. Cholesterol metabolism, transport, and hepatic regulation in dairy cows during transition and early lactation.

    PubMed

    Kessler, E C; Gross, J J; Bruckmaier, R M; Albrecht, C

    2014-09-01

    The transition from the nonlactating to the lactating state represents a critical period for dairy cow lipid metabolism because body reserves have to be mobilized to meet the increasing energy requirements for the initiation of milk production. The purpose of this study was to provide a comprehensive overview on cholesterol homeostasis in transition dairy cows by assessing in parallel plasma, milk, and hepatic tissue for key factors of cholesterol metabolism, transport, and regulation. Blood samples and liver biopsies were taken from 50 multiparous Holstein dairy cows in wk 3 antepartum (a.p.), wk 1 postpartum (p.p.), wk 4 p.p., and wk 14 p.p. Milk sampling was performed in wk 1, 4, and 14 p.p. Blood and milk lipid concentrations [triglycerides (TG), cholesterol, and lipoproteins], enzyme activities (phospholipid transfer protein and lecithin:cholesterol acyltransferase) were analyzed using enzymatic assays. Hepatic gene expression patterns of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGC) synthase 1 (HMGCS1) and HMGC reductase (HMGCR), sterol regulatory element-binding factor (SREBF)-1 and -2, microsomal triglyceride transfer protein (MTTP), ATP-binding cassette transporter (ABC) A1 and ABCG1, liver X receptor (LXR) α and peroxisome proliferator activated receptor (PPAR) α and γ were measured using quantitative RT-PCR. Plasma TG, cholesterol, and lipoprotein concentrations decreased from wk 3 a.p. to a minimum in wk 1 p.p., and then gradually increased until wk 14 p.p. Compared with wk 4 p.p., phospholipid transfer protein activity was increased in wk 1 p.p., whereas lecithin:cholesterol acyltransferase activity was lowest at this period. Total cholesterol concentration and mass, and cholesterol concentration in the milk fat fraction decreased from wk 1 p.p. to wk 4 p.p. Both total and milk fat cholesterol concentration were decreased in wk 4 p.p. compared with wk 1 and 14 p.p. The mRNA abundance of genes involved in cholesterol synthesis (SREBF-2, HMGCS1, and

  17. Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport

    PubMed Central

    Ikhlef, Souade; Berrougui, Hicham; Kamtchueng Simo, Olivier; Zerif, Echarki

    2017-01-01

    This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport. PMID:28278274

  18. Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites.

    PubMed

    Prasanna, Xavier; Chattopadhyay, Amitabha; Sengupta, Durba

    2014-03-18

    The β2-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the β2-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the β2-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets.

  19. Dietary Cholesterol Impairs Memory and Memory Increases Brain Cholesterol and Sulfatide Levels

    PubMed Central

    Darwish, Deya S.; Wang, Desheng; Konat, Gregory W.; Schreurs, Bernard G.

    2011-01-01

    Cholesterol and sulfatides play many important roles in learning and memory. To date, our observations about the effects of cholesterol on learning have been assessed during response acquisition i.e., the learning of a new memory. Here we report for the first time on the effect of a cholesterol diet on a previously formed memory. Rabbits were given trace conditioning of the nictitating membrane response for ten days, then fed a 2% cholesterol diet for eight weeks, and then assessed for memory recall of the initially learned task. We show that dietary cholesterol had an adverse effect on memory recall. Second, we investigated whether dietary cholesterol caused an increase in brain cholesterol and sulfatide levels in four major brain structures (hippocampus, frontal lobe, brainstem, and cerebellum) using a technique for analyzing myelin and myelin-free fractions separately. Although our data confirm previous findings that dietary cholesterol does not directly affect cholesterol and establish that it does not affect sulfatide levels in the brain, these levels did increase rather significantly in the hippocampus and frontal lobe as a function of learning and memory. PMID:20141286

  20. Role of cholesterol in parasitic infections

    PubMed Central

    Bansal, Devendra; Bhatti, Harinderpal Singh; Sehgal, Rakesh

    2005-01-01

    The requirement of cholesterol for internalization of eukaryotic pathogens like protozoa (Leishmaniasis, Malaria and Toxoplasmosis) and the exchange of cholesterol along with other metabolites during reproduction in Schistosomes (helminths) under variable circumstances are poorly understood. In patients infected with some other helminthes, alterations in the lipid profile have been observed. Also, the mechanisms involved in lipid changes especially in membrane proteins related to parasite infections remain uncertain. Present review of literature shows that parasites induce significant changes in lipid parameters, as has been shown in the in vitro study where substitution of serum by lipid/cholesterol in medium and in experimental models (in vivo). Thus changes in lipid profile occur in patients having active infections with most of the parasites. Membrane proteins are probably involved in such reactions. All parasites may be metabolising cholesterol, but the exact relationship with pathogenic mechanism is not clear. So far, studies suggest that there may be some factors or enzymes, which allow the parasite to breakup and consume lipid/cholesterol. Further studies are needed for better understanding of the mechanisms involved in vivo. The present review analysis the various studies till date and the role of cholesterol in pathogenesis of different parasitic infections. PMID:15882457

  1. Development of cholesterol biosensor based on immobilized cholesterol esterase and cholesterol oxidase on oxygen electrode for the determination of total cholesterol in food samples.

    PubMed

    Basu, Anjan Kumar; Chattopadhyay, Parimal; Roychoudhuri, Utpal; Chakraborty, Runu

    2007-05-01

    The development of a cholesterol biosensor by co-immobilization of cholesterol esterase (ChEt) and cholesterol oxidase (ChOX) on oxygen electrode is described. The electrode consists of gold cathode and Ag/AgCl anode. The enzymes were immobilized by cross-linking with glutaraldehyde and Bovine Serum Albumin (BSA). The immobilized enzymatic membrane was attached to the tip of the electrode by a push cap system. The optimum pH and temperature of the sensor was determined, these are 6 and 25 degrees C respectively. The developed sensor was calibrated from 1-75 mg/dl of cholesterol palmiate and found linear in the range of 2-50 mg/dL. The calibration curve was drawn with V(i) (ppm/min)(initial velocity) vs different concentrations of cholesterol palmiate (mg/dL). The application of the sensor to determine the total cholesterol in different real food samples such as egg, meat was investigated. The immobilized enzymatic layer can be reused over 30 times and the stability of the enzymatic layer was studied up to 9 weeks.

  2. Obesity, Cholesterol Metabolism and Breast Cancer Pathogenesis

    PubMed Central

    McDonnell, Donald P.; Park, Sunghee; Goulet, Matthew T.; Jasper, Jeff; Wardell, Suzanne E.; Chang, Ching-yi; Norris, John D.; Guyton, John R.; Nelson, Erik R.

    2014-01-01

    Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the influence of these changes on signaling events initiated at the membrane. However, more recent studies have indicated that the oxysterol 27-hydroxycholesterol (27HC), and not cholesterol per se, may be the primary biochemical link between lipid metabolism and cancer. The enzyme responsible for production of 27HC from cholesterol, CYP27A1, is expressed primarily in the liver and in macrophages. In addition significantly elevated expression of this enzyme within breast tumors has also been observed. It is believed that 27HC, acting through the liver X receptor (LXR) in macrophages and possibly other cells is involved in maintaining organismal cholesterol homeostasis. It has also been shown recently that 27HC is an estrogen receptor (ER) agonist in breast cancer cells and that it stimulates the growth and metastasis of tumors in several models of breast cancer. These findings provide the rationale for the clinical evaluation of pharmaceutical approaches that interfere with cholesterol/27HC synthesis as a means to mitigate the impact of cholesterol on breast cancer pathogenesis. PMID:25060521

  3. PCLIPS: Parallel CLIPS

    NASA Technical Reports Server (NTRS)

    Hall, Lawrence O.; Bennett, Bonnie H.; Tello, Ivan

    1994-01-01

    A parallel version of CLIPS 5.1 has been developed to run on Intel Hypercubes. The user interface is the same as that for CLIPS with some added commands to allow for parallel calls. A complete version of CLIPS runs on each node of the hypercube. The system has been instrumented to display the time spent in the match, recognize, and act cycles on each node. Only rule-level parallelism is supported. Parallel commands enable the assertion and retraction of facts to/from remote nodes working memory. Parallel CLIPS was used to implement a knowledge-based command, control, communications, and intelligence (C(sup 3)I) system to demonstrate the fusion of high-level, disparate sources. We discuss the nature of the information fusion problem, our approach, and implementation. Parallel CLIPS has also be used to run several benchmark parallel knowledge bases such as one to set up a cafeteria. Results show from running Parallel CLIPS with parallel knowledge base partitions indicate that significant speed increases, including superlinear in some cases, are possible.

  4. Application Portable Parallel Library

    NASA Technical Reports Server (NTRS)

    Cole, Gary L.; Blech, Richard A.; Quealy, Angela; Townsend, Scott

    1995-01-01

    Application Portable Parallel Library (APPL) computer program is subroutine-based message-passing software library intended to provide consistent interface to variety of multiprocessor computers on market today. Minimizes effort needed to move application program from one computer to another. User develops application program once and then easily moves application program from parallel computer on which created to another parallel computer. ("Parallel computer" also include heterogeneous collection of networked computers). Written in C language with one FORTRAN 77 subroutine for UNIX-based computers and callable from application programs written in C language or FORTRAN 77.

  5. Parallel Algorithms and Patterns

    SciTech Connect

    Robey, Robert W.

    2016-06-16

    This is a powerpoint presentation on parallel algorithms and patterns. A parallel algorithm is a well-defined, step-by-step computational procedure that emphasizes concurrency to solve a problem. Examples of problems include: Sorting, searching, optimization, matrix operations. A parallel pattern is a computational step in a sequence of independent, potentially concurrent operations that occurs in diverse scenarios with some frequency. Examples are: Reductions, prefix scans, ghost cell updates. We only touch on parallel patterns in this presentation. It really deserves its own detailed discussion which Gabe Rockefeller would like to develop.

  6. Distribution and Spectroscopy of Green Fluorescent Protein and Acyl-CoA: Cholesterol Acytransferase in Sf21 Insect Cells

    NASA Technical Reports Server (NTRS)

    Richmond, R. C.; Mahtani, H.; Lu, X.; Chang, T. Y.; Malak, H.; Rose, M. Franklin (Technical Monitor)

    2001-01-01

    Acyl-CoA: cholesterol acyltransferase (ACAT) is thought to significantly participate in the pathway of cholesterol esterification that underlies the pathology of artherosclerosis. This enzyme is a membrane protein known to be preferentially bound within the endoplasmic reticulum of mammalian cells, from which location it esterifies cholesterol derived from low density lipoprotein. Cultures of insect cells were separately infected with baculovirus containing the gene for green fluroescent protein (GFP) and with baculovirus containing tandem genes for GFP and ACAT. These infected cultures expressed GFP and the fusion protein GCAT, respectively, with maximum expression occurring on the fourth day after infection. Extraction of GFP- and of GCAT-expressing cells with urea and detergent resulted in recovery of fluorescent protein in aqueous solution. Fluorescence spectra at neutral pH were identical for both GFP and GCAT extracts in aqueous solution, indicating unperturbed tertiary structure for the GFP moiety within GCAT. In a cholesterol esterification assay, GCAT demonstrated ACAT activity, but with less efficiency compared to native ACAT. It was hypothesized that the membrane protein ACAT would lead to differences in localization of GCAT compared to GFP within the respective expressing insect cells. The GFP marker directly and also within the fusion protein GCAT was accordingly used as the intracellular probe that was fluorescently analyzed by the new biophotonics technique of hyperspectral imaging. In that technique, fluorescence imaging was obtained from two dimensional arrays of cells, and regions of interest from within those images were then retrospectively analyzed for the emission spectra that comprises the image. Results of hyperspectral imaging of insect cells on day 4 postinfection showed that GCAT was preferentially localized to the cytoplasm of these cells compared to GFP. Furthermore, the emission spectra obtained for the localized GCAT displayed a peak

  7. Human Trafficking in Nepal: Post-Earthquake Risk and Response.

    PubMed

    Gyawali, Bishal; Keeling, June; Kallestrup, Per

    2016-09-15

    As Nepal mourns the 1-year commemoration of the April 2015 earthquake and its aftershocks that killed more than 8500 people and left thousands injured and displaced, other more hidden repercussions of the resultant chaotic environment need attention: the increased risk of human trafficking. Considering that natural disasters provide a milieu for this illicit trade, there is a need for a robust response from stakeholders such as donors, civil society organizations, and government organizations against human trafficking following disasters such as the Nepal earthquake. Responsibility to prevent and fight trafficking should be explicitly included in the mandate of relief and rehabilitation mechanisms set up at the national level to coordinate the disaster relief response, serving to support populations in both rural and urban areas. (Disaster Med Public Health Preparedness. 2016;page 1 of 2).

  8. Roles of membrane trafficking in plant cell wall dynamics

    PubMed Central

    Ebine, Kazuo; Ueda, Takashi

    2015-01-01

    The cell wall is one of the characteristic components of plant cells. The cell wall composition differs among cell types and is modified in response to various environmental conditions. To properly generate and modify the cell wall, many proteins are transported to the plasma membrane or extracellular space through membrane trafficking, which is one of the key protein transport mechanisms in eukaryotic cells. Given the diverse composition and functions of the cell wall in plants, the transport of the cell wall components and proteins that are involved in cell wall-related events could be specialized for each cell type, i.e., the machinery for cell wall biogenesis, modification, and maintenance could be transported via different trafficking pathways. In this review, we summarize the recent progress in the current understanding of the roles and mechanisms of membrane trafficking in plant cells and focus on the biogenesis and regulation of the cell wall. PMID:26539200

  9. Virus trafficking – learning from single-virus tracking

    PubMed Central

    Brandenburg, Boerries; Zhuang, Xiaowei

    2009-01-01

    What could be a better way to study virus trafficking than ‘miniaturizing oneself’ and ‘taking a ride with the virus particle’ on its journey into the cell? Single-virus tracking in living cells potentially provides us with the means to visualize the virus journey. This approach allows us to follow the fate of individual virus particles and monitor dynamic interactions between viruses and cellular structures, revealing previously unobservable infection steps. The entry, trafficking and egress mechanisms of various animal viruses have been elucidated using this method. The combination of single-virus trafficking with systems approaches and state-of-the-art imaging technologies should prove exciting in the future. PMID:17304249

  10. Inositol lipid phosphatases in membrane trafficking and human disease.

    PubMed

    Billcliff, Peter G; Lowe, Martin

    2014-07-15

    The specific interaction of phosphoinositides with proteins is critical for a plethora of cellular processes, including cytoskeleton remodelling, mitogenic signalling, ion channel regulation and membrane traffic. The spatiotemporal restriction of different phosphoinositide species helps to define compartments within the cell, and this is particularly important for membrane trafficking within both the secretory and endocytic pathways. Phosphoinositide homoeostasis is tightly regulated by a large number of inositol kinases and phosphatases, which respectively phosphorylate and dephosphorylate distinct phosphoinositide species. Many of these enzymes have been implicated in regulating membrane trafficking and, accordingly, their dysregulation has been linked to a number of human diseases. In the present review, we focus on the inositol phosphatases, concentrating on their roles in membrane trafficking and the human diseases with which they have been associated.

  11. Endocytic Trafficking at the Mature Podocyte Slit Diaphragm

    PubMed Central

    Swiatecka-Urban, Agnieszka

    2017-01-01

    Endocytic trafficking couples cell signaling with the cytoskeletal dynamics by organizing a crosstalk between protein networks in different subcellular compartments. Proteins residing in the plasma membrane are internalized and transported as cargo in endocytic vesicles (i.e., endocytosis). Subsequently, cargo proteins can be delivered to lysosomes for degradation or recycled back to the plasma membrane. The slit diaphragm is a modified tight junction connecting foot processes of the glomerular epithelial cells, podocytes. Signaling at the slit diaphragm plays a critical role in the kidney while its dysfunction leads to glomerular protein loss (proteinuria), manifesting as nephrotic syndrome, a rare condition with an estimated incidence of 2–4 new cases per 100,000 each year. Relatively little is known about the role of endocytic trafficking in podocyte signaling and maintenance of the slit diaphragm integrity. This review will focus on the role of endocytic trafficking at the mature podocyte slit diaphragm. PMID:28286744

  12. Minors travelling alone: a risk group for human trafficking?

    PubMed

    Derluyn, Ilse; Lippens, Valesca; Verachtert, Tony; Bruggeman, Willy; Broekaert, Eric

    2010-01-01

    Minors travelling without their parent(s) or guardian are an increasing phenomenon. Although their travel objectives might differ importantly, varying from holiday purposes to migration objectives, an important subgroup of them might be at risk to fall into exploitative circumstances, such as human trafficking. Studying the group of minors travelling alone arriving at Brussels Airport (Belgium), this research investigates the population's characteristics, the procedures used, and the risks some of these minors run of falling into exploitative situations. Firstly, registration revealed that tens of thousands minors travelling alone arrive at Brussels Airport each year, with an important part of them coming from African countries. Secondly, participant observations showed that detection of possible cases of human trafficking is a very complex issue, resulting in the alarming hypothesis that many cases of trafficking of minors travelling alone might not be detected during their journey or at their arrival at the airport.

  13. Physician Encounters with Human Trafficking: Legal Consequences and Ethical Considerations.

    PubMed

    Todres, Jonathan

    2017-01-01

    There is growing recognition and evidence that health care professionals regularly encounter-though they may not identify-victims of human trafficking in a variety of health care settings. Identifying and responding appropriately to trafficking victims or survivors requires not only training in trauma-informed care but also consideration of the legal and ethical issues that arise when serving this vulnerable population. This essay examines three areas of law that are relevant to this case scenario: criminal law, with a focus on conspiracy; service provider regulations, with a focus on mandatory reporting laws; and human rights law. In addition to imposing a legal mandate, the law can inform ethical considerations about how health care professionals should respond to human trafficking.

  14. Protein trafficking to the complex chloroplasts of Euglena.

    PubMed

    Vacula, Rostislav; Sláviková, Silvia; Schwartzbach, Steven D

    2007-01-01

    Proteins are delivered to Euglena chloroplasts using the secretory pathway. We describe analytical methods to study the intracellular trafficking of Euglena chloroplast proteins and a method to isolate preparative amounts of intact import competent chloroplasts for biochemical studies. Cells are pulse labeled with 35S-sulfate and chased with unlabeled sulfate allowing the trafficking and posttranslational processing of the labeled protein to be followed. Sucrose gradients are used to separate a 35S-labeled cell lysate into cytoplasmic, endoplasmic reticuum (ER), Golgi apparatus, chloroplast and mitochondrial fractions. Immunoprecipitation of each gradient fraction allows identification of the intracellular compartment containing a specific 35S-labeled protein at different times after synthesis delineating the trafficking pathway. Because sucrose gradients cannot be used to isolate preparative amounts of highly purified chloroplasts for biochemical characterization, a preparative high-yield procedure using Percoll gradients to isolate highly purified import competent chloroplasts is also presented.

  15. The transport of cholesterol through the plasma in normal man.

    PubMed

    Myant, N B

    1983-09-30

    This review includes a brief account of the routes of entry of cholesterol into the plasma by (a) secretion of lipoproteins and (b) uptake of tissue free cholesterol by lipoproteins in the interstitial fluid, the metabolic transformation undergone by cholesterol within the plasma, with particular reference to the esterification of plasma free cholesterol by lecithin:cholesteryl acyltransferase and the redistribution of esterified cholesterol from high-density to low-density and very-low-density lipoprotein, and the routes by which cholesterol is removed from the plasma by bulk transport. The review end with a balance sheet showing the approximate amounts of cholesterol entering and leaving the plasma by different routes.

  16. The Role of Macrophage Lipophagy in Reverse Cholesterol Transport

    PubMed Central

    2017-01-01

    Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis. PMID:28345315

  17. Biodistribution and Trafficking of Hydrogel Nanoparticles in Adult Mosquitoes

    PubMed Central

    Paquette, Cynthia C. H.; Phanse, Yashdeep; Perry, Jillian L.; Sanchez-Vargas, Irma; Airs, Paul M.; Dunphy, Brendan M.; Xu, Jing; Carlson, Jonathan O.; Luft, J. Christopher; DeSimone, Joseph M.; Bartholomay, Lyric C.; Beaty, Barry J.

    2015-01-01

    Background Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes. Methodology/Principal Findings PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract. Conclusions/Significance Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector

  18. Trafficking of Neuronal Two Pore Domain Potassium Channels

    PubMed Central

    Mathie, Alistair; Rees, Kathryn A; El Hachmane, Mickael F; Veale, Emma L

    2010-01-01

    The activity of two pore domain potassium (K2P) channels regulates neuronal excitability and cell firing. Post-translational regulation of K2P channel trafficking to the membrane controls the number of functional channels at the neuronal membrane affecting the functional properties of neurons. In this review, we describe the general features of K channel trafficking from the endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus then focus on established regulatory mechanisms for K2P channel trafficking. We describe the regulation of trafficking of TASK channels from the ER or their retention within the ER and consider the competing hypotheses for the roles of the chaperone proteins 14-3-3, COP1 and p11 in these processes and where these proteins bind to TASK channels. We also describe the localisation of TREK channels to particular regions of the neuronal membrane and the involvement of the TREK channel binding partners AKAP150 and Mtap2 in this localisation. We describe the roles of other K2P channel binding partners including Arf6, EFA6 and SUMO for TWIK1 channels and Vpu for TASK1 channels. Finally, we consider the potential importance of K2P channel trafficking in a number of disease states such as neuropathic pain and cancer and the protection of neurons from ischemic damage. We suggest that a better understanding of the mechanisms and regulations that underpin the trafficking of K2P channels to the plasma membrane and to localised regions therein may considerably enhance the probability of future therapeutic advances in these areas. PMID:21358977

  19. Identification and Management of Human Trafficking Victims in the Emergency Department.

    PubMed

    Hachey, Lisa M; Phillippi, Julia C

    Health care practitioners serve an important role in identification and assistance of human trafficking victims. Advanced practice registered nurses, including certified nurse midwives, clinical nurse specialists, and nurse practitioners, are in a unique position to interact with persons trafficked and seen in the clinical setting, yet they require knowledge to identify the signs of human trafficking. Lack of training and education has been identified as a barrier for health care professionals to recognize human trafficking victims and implement needed health care services (; ). Barriers to identification and management include gap in knowledge about the process to screen for trafficking, to assist victims, and to make referrals. A patient-centered, trauma-informed approach can provide a safe environment to sensitively screen patients for human trafficking. Advanced practice registered nurses should be able to assess for trafficking indicators, collaborate with multidisciplinary service providers, and ensure understanding and availability of federal, state, and local resources to manage the care of victims of trafficking.

  20. A model for assessing the risk of human trafficking on a local level

    NASA Astrophysics Data System (ADS)

    Colegrove, Amanda

    Human trafficking is a human rights violation that is difficult to quantify. Models for estimating the number of victims of trafficking presented by previous researchers depend on inconsistent, poor quality data. As an intermediate step to help current efforts by nonprofits to combat human trafficking, this project presents a model that is not dependent on quantitative data specific to human trafficking, but rather profiles the risk of human trafficking at the local level through causative factors. Businesses, indicated by the literature, were weighted based on the presence of characteristics that increase the likelihood of trafficking in persons. The mean risk was calculated by census tract to reveal the multiplicity of risk levels in both rural and urban settings. Results indicate that labor trafficking may be a more diffuse problem in Missouri than sex trafficking. Additionally, spatial patterns of risk remained largely the same regardless of adjustments made to the model.

  1. Attitudes About Human Trafficking: Individual Differences Related to Belief and Victim Blame.

    PubMed

    Cunningham, Katherine C; Cromer, Lisa DeMarni

    2016-01-01

    Human trafficking is believed to oppress millions of people worldwide. Despite increased media attention and public awareness campaigns in recent years, no empirical research has examined public attitudes about human trafficking. The present study examined gender, sexual trauma history, and attitudes about human trafficking as they related to belief of a sex-trafficking scenario and willingness to blame the victim for the situation. Undergraduate students (N = 409) at a large private university in the Northeastern United States completed measures in which they responded to a vignette portraying sex trafficking in the United States. Participants also reported their personal trauma history and completed a Human Trafficking Myths Scale. Results indicated that gender and human trafficking myth acceptance, but not sexual trauma history, were significantly related to participants' belief of the sex-trafficking scenario and their perception of the victim's responsibility. Potential implications and directions for future research are discussed.

  2. Parallel Lisp simulator

    SciTech Connect

    Weening, J.S.

    1988-05-01

    CSIM is a simulator for parallel Lisp, based on a continuation passing interpreter. It models a shared-memory multiprocessor executing programs written in Common Lisp, extended with several primitives for creating and controlling processes. This paper describes the structure of the simulator, measures its performance, and gives an example of its use with a parallel Lisp program.

  3. Parallel and Distributed Computing.

    DTIC Science & Technology

    1986-12-12

    program was devoted to parallel and distributed computing . Support for this part of the program was obtained from the present Army contract and a...Umesh Vazirani. A workshop on parallel and distributed computing was held from May 19 to May 23, 1986 and drew 141 participants. Keywords: Mathematical programming; Protocols; Randomized algorithms. (Author)

  4. A human rights approach to human trafficking for organ removal.

    PubMed

    Budiani-Saberi, Debra; Columb, Seán

    2013-11-01

    Human trafficking for organ removal (HTOR) should not be reduced to a problem of supply and demand of organs for transplantation, a problem of organized crime and criminal justice, or a problem of voiceless, abandoned victims. Rather, HTOR is at once an egregious human rights abuse and a form of human trafficking. As such, it demands a human-rights based approach in analysis and response to this problem, placing the victim at the center of initiatives to combat this phenomenon. Such an approach requires us to consider how various measures impact or disregard victims/potential victims of HTOR and gives us tools to better advocate their interests, rights and freedoms.

  5. Synthesis, Trafficking, and Localization of Muscarinic Acetylcholine Receptors

    PubMed Central

    Nathanson, Neil M.

    2008-01-01

    Muscarinic acetylcholine receptors are members of the G-protein coupled receptor superfamily that are expressed in and regulate the function of neurons, cardiac and smooth muscle, glands, and many other cell types and tissues. The correct trafficking of membrane proteins to the cell surface and their subsequent localization at appropriate sites in polarized cells are required for normal cellular signaling and physiological responses. This review will summarize work on the synthesis and trafficking of muscarinic receptors to the plasma membrane and their localization at the cell surface. PMID:18558434

  6. CHOLESTEROL UPTAKE IN THE SERUM OF NORMAL AND HOSPITALIZED INDIVIDUALS.

    DTIC Science & Technology

    cardiovascular disease . All sera dissolved additional cholesterol. Sera from the hospitalized group dissolved at least as much additional cholesterol as did sera from the normal group. This finding suggests that in atherosclerosis the reserve cholesterol transport capacity is not diminished. This statement, however, must be accepted within the limitations of the method and the unknown effects of therapeutic regimens. The amount of additional cholesterol dissolved by a sample of serum is not correlated with the original concentration of cholesterol in the serum.

  7. Metabolism of adrenal cholesterol in man

    PubMed Central

    Borkowski, Abraham; Delcroix, Claude; Levin, Sam

    1972-01-01

    The synthesis of adrenal cholesterol, its esterification and the synthesis of the glucocorticosteroid hormones were studied in vitro on human adrenal tissue. It was found that the synthesis of adrenal cholesterol may normally be small in the zona “fasciculata,” particularly when compared with the synthesis of the glucocorticosteroid hormones, that it is several times higher in the zona “reticularis” where esterified cholesterol is less abundant, and that under ACTH stimulation it increases strikingly and proportionally to the degree of esterified adrenal cholesterol depletion. On the other hand, the relative rate of esterification as well as the concentration of free adrenal cholesterol are remarkably stable: they do not differ according to the adrenal zonation and are unaffected by ACTH. Furthermore, from a qualitative point of view, the relative proportions of Δ1 and Δ2 cholesteryl esters formed in situ are similar to those anticipated from their relative concentrations, suggesting that the characteristic fatty acid distribution of the adrenal cholesteryl esters results from an in situ esterification rather than from a selective uptake of the plasma cholesteryl esters. Besides, the in vitro esterification reveals a propensity to the formation of the most unsaturated cholesteryl esters. Regarding hydrocortisone and corticosterone, their synthesis tends to be more elevated in the zona “fasciculata.” Despite its higher cholesterol concentration the zona “fasciculata” should not therefore be viewed as a quiescent functional complement to the zona “reticularis” and the cortical distribution of glucocorticosteroid hormone synthesis is quite distinct from that of adrenal cholesterol synthesis. PMID:4338120

  8. Massively parallel mathematical sieves

    SciTech Connect

    Montry, G.R.

    1989-01-01

    The Sieve of Eratosthenes is a well-known algorithm for finding all prime numbers in a given subset of integers. A parallel version of the Sieve is described that produces computational speedups over 800 on a hypercube with 1,024 processing elements for problems of fixed size. Computational speedups as high as 980 are achieved when the problem size per processor is fixed. The method of parallelization generalizes to other sieves and will be efficient on any ensemble architecture. We investigate two highly parallel sieves using scattered decomposition and compare their performance on a hypercube multiprocessor. A comparison of different parallelization techniques for the sieve illustrates the trade-offs necessary in the design and implementation of massively parallel algorithms for large ensemble computers.

  9. Totally parallel multilevel algorithms

    NASA Technical Reports Server (NTRS)

    Frederickson, Paul O.

    1988-01-01

    Four totally parallel algorithms for the solution of a sparse linear system have common characteristics which become quite apparent when they are implemented on a highly parallel hypercube such as the CM2. These four algorithms are Parallel Superconvergent Multigrid (PSMG) of Frederickson and McBryan, Robust Multigrid (RMG) of Hackbusch, the FFT based Spectral Algorithm, and Parallel Cyclic Reduction. In fact, all four can be formulated as particular cases of the same totally parallel multilevel algorithm, which are referred to as TPMA. In certain cases the spectral radius of TPMA is zero, and it is recognized to be a direct algorithm. In many other cases the spectral radius, although not zero, is small enough that a single iteration per timestep keeps the local error within the required tolerance.

  10. Parallel computing works

    SciTech Connect

    Not Available

    1991-10-23

    An account of the Caltech Concurrent Computation Program (C{sup 3}P), a five year project that focused on answering the question: Can parallel computers be used to do large-scale scientific computations '' As the title indicates, the question is answered in the affirmative, by implementing numerous scientific applications on real parallel computers and doing computations that produced new scientific results. In the process of doing so, C{sup 3}P helped design and build several new computers, designed and implemented basic system software, developed algorithms for frequently used mathematical computations on massively parallel machines, devised performance models and measured the performance of many computers, and created a high performance computing facility based exclusively on parallel computers. While the initial focus of C{sup 3}P was the hypercube architecture developed by C. Seitz, many of the methods developed and lessons learned have been applied successfully on other massively parallel architectures.

  11. Sex trafficking in Nepal: a review of intervention and prevention programs.

    PubMed

    Kaufman, Michelle R; Crawford, Mary

    2011-05-01

    Trafficking of girls and women for the purpose of sexual exploitation is a problem worldwide, particularly in South Asia. This review focuses on Nepal-to-India sex trafficking with an examination of current anti-trafficking intervention and prevention programs. The activities of both governmental agencies and nongovernment organizations are described and critically analyzed. Suggestions for evaluating and improving interventions, and thereby reducing the trafficking of girls and women, are discussed.

  12. A novel alkyne cholesterol to trace cellular cholesterol metabolism and localization[S

    PubMed Central

    Hofmann, Kristina; Thiele, Christoph; Schött, Hans-Frieder; Gaebler, Anne; Schoene, Mario; Kiver, Yuriy; Friedrichs, Silvia; Lütjohann, Dieter; Kuerschner, Lars

    2014-01-01

    Cholesterol is an important lipid of mammalian cells and plays a fundamental role in many biological processes. Its concentration in the various cellular membranes differs and is tightly regulated. Here, we present a novel alkyne cholesterol analog suitable for tracing both cholesterol metabolism and localization. This probe can be detected by click chemistry employing various reporter azides. Alkyne cholesterol is accepted by cellular enzymes from different biological species (Brevibacterium, yeast, rat, human) and these enzymes include cholesterol oxidases, hydroxylases, and acyl transferases that generate the expected metabolites in in vitro and in vivo assays. Using fluorescence microscopy, we studied the distribution of cholesterol at subcellular resolution, detecting the lipid in the Golgi and at the plasma membrane, but also in the endoplasmic reticulum and mitochondria. In summary, alkyne cholesterol represents a versatile, sensitive, and easy-to-use tool for tracking cellular cholesterol metabolism and localization as it allows for manifold detection methods including mass spectrometry, thin-layer chromatography/fluorography, and fluorescence microscopy. PMID:24334219

  13. Cholesterol content and methods for cholesterol determination in meat and poultry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Available data for cholesterol content of beef, pork, poultry, and processed meat products were reported. Although the cholesterol concentration in meat and poultry can be influenced by various factors, effects of animal species, muscle fiber type, and muscle fat content are focused on in this revi...

  14. Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes.

    PubMed

    Zhornitsky, Simon; McKay, Kyla A; Metz, Luanne M; Teunissen, Charlotte E; Rangachari, Manu

    2016-01-01

    Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS. Studies suggest that elevated levels of circulating low density lipoprotein cholesterol (LDL), total cholesterol, and particularly, apolipoprotein B and oxidized LDL are associated with adverse clinical and MRI outcomes in MS. These relationships were observed as early as CIS. The studies also suggest that oxysterols, cholesterol precursors, and apolipoprotein E may be markers of specific disease processes in MS, but more research is required to elucidate these processes and relationships. Taken together, the data indicate that cholesterol and markers of cholesterol turnover have potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS.

  15. 3 CFR - Presidential Determination With Respect to Foreign Governments' Efforts Regarding Trafficking in...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Governments' Efforts Regarding Trafficking in Persons Presidential Documents Other Presidential Documents... Governments' Efforts Regarding Trafficking in Persons Memorandum for the Secretary of State Consistent with section 110 of the Trafficking Victims Protection Act of 2000 (Division A of Public Law 106-386),...

  16. 8 CFR 214.11 - Alien victims of severe forms of trafficking in persons.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... prosecuting activity relating to human trafficking certifies that the presence of the alien in the United... trafficking in persons. 214.11 Section 214.11 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS NONIMMIGRANT CLASSES § 214.11 Alien victims of severe forms of trafficking in...

  17. 3 CFR 9074 - Proclamation 9074 of December 31, 2013. National Slavery and Human Trafficking Prevention Month...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Slavery and Human Trafficking Prevention Month, 2014 9074 Proclamation 9074 Presidential Documents Proclamations Proclamation 9074 of December 31, 2013 Proc. 9074 National Slavery and Human Trafficking... National Slavery and Human Trafficking Prevention Month, we renew our commitment to ending this scourge...

  18. 3 CFR - Presidential Determination With Respect to Foreign Governments' Efforts Regarding Trafficking in...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Governments' Efforts Regarding Trafficking in Persons Presidential Documents Other Presidential Documents... Governments' Efforts Regarding Trafficking in Persons Memorandum for the Secretary of State Consistent with section 110 of the Trafficking Victims Protection Act of 2000 (Division A of Public Law 106-386),...

  19. 3 CFR - Presidential Determination With Respect to Foreign Governments' Efforts Regarding Trafficking in...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Governments' Efforts Regarding Trafficking in Persons Presidential Documents Other Presidential Documents... Governments' Efforts Regarding Trafficking in Persons Memorandum for the Secretary of State Consistent with section 110 of the Trafficking Victims Protection Act of 2000 (Division A of Public Law 106-386),...

  20. 75 FR 1267 - National Slavery and Human Trafficking Prevention Month, 2010

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-08

    ... 8471 of January 4, 2010 National Slavery and Human Trafficking Prevention Month, 2010 By the President.... During National Slavery and Human Trafficking Prevention Month, we acknowledge that forms of slavery..., human trafficking victims cannot walk away, but are held in service through force, threats, and...

  1. 8 CFR 214.11 - Alien victims of severe forms of trafficking in persons.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... prosecuting activity relating to human trafficking certifies that the presence of the alien in the United... trafficking in persons. 214.11 Section 214.11 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS NONIMMIGRANT CLASSES § 214.11 Alien victims of severe forms of trafficking in...

  2. 3 CFR - Presidential Determination With Respect to Foreign Governments' Efforts Regarding Trafficking in...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Governments' Efforts Regarding Trafficking in Persons Presidential Documents Other Presidential Documents... Governments' Efforts Regarding Trafficking in Persons Memorandum for the Secretary of State Consistent with section 110 of the Trafficking Victims Protection Act of 2000 (Division A of Public Law 106-386),...

  3. 3 CFR - Presidential Determination With Respect to Foreign Governments' Efforts Regarding Trafficking in...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Governments' Efforts Regarding Trafficking in Persons Presidential Documents Other Presidential Documents... Governments' Efforts Regarding Trafficking in Persons Memorandum for the Secretary of State Consistent with section 110 of the Trafficking Victims Protection Act of 2000 (Division A of Public Law 106-386),...

  4. 77 FR 1005 - National Slavery and Human Trafficking Prevention Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-06

    ... January 6, 2012 Part VI The President Proclamation 8772--National Slavery and Human Trafficking Prevention... December 30, 2011 National Slavery and Human Trafficking Prevention Month, 2012 By the President of the... intolerable yoke of modern slavery. During National Slavery and Human Trafficking Prevention Month, we...

  5. Combating trafficking in persons: a call to action for global health professionals.

    PubMed

    CdeBaca, Luis; Sigmon, Jane Nady

    2014-08-01

    Health care professionals can help identify victims of human trafficking, who commonly come into contact with providers during captivity. Providers can also help restore the physical and mental health of trafficking survivors. Training should focus on recognizing trafficking signs, interviewing techniques, and recommended responses when a victim is identified.

  6. Trafficking in Persons: U.S. Policy and Issues for Congress

    DTIC Science & Technology

    2010-02-18

    Kuwait, Malaysia , Mauritania, Niger, North Korea, Papua New Guinea, Saudi Arabia, Sudan, Swaziland, Syria, and Zimbabwe. In September 2009, President...Regarding Prostitution and Sex Trafficking ............................................................ 31 Distinctions between Trafficking and Alien...severe forms of human trafficking” as: Sex trafficking in which a commercial sex act is induced by force, fraud, or coercion, or in which the person

  7. 76 FR 1660 - Request for Information for the 2011 Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-11

    ... and punish acts of such trafficking. (2) For the knowing commission of any act of sex trafficking involving force, fraud, coercion, or in which the victim of sex trafficking is a child incapable of giving... government of the country has made serious and sustained efforts to reduce the demand for (A) commercial...

  8. 78 FR 76183 - Request for Information for the 2014; Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-16

    ... trafficking. (2) For the knowing commission of any act of sex trafficking involving force, fraud, coercion, or in which the victim of sex trafficking is a child incapable of giving meaningful consent, or of... made serious and sustained efforts to reduce the demand for (A) commercial sex acts; and...

  9. 75 FR 82215 - National Slavery and Human Trafficking Prevention Month, 2011

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-30

    ... and Human Trafficking Prevention Month, 2011 By the President of the United States of America A.... During National Slavery and Human Trafficking Prevention Month, we rededicate ourselves to preventing and ending human trafficking, and we recognize all who continue to fight this serious human rights...

  10. A diet rich in leafy vegetable fiber improves cholesterol metabolism in high-cholesterol fed rats.

    PubMed

    Ezz El-Arab, A M

    2009-10-01

    In the present study, the hypocholesterolemic effect of leaf vegetable (Jew's mallow) was studied in high-cholesterol fed rats. The animals were fed diets supplemented with cholesterol (0.25%) for 4 weeks. Leaf vegetable diet produced an important hypocholesterolemic action: it led to a significant lowering (p<0.05) of cholesterol in the plasma and liver, as well as of the atherogenic index and a significant increase (p<0.05) in cecal short chain fatty acids, with respect to the control group. Concurrently, total fecal neutral sterols in the excretion increased (p<0.05) and apparent absorption of dietary cholesterol was significantly depressed (-58%). The consumption of leaf vegetable (Jew's mallow) with a hypercholesterolemic diet improved the lipidemic profile and increased excretion of the total cholesterol end-products.

  11. [Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

    PubMed

    Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

    2014-10-01

    The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases.

  12. Localization of cholesterol in sphingomyelinase-treated fibroblasts.

    PubMed

    Pörn, M I; Slotte, J P

    1995-05-15

    The distribution of cellular unesterified cholesterol was studied in fibroblasts, which had been depleted of plasma membrane sphingomyelin by exposure to exogenous sphingomyelinase. This treatment has previously been shown to induce an increase in cholesterol esterification, a decrease in the biosynthesis of cholesterol, and a decreased susceptibility of cell cholesterol to oxidation with cholesterol oxidase. When the cellular localization of cholesterol was studied with fluorescent filipin staining, sphingomyelin depletion did not cause any visible changes in the filipin-cholesterol staining pattern, suggesting that the major part of cellular cholesterol was retained in the plasma membrane after sphingomyelinase treatment. After the oxidation of cell-surface cholesterol with cholesterol oxidase, the plasma membrane was no longer stained by filipin, but the plasma membrane cholesterol of sphingomyelin-depleted cells appeared to be resistant to oxidation with cholesterol oxidase when sphingomyelinase was used as an oxidation-promoting agent. However, the use of hypotonic buffer or phosphatidylcholine-specific phospholipase C together with cholesterol oxidase resulted in a complete oxidation of the cell-surface cholesterol in sphingomyelin-depleted cells, as evidenced by the filipin-cholesterol staining pattern. Similar results were obtained when [3H]cholesterol-labelled fibroblasts were used for determination of the susceptibility to cholesterol oxidation. The kinetics of [3H]cholesterol oxidation in sphingomyelin-depleted cells with cholesterol oxidase in hypotonic buffer indicated that approximately 85% of the cellular cholesterol still resided in the plasma membrane after sphingomyelin depletion. These results are contradictory to earlier reports on sphingomyelinase-induced changes in cellular cholesterol distribution and suggest that minor changes in the kinetics of cholesterol transport from the plasma membrane to the endoplasmic reticulum may be responsible

  13. Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis.

    PubMed

    Pandak, W M; Schwarz, C; Hylemon, P B; Mallonee, D; Valerie, K; Heuman, D M; Fisher, R A; Redford, K; Vlahcevic, Z R

    2001-10-01

    The initial and rate-limiting step in the classic pathway of bile acid biosynthesis is 7alpha-hydroxylation of cholesterol, a reaction catalyzed by cholesterol 7alpha-hydroxylase (CYP7A1). The effect of CYP7A1 overexpression on cholesterol homeostasis in human liver cells has not been examined. The specific aim of this study was to determine the effects of overexpression of CYP7A1 on key regulatory steps involved in hepatocellular cholesterol homeostasis, using primary human hepatocytes (PHH) and HepG2 cells. Overexpression of CYP7A1 in HepG2 cells and PHH was accomplished by using a recombinant adenovirus encoding a CYP7A1 cDNA (AdCMV-CYP7A1). CYP7A1 overexpression resulted in a marked activation of the classic pathway of bile acid biosynthesis in both PHH and HepG2 cells. In response, there was decreased HMG-CoA-reductase (HMGR) activity, decreased acyl CoA:cholesterol acyltransferase (ACAT) activity, increased cholesteryl ester hydrolase (CEH) activity, and increased low-density lipoprotein receptor (LDLR) mRNA expression. Changes observed in HMGR, ACAT, and CEH mRNA levels paralleled changes in enzyme specific activities. More specifically, LDLR expression, ACAT activity, and CEH activity appeared responsive to an increase in cholesterol degradation after increased CYP7A1 expression. Conversely, accumulation of the oxysterol 7alpha-hydroxycholesterol in the microsomes after CYP7A1 overexpression was correlated with a decrease in HMGR activity.

  14. Enzymatic Quantification of Cholesterol and Cholesterol Esters from Silicone Hydrogel Contact Lenses

    PubMed Central

    Pucker, Andrew D.; Thangavelu, Mirunalni

    2010-01-01

    Purpose. The purpose of this work was to develop an enzymatic method of quantification of cholesterol and cholesterol esters derived from contact lenses, both in vitro and ex vivo. Methods. Lotrafilcon B (O2 Optix; CIBA Vision, Inc., Duluth, GA) and galyfilcon A (Acuvue Advance; Vistakon, Inc., Jacksonville, FL) silicone hydrogel contact lenses were independently incubated in cholesterol oleate solutions varying in concentrations. After incubation, the lenses were removed and underwent two separate 2:1 chloroform-methanol extractions. After in vitro studies, 10 human subjects wore both lotrafilcon B and galyfilcon A contact lenses for 7 days. The lenses also underwent two separate 2:1 chloroform-methanol extractions. All in vitro and ex vivo samples were quantified with a cholesterol esterase enzymatic reaction. Results. Calibration curves from quantifications of in vitro contact lens samples soaked in successively decreasing concentrations of cholesterol oleate yielded coefficients of determination (R2) of 0.99 (lotrafilcon B) and 0.97 (galyfilcon A). For in vitro contact lens samples, galyfilcon A was associated with an average cholesterol oleate extraction of 39.85 ± 48.65 μg/lens, whereas lotrafilcon B was associated with 5.86 ± 3.36 μg/lens (P = 0.05) across both extractions and all incubation concentrations. For ex vivo contact lens samples, there was significantly more cholesterol and cholesterol esters deposited on galyfilcon A (5.77 ± 1.87 μg/lens) than on lotrafilcon B (2.03 ± 1.62 μg/lens; P = 0.0005). Conclusions. This is an efficient and simple method of quantifying total cholesterol extracted from silicone hydrogel contact lenses and, potentially, the meibum and/or tear film. Certain silicone hydrogel materials demonstrate more affinity for cholesterol and its esters than do others. PMID:20089871

  15. The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

    PubMed Central

    Stellaard, Frans

    2017-01-01

    The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath) as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1) The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2) The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3) The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded. PMID:28321334

  16. The NAS parallel benchmarks

    NASA Technical Reports Server (NTRS)

    Bailey, David (Editor); Barton, John (Editor); Lasinski, Thomas (Editor); Simon, Horst (Editor)

    1993-01-01

    A new set of benchmarks was developed for the performance evaluation of highly parallel supercomputers. These benchmarks consist of a set of kernels, the 'Parallel Kernels,' and a simulated application benchmark. Together they mimic the computation and data movement characteristics of large scale computational fluid dynamics (CFD) applications. The principal distinguishing feature of these benchmarks is their 'pencil and paper' specification - all details of these benchmarks are specified only algorithmically. In this way many of the difficulties associated with conventional benchmarking approaches on highly parallel systems are avoided.

  17. CHOBIMALT: A Cholesterol-Based Detergent†

    PubMed Central

    Howell, Stanley C.; Mittal, Ritesh; Huang, Lijun; Travis, Benjamin; Breyer, Richard M.; Sanders, Charles R.

    2010-01-01

    Cholesterol and its hemisuccinate and sulfate derivatives are widely used in studies of purified membrane proteins, but are difficult to solubilize in aqueous solution, even in the presence of detergent micelles. Other cholesterol derivatives do not form conventional micelles and lead to viscous solutions. To address these problems a cholesterol-based detergent, CHOBIMALT, has been synthesized and characterized. At concentrations above 3–4μM, CHOBIMALT forms micelles without the need for elevated temperatures or sonic disruption. Diffusion and fluorescence measurements indicated that CHOBIMALT micelles are large (210 ± 30 kDa). The ability to solubilize a functional membrane protein was explored using a G-protein coupled receptor, the human kappa opioid receptor type 1 (hKOR1). While CHOBIMALT alone was not found to be effective as a surfactant for membrane extraction, when added to classical detergent micelles CHOBIMALT was observed to dramatically enhance the thermal stability of solubilized hKOR1. PMID:20919740

  18. Child Trafficking in West Africa: Policy Responses. Innocenti Insight.

    ERIC Educational Resources Information Center

    United Nations Children's Fund, Florence (Italy). Innocenti Research Centre.

    This report examines policy responses and programming trends to combat the growing specter of child trafficking, focusing on the region of west and central Africa where strenuous advocacy efforts by UNICEF and its partners have helped to bring this problem to national and international attention. The report focuses on policy trends on child…

  19. Human Trafficking: A Call for Counselor Awareness and Action

    ERIC Educational Resources Information Center

    Stotts, Edward L., Jr.; Ramey, Luellen

    2009-01-01

    The counseling profession has given little attention to human trafficking, a form of modern slavery that is one of the most damaging forms of social injustice that exists today. Focusing on victims within the United States, the authors provide advocacy suggestions, treatment recommendations, and directions for research for this population.

  20. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term...