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Sample records for model membrane disruption

  1. The antimicrobial peptide aurein 1.2 disrupts model membranes via the carpet mechanism.

    Science.gov (United States)

    Fernandez, David I; Le Brun, Anton P; Whitwell, Thomas C; Sani, Marc-Antoine; James, Michael; Separovic, Frances

    2012-12-05

    The membrane interactions of the antimicrobial peptide aurein 1.2 were studied using a range of biophysical techniques to determine the location and the mechanism of action in DMPC (dimyristoylphosphatidylcholine) and DMPC/DMPG (dimyristoylphosphatidylglycerol) model membranes that mimic characteristics of eukaryotic and prokaryotic membranes, respectively. Neutron reflectometry and solid-state NMR revealed subtle changes in membrane structure caused by the peptide. Quartz crystal microbalance with dissipation, vesicle dye leakage and atomic force microscopy measurements were used to investigate the global mode of peptide interaction. Aurein 1.2 displayed an enhanced interaction with the anionic DMPC/DMPG membrane while exhibiting primarily a surface interaction with both types of model membranes, which led to bilayer disruption and membrane lysis. The antimicrobial peptide interaction is consistent with the carpet mechanism for aurein 1.2 with discrete structural changes depending on the type of phospholipid membrane.

  2. Contribution of the Tyr-1 in Plantaricin149a to Disrupt Phospholipid Model Membranes

    Directory of Open Access Journals (Sweden)

    Georgina Tonarelli

    2013-06-01

    Full Text Available Plantaricin149a (Pln149a is a cationic antimicrobial peptide, which was suggested to cause membrane destabilization via the carpet mechanism. The mode of action proposed to this antimicrobial peptide describes the induction of an amphipathic α-helix from Ala7 to Lys20, while the N-terminus residues remain in a coil conformation after binding. To better investigate this assumption, the purpose of this study was to determine the contributions of the Tyr1 in Pln149a in the binding to model membranes to promote its destabilization. The Tyr to Ser substitution increased the dissociation constant (KD of the antimicrobial peptide from the liposomes (approximately three-fold higher, and decreased the enthalpy of binding to anionic vesicles from −17.2 kcal/mol to −10.2 kcal/mol. The peptide adsorption/incorporation into the negatively charged lipid vesicles was less effective with the Tyr1 substitution and peptide Pln149a perturbed the liposome integrity more than the analog, Pln149S. Taken together, the peptide-lipid interactions that govern the Pln149a antimicrobial activity are found not only in the amphipathic helix, but also in the N-terminus residues, which take part in enthalpic contributions due to the allocation at a lipid-aqueous interface.

  3. Real-Time Observation of Antimicrobial Polycation Effects on Escherichia coli: Adapting the Carpet Model for Membrane Disruption to Quaternary Copolyoxetanes.

    Science.gov (United States)

    Wang, Congzhou; Zolotarskaya, Olga Y; Nair, Sithara S; Ehrhardt, Christopher J; Ohman, Dennis E; Wynne, Kenneth J; Yadavalli, Vamsi K

    2016-03-29

    Real-time atomic force microscopy (AFM) was used for analyzing effects of the antimicrobial polycation copolyoxetane P[(C12)-(ME2Ox)-50/50], C12-50 on the membrane of a model bacterium, Escherichia coli (ATCC# 35218). AFM imaging showed cell membrane changes with increasing C12-50 concentration and time including nanopore formation and bulges associated with outer bacterial membrane disruption. A macroscale bactericidal concentration study for C12-50 showed a 4 log kill at 15 μg/mL with conditions paralleling imaging (1 h, 1x PBS, physiological pH, 25 °C). The dramatic changes from the control image to 1 h after introducing 15 μg/mL C12-50 are therefore reasonably attributed to cell death. At the highest concentration (60 μg/mL) further cell membrane disruption results in leakage of cytoplasm driven by detergent-like action. The sequence of processes for initial membrane disruption by the synthetic polycation C12-50 follows the carpet model posited for antimicrobial peptides (AMPs). However, the nanoscale details are distinctly different as C12-50 is a synthetic, water-soluble copolycation that is best modeled as a random coil. In a complementary AFM study, chemical force microscopy shows that incubating cells with C12-50 decreased the hydrophobicity across the entire cell surface at an early stage. This finding provides additional evidence indicating that C12-50 polycations initially bind with the cell membrane in a carpet-like fashion. Taken together, real time AFM imaging elucidates the mechanism of antimicrobial action for copolyoxetane C12-50 at the single cell level. In future work this approach will provide important insights into structure-property relationships and improved antimicrobial effectiveness for synthetic amphiphilic polycations.

  4. The disruption management model.

    Science.gov (United States)

    McAlister, James

    2011-10-01

    Within all organisations, business continuity disruptions present a set of dilemmas that managers may not have dealt with before in their normal daily duties. The disruption management model provides a simple but effective management tool to enable crisis management teams to stay focused on recovery in the midst of a business continuity incident. The model has four chronological primary headlines, which steer the team through a quick-time crisis decision-making process. The procedure facilitates timely, systematic, rationalised and justified decisions, which can withstand post-event scrutiny. The disruption management model has been thoroughly tested within an emergency services environment and is proven to significantly support clear and concise decision making in a business continuity context.

  5. Atmospheric-pressure guided streamers for liposomal membrane disruption

    Science.gov (United States)

    Svarnas, P.; Matrali, S. H.; Gazeli, K.; Aleiferis, Sp.; Clément, F.; Antimisiaris, S. G.

    2012-12-01

    The potential to use liposomes (LIPs) as a cellular model in order to study interactions of cold atmospheric-pressure plasma with cells is herein investigated. Cold atmospheric-pressure plasma is formed by a dielectric-barrier discharge reactor. Large multilamellar vesicle liposomes, consisted of phosphatidylcholine and cholesterol, are prepared by the thin film hydration technique, to encapsulate a small hydrophilic dye, i.e., calcein. The plasma-induced release of calcein from liposomes is then used as a measure of liposome membrane integrity and, consequently, interaction between the cold atmospheric plasma and lipid bilayers. Physical mechanisms leading to membrane disruption are suggested, based on the plasma characterization including gas temperature calculation.

  6. Atmospheric-pressure guided streamers for liposomal membrane disruption

    Energy Technology Data Exchange (ETDEWEB)

    Svarnas, P.; Aleiferis, Sp. [High Voltage Laboratory, Department of Electrical and Computer Engineering, University of Patras, Rion 26504 (Greece); Matrali, S. H. [Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion 26504 (Greece); Gazeli, K. [High Voltage Laboratory, Department of Electrical and Computer Engineering, University of Patras, Rion 26504 (Greece); IPREM-LCABIE, Plasmas et Applications, UPPA, 64000 Pau (France); Clement, F. [IPREM-LCABIE, Plasmas et Applications, UPPA, 64000 Pau (France); Antimisiaris, S. G. [Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion 26504 (Greece); Institute of Chemical Engineering Sciences (ICES)-FORTH, Rion 26504 (Greece)

    2012-12-24

    The potential to use liposomes (LIPs) as a cellular model in order to study interactions of cold atmospheric-pressure plasma with cells is herein investigated. Cold atmospheric-pressure plasma is formed by a dielectric-barrier discharge reactor. Large multilamellar vesicle liposomes, consisted of phosphatidylcholine and cholesterol, are prepared by the thin film hydration technique, to encapsulate a small hydrophilic dye, i.e., calcein. The plasma-induced release of calcein from liposomes is then used as a measure of liposome membrane integrity and, consequently, interaction between the cold atmospheric plasma and lipid bilayers. Physical mechanisms leading to membrane disruption are suggested, based on the plasma characterization including gas temperature calculation.

  7. An enhancer peptide for membrane-disrupting antimicrobial peptides

    Directory of Open Access Journals (Sweden)

    Zhang Hong

    2010-02-01

    Full Text Available Abstract Background NP4P is a synthetic peptide derived from a natural, non-antimicrobial peptide fragment (pro-region of nematode cecropin P4 by substitution of all acidic amino acid residues with amides (i.e., Glu → Gln, and Asp → Asn. Results In the presence of NP4P, some membrane-disrupting antimicrobial peptides (ASABF-α, polymyxin B, and nisin killed microbes at lower concentration (e.g., 10 times lower minimum bactericidal concentration for ASABF-α against Staphylococcus aureus, whereas NP4P itself was not bactericidal and did not interfere with bacterial growth at ≤ 300 μg/mL. In contrast, the activities of antimicrobial agents with a distinct mode of action (indolicidin, ampicillin, kanamycin, and enrofloxacin were unaffected. Although the membrane-disrupting activity of NP4P was slight or undetectable, ASABF-α permeabilized S. aureus membranes with enhanced efficacy in the presence of NP4P. Conclusions NP4P selectively enhanced the bactericidal activities of membrane-disrupting antimicrobial peptides by increasing the efficacy of membrane disruption against the cytoplasmic membrane.

  8. Market Susceptibility Toward Disruptive Business Model Innovation

    OpenAIRE

    Dover, Oliver; Nord, Erik

    2015-01-01

    This paper discusses the conditional factors indicating market susceptibility toward disruptive innovation. There is a need to separate the different forms of disruptive innovation into segments targeting; technology, product or business model disruption. The concepts are fundamentally different and the literature to date is very one sided toward disruptive technology/product innovation. A shortage of studies on disruptive business model innovation has been discovered. This study therefore pr...

  9. Model cell membranes

    DEFF Research Database (Denmark)

    Günther-Pomorski, Thomas; Nylander, Tommy; Cardenas Gomez, Marite

    2014-01-01

    The high complexity of biological membranes has motivated the development and application of a wide range of model membrane systems to study biochemical and biophysical aspects of membranes in situ under well defined conditions. The aim is to provide fundamental understanding of processes...... controlled by membrane structure, permeability and curvature as well as membrane proteins by using a wide range of biochemical, biophysical and microscopic techniques. This review gives an overview of some currently used model biomembrane systems. We will also discuss some key membrane protein properties...... that are relevant for protein-membrane interactions in terms of protein structure and how it is affected by membrane composition, phase behavior and curvature....

  10. From Digital Disruption to Business Model Scalability

    DEFF Research Database (Denmark)

    Nielsen, Christian; Lund, Morten; Thomsen, Peter Poulsen

    2017-01-01

    This article discusses the terms disruption, digital disruption, business models and business model scalability. It illustrates how managers should be using these terms for the benefit of their business by developing business models capable of achieving exponentially increasing returns to scale...... will seldom lead to business model scalability capable of competing with digital disruption(s)....... as a response to digital disruption. A series of case studies illustrate that besides frequent existing messages in the business literature relating to the importance of creating agile businesses, both in growing and declining economies, as well as hard to copy value propositions or value propositions that take...

  11. Liposomal membrane disruption by means of miniaturized dielectric-barrier discharge in air: liposome characterization

    Science.gov (United States)

    Svarnas, P.; Asimakoulas, L.; Katsafadou, M.; Pachis, K.; Kostazos, N.; Antimisiaris, S. G.

    2017-08-01

    The increasing interest of the plasma community in the application of atmospheric-pressure cold plasmas to bio-specimen treatment has led to the creation of the emerging field of plasma biomedicine. Accordingly, plasma setups based on dielectric-barrier discharges have already been widely tested for the inactivation of various cells. Most of these systems refer to the plasma jet concept where noble gases penetrate atmospheric air and are subjected to the influence of high electric fields, thus forming guided streamers. Following the original works of our group where liposomal membranes were proposed as models for studying the interaction between plasma jets and cells, we present herein a study on liposomal membrane disruption by means of miniaturized dielectric-barrier discharge running in atmospheric air. Liposomal membranes of various lipid compositions, lamellarities, and sizes are treated at different times. It is shown that the dielectric-barrier discharge of low mean power leads to efficient liposomal membrane disruption. The latter is achieved in a controllable manner and depends on liposome properties. Additionally, it is clearly demonstrated that liposomal membrane disruption takes place even after plasma extinction, i.e. during post-treatment, resembling thus an ‘apoptosis’ effect, which is well known today mainly for cell membranes. Thus, the adoption of the present concept would be beneficial for tailoring studies on plasma-treated cell-mimics. Finally, the liposome treatment is discussed with respect to possible physicochemical mechanisms and potential discharge modification due to the various compositions of the liquid electrode.

  12. Isolation of mitochondria by gentle cell membrane disruption, and their subsequent characterization.

    Science.gov (United States)

    Shibata, Takahiro; Yamashita, Saki; Hirusaki, Kotoe; Katoh, Kaoru; Ohta, Yoshihiro

    2015-08-07

    Mitochondria play a key role in several physiological processes as in integrating signals in the cell. However, understanding of the mechanism by which mitochondria sense and respond to signals has been limited due to the lack of an appropriate model system. In this study, we developed a method to isolate and characterize mitochondria without cell homogenization. By gently pipetting cells treated with streptolysin-O, a pore-forming membrane protein, we disrupted the cell membrane and were able to isolate both elongated and spherical mitochondria. Fluorescence imaging combined with super resolution microscopy showed that both the outer and inner membranes of the elongated mitochondria isolated using the newly developed method were intact. In addition, a FRET-based ATP sensor expressed in the mitochondrial matrix demonstrated that ATP generation by FoF1-ATPase in the isolated elongated mitochondria was as high as that in intracellular mitochondria. On the other hand, some of the spherical mitochondria isolated with this method had the outer membrane that no longer encapsulated the inner membrane. In addition, all mitochondria isolated using conventional procedures involving homogenization were spherical, many of them had damaged membranes, and low levels of ATP generation. Our results suggest that elongated mitochondria isolated from cells through gentle cell membrane disruption using a pore-forming protein tend to be more similar to intracellular mitochondria, having an intact membrane system and higher activity than spherical mitochondria. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Bacillus thuringiensis Cyt2Aa2 toxin disrupts cell membranes by forming large protein aggregates

    Science.gov (United States)

    Tharad, Sudarat; Toca-Herrera, José L.; Promdonkoy, Boonhiang; Krittanai, Chartchai

    2016-01-01

    Bacillus thuringiensis (Bt) Cyt2Aa2 showed toxicity against Dipteran insect larvae and in vitro lysis activity on several cells. It has potential applications in the biological control of insect larvae. Although pore-forming and/or detergent-like mechanisms were proposed, the mechanism underlying cytolytic activity remains unclear. Analysis of the haemolytic activity of Cyt2Aa2 with osmotic stabilizers revealed partial toxin inhibition, suggesting a distinctive mechanism from the putative pore formation model. Membrane permeability was studied using fluorescent dye entrapped in large unilamellar vesicles (LUVs) at various protein/lipid molar ratios. Binding of Cyt2Aa2 monomer to the lipid membrane did not disturb membrane integrity until the critical protein/lipid molar ratio was reached, when Cyt2Aa2 complexes and cytolytic activity were detected. The complexes are large aggregates that appeared as a ladder when separated by agarose gel electrophoresis. Interaction of Cyt2Aa2 with Aedes albopictus cells was investigated by confocal microscopy and total internal reflection fluorescent microscopy (TIRF). The results showed that Cyt2Aa2 binds on the cell membrane at an early stage without cell membrane disruption. Protein aggregation on the cell membrane was detected later which coincided with cell swelling. Cyt2Aa2 aggregations on supported lipid bilayers (SLBs) were visualized by AFM. The AFM topographic images revealed Cyt2Aa2 aggregates on the lipid bilayer at low protein concentration and subsequently disrupts the lipid bilayer by forming a lesion as the protein concentration increased. These results supported the mechanism whereby Cyt2Aa2 binds and aggregates on the lipid membrane leading to the formation of non-specific hole and disruption of the cell membrane. PMID:27612497

  14. A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli.

    Science.gov (United States)

    Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H; Pessi, Gabriella; Eberl, Leo; Robinson, John A

    2016-01-22

    Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM.

  15. From biological membranes to biomimetic model membranes

    Directory of Open Access Journals (Sweden)

    Eeman, M.

    2010-01-01

    Full Text Available Biological membranes play an essential role in the cellular protection as well as in the control and the transport of nutrients. Many mechanisms such as molecular recognition, enzymatic catalysis, cellular adhesion and membrane fusion take place into the biological membranes. In 1972, Singer et al. provided a membrane model, called fluid mosaic model, in which each leaflet of the bilayer is formed by a homogeneous environment of lipids in a fluid state including globular assembling of proteins and glycoproteins. Since its conception in 1972, many developments were brought to this model in terms of composition and molecular organization. The main development of the fluid mosaic model was made by Simons et al. (1997 and Brown et al. (1997 who suggested that membrane lipids are organized into lateral microdomains (or lipid rafts with a specific composition and a molecular dynamic that are different to the composition and the dynamic of the surrounding liquid crystalline phase. The discovery of a phase separation in the plane of the membrane has induced an explosion in the research efforts related to the biology of cell membranes but also in the development of new technologies for the study of these biological systems. Due to the high complexity of biological membranes and in order to investigate the biological processes that occur on the membrane surface or within the membrane lipid bilayer, a large number of studies are performed using biomimicking model membranes. This paper aims at revisiting the fundamental properties of biological membranes in terms of membrane composition, membrane dynamic and molecular organization, as well as at describing the most common biomimicking models that are frequently used for investigating biological processes such as membrane fusion, membrane trafficking, pore formation as well as membrane interactions at a molecular level.

  16. Interaction of Defensins with Model Cell Membranes

    Science.gov (United States)

    Sanders, Lori K.; Schmidt, Nathan W.; Yang, Lihua; Mishra, Abhijit; Gordon, Vernita D.; Selsted, Michael E.; Wong, Gerard C. L.

    2009-03-01

    Antimicrobial peptides (AMPs) comprise a key component of innate immunity for a wide range of multicellular organisms. For many AMPs, activity comes from their ability to selectively disrupt and lyse bacterial cell membranes. There are a number of proposed models for this action, but the detailed molecular mechanism of selective membrane permeation remains unclear. Theta defensins are circularized peptides with a high degree of selectivity. We investigate the interaction of model bacterial and eukaryotic cell membranes with theta defensins RTD-1, BTD-7, and compare them to protegrin PG-1, a prototypical AMP, using synchrotron small angle x-ray scattering (SAXS). The relationship between membrane composition and peptide induced changes in membrane curvature and topology is examined. By comparing the membrane phase behavior induced by these different peptides we will discuss the importance of amino acid composition and placement on membrane rearrangement.

  17. Potential of novel antimicrobial peptide P3 from bovine erythrocytes and its analogs to disrupt bacterial membranes in vitro and display activity against drug-resistant bacteria in a mouse model.

    Science.gov (United States)

    Zhang, Qinghua; Xu, Yanzhao; Wang, Qing; Hang, Bolin; Sun, Yawei; Wei, Xiaoxiao; Hu, Jianhe

    2015-05-01

    With the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activity in vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, both in vitro and in vivo. The MICs of P3 and JH-3 ranged from 3.125 μg/ml to 50 μg/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an α-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD50) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria.

  18. BUSINESS MODEL PATTERNS FOR DISRUPTIVE TECHNOLOGIES

    OpenAIRE

    BENJAMIN AMSHOFF; CHRISTIAN DÜLME; JULIAN ECHTERFELD; JÜRGEN GAUSEMEIER

    2015-01-01

    Companies nowadays face a myriad of business opportunities as a direct consequence of manifold disruptive technology developments. As a basic characteristic, disruptive technologies lead to a severe shift in value-creation networks giving rise to new market segments. One of the key challenges is to anticipate the business logics within these nascent and formerly unknown markets. Business model patterns promise to tackle this challenge. They can be interpreted as proven business model elements...

  19. Cationic peptide exposure enhances pulsed-electric-field-mediated membrane disruption.

    Directory of Open Access Journals (Sweden)

    Stephen M Kennedy

    Full Text Available The use of pulsed electric fields (PEFs to irreversibly electroporate cells is a promising approach for destroying undesirable cells. This approach may gain enhanced applicability if the intensity of the PEF required to electrically disrupt cell membranes can be reduced via exposure to a molecular deliverable. This will be particularly impactful if that reduced PEF minimally influences cells that are not exposed to the deliverable. We hypothesized that the introduction of charged molecules to the cell surfaces would create regions of enhanced transmembrane electric potential in the vicinity of each charged molecule, thereby lowering the PEF intensity required to disrupt the plasma membranes. This study will therefore examine if exposure to cationic peptides can enhance a PEF's ability to disrupt plasma membranes.We exposed leukemia cells to 40 μs PEFs in media containing varying concentrations of a cationic peptide, polyarginine. We observed the internalization of a membrane integrity indicator, propidium iodide (PI, in real time. Based on an individual cell's PI fluorescence versus time signature, we were able to determine the relative degree of membrane disruption. When using 1-2 kV/cm, exposure to >50 μg/ml of polyarginine resulted in immediate and high levels of PI uptake, indicating severe membrane disruption, whereas in the absence of peptide, cells predominantly exhibited signatures indicative of no membrane disruption. Additionally, PI entered cells through the anode-facing membrane when exposed to cationic peptide, which was theoretically expected.Exposure to cationic peptides reduced the PEF intensity required to induce rapid and irreversible membrane disruption. Critically, peptide exposure reduced the PEF intensities required to elicit irreversible membrane disruption at normally sub-electroporation intensities. We believe that these cationic peptides, when coupled with current advancements in cell targeting techniques will be

  20. Loss of elongation factor P disrupts bacterial outer membrane integrity

    DEFF Research Database (Denmark)

    Zou, S Betty; Hersch, Steven J; Roy, Hervé;

    2012-01-01

    increased uptake of the hydrophobic dye 1-N-phenylnaphthylamine (NPN). Analysis of the membrane proteomes of wild-type and efp mutant Salmonella strains reveals few changes, including the prominent overexpression of a single porin, KdgM, in the efp mutant outer membrane. Removal of KdgM in the efp mutant...... overexpression of an outer membrane porin....

  1. The intra-operative radius joystick test to diagnose complete disruption of the interosseous membrane.

    Science.gov (United States)

    Soubeyrand, M; Ciais, G; Wassermann, V; Kalouche, I; Biau, D; Dumontier, C; Gagey, O

    2011-10-01

    Disruption of the interosseous membrane is easily missed in patients with Essex-Lopresti syndrome. None of the imaging techniques available for diagnosing disruption of the interosseous membrane are completely dependable. We undertook an investigation to identify whether a simple intra-operative test could be used to diagnose disruption of the interosseous membrane during surgery for fracture of the radial head and to see if the test was reproducible. We studied 20 cadaveric forearms after excision of the radial head, ten with and ten without disruption of the interosseous membrane. On each forearm, we performed the radius joystick test: moderate lateral traction was applied to the radial neck with the forearm in maximal pronation, to look for lateral displacement of the proximal radius indicating that the interosseous membrane had been disrupted. Each of six surgeons (three junior and three senior) performed the test on two consecutive days. Intra-observer agreement was 77% (95% confidence interval (CI) 67 to 85) and interobserver agreement was 97% (95% CI 92 to 100). Sensitivity was 100% (95% CI 97 to 100), specificity 88% (95% CI 81 to 93), positive predictive value 90% (95% CI 83 to 94), and negative predictive value 100%). This cadaveric study suggests that the radius joystick test may be useful for detecting disruption of the interosseous membrane in patients undergoing open surgery for fracture of the radial head and is reproducible. A confirmatory study in vivo is now required.

  2. Applying fluorescence correlation spectroscopy to investigate peptide-induced membrane disruption

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Henriksen, Jonas Rosager; Andresen, Thomas Lars

    2017-01-01

    to quantify leakage of fluorescent molecules of different sizes from large unilamellar lipid vesicles, thereby providing a tool for estimating the size of peptide-induced membrane disruptions. If fluorescently labeled lipids are incorporated into the membranes of the vesicles, FCS can also be used to obtain...

  3. Amphibians as model to study endocrine disrupters.

    Science.gov (United States)

    Kloas, Werner; Lutz, Ilka

    2006-10-13

    Environmental compounds can interfere with endocrine systems of wildlife and humans. These so-called endocrine disrupters (ED) are known to affect reproductive biology and thyroid system. The classical model species for these endocrine systems are amphibians and therefore they can serve as sentinels for detection of the modes of action (MOAs) of ED. Recently, amphibians are being reviewed as suitable models to assess (anti)estrogenic and (anti)androgenic MOAs influencing reproductive biology as well as (anti)thyroidal MOAs interfering with the thyroid system. The development of targeted bioassays in combination with adequate chemical analyses is the prerequisite for a concise risk assessment of ED.

  4. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  5. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  6. On "spinning" membrane models

    NARCIS (Netherlands)

    Bergshoeff, E.; Sezgin, E.; Townsend, P.K.

    1988-01-01

    Several alternative actions for a bosonic membrane have recently been proposed. We show that a linearly realized locally world-volume-supersymmetric (spinning membrane) extension of any of these actions implies an analogous extension of the standard Dirac membrane action. We further show that a

  7. Modeling Steroidogenesis Disruption Using High-Throughput ...

    Science.gov (United States)

    Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on steroidogenesis. The steroidogenic pathway is a series of hydroxylation and dehydrogenation steps carried out by CYP450 and hydroxysteroid dehydrogenase enzymes, yet the only enzyme in the pathway for which a high-throughput screening (HTS) assay has been developed is aromatase (CYP19A1), responsible for the aromatization of androgens to estrogens. Recently, the ToxCast HTS program adapted the OECD validated H295R steroidogenesis assay using human adrenocortical carcinoma cells into a high-throughput model to quantitatively assess the concentration-dependent (0.003-100 µM) effects of chemicals on 10 steroid hormones including progestagens, androgens, estrogens and glucocorticoids. These results, in combination with two CYP19A1 inhibition assays, comprise a large dataset amenable to clustering approaches supporting the identification and characterization of putative mechanisms of action (pMOA) for steroidogenesis disruption. In total, 514 chemicals were tested in all CYP19A1 and steroidogenesis assays. 216 chemicals were identified as CYP19A1 inhibitors in at least one CYP19A1 assay. 208 of these chemicals also altered hormone levels in the H295R assay, suggesting 96% sensitivity in the

  8. Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes.

    Science.gov (United States)

    Svangård, Erika; Burman, Robert; Gunasekera, Sunithi; Lövborg, Henrik; Gullbo, Joachim; Göransson, Ulf

    2007-04-01

    In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.

  9. Marine sponge cyclic peptide theonellamide A disrupts lipid bilayer integrity without forming distinct membrane pores.

    Science.gov (United States)

    Espiritu, Rafael Atillo; Cornelio, Kimberly; Kinoshita, Masanao; Matsumori, Nobuaki; Murata, Michio; Nishimura, Shinichi; Kakeya, Hideaki; Yoshida, Minoru; Matsunaga, Shigeki

    2016-06-01

    Theonellamides (TNMs) are antifungal and cytotoxic bicyclic dodecapeptides derived from the marine sponge Theonella sp. These peptides specifically bind to 3β-hydroxysterols, resulting in 1,3-β-D-glucan overproduction and membrane damage in yeasts. The inclusion of cholesterol or ergosterol in phosphatidylcholine membranes significantly enhanced the membrane affinity of theonellamide A (TNM-A) because of its direct interaction with 3β-hydroxyl groups of sterols. To better understand TNM-induced membrane alterations, we investigated the effects of TNM-A on liposome morphology. (31)P nuclear magnetic resonance (NMR) and dynamic light scattering (DLS) measurements revealed that the premixing of TNM-A with lipids induced smaller vesicle formation. When giant unilamellar vesicles were incubated with exogenously added TNM-A, confocal micrographs showed dynamic changes in membrane morphology, which were more frequently observed in cholesterol-containing than sterol-free liposomes. In conjunction with our previous data, these results suggest that the membrane action of TNM-A proceeds in two steps: 1) TNM-A binds to the membrane surface through direct interaction with sterols and 2) accumulated TNM-A modifies the local membrane curvature in a concentration-dependent manner, resulting in dramatic membrane morphological changes and membrane disruption.

  10. Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein

    Directory of Open Access Journals (Sweden)

    Masahiro Kawahara

    2011-01-01

    Full Text Available Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP play crucial roles in the pathogenesis of Alzheimer's disease (AD. Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AβPs directly incorporate into neuronal membranes, form cation-sensitive ion channels (“amyloid channels”, and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or α-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AβP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed.

  11. Engineering bioinspired bacteria-adhesive clay nanoparticles with a membrane-disruptive property for the treatment of Helicobacter pylori infection.

    Science.gov (United States)

    Ping, Yuan; Hu, Xiurong; Yao, Qi; Hu, Qida; Amini, Shahrouz; Miserez, Ali; Tang, Guping

    2016-09-28

    We present a bioinspired design strategy to engineer bacteria-targeting and membrane-disruptive nanoparticles for the effective antibiotic therapy of Helicobacter pylori (H. pylori) infection. Antibacterial nanoparticles were self-assembled from highly exfoliated montmorillonite (eMMT) and cationic linear polyethyleneimine (lPEI) via electrostatic interactions. eMMT functions as a bioinspired 'sticky' building block for anchoring antibacterial nanoparticles onto the bacterial cell surface via bacteria-secreted extracellular polymeric substances (EPS), whereas membrane-disruptive lPEI is able to efficiently lyse the bacterial outer membrane to allow topical transmembrane delivery of antibiotics into the intracellular cytoplasm. As a result, eMMT-lPEI nanoparticles intercalated with the antibiotic metronidazole (MTZ) not only efficiently target bacteria via EPS-mediated adhesion and kill bacteria in vitro, but also can effectively remain in the stomach where H. pylori reside, thereby serving as an efficient drug carrier for the direct on-site release of MTZ into the bacterial cytoplasm. Importantly, MTZ-intercalated eMMT-lPEI nanoparticles were able to efficiently eradicate H. pylori in vivo and to significantly improve H. pylori-associated gastric ulcers and the inflammatory response in a mouse model, and also showed superior therapeutic efficacy as compared to standard triple therapy. Our findings reveal that bacterial adhesion plays a critical role in promoting efficient antimicrobial delivery and also represent an original bioinspired targeting strategy via specific EPS-mediated adsorption. The bacteria-adhesive eMMT-lPEI nanoparticles with membrane-disruptive ability may constitute a promising drug carrier system for the efficacious targeted delivery of antibiotics in the treatment of bacterial infections.

  12. Modelling of proteins in membranes

    DEFF Research Database (Denmark)

    Sperotto, Maria Maddalena; May, S.; Baumgaertner, A.

    2006-01-01

    This review describes some recent theories and simulations of mesoscopic and microscopic models of lipid membranes with embedded or attached proteins. We summarize results supporting our understanding of phenomena for which the activities of proteins in membranes are expected to be significantly...... affected by the lipid environment. Theoretical predictions are pointed out, and compared to experimental findings, if available. Among others, the following phenomena are discussed: interactions of interfacially adsorbed peptides, pore-forming amphipathic peptides, adsorption of charged proteins onto...... oppositely charged lipid membranes, lipid-induced tilting of proteins embedded in lipid bilayers, protein-induced bilayer deformations, protein insertion and assembly, and lipid-controlled functioning of membrane proteins....

  13. Modelling of proteins in membranes

    DEFF Research Database (Denmark)

    Sperotto, Maria Maddalena; May, S.; Baumgaertner, A.

    2006-01-01

    This review describes some recent theories and simulations of mesoscopic and microscopic models of lipid membranes with embedded or attached proteins. We summarize results supporting our understanding of phenomena for which the activities of proteins in membranes are expected to be significantly ...

  14. Disruption in a Neurodevelopmental Model of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Benjamin Rolland

    2012-01-01

    Full Text Available Oxidative stress has been implicated in neurodevelopmental theories of schizophrenia. Antioxidant Peroxysome Proliferator-Activated Receptors α (PPARα agonist fenofibrate has neuroprotective properties and could reverse early preclinical infringements that could trigger the illness. We have evaluated the neuroprotective interest of fenofibrate in a neurodevelopmental rat model of schizophrenia. The oxidative lesion induced by Kainic Acid (KA injection at postnatal day (PND 7 has previously been reported to disrupt Prepulse Inhibition (PPI at PND56 but not at PND35. In 4 groups of 15 male rats each, KN (KA-PND7 + normal postweaning food, KF (KA-PND7 + fenofibrate 0.2% food, ON (saline-PND7 + normal food, and OF (saline + fenofibrate food, PPI was recorded at PND35 and PND56. Three levels of prepulse were used: 73 dB, 76 dB, and 82 dB for a pulse at 120 dB. Four PPI scores were analyzed: PPI73, PPI76, PPI82, and mean PPI (PPIm. Two-way ANOVAs were used to evaluate the effects of both factors (KA + fenofibrate, and, in case of significant results, intergroup Student’s t-tests were performed. We notably found a significant difference (P<0.05 in PPIm between groups KN and KF at PND56, which supposes that fenofibrate could be worthy of interest for early neuroprotection in schizophrenia.

  15. A Model for Membrane Fusion

    Science.gov (United States)

    Ngatchou, Annita

    2010-01-01

    Pheochromocytoma is a tumor of the adrenal gland which originates from chromaffin cells and is characterized by the secretion of excessive amounts of neurotransmitter which lead to high blood pressure and palpitations. Pheochromocytoma contain membrane bound granules that store neurotransmitter. The release of these stored molecules into the extracellular space occurs by fusion of the granule membrane with the cell plasma membrane, a process called exocytosis. The molecular mechanism of this membrane fusion is not well understood. It is proposed that the so called SNARE proteins [1] are the pillar of vesicle fusion as their cleavage by clostridial toxin notably, Botulinum neurotoxin and Tetanus toxin abrogate the secretion of neurotransmitter [2]. Here, I describe how physical principles are applied to a biological cell to explore the role of the vesicle SNARE protein synaptobrevin-2 in easing granule fusion. The data presented here suggest a paradigm according to which the movement of the C-terminal of synaptobrevin-2 disrupts the lipid bilayer to form a fusion pore through which molecules can exit.

  16. Biomembrane disruption by silica-core nanoparticles: effect of surface functional group measured using a tethered bilayer lipid membrane.

    Science.gov (United States)

    Liu, Ying; Zhang, Zhen; Zhang, Quanxuan; Baker, Gregory L; Worden, R Mark

    2014-01-01

    Engineered nanomaterials (ENM) have desirable properties that make them well suited for many commercial applications. However, a limited understanding of how ENM's properties influence their molecular interactions with biomembranes hampers efforts to design ENM that are both safe and effective. This paper describes the use of a tethered bilayer lipid membrane (tBLM) to characterize biomembrane disruption by functionalized silica-core nanoparticles. Electrochemical impedance spectroscopy was used to measure the time trajectory of tBLM resistance following nanoparticle exposure. Statistical analysis of parameters from an exponential resistance decay model was then used to quantify and analyze differences between the impedance profiles of nanoparticles that were unfunctionalized, amine-functionalized, or carboxyl-functionalized. All of the nanoparticles triggered a decrease in membrane resistance, indicating nanoparticle-induced disruption of the tBLM. Hierarchical clustering allowed the potency of nanoparticles for reducing tBLM resistance to be ranked in the order amine>carboxyl~bare silica. Dynamic light scattering analysis revealed that tBLM exposure triggered minor coalescence for bare and amine-functionalized silica nanoparticles but not for carboxyl-functionalized silica nanoparticles. These results indicate that the tBLM method can reproducibly characterize ENM-induced biomembrane disruption and can distinguish the BLM-disruption patterns of nanoparticles that are identical except for their surface functional groups. The method provides insight into mechanisms of molecular interaction involving biomembranes and is suitable for miniaturization and automation for high-throughput applications to help assess the health risk of nanomaterial exposure or identify ENM having a desired mode of interaction with biomembranes. © 2013. Published by Elsevier B.V. All rights reserved.

  17. A model of disruptive surgeon behavior in the perioperative environment.

    Science.gov (United States)

    Cochran, Amalia; Elder, William B

    2014-09-01

    Surgeons are the physicians with the highest rates of documented disruptive behavior. We hypothesized that a unified conceptual model of disruptive surgeon behavior could be developed based on specific individual and system factors in the perioperative environment. Semi-structured interviews were conducted with 19 operating room staff of diverse occupations at a single institution. Interviews were analyzed using grounded theory methods. Participants described episodes of disruptive surgeon behavior, personality traits of perpetrators, environmental conditions of power, and situations when disruptive behavior was demonstrated. Verbal hostility and throwing or hitting objects were the most commonly described disruptive behaviors. Participants indicated that surgical training attracts and creates individuals with particular personality traits, including a sense of shame. Interviewees stated this behavior is tolerated because surgeons have unchecked power, have strong money-making capabilities for the institution, and tend to direct disruptive behavior toward the least powerful employees. The most frequent situational stressors were when something went wrong during an operation and working with unfamiliar team members. Each factor group (ie, situational stressors, cultural conditions, and personality factors) was viewed as being necessary, but none of them alone were sufficient to catalyze disruptive behavior events. Disruptive physician behavior has strong implications for the work environment and patient safety. This model can be used by hospitals to better conceptualize conditions that facilitate disruptive surgeon behavior and to establish programs to mitigate conduct that threatens patient safety and employee satisfaction. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  18. Mathematical modelling of membrane separation

    DEFF Research Database (Denmark)

    Vinther, Frank

    This thesis concerns mathematical modelling of membrane separation. The thesis consists of introductory theory on membrane separation, equations of motion, and properties of dextran, which will be the solute species throughout the thesis. Furthermore, the thesis consist of three separate mathemat......This thesis concerns mathematical modelling of membrane separation. The thesis consists of introductory theory on membrane separation, equations of motion, and properties of dextran, which will be the solute species throughout the thesis. Furthermore, the thesis consist of three separate....... It is found that the probability of entering the pore is highest when the largest of the radii in the ellipse is equal to half the radius of the pore, in case of molecules with circular radius less than the pore radius. The results are directly related to the macroscopic distribution coefficient...

  19. Tracking membrane protein association in model membranes.

    Directory of Open Access Journals (Sweden)

    Myriam Reffay

    Full Text Available Membrane proteins are essential in the exchange processes of cells. In spite of great breakthrough in soluble proteins studies, membrane proteins structures, functions and interactions are still a challenge because of the difficulties related to their hydrophobic properties. Most of the experiments are performed with detergent-solubilized membrane proteins. However widely used micellar systems are far from the biological two-dimensions membrane. The development of new biomimetic membrane systems is fundamental to tackle this issue.We present an original approach that combines the Fluorescence Recovery After fringe Pattern Photobleaching technique and the use of a versatile sponge phase that makes it possible to extract crucial informations about interactions between membrane proteins embedded in the bilayers of a sponge phase. The clear advantage lies in the ability to adjust at will the spacing between two adjacent bilayers. When the membranes are far apart, the only possible interactions occur laterally between proteins embedded within the same bilayer, whereas when membranes get closer to each other, interactions between proteins embedded in facing membranes may occur as well.After validating our approach on the streptavidin-biotinylated peptide complex, we study the interactions between two membrane proteins, MexA and OprM, from a Pseudomonas aeruginosa efflux pump. The mode of interaction, the size of the protein complex and its potential stoichiometry are determined. In particular, we demonstrate that: MexA is effectively embedded in the bilayer; MexA and OprM do not interact laterally but can form a complex if they are embedded in opposite bilayers; the population of bound proteins is at its maximum for bilayers separated by a distance of about 200 A, which is the periplasmic thickness of Pseudomonas aeruginosa. We also show that the MexA-OprM association is enhanced when the position and orientation of the protein is restricted by the

  20. Geometry of Membrane Sigma Models

    CERN Document Server

    Vysoky, Jan

    2015-01-01

    String theory still remains one of the promising candidates for a unification of the theory of gravity and quantum field theory. One of its essential parts is relativistic description of moving multi-dimensional objects called membranes (or p-branes) in a curved spacetime. On the classical field theory level, they are described by an action functional extremalising the volume of a manifold swept by a propagating membrane. This and related field theories are collectively called membrane sigma models. Differential geometry is an important mathematical tool in the study of string theory. It turns out that string and membrane backgrounds can be conveniently described using objects defined on a direct sum of tangent and cotangent bundles of the spacetime manifold. Mathematical field studying such object is called generalized geometry. Its integral part is the theory of Leibniz algebroids, vector bundles with a Leibniz algebra bracket on its module of smooth sections. Special cases of Leibniz algebroids are better ...

  1. Supply chain disruption assessment based on the newsvendor model

    Directory of Open Access Journals (Sweden)

    Yisong Li

    2013-03-01

    Full Text Available Purpose: This paper focuses on supply chain disruption assessment.Design/methodology/approach: Newsvendor ModelFindings: As both cost and income principle will be taken into account in supply chain disruption assessment, we proposed in this paper: (1 the problem of supply chain disruption assessment is the trade-off problem. (2 the generic single period - newsvendor model can be used for capturing the critical point, which in tradition model stands for the demarcation point of profit but in this paper is the least costs considering disruption costs and expected revenues.Research limitations/implications: single period - newsvendor modelPractical implications: we give an example for test the effectiveness of this methodOriginality/value: to research supply chain risk in a new approach, that is: supply chain risk has both cost and profit. So we can assess it with trade-off method

  2. Modeling electrically active viscoelastic membranes.

    Directory of Open Access Journals (Sweden)

    Sitikantha Roy

    Full Text Available The membrane protein prestin is native to the cochlear outer hair cell that is crucial to the ear's amplification and frequency selectivity throughout the whole acoustic frequency range. The outer hair cell exhibits interrelated dimensional changes, force generation, and electric charge transfer. Cells transfected with prestin acquire unique active properties similar to those in the native cell that have also been useful in understanding the process. Here we propose a model describing the major electromechanical features of such active membranes. The model derived from thermodynamic principles is in the form of integral relationships between the history of voltage and membrane resultants as independent variables and the charge density and strains as dependent variables. The proposed model is applied to the analysis of an active force produced by the outer hair cell in response to a harmonic electric field. Our analysis reveals the mechanism of the outer hair cell active (isometric force having an almost constant amplitude and phase up to 80 kHz. We found that the frequency-invariance of the force is a result of interplay between the electrical filtering associated with prestin and power law viscoelasticity of the surrounding membrane. Paradoxically, the membrane viscoelasticity boosts the force balancing the electrical filtering effect. We also consider various modes of electromechanical coupling in membrane with prestin associated with mechanical perturbations in the cell. We consider pressure or strains applied step-wise or at a constant rate and compute the time course of the resulting electric charge. The results obtained here are important for the analysis of electromechanical properties of membranes, cells, and biological materials as well as for a better understanding of the mechanism of hearing and the role of the protein prestin in this mechanism.

  3. Nanosecond pulsed electric field (nsPEF) enhance cytotoxicity of cisplatin to hepatocellular cells by microdomain disruption on plasma membrane.

    Science.gov (United States)

    Yin, Shengyong; Chen, Xinhua; Xie, Haiyang; Zhou, Lin; Guo, Danjing; Xu, Yuning; Wu, Liming; Zheng, Shusen

    2016-08-15

    Previous studies showed nanosecond pulsed electric field (nsPEF) can ablate solid tumors including hepatocellular carcinoma (HCC) but its effect on cell membrane is not fully understood. We hypothesized nsPEF disrupt the microdomains on outer-cellular membrane with direct mechanical force and as a result the plasma membrane permeability increases to facilitate the small molecule intake. Three HCC cells were pulsed one pulse per minute, an interval longer than nanopore resealing time. The cationized ferritin was used to mark up the electronegative microdomains, propidium iodide (PI) for membrane permeabilization, energy dispersive X-ray spectroscopy (EDS) for the negative cell surface charge and cisplatin for inner-cellular cytotoxicity. We demonstrated that the ferritin marked-microdomain and negative cell surface charge were disrupted by nsPEF caused-mechanical force. The cell uptake of propidium and cytotoxicity of DNA-targeted cisplatin increased with a dose effect. Cisplatin gains its maximum inner-cellular cytotoxicity when combining with nsPEF stimulation. We conclude that nsPEF disrupt the microdomains on the outer cellular membrane directly and increase the membrane permeabilization for PI and cisplatin. The microdomain disruption and membrane infiltration changes are caused by the mechanical force from the changes of negative cell surface charge.

  4. Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

    Science.gov (United States)

    Datta, Sandipan; Mahdi, Fakhri; Ali, Zulfiqar; Jekabsons, Mika B.; Khan, Ikhlas A.; Nagle, Dale G.; Zhou, Yu-Dong

    2014-01-01

    Certain botanical dietary supplements have been associated with idiosyncratic organ-specific toxicity. Similar toxicological events, caused by drug-induced mitochondrial dysfunction, have forced the withdrawal or U.S. FDA “Black Box” warnings of major pharmaceuticals. To assess the potential mitochondrial liability of botanical dietary supplements, extracts from 352 authenticated plant samples used in traditional Chinese, Ayurvedic, and Western herbal medicine were evaluated for the ability to disrupt cellular respiration. Blue cohosh (Caulophyllum thalictroides) methanol extract exhibited mitochondriotoxic activity. Used by some U.S. midwives to help induce labor, blue cohosh has been associated with perinatal stroke, acute myocardial infarction, congestive heart failure, multiple organ injury, and neonatal shock. The potential link between mitochondrial disruption and idiosyncratic herbal intoxication prompted further examination. The C. thalictroides methanol extract and three saponins, cauloside A (1), saponin PE (2), and cauloside C (3) exhibited concentration- and time-dependent mitochondriotoxic activities. Upon treatment, cell respiration rate rapidly increased and then dramatically decreased within minutes. Mechanistic studies revealed that C. thalictroides constituents impair mitochondrial function by disrupting membrane integrity. These studies provide a potential etiological link between this mitochondria-sensitive form of cytotoxicity and idiosyncratic organ damage. PMID:24328138

  5. Toxins in botanical dietary supplements: blue cohosh components disrupt cellular respiration and mitochondrial membrane potential.

    Science.gov (United States)

    Datta, Sandipan; Mahdi, Fakhri; Ali, Zulfiqar; Jekabsons, Mika B; Khan, Ikhlas A; Nagle, Dale G; Zhou, Yu-Dong

    2014-01-24

    Certain botanical dietary supplements have been associated with idiosyncratic organ-specific toxicity. Similar toxicological events, caused by drug-induced mitochondrial dysfunction, have forced the withdrawal or U.S. FDA "black box" warnings of major pharmaceuticals. To assess the potential mitochondrial liability of botanical dietary supplements, extracts from 352 authenticated plant samples used in traditional Chinese, Ayurvedic, and Western herbal medicine were evaluated for the ability to disrupt cellular respiration. Blue cohosh (Caulophyllum thalictroides) methanol extract exhibited mitochondriotoxic activity. Used by some U.S. midwives to help induce labor, blue cohosh has been associated with perinatal stroke, acute myocardial infarction, congestive heart failure, multiple organ injury, and neonatal shock. The potential link between mitochondrial disruption and idiosyncratic herbal intoxication prompted further examination. The C. thalictroides methanol extract and three saponins, cauloside A (1), saponin PE (2), and cauloside C (3), exhibited concentration- and time-dependent mitochondriotoxic activities. Upon treatment, cell respiration rate rapidly increased and then dramatically decreased within minutes. Mechanistic studies revealed that C. thalictroides constituents impair mitochondrial function by disrupting membrane integrity. These studies provide a potential etiological link between this mitochondria-sensitive form of cytotoxicity and idiosyncratic organ damage.

  6. Spermicidal efficacy of VRP, a synthetic cationic antimicrobial peptide, inducing apoptosis and membrane disruption.

    Science.gov (United States)

    Ghosh, Prasanta; Bhoumik, Arpita; Saha, Sudipta; Mukherjee, Sandipan; Azmi, Sarfuddin; Ghosh, Jimut K; Dungdung, Sandhya R

    2017-04-14

    Presently available contraceptives are mostly hormonal or detergent in nature with numerous side effects like irritation, lesion, inflammation in vagina, alteration of body homeostasis, etc. Antimicrobial peptides with spermicidal activity but without adverse effects may be suitable alternatives. In the present study, spermicidal activity of a cationic antimicrobial peptide VRP on human spermatozoa has been elucidated. Progressive forward motility of human spermatozoa was instantly stopped after 100 μM VRP treatment and at 350 μM, all kinds of sperm motility ceased within 20 s as assessed by the Sander-Cramer assay. The spermicidal effect was confirmed by eosin-nigrosin assay and HOS test. VRP treatment (100 μM) in human spermatozoa induced both the intrinsic and extrinsic pathways of apoptosis. TUNEL assay showed VRP treatment significantly disrupted the DNA integrity and changed the mitochondrial membrane permeability as evident from MPTP assay. AFM and SEM results depicted ultra structural changes including disruption of the acrosomal cap and plasma membrane of the head and midpiece region after treatment with 350 μM VRP. MTT assay showed after treatments with 100 and 350 μM of VRP for 24 hr, a substantial amount of Lactobacillus acidophilus (about 90% and 75%, respectively) remained viable. Hence, VRP being a small synthetic peptide with antimicrobial and spermicidal activity but tolerable to normal vaginal microflora, may be a suitable target for elucidating its contraceptive potentiality. © 2017 Wiley Periodicals, Inc.

  7. Giant plasma membrane vesicles: models for understanding membrane organization.

    Science.gov (United States)

    Levental, Kandice R; Levental, Ilya

    2015-01-01

    The organization of eukaryotic membranes into functional domains continues to fascinate and puzzle cell biologists and biophysicists. The lipid raft hypothesis proposes that collective lipid interactions compartmentalize the membrane into coexisting liquid domains that are central to membrane physiology. This hypothesis has proven controversial because such structures cannot be directly visualized in live cells by light microscopy. The recent observations of liquid-liquid phase separation in biological membranes are an important validation of the raft hypothesis and enable application of the experimental toolbox of membrane physics to a biologically complex phase-separated membrane. This review addresses the role of giant plasma membrane vesicles (GPMVs) in refining the raft hypothesis and expands on the application of GPMVs as an experimental model to answer some of key outstanding problems in membrane biology. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Naja naja oxiana Cobra Venom Cytotoxins CTI and CTII Disrupt Mitochondrial Membrane Integrity: Implications for Basic Three-Fingered Cytotoxins.

    Science.gov (United States)

    Gasanov, Sardar E; Shrivastava, Indira H; Israilov, Firuz S; Kim, Aleksandr A; Rylova, Kamila A; Zhang, Boris; Dagda, Ruben K

    2015-01-01

    Cobra venom cytotoxins are basic three-fingered, amphipathic, non-enzymatic proteins that constitute a major fraction of cobra venom. While cytotoxins cause mitochondrial dysfunction in different cell types, the mechanisms by which cytotoxins bind to mitochondria remain unknown. We analyzed the abilities of CTI and CTII, S-type and P-type cytotoxins from Naja naja oxiana respectively, to associate with isolated mitochondrial fractions or with model membranes that simulate the mitochondrial lipid environment by using a myriad of biophysical techniques. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy data suggest that both cytotoxins bind to isolated mitochondrial fractions and promote the formation of aberrant non-bilayer structures. We then hypothesized that CTI and CTII bind to cardiolipin (CL) to disrupt mitochondrial membranes. Collectively, 31P-NMR, electron paramagnetic resonance (EPR), proton NMR (1H-NMR), deuterium NMR (2H-NMR) spectroscopy, differential scanning calorimetry, and erythrosine phosphorescence assays suggest that CTI and CTII bind to CL to generate non-bilayer structures and promote the permeabilization, dehydration and fusion of large unilamellar phosphatidylcholine (PC) liposomes enriched with CL. On the other hand, CTII but not CTI caused biophysical alterations of large unilamellar PC liposomes enriched with phosphatidylserine (PS). Mechanistically, single molecule docking simulations identified putative CL, PS and PC binding sites in CTI and CTII. While the predicted binding sites for PS and PC share a high number of interactive amino acid residues in CTI and CTII, the CL biding sites in CTII and CTI are more divergent as it contains additional interactive amino acid residues. Overall, our data suggest that cytotoxins physically associate with mitochondrial membranes by binding to CL to disrupt mitochondrial structural integrity.

  9. Helicobacter pylori Disrupts Host Cell Membranes, Initiating a Repair Response and Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Hsueh-Fen Juan

    2012-08-01

    Full Text Available Helicobacter pylori (H. pylori, the human stomach pathogen, lives on the inner surface of the stomach and causes chronic gastritis, peptic ulcer, and gastric cancer. Plasma membrane repair response is a matter of life and death for human cells against physical and biological damage. We here test the hypothesis that H. pylori also causes plasma membrane disruption injury, and that not only a membrane repair response but also a cell proliferation response are thereby activated. Vacuolating cytotoxin A (VacA and cytotoxin-associated gene A (CagA have been considered to be major H. pylori virulence factors. Gastric cancer cells were infected with H. pylori wild type (vacA+/cagA+, single mutant (ΔvacA or ΔcagA or double mutant (ΔvacA/ΔcagA strains and plasma membrane disruption events and consequent activation of membrane repair components monitored. H. pylori disrupts the host cell plasma membrane, allowing localized dye and extracellular Ca2+ influx. Ca2+-triggered members of the annexin family, A1 and A4, translocate, in response to injury, to the plasma membrane, and cell surface expression of an exocytotic maker of repair, LAMP-2, increases. Additional forms of plasma membrane disruption, unrelated to H. pylori exposure, also promote host cell proliferation. We propose that H. pylori activation of a plasma membrane repair is pro-proliferative. This study might therefore provide new insight into potential mechanisms of H. pylori-induced gastric carcinogenesis.

  10. Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies

    Directory of Open Access Journals (Sweden)

    Masaaki Nameta

    2016-09-01

    Full Text Available Aquaporin-2 (AQP2 is present in urine extracellular vesicles (EVs and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA measurement. We speculated that disruptions of EVs membranes are necessary to allow for the direct contact of antibodies with their epitopes. Human urine EVs were prepared using an ultracentrifugation method. Urine EV samples were stored at different temperatures for a week. Electron microscopy showed abundant EVs with diameters of 20–100 nm, consistent with those of exosomes, in normal urine, whereas samples from alkali/detergent pre-treated urine showed fewer EVs with large swollen shapes and frequent membrane disruptions. The abundance and structures of EVs were maintained during storage at −80 °C, but were severely damaged at −25 °C. Binding and competitive inhibition assays showed that epitopes of monoclonal antibody and polyclonal antibody were the hydrophilic Loop D and C-terminus of AQP2, respectively, both of which are present on the inner surface of EVs. Thus, urine storage at −25 °C or pre-treatment with alkali/detergent disrupt EVs membranes and allow AQP2 antibodies to bind to their epitopes located inside EVs.

  11. Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies

    Science.gov (United States)

    Nameta, Masaaki; Saijo, Yoko; Ohmoto, Yasukazu; Katsuragi, Kiyonori; Yamamoto, Keiko; Yamamoto, Tadashi; Ishibashi, Kenichi; Sasaki, Sei

    2016-01-01

    Aquaporin-2 (AQP2) is present in urine extracellular vesicles (EVs) and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA) measurement. We speculated that disruptions of EVs membranes are necessary to allow for the direct contact of antibodies with their epitopes. Human urine EVs were prepared using an ultracentrifugation method. Urine EV samples were stored at different temperatures for a week. Electron microscopy showed abundant EVs with diameters of 20–100 nm, consistent with those of exosomes, in normal urine, whereas samples from alkali/detergent pre-treated urine showed fewer EVs with large swollen shapes and frequent membrane disruptions. The abundance and structures of EVs were maintained during storage at −80 °C, but were severely damaged at −25 °C. Binding and competitive inhibition assays showed that epitopes of monoclonal antibody and polyclonal antibody were the hydrophilic Loop D and C-terminus of AQP2, respectively, both of which are present on the inner surface of EVs. Thus, urine storage at −25 °C or pre-treatment with alkali/detergent disrupt EVs membranes and allow AQP2 antibodies to bind to their epitopes located inside EVs. PMID:27681727

  12. Conversations about Art: A Disruptive Model of Interpretation.

    Science.gov (United States)

    Gooding-Brown, Jane

    This paper describes a disruptive model of interpretation which explores positions in discursive practices embedded in visual culture as a means of understanding self and difference. The model understands interpretation as a Foucauldian technique of the self, and its use may give art teachers and students strategies for understanding the social…

  13. Dealing with Disruptive and Emotional College Students: A Systems Model.

    Science.gov (United States)

    Hernandez, Thomas J.; Fister, Deborah L.

    2001-01-01

    Proposes a systemic model for handling disruptive behaviors among college students. The model, in which college counselors have a leading role, uses faculty liaisons, a faculty and staff handbook, faculty and staff training, and policy development to address the problem. (Contains 22 references.) (Author/GCP)

  14. Computational modeling of membrane proteins.

    Science.gov (United States)

    Koehler Leman, Julia; Ulmschneider, Martin B; Gray, Jeffrey J

    2015-01-01

    The determination of membrane protein (MP) structures has always trailed that of soluble proteins due to difficulties in their overexpression, reconstitution into membrane mimetics, and subsequent structure determination. The percentage of MP structures in the protein databank (PDB) has been at a constant 1-2% for the last decade. In contrast, over half of all drugs target MPs, only highlighting how little we understand about drug-specific effects in the human body. To reduce this gap, researchers have attempted to predict structural features of MPs even before the first structure was experimentally elucidated. In this review, we present current computational methods to predict MP structure, starting with secondary structure prediction, prediction of trans-membrane spans, and topology. Even though these methods generate reliable predictions, challenges such as predicting kinks or precise beginnings and ends of secondary structure elements are still waiting to be addressed. We describe recent developments in the prediction of 3D structures of both α-helical MPs as well as β-barrels using comparative modeling techniques, de novo methods, and molecular dynamics (MD) simulations. The increase of MP structures has (1) facilitated comparative modeling due to availability of more and better templates, and (2) improved the statistics for knowledge-based scoring functions. Moreover, de novo methods have benefited from the use of correlated mutations as restraints. Finally, we outline current advances that will likely shape the field in the forthcoming decade.

  15. Needle-shaped polymeric particles induce transient disruption of cell membranes.

    Science.gov (United States)

    Doshi, Nishit; Mitragotri, Samir

    2010-08-06

    Nano- and microparticles of various shapes have recently been introduced for various drug-delivery applications. Shape of particles has been shown to have an impact on various processes including circulation, vascular adhesion and phagocytosis. Here, we assess the role of particle geometry and surface chemistry in their interactions with cell membranes. Using representative particles of different shape (spheres, elongated and flat particles), size (500 nm-1 microm) and surface chemistry (positively and negatively charged), we evaluated the response of endothelial cells to particles. While spherical and elliptical disc-shaped particles did not have an impact on cell spreading and motility, needle-shaped particles induced significant changes in the same. Further studies revealed that needle-shaped particles induced disruption of cell membranes as indicated by the release of lactate dehydrogenase and uptake of extracellular calcein. The effect of needle-shaped particles on cells was transient and was reversed over a time period of 1-48 h depending on particle parameters.

  16. Anti-Candida activity of geraniol involves disruption of cell membrane integrity and function.

    Science.gov (United States)

    Sharma, Y; Khan, L A; Manzoor, N

    2016-09-01

    Candidiasis is a major problem in immunocompromised patients. Candida, an opportunistic fungal pathogen, is a major health concern today as conventional drugs are highly toxic with undesirable side effects. Their fungistatic nature is responsible for drug resistance in continuously evolving strains. Geraniol, an acyclic monoterpene alcohol, is a component of several plant essential oils. In the present study, an attempt has been made to understand the antifungal activity of geraniol at the cell membrane level in three Candida species. With an MIC of 30-130μg/mL, this natural compound was fungicidal at concentrations 2×MIC. There was complete suppression of fungal growth at MIC values (growth curves) and encouragingly geraniol is non-toxic even at the concentrations approaching 5×MIC (hemolysis assay). Exposed cells showed altered morphology, wherein the cells appeared either broken or shrivelled up (SEM studies). Significant reduction was seen in ergosterol levels at sub-MIC and glucose-induced H(+) efflux at concentrations>MIC values. Our results suggest that geraniol disrupts cell membrane integrity by interfering with ergosterol biosynthesis and inhibiting the very crucial PM-ATPase. It may hence be used in the management and treatment of both superficial and invasive candidiasis but further studies are required to elaborate its mode of action.

  17. Removal of typical endocrine disrupting chemicals by membrane bioreactor: in comparison with sequencing batch reactor.

    Science.gov (United States)

    Zhou, Yingjun; Huang, Xia; Zhou, Haidong; Chen, Jianhua; Xue, Wenchao

    2011-01-01

    The removal of endocrine disrupting chemicals (EDCs) by a laboratory-scale membrane bioreactor (MBR) fed with synthetic sewage was evaluated and moreover, compared with that by a sequencing batch reactor (SBR) operated under same conditions in parallel. Eight kinds of typical EDCs, including 17β-estradiol (E2), estrone (E1), estriol (E3), 17α-ethynilestradiol (EE2), 4-octylphenol (4-OP), 4-nonylphenol (4-NP), bisphenol A (BPA) and nonylphenol ethoxylates (NPnEO), were spiked into the feed. Their concentrations in influent, effluent and supernatant were determined by gas chromatography-mass spectrometry method. The overall estrogenecity was evaluated as 17β-estradiol equivalent quantity (EEQ), determined via yeast estrogen screen (YES) assay. E2, E3, BPA and 4-OP were well removed by both MBR and SBR, with removal rates more than 95% and no significant differences between the two reactors. However, with regard to the other four EDCs, of which the removal rates were lower, MBR performed better. Comparison between supernatant and effluent of the two reactors indicated that membrane separation of sludge and effluent, compared with sedimentation, can relatively improve elimination of target EDCs and total estrogenecity. By applying different solids retention times (SRTs) (5, 10, 20 and 40 d) to the MBR, 10 and 5 d were found to be the lower critical SRTs for efficient target EDCs and EEQ removal, respectively.

  18. N-3 fatty acids and membrane microdomains: from model membranes to lymphocyte function.

    Science.gov (United States)

    Shaikh, Saame Raza; Teague, Heather

    2012-12-01

    This article summarizes the author's research on fish oil derived n-3 fatty acids, plasma membrane organization and B cell function. We first cover basic model membrane studies that investigated how docosahexaenoic acid (DHA) targeted the organization of sphingolipid-cholesterol enriched lipid microdomains. A key finding here was that DHA had a relatively poor affinity for cholesterol. This work led to a model that predicted DHA acyl chains in cells would manipulate lipid-protein microdomain organization and thereby function. We then review how the predictions of the model were tested with B cells in vitro followed by experiments using mice fed fish oil. These studies reveal a highly complex picture on how n-3 fatty acids target lipid-protein organization and B cell function. Key findings are as follows: (1) n-3 fatty acids target not just the plasma membrane but also endomembrane organization; (2) DHA, but not eicosapentaenoic acid (EPA), disrupts microdomain spatial distribution (i.e. clustering), (3) DHA alters protein lateral organization and (4) changes in membrane organization are accompanied by functional effects on both innate and adaptive B cell function. Altogether, the research over the past 10 years has led to an evolution of the original model on how DHA reorganizes membrane microdomains. The work raises the intriguing possibility of testing the model at the human level to target health and disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. A new approach to modelling the impact of disruptive events

    NARCIS (Netherlands)

    Oosterhaven, Jan; Bouwmeester, Maaike

    This paper develops a new methodology to predict the interregional and interindustry impacts of disruptive events. We model the reactions of economic agents by minimizing the information gain between the pre- and postevent pattern of economic transactions. The resulting nonlinear program reproduces,

  20. Cholesterol transport in model membranes

    Science.gov (United States)

    Garg, Sumit; Porcar, Lionel; Butler, Paul; Perez-Salas, Ursula

    2010-03-01

    Physiological processes distribute cholesterol unevenly within the cell. The levels of cholesterol are maintained by intracellular transport and a disruption in the cell's ability to keep these normal levels will lead to disease. Exchange rates of cholesterol are generally studied in model systems using labeled lipid vesicles. Initially donor vesicles have all the cholesterol and acceptor vesicles are devoid of it. They are mixed and after some time the vesicles are separated and cholesterol is traced in each vesicle. The studies performed up to date have significant scatter indicating that the methodologies are not consistent. The present work shows in-situ Time-Resolved SANS studies of cholesterol exchange rates in unsaturated PC lipid vesicles. Molecular dynamics simulations were done to investigate the energetic and kinetic behavior of cholesterol in this system. This synergistic approach will provide insight into our efforts to understand cholesterol traffic.

  1. Mesoscopic models of biological membranes

    DEFF Research Database (Denmark)

    Venturoli, M.; Sperotto, Maria Maddalena; Kranenburg, M.;

    2006-01-01

    , as model systems to understand the fundamental properties of biomembranes. The properties of lipid bilayers can be studied at different time and length scales. For some properties it is sufficient to envision a membrane as an elastic sheet, while for others it is important to take into account the details...... of the individual atoms. In this review, we focus on an intermediate level, where groups of atoms are lumped into pseudo-particles to arrive at a coarse-grained, or mesoscopic, description of a bilayer, which is subsequently studied using molecular simulation. The aim of this review is to compare various strategies...

  2. Delay and Disruption Tolerant Networking MACHETE Model

    Science.gov (United States)

    Segui, John S.; Jennings, Esther H.; Gao, Jay L.

    2011-01-01

    To verify satisfaction of communication requirements imposed by unique missions, as early as 2000, the Communications Networking Group at the Jet Propulsion Laboratory (JPL) saw the need for an environment to support interplanetary communication protocol design, validation, and characterization. JPL's Multi-mission Advanced Communications Hybrid Environment for Test and Evaluation (MACHETE), described in Simulator of Space Communication Networks (NPO-41373) NASA Tech Briefs, Vol. 29, No. 8 (August 2005), p. 44, combines various commercial, non-commercial, and in-house custom tools for simulation and performance analysis of space networks. The MACHETE environment supports orbital analysis, link budget analysis, communications network simulations, and hardware-in-the-loop testing. As NASA is expanding its Space Communications and Navigation (SCaN) capabilities to support planned and future missions, building infrastructure to maintain services and developing enabling technologies, an important and broader role is seen for MACHETE in design-phase evaluation of future SCaN architectures. To support evaluation of the developing Delay Tolerant Networking (DTN) field and its applicability for space networks, JPL developed MACHETE models for DTN Bundle Protocol (BP) and Licklider/Long-haul Transmission Protocol (LTP). DTN is an Internet Research Task Force (IRTF) architecture providing communication in and/or through highly stressed networking environments such as space exploration and battlefield networks. Stressed networking environments include those with intermittent (predictable and unknown) connectivity, large and/or variable delays, and high bit error rates. To provide its services over existing domain specific protocols, the DTN protocols reside at the application layer of the TCP/IP stack, forming a store-and-forward overlay network. The key capabilities of the Bundle Protocol include custody-based reliability, the ability to cope with intermittent connectivity

  3. Modeling and simulation of membrane process

    Science.gov (United States)

    Staszak, Maciej

    2017-06-01

    The article presents the different approaches to polymer membrane mathematical modeling. Traditional models based on experimental physicochemical correlations and balance models are presented in the first part. Quantum and molecular mechanics models are presented as they are more popular for polymer membranes in fuel cells. The initial part is enclosed by neural network models which found their use for different types of processes in polymer membranes. The second part is devoted to models of fluid dynamics. The computational fluid dynamics technique can be divided into solving of Navier-Stokes equations and into Boltzmann lattice models. Both approaches are presented focusing on membrane processes.

  4. Permethrin may disrupt testosterone biosynthesis via mitochondrial membrane damage of Leydig cells in adult male mouse.

    Science.gov (United States)

    Zhang, Shu-Yun; Ito, Yuki; Yamanoshita, Osamu; Yanagiba, Yukie; Kobayashi, Miya; Taya, Kazuyoshi; Li, ChunMei; Okamura, Ai; Miyata, Maiko; Ueyama, Jun; Lee, Chul-Ho; Kamijima, Michihiro; Nakajima, Tamie

    2007-08-01

    Permethrin, a popular synthetic pyrethroid insecticide used to control noxious insects in agriculture, forestry, households, horticulture, and public health throughout the world, poses risks of environmental exposure. Here we evaluate the reproductive toxicity of cis-permethrin in adult male ICR mice that were orally administered cis-permethrin (0, 35, or 70 mg/kg d) for 6 wk. Caudal epididymal sperm count and sperm motility in the treated groups were statistically reduced in a dose-dependent manner. Testicular testosterone production and plasma testosterone concentration were significantly and dose-dependently decreased with an increase in LH, and a significant regression was observed between testosterone levels and cis-permethrin residues in individual mice testes after exposure. However, no significant changes were observed in body weight, reproductive organ absolute and relative weights, sperm morphology, and plasma FSH concentration after cis-permethrin treatment. Moreover, cis-permethrin exposure significantly diminished the testicular mitochondrial mRNA expression levels of peripheral benzodiazepine receptor (PBR), steroidogenic acute regulatory protein (StAR), and cytochrome P450 side-chain cleavage (P450scc) and enzyme and protein expression levels of StAR and P450scc. At the electron microscopic level, mitochondrial membrane damage was found in Leydig cells of the exposed mouse testis. Our results suggest that the insecticide permethrin may cause mitochondrial membrane impairment in Leydig cells and disrupt testosterone biosynthesis by diminishing the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone in the cells, thus reducing subsequent testosterone production.

  5. Modeling branching pore structures in membrane filters

    Science.gov (United States)

    Sanaei, Pejman; Cummings, Linda J.

    2016-11-01

    Membrane filters are in widespread industrial use, and mathematical models to predict their efficacy are potentially very useful, as such models can suggest design modifications to improve filter performance and lifetime. Many models have been proposed to describe particle capture by membrane filters and the associated fluid dynamics, but most such models are based on a very simple structure in which the pores of the membrane are assumed to be simple circularly-cylindrical tubes spanning the depth of the membrane. Real membranes used in applications usually have much more complex geometry, with interconnected pores which may branch and bifurcate. Pores are also typically larger on the upstream side of the membrane than on the downstream side. We present an idealized mathematical model, in which a membrane consists of a series of bifurcating pores, which decrease in size as the membrane is traversed. Feed solution is forced through the membrane by applied pressure, and particles are removed from the feed either by sieving, or by particle adsorption within pores (which shrinks them). Thus the membrane's permeability decreases as the filtration progresses, ultimately falling to zero. We discuss how filtration efficiency depends on the characteristics of the branching structure. Partial support from NSF DMS 1261596 is gratefully acknowledged.

  6. Functional analysis of Plasmodium falciparum parasitophorous vacuole membrane protein (Pfs16) during gametocytogenesis and gametogenesis by targeted gene disruption.

    Science.gov (United States)

    Kongkasuriyachai, Darin; Fujioka, Hisashi; Kumar, Nirbhay

    2004-02-01

    Gametocytogenesis is a tightly regulated process marked by differentiation through distinct morphological forms and coordinated expression of sexual stage gene products. The earliest known gene product expressed at the onset of Plasmodium falciparum gametocytogenesis is Pfs16 localized on the parasitophorous vacuole membrane (PVM). Targeted gene disruption was undertaken to disrupt expression of Pfs16 and examine its potential role during sexual development. Three independent clones were demonstrated to have the coding sequence of Ps16 gene disrupted by the targeting plasmid by homologous recombination. No full-length transcripts and PVM localized 16 kDa protein were detected. Instead, all three "16ko" clones expressed a protein of 14 kDa recognized by Pfs16 specific antibodies that was mislocalized to an unidentified double membrane compartment in the parasites. Disruption of Pfs16 gene resulted in a significant reduction in gametocyte production, although the small number of gametocytes produced appeared to be normal by molecular and phenotypic evidences. Preliminary observation also suggested impaired ability of male gametocytes to exflagellate in vitro. Pfs16 does not appear to be essential for sexual development, instead may be required for optimal production of sexual parasites. Understanding mechanisms involved in the development of sexual stages of P. falciparum may identify novel targets for drugs and vaccines effective in reducing malaria transmission.

  7. Macroscopic Modeling of Polymer-Electrolyte Membranes

    Energy Technology Data Exchange (ETDEWEB)

    Weber, A.Z.; Newman, J.

    2007-04-01

    In this chapter, the various approaches for the macroscopic modeling of transport phenomena in polymer-electrolyte membranes are discussed. This includes general background and modeling methodologies, as well as exploration of the governing equations and some membrane-related topic of interest.

  8. Membrane-disruptive properties of the bioinsecticide Jaburetox-2Ec: implications to the mechanism of the action of insecticidal peptides derived from ureases.

    Science.gov (United States)

    Barros, Pedro R; Stassen, Hubert; Freitas, Mônica S; Carlini, Célia R; Nascimento, Marco A C; Follmer, Cristian

    2009-12-01

    Jaburetox-2Ec, a recombinant peptide derived from an urease isoform (JBURE-II), displays high insecticidal activity against important pests such as Spodoptera frugiperda and Dysdercus peruvianus. Although the molecular mechanism of action of ureases-derived peptides remains unclear, previous ab initio data suggest the presence of structural motifs in Jaburetox-2Ec with characteristics similar to those found in a class of pore-forming peptides. Here, we investigated the molecular aspects of the interaction between Jaburetox-2Ec and large unilamellar vesicles. Jaburetox-2Ec displays membrane-disruptive ability on acidic lipid bilayers and this effect is greatly influenced by peptide aggregation. Corroborating with this finding, molecular modeling studies revealed that Jaburetox-2Ec might adopt a well-defined beta-hairpin conformation similar to those found in antimicrobial peptides with membrane disruption properties. In addition, molecular dynamics simulations suggest that the protein is able to anchor at a polar/non-polar interface. In the light of these findings, for the first time it was possible to point out some evidence that the peptide Jaburetox-2Ec interacting with lipid vesicles promotes membrane permeabilization.

  9. QSAR Models for Reproductive Toxicity and Endocrine Disruption Activity

    Directory of Open Access Journals (Sweden)

    Marjan Vračko

    2010-03-01

    Full Text Available Reproductive toxicity is an important regulatory endpoint, which is required in registration procedures of chemicals used for different purposes (for example pesticides. The in vivo tests are expensive, time consuming and require large numbers of animals, which must be sacrificed. Therefore an effort is ongoing to develop alternative In vitro and in silico methods to evaluate reproductive toxicity. In this review we describe some modeling approaches. In the first example we describe the CAESAR model for prediction of reproductive toxicity; the second example shows a classification model for endocrine disruption potential based on counter propagation artificial neural networks; the third example shows a modeling of relative binding affinity to rat estrogen receptor, and the fourth one shows a receptor dependent modeling experiment.

  10. Analytical model of impact disruption of satellites and asteroids

    Science.gov (United States)

    Leliwa-Kopystyński, J.; Włodarczyk, I.; Burchell, M. J.

    2016-04-01

    A model of impact disruption of the bodies with sizes from the laboratory scale to that of an order of 100 km is developed. On the lowermost end of the target size the model is based on the numerous laboratory data related to the mass-velocity distribution of the impact produced fragments. On the minor-planets scale the model is supported by the data related to the largest observed craters on small icy satellites and on some asteroids (Leliwa-Kopystynski, J., Burchell, M.J., Lowen, D. [2008]. Icarus 195, 817-826). The model takes into account the target disruption and the dispersion of the impact produced fragments against the intermolecular forces acting on the surfaces of the contacts of the fragments and against self-gravitation of the target. The head-on collisions of non-rotating and non-porous targets and impactors are considered. The impactor delivers kinetic energy but its mass is neglected in comparison to mass of the target. For this simple case the analytical formulae for specific disruption energy as well as for specific energy of formation of the largest craters are found. They depend on a set of parameters. Of these the most important (i.e. with the greatest influence on the final result) are three rather weakly known parameters. They are: (i) The exponent γ in the distribution function of the fragments. (ii) The characteristic velocity v0 that appears in the velocity distribution of the ejected fragments. (iii) The exponent β in the mass-velocity distribution. The influence of the choice of the numerical values of these parameters on the final results has been studied. Another group of parameters contains the relevant material data. They are: (a) The energy σ of breaking of the intermolecular bonds of the target material per unit of the fragment surface and (b) the density ρ of the target. According to our calculations the transition between the strength regime and the gravitational regime is in the range of the target radius from ∼0.4 km to

  11. Mutations in Lama1 disrupt retinal vascular development and inner limiting membrane formation.

    Science.gov (United States)

    Edwards, Malia M; Mammadova-Bach, Elmina; Alpy, Fabien; Klein, Annick; Hicks, Wanda L; Roux, Michel; Simon-Assmann, Patricia; Smith, Richard S; Orend, Gertraud; Wu, Jiang; Peachey, Neal S; Naggert, Jürgen K; Lefebvre, Olivier; Nishina, Patsy M

    2010-03-05

    The Neuromutagenesis Facility at the Jackson Laboratory generated a mouse model of retinal vasculopathy, nmf223, which is characterized clinically by vitreal fibroplasia and vessel tortuosity. nmf223 homozygotes also have reduced electroretinogram responses, which are coupled histologically with a thinning of the inner nuclear layer. The nmf223 locus was mapped to chromosome 17, and a missense mutation was identified in Lama1 that leads to the substitution of cysteine for a tyrosine at amino acid 265 of laminin alpha1, a basement membrane protein. Despite normal localization of laminin alpha1 and other components of the inner limiting membrane, a reduced integrity of this structure was suggested by ectopic cells and blood vessels within the vitreous. Immunohistochemical characterization of nmf223 homozygous retinas demonstrated the abnormal migration of retinal astrocytes into the vitreous along with the persistence of hyaloid vasculature. The Y265C mutation significantly reduced laminin N-terminal domain (LN) interactions in a bacterial two-hybrid system. Therefore, this mutation could affect interactions between laminin alpha1 and other laminin chains. To expand upon these findings, a Lama1 null mutant, Lama1(tm1.1Olf), was generated that exhibits a similar but more severe retinal phenotype than that seen in nmf223 homozygotes. The increased severity of the Lama1 null mutant phenotype is probably due to the complete loss of the inner limiting membrane in these mice. This first report of viable Lama1 mouse mutants emphasizes the importance of this gene in retinal development. The data presented herein suggest that hypomorphic mutations in human LAMA1 could lead to retinal disease.

  12. Metabolic disruption identified in the Huntington's disease transgenic sheep model.

    Science.gov (United States)

    Handley, Renee R; Reid, Suzanne J; Patassini, Stefano; Rudiger, Skye R; Obolonkin, Vladimir; McLaughlan, Clive J; Jacobsen, Jessie C; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

    2016-02-11

    Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.

  13. Tethered bimolecular lipid membranes - A novel model membrane platform

    Energy Technology Data Exchange (ETDEWEB)

    Knoll, Wolfgang; Koeper, Ingo; Naumann, Renate; Sinner, Eva-Kathrin [Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz (Germany)

    2008-10-01

    stabilization of lipid bilayers, i.e., the protein-tethered membrane. Our efforts in experimentally characterizing the resulting membrane functions and correlating the data with the structural details of the bilayer architectures are complemented by theoretical studies modeling the electrical and electrochemical response of functional tethered lipid bilayer membranes by extended SPICE simulations. (author)

  14. Modelling and simulation of affinity membrane adsorption.

    Science.gov (United States)

    Boi, Cristiana; Dimartino, Simone; Sarti, Giulio C

    2007-08-24

    A mathematical model for the adsorption of biomolecules on affinity membranes is presented. The model considers convection, diffusion and adsorption kinetics on the membrane module as well as the influence of dead end volumes and lag times; an analysis of flow distribution on the whole system is also included. The parameters used in the simulations were obtained from equilibrium and dynamic experimental data measured for the adsorption of human IgG on A2P-Sartoepoxy affinity membranes. The identification of a bi-Langmuir kinetic mechanisms for the experimental system investigated was paramount for a correct process description and the simulated breakthrough curves were in good agreement with the experimental data. The proposed model provides a new insight into the phenomena involved in the adsorption on affinity membranes and it is a valuable tool to assess the use of membrane adsorbers in large scale processes.

  15. Modeling anisotropic elasticity of fluid membranes

    CERN Document Server

    Ramakrishnan, N; Ipsen, John H; 10.1002/mats.201100002

    2011-01-01

    The biological membrane, which compartmentalizes the cell and its organelles, exhibit wide variety of macroscopic shapes of varying morphology and topology. A systematic understanding of the relation of membrane shapes to composition, external field, environmental conditions etc. have important biological relevance. Here we review the triangulated surface model, used in the macroscopic simulation of membranes and the associated Monte Carlo (DTMC) methods. New techniques to calculate surface quantifiers, that will facilitate the study of additional in-plane orientational degrees of freedom, has been introduced. The mere presence of a polar and nematic fields in the ordered phase drives the ground state conformations of the membrane to a cylinder and tetrahedron respectively.

  16. Atomistic MD simulations reveal the protective role of cholesterol in dimeric beta-amyloid induced disruptions in neuronal membrane mimics

    Science.gov (United States)

    Qiu, Liming; Buie, Creighton; Cheng, Sara; Chou, George; Vaughn, Mark; Cheng, K.

    2011-10-01

    Interactions of oligomeric beta-amyloid peptides with neuronal membranes have been linked to the pathogenesis of Alzheimer's disease (AD). The molecular details of the interactions of different lipid components, particularly cholesterol (CHOL), of the membranes with the peptides are not clear. Using an atomistic MD simulations approach, the water permeability barrier, structural geometry and order parameters of binary phosphatidylcholine (PC) and PC/CHOL lipid bilayers were examined from various 200 ns-simulation replicates. Our results suggest that the longer length dimer (2 x 42 residues) perturbs the membrane more than the shorter one (2 x 40 residues). In addition, we discovered a significant protective role of cholesterol in protein-induced disruptions of the membranes. The use of a new Monte-Carlo method in characterizing the structures of the conformal annular lipids in close proximity with the proteins will be introduced. We propose that the neurotoxicity of beta-amyloid peptide may be associated with the nanodomain or raft-like structures of the neuronal membranes in-vivo in the development of AD.

  17. Diffusion through thin membranes: Modeling across scales

    Science.gov (United States)

    Aho, Vesa; Mattila, Keijo; Kühn, Thomas; Kekäläinen, Pekka; Pulkkinen, Otto; Minussi, Roberta Brondani; Vihinen-Ranta, Maija; Timonen, Jussi

    2016-04-01

    From macroscopic to microscopic scales it is demonstrated that diffusion through membranes can be modeled using specific boundary conditions across them. The membranes are here considered thin in comparison to the overall size of the system. In a macroscopic scale the membrane is introduced as a transmission boundary condition, which enables an effective modeling of systems that involve multiple scales. In a mesoscopic scale, a numerical lattice-Boltzmann scheme with a partial-bounceback condition at the membrane is proposed and analyzed. It is shown that this mesoscopic approach provides a consistent approximation of the transmission boundary condition. Furthermore, analysis of the mesoscopic scheme gives rise to an expression for the permeability of a thin membrane as a function of a mesoscopic transmission parameter. In a microscopic model, the mean waiting time for a passage of a particle through the membrane is in accordance with this permeability. Numerical results computed with the mesoscopic scheme are then compared successfully with analytical solutions derived in a macroscopic scale, and the membrane model introduced here is used to simulate diffusive transport between the cell nucleus and cytoplasm through the nuclear envelope in a realistic cell model based on fluorescence microscopy data. By comparing the simulated fluorophore transport to the experimental one, we determine the permeability of the nuclear envelope of HeLa cells to enhanced yellow fluorescent protein.

  18. ASASSN-14li: A Model Tidal Disruption Event

    CERN Document Server

    Krolik, Julian; Svirski, Gilad; Cheng, Roseanne M

    2016-01-01

    ASASSN-14li is a recently-discovered tidal disruption event with an exceptionally rich data-set: spectra and lightcurves in soft X-rays, UV, optical, and radio. To understand its emission properties in all these bands, we have extended our model for post-tidal disruption accretion and photon production to estimate both soft X-ray radiation produced by the prompt accretion phase and synchrotron emission associated with the bow shock driven through an external medium by the unbound tidal debris, as well as optical and UV light. We find that fiducial values of the stellar mass ($1 M_\\odot$) and black hole mass ($10^{6.5} M_{\\odot}$) yield: quantitative agreement with the optical/UV luminosity, lightcurve, and color temperature; approximate agreement with the somewhat uncertain soft X-ray spectrum and lightcurve; and quantitative agreement with the radio luminosity, spectrum and lightcurve. Equipartition analysis of the radio data implies that the radio-emitting region expands with a constant speed, and its magni...

  19. Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption.

    Science.gov (United States)

    Matarazzo, Sara; Quitadamo, Maria Chiara; Mango, Ruggiero; Ciccone, Sarah; Novelli, Giuseppe; Biocca, Silvia

    2012-08-01

    Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is up-regulated in atherosclerotic lesions. Statins are the principal therapeutic agents for cardiovascular diseases and are known to down-regulate LOX-1 expression. Whether the effect on the LOX-1 receptor is related to statin-mediated cholesterol-lowering activity is unknown. We investigate the requirement of cholesterol for LOX-1-mediated lipid particle internalization, trafficking, and processing and the role of statins as inhibitors of LOX-1 function. Disruption of cholesterol-rich membrane microdomains by acute exposure of cells to methyl-β-cyclodextrin or chronic exposure to different statins (lovastatin and atorvastatin) led to a spatial disorganization of LOX-1 in plasma membranes and a marked loss of specific LOX-1 function in terms of ox-LDL binding and internalization. Subcellular fractionation and immunochemical studies indicate that LOX-1 is naturally present in caveolae-enriched lipid rafts and, by cholesterol reduction, the amount of LOX-1 in this fraction is highly decreased (≥60%). In contrast, isoprenylation inhibition had no effect on the distribution and function of LOX-1 receptors. Furthermore, in primary cultures from atherosclerotic human aorta lesions, we confirm the presence of LOX-1 in caveolae-enriched lipid rafts and demonstrate that lovastatin treatment led to down-regulation of LOX-1 in lipid rafts and rescue of the ox-LDL-induced apoptotic phenotype. Taken together, our data reveal a previously unrecognized essential role of membrane cholesterol for LOX-1 receptor activity and suggest that statins protect vascular endothelium against the adverse effect of ox-LDL by disruption of membrane rafts and impairment of LOX-1 receptor function.

  20. Rejection of pharmaceuticals and personal care products (PPCPs) and endocrine disrupting chemicals (EDCs) by low pressure reverse osmosis membranes.

    Science.gov (United States)

    Ozaki, H; Ikejima, N; Shimizu, Y; Fukami, K; Taniguchi, S; Takanami, R; Giri, R R; Matsui, S

    2008-01-01

    This paper aims to elucidate retention characteristics of some pharmaceuticals and personal care products (PPCPs), and endocrine disrupting chemicals (EDCs), by two polyamide low pressure reverse osmosis (LPRO) membranes. Feed solution pH did not have an influence on rejections of undissociated solutes, which was most likely governed by adsorption, size exclusion and diffusion simultaneously. Size exclusion was presumably dominant, especially with tight membranes (UTC-70U). Rejections of the solutes with low dipole moment (diffusion coefficient (D(p)). The rejections decreased with increasing D(p) values irrespective of their dipole moments. Rejections of solutes with comparatively larger dipole moments might be dominated by diffusion and/or convection rather than their hydrophobicity. However, rejections of solutes with hydroxyl and carboxyl functional groups by UTC-60 increased with solution pH. More than 80% rejections were obtained for degree of dissociation (alpha)>0.5. Electrostatic repulsion played a key role for rejection of dissociated solutes, especially by loose LPRO membranes. Therefore, assessing the dissociation degree at desired pH values can be a key step to obtain an insight of rejection mechanisms by polyamide membranes.

  1. Understanding transport in model water desalination membranes

    Science.gov (United States)

    Chan, Edwin

    Polyamide based thin film composites represent the the state-of-the-art nanofiltration and reverse osmosis membranes used in water desalination. The performance of these membranes is enabled by the ultrathin (~100 nm) crosslinked polyamide film in facilitating the selective transport of water over salt ions. While these materials have been refined over the last several decades, understanding the relationships between polyamide structure and membrane performance remains a challenge because of the complex and heterogeneous nature of the polyamide film. In this contribution, we present our approach to addressing this challenge by studying the transport properties of model polyamide membranes synthesized via molecular layer-by-layer (mLbL) assembly. First, we demonstrate that mLbL can successfully construct polyamide membranes with well-defined nanoscale thickness and roughness using a variety of monomer formulations. Next, we present measurement tools for characterizing the network structure and transport of these model polyamide membranes. Specifically, we used X-ray and neutron scattering techniques to characterize their structure as well as a recently-developed indentation based poromechanics approach to extrapolate their water diffusion coefficient. Finally, we illustrate how these measurements can provide insight into the original problem by linking the key polyamide network properties, i.e. water-polyamide interaction parameter and characteristic network mesh size, to the membrane performance.

  2. Impact of operating conditions on the removal of endocrine disrupting chemicals by membrane photocatalytic reactor.

    Science.gov (United States)

    López Fernández, Raquel; Coleman, Heather M; Le-Clech, Pierre

    2014-08-01

    This study focuses on the performance of a submerged membrane photocatalytic reactor for the removal of 17beta-oestradiol (E2) in the presence of humic acid (HA). In addition to the impact of operating parameters, such as membrane pore size, ultraviolet (UV) intensity and hydraulic retention time (HRT), the influence of long-term operation was also assessed by advanced characterization of the fouling layer formed on the membrane. The tighter (0.04 microm) hollow fibre polyvinylydene fluoride (PVDF) membrane was found to exhibit not only higher HA removal than the (0.2 microm) module (85% and 75%, respectively), but also greater transmembrane pressure (TMP) values and higher irreversible fouling. Long-term operation conditions have been simulated by conducting an ageing catalyst process and demonstrated a decrease in performance obtained with time. The artificially aged TiO2 resulted in higher TMP values and lower HA removals (about 10-20% decrease) compared with the non-aged catalyst. For E2 removal in the presence of HA, the passive adsorption of the oestrogen onto the organic matter was found to be significant (40% of the E2 adsorbed after I h), demonstrating the importance of the nature of the water matrix for this type of treatment process. An increase in the UV light intensity was observed to favour the E2 elimination, leading to more than 90% removal when using 64 W combined with PVDF membrane and an HRT of 3 h.

  3. Modeling of ion conductivity in Nafion membranes

    Institute of Scientific and Technical Information of China (English)

    YANG Zhen; PENG Xiaofeng; WANG Buxuan; LEE Duujong; DUAN Yuanyuan

    2007-01-01

    A theoretical investigation was conducted to describe the ion transport behavior in a Nafion Membrane of proton exchange membrane fuel cells (PEMFC).By analyzing the surface energy configuration of the ionic clusters in a Nafion membrane,an equivalent field intensity,Ee,was introduced to facilitate the analysis of surface resistance against ion conduction in the central region of clusters.An expression was derived for ionic conductivity incorporating the influence of surface resistance.A face-centered cubic (FCC)lattice model for a spatial cluster distribution was used to modify the effect of water content on ionic conductivity in the polymeric matrix,i.e.,the regions between clusters.Compared with the available empirical correlations,the new expression showed much better agreement with the available experimental results,which indicates the rationality to consider the structural influence on ion conduction in water-swollen Nation membranes.

  4. Disruptive innovation in health care delivery: a framework for business-model innovation.

    Science.gov (United States)

    Hwang, Jason; Christensen, Clayton M

    2008-01-01

    Disruptive innovation has brought affordability and convenience to customers in a variety of industries. However, health care remains expensive and inaccessible to many because of the lack of business-model innovation. This paper explains the theory of disruptive innovation and describes how disruptive technologies must be matched with innovative business models. The authors present a framework for categorizing and developing business models in health care, followed by a discussion of some of the reasons why disruptive innovation in health care delivery has been slow.

  5. Simulation Model of Membrane Gas Separator Using Aspen Custom Modeler

    Energy Technology Data Exchange (ETDEWEB)

    Song, Dong-keun [Korea Institute of Machinery and Materials, Daejeon (Korea, Republic of); Shin, Gahui; Yun, Jinwon; Yu, Sangseok [Chungnam Nat’l Univ., Daejeon (Korea, Republic of)

    2016-12-15

    Membranes are used to separate pure gas from gas mixtures. In this study, three different types of mass transport through a membrane were developed in order to investigate the gas separation capabilities of a membrane. The three different models typically used are a lumped model, a multi-cell model, and a discretization model. Despite the multi-cell model producing similar results to a discretization model, the discretization model was selected for this investigation, due to the cell number dependence of a multi-cell model. The mass transport model was then used to investigate the effects of pressure difference, flow rate, total exposed area, and permeability. The results showed that the pressure difference increased with the stage cut, but the selectivity was a trade-off for the increasing pressure difference. Additionally, even though permeability is an important parameter, the selectivity and stage cut of the membrane converged as permeability increased.

  6. Membrane Vesicles of Group B Streptococcus Disrupt Feto-Maternal Barrier Leading to Preterm Birth.

    Science.gov (United States)

    Surve, Manalee Vishnu; Anil, Anjali; Kamath, Kshama Ganesh; Bhutda, Smita; Sthanam, Lakshmi Kavitha; Pradhan, Arpan; Srivastava, Rohit; Basu, Bhakti; Dutta, Suryendu; Sen, Shamik; Modi, Deepak; Banerjee, Anirban

    2016-09-01

    Infection of the genitourinary tract with Group B Streptococcus (GBS), an opportunistic gram positive pathogen, is associated with premature rupture of amniotic membrane and preterm birth. In this work, we demonstrate that GBS produces membrane vesicles (MVs) in a serotype independent manner. These MVs are loaded with virulence factors including extracellular matrix degrading proteases and pore forming toxins. Mice chorio-decidual membranes challenged with MVs ex vivo resulted in extensive collagen degradation leading to loss of stiffness and mechanical weakening. MVs when instilled vaginally are capable of anterograde transport in mouse reproductive tract. Intra-amniotic injections of GBS MVs in mice led to upregulation of pro-inflammatory cytokines and inflammation mimicking features of chorio-amnionitis; it also led to apoptosis in the chorio-decidual tissue. Instillation of MVs in the amniotic sac also resulted in intrauterine fetal death and preterm delivery. Our findings suggest that GBS MVs can independently orchestrate events at the feto-maternal interface causing chorio-amnionitis and membrane damage leading to preterm birth or fetal death.

  7. Triangle-hinge models for unoriented membranes

    Science.gov (United States)

    Fukuma, Masafumi; Sugishita, Sotaro; Umeda, Naoya

    2016-07-01

    Triangle-hinge models [M. Fukuma, S. Sugishita, and N. Umeda, J. High Energy Phys. 1507, 088 (2015)] are introduced to describe worldvolume dynamics of membranes. The Feynman diagrams consist of triangles glued together along hinges and can be restricted to tetrahedral decompositions in a large-N limit. In this paper, after clarifying that all the tetrahedra resulting in the original models are orientable, we define a version of triangle-hinge models that can describe the dynamics of unoriented membranes. By regarding each triangle as representing a propagation of an open membrane of disk topology, we introduce a local worldvolume parity transformation which inverts the orientation of a triangle, and define unoriented triangle-hinge models by gauging the transformation. Unlike two-dimensional cases, this local transformation generally relates a manifold to a nonmanifold, but still is a well-defined manipulation among tetrahedral decompositions. We further show that matter fields can be introduced in the same way as in the original oriented models. In particular, the models will describe unoriented membranes in a target spacetime by taking matter fields to be the target space coordinates.

  8. A dual antibacterial mechanism involved in membrane disruption and DNA binding of 2R,3R-dihydromyricetin from pine needles of Cedrus deodara against Staphylococcus aureus.

    Science.gov (United States)

    Wu, Yanping; Bai, Jinrong; Zhong, Kai; Huang, Yina; Gao, Hong

    2017-03-01

    The antibacterial activity and mechanism of 2R,3R-dihydromyricetin (DMY) against Staphylococcus aureus were investigated. The minimum inhibitory concentration of DMY against S. aureus was 0.125mg/ml, and the growth inhibitory assay also revealed that DMY showed a potent antibacterial activity against S. aureus. Massive nucleotide leakage and flow cytometric analysis demonstrated that DMY disrupted the membrane integrity of S. aureus. Morphological changes and membrane hyperpolarization of S. aureus cells treated with DMY further suggested that DMY destroyed cell membrane. Meanwhile, DMY probably interacted with membrane lipids and proteins, causing a significant reduction in membrane fluidity and changes in conformation of membrane protein. Moreover, DMY could interact with S. aureus DNA through the groove binding mode. Overall, the results suggested that DMY could be applied as a candidate for the development of new food preservatives as it achieved bactericidal activity by damaging cell membrane and binding to intracellular DNA.

  9. Mouse models for preeclampsia: disruption of redox-regulated signaling

    Directory of Open Access Journals (Sweden)

    Chambers Anne E

    2009-01-01

    Full Text Available Abstract The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-O-methyl transferase (Comt-/- in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2 which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha at late pregnancy. We propose that in wild type (Comt++ pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD. Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/- stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD. We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD.

  10. A Membrane Model from Implicit Elasticity Theory

    Science.gov (United States)

    Freed, A. D.; Liao, J.; Einstein, D. R.

    2014-01-01

    A Fungean solid is derived for membranous materials as a body defined by isotropic response functions whose mathematical structure is that of a Hookean solid where the elastic constants are replaced by functions of state derived from an implicit, thermodynamic, internal-energy function. The theory utilizes Biot’s (1939) definitions for stress and strain that, in 1-dimension, are the stress/strain measures adopted by Fung (1967) when he postulated what is now known as Fung’s law. Our Fungean membrane model is parameterized against a biaxial data set acquired from a porcine pleural membrane subjected to three, sequential, proportional, planar extensions. These data support an isotropic/deviatoric split in the stress and strain-rate hypothesized by our theory. These data also demonstrate that the material response is highly non-linear but, otherwise, mechanically isotropic. These data are described reasonably well by our otherwise simple, four-parameter, material model. PMID:24282079

  11. Interaction of Mastoparan with Model Membranes

    Science.gov (United States)

    Haloot, Justin

    2010-10-01

    The use of antimicrobial agents began during the 20th century to reduce the effects of infectious diseases. Since the 1990s, antimicrobial resistance has become an ever-increasing global problem. Our laboratory recently found that small antimicrobial peptides (AMPs) have potent antimicrobial activity against a wide range of Gram-negative and Gram-positive organisms including antibiotic resistant organisms. These AMPs are potential therapeutic agents against the growing problem of antimicrobial resistance. AMPs are small peptides produced by plants, insects and animals. Several hypotheses concede that these peptides cause some type of structural perturbations and increased membrane permeability in bacteria however, how AMPs kill bacteria remains unclear. The goal of this study was to design an assay that would allow us to evaluate and monitor the pore forming ability of an AMP, Mastoparan, on model membrane structures called liposomes. Development of this model will facilitate the study of how mastoparan and related AMPs interact with the bacterial membrane.

  12. Interaction of Artepillin C with model membranes.

    Science.gov (United States)

    Pazin, Wallance Moreira; Olivier, Danilo da Silva; Vilanova, Neus; Ramos, Ana Paula; Voets, Ilja Karina; Soares, Ademilson Espencer Egea; Ito, Amando Siuiti

    2017-05-01

    Green propolis, a mixture of beeswax and resinous compounds processed by Apis mellifera, displays several pharmacological properties. Artepillin C, the major compound in green propolis, consists of two prenylated groups bound to a phenyl group. Several studies have focused on the therapeutic effects of Artepillin C, but there is no evidence that it interacts with amphiphilic aggregates to mimic cell membranes. We have experimentally and computationally examined the interaction between Artepillin C and model membranes composed of dimyristoylphosphatidylcholine (DMPC) because phosphatidylcholine (PC) is one of the most abundant phospholipids in eukaryotic cell membranes. PC is located in both outer and inner leaflets and has been used as a simplified membrane model and a non-specific target to study the action of amphiphilic molecules with therapeutic effects. Experimental results indicated that Artepillin C adsorbed onto the DMPC monolayers. Its presence in the lipid suspension pointed to an increased tendency toward unilamellar vesicles and to decreased bilayer thickness. Artepillin C caused point defects in the lipid structure, which eliminated the ripple phase and the pre-transition in thermotropic chain melting. According to molecular dynamics (MD) simulations, (1) Artepillin C aggregated in the aqueous phase before it entered the bilayer; (2) Artepillin C was oriented along the direction normal to the surface; (3) the negatively charged group on Artepillin C was accommodated in the polar region of the membrane; and (4) thinner regions emerged around the Artepillin C molecules. These results help an understanding of the molecular mechanisms underlying the biological action of propolis.

  13. Disruption of Saccharomyces cerevisiae by Plantaricin 149 and investigation of its mechanism of action with biomembrane model systems.

    Science.gov (United States)

    Lopes, José Luiz S; Nobre, Thatyane M; Siano, Alvaro; Humpola, Verónica; Bossolan, Nelma R S; Zaniquelli, Maria E D; Tonarelli, Georgina; Beltramini, Leila M

    2009-10-01

    The action of a synthetic antimicrobial peptide analog of Plantaricin 149 (Pln149a) against Saccharomyces cerevisiae and its interaction with biomembrane model systems were investigated. Pln149a was shown to inhibit S. cerevisiae growth by more than 80% in YPD medium, causing morphological changes in the yeast wall and remaining active and resistant to the yeast proteases even after 24 h of incubation. Different membrane model systems and carbohydrates were employed to better describe the Pln149a interaction with cellular components using circular dichroism and fluorescence spectroscopies, adsorption kinetics and surface elasticity in Langmuir monolayers. These assays showed that Pln149a does not interact with either mono/polysaccharides or zwitterionic LUVs, but is strongly adsorbed to and incorporated into negatively charged surfaces, causing a conformational change in its secondary structure from random-coil to helix upon adsorption. From the concurrent analysis of Pln149a adsorption kinetics and dilatational surface elasticity data, we determined that 2.5 muM is the critical concentration at which Pln149a will disrupt a negative DPPG monolayer. Furthermore, Pln149a exhibited a carpet-like mechanism of action, in which the peptide initially binds to the membrane, covering its surface and acquiring a helical structure that remains associated to the negatively charged phospholipids. After this electrostatic interaction, another peptide region causes a strain in the membrane, promoting its disruption.

  14. Model-building codes for membrane proteins.

    Energy Technology Data Exchange (ETDEWEB)

    Shirley, David Noyes; Hunt, Thomas W.; Brown, W. Michael; Schoeniger, Joseph S. (Sandia National Laboratories, Livermore, CA); Slepoy, Alexander; Sale, Kenneth L. (Sandia National Laboratories, Livermore, CA); Young, Malin M. (Sandia National Laboratories, Livermore, CA); Faulon, Jean-Loup Michel; Gray, Genetha Anne (Sandia National Laboratories, Livermore, CA)

    2005-01-01

    We have developed a novel approach to modeling the transmembrane spanning helical bundles of integral membrane proteins using only a sparse set of distance constraints, such as those derived from MS3-D, dipolar-EPR and FRET experiments. Algorithms have been written for searching the conformational space of membrane protein folds matching the set of distance constraints, which provides initial structures for local conformational searches. Local conformation search is achieved by optimizing these candidates against a custom penalty function that incorporates both measures derived from statistical analysis of solved membrane protein structures and distance constraints obtained from experiments. This results in refined helical bundles to which the interhelical loops and amino acid side-chains are added. Using a set of only 27 distance constraints extracted from the literature, our methods successfully recover the structure of dark-adapted rhodopsin to within 3.2 {angstrom} of the crystal structure.

  15. Modelling Of Manufacturing Processes With Membranes

    Science.gov (United States)

    Crăciunean, Daniel Cristian; Crăciunean, Vasile

    2015-07-01

    The current objectives to increase the standards of quality and efficiency in manufacturing processes can be achieved only through the best combination of inputs, independent of spatial distance between them. This paper proposes modelling production processes based on membrane structures introduced in [4]. Inspired from biochemistry, membrane computation [4] is based on the concept of membrane represented in its formalism by the mathematical concept of multiset. The manufacturing process is the evolution of a super cell system from its initial state according to the given actions of aggregation. In this paper we consider that the atomic production unit of the process is the action. The actions and the resources on which the actions are produced, are distributed in a virtual network of companies working together. The destination of the output resources is specified by corresponding output events.

  16. Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane.

    Science.gov (United States)

    Alakomi, H L; Skyttä, E; Saarela, M; Mattila-Sandholm, T; Latva-Kala, K; Helander, I M

    2000-05-01

    The effect of lactic acid on the outer membrane permeability of Escherichia coli O157:H7, Pseudomonas aeruginosa, and Salmonella enterica serovar Typhimurium was studied utilizing a fluorescent-probe uptake assay and sensitization to bacteriolysis. For control purposes, similar assays were performed with EDTA (a permeabilizer acting by chelation) and with hydrochloric acid, the latter at pH values corresponding to those yielded by lactic acid, and also in the presence of KCN. Already 5 mM (pH 4.0) lactic acid caused prominent permeabilization in each species, the effect in the fluorescence assay being stronger than that of EDTA or HCl. Similar results were obtained in the presence of KCN, except for P. aeruginosa, for which an increase in the effect of HCl was observed in the presence of KCN. The permeabilization by lactic and hydrochloric acid was partly abolished by MgCl(2). Lactic acid sensitized E. coli and serovar Typhimurium to the lytic action of sodium dodecyl sulfate (SDS) more efficiently than did HCl, whereas both acids sensitized P. aeruginosa to SDS and to Triton X-100. P. aeruginosa was effectively sensitized to lysozyme by lactic acid and by HCl. Considerable proportions of lipopolysaccharide were liberated from serovar Typhimurium by these acids; analysis of liberated material by electrophoresis and by fatty acid analysis showed that lactic acid was more active than EDTA or HCl in liberating lipopolysaccharide from the outer membrane. Thus, lactic acid, in addition to its antimicrobial property due to the lowering of the pH, also functions as a permeabilizer of the gram-negative bacterial outer membrane and may act as a potentiator of the effects of other antimicrobial substances.

  17. p53's mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity

    Institute of Scientific and Technical Information of China (English)

    Sonja Wolff; Susan Erster; Gustavo Palacios; Ute M Moll

    2008-01-01

    p53's apoptotic program consists of transcription-dependent and transcription-independent pathways. In the latter, physical interactions between mitochondrial p53 and anti-and pro-apoptotic members of the Bcl2 family of mitochondrial permeability regulators are central. Using isogenic cell systems with defined deficiencies, we characterize in detail how mitochondrial p53 contributes to mitochondrial permeabilization, to what extent its action depends on other key Bcl2 family members and define its release activity. We show that mitochondrial p53 is highly efficient in inducing the release of soluble and insoluble apoptogenic factors by severely disrupting outer and inner mitochondrial membrane integrity. This action is associated with wild-type p53-induced oligomerization of Bax, Bak and VDAC and the formation of a stress-induced endogenous complex between p53 and cyclophilin D, normally located at the inner membrane. Tumor-derived p53 mutants are deficient in activating the Bax/Bak lipid pore. These actions are independent of Puma and Bax. Importantly, the latter distinguishes the mitochondrial from the cytosolic p53 death pathway.

  18. Lactic Acid Permeabilizes Gram-Negative Bacteria by Disrupting the Outer Membrane

    OpenAIRE

    Alakomi, H.-L.; Skyttä, E.; Saarela, M; Mattila-Sandholm, T.; Latva-Kala, K.; Helander, I M

    2000-01-01

    The effect of lactic acid on the outer membrane permeability of Escherichia coli O157:H7, Pseudomonas aeruginosa, and Salmonella enterica serovar Typhimurium was studied utilizing a fluorescent-probe uptake assay and sensitization to bacteriolysis. For control purposes, similar assays were performed with EDTA (a permeabilizer acting by chelation) and with hydrochloric acid, the latter at pH values corresponding to those yielded by lactic acid, and also in the presence of KCN. Already 5 mM (pH...

  19. Focal junctions retard lateral movement and disrupt fluid phase connectivity in the plasma membrane

    DEFF Research Database (Denmark)

    Vind-Kezunovic, D.; Wojewodzka, U.; Gniadecki, R.

    2008-01-01

    containing liquid-ordered (L-o) lipids. Indeed, values of maximal fluorescence recovery after photobleaching revealed that the long-range mobility of cholera toxin B subunit (CTB, marker of L-o) was similar to 1.5-fold retarded within the focal junctions compared to the surrounding membrane. However, 1......,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-C-18:0), which specifically partitions to the liquid-disordered (L-d), non-raft phase, was also enriched in focal junctions and its mobility was slightly retarded. Cross-linking of GM(1) by CTB or raft aggregation by methyl...

  20. Structural elucidation of the interaction between neurodegenerative disease-related tau protein with model lipid membranes

    Science.gov (United States)

    Jones, Emmalee M.

    A protein's sequence of amino acids determines how it folds. That folded structure is linked to protein function, and misfolding to dysfunction. Protein misfolding and aggregation into beta-sheet rich fibrillar aggregates is connected with over 20 neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized in part by misfolding, aggregation and deposition of the microtubule associated tau protein into neurofibrillary tangles (NFTs). However, two questions remain: What is tau's fibrillization mechanism, and what is tau's cytotoxicity mechanism? Tau is prone to heterogeneous interactions, including with lipid membranes. Lipids have been found in NFTs, anionic lipid vesicles induced aggregation of the microtubule binding domain of tau, and other protein aggregates induced ion permeability in cells. This evidence prompted our investigation of tau's interaction with model lipid membranes to elucidate the structural perturbations those interactions induced in tau protein and in the membrane. We show that although tau is highly charged and soluble, it is highly surface active and preferentially interacts with anionic membranes. To resolve molecular-scale structural details of tau and model membranes, we utilized X-ray and neutron scattering techniques. X-ray reflectivity indicated tau aggregated at air/water and anionic lipid membrane interfaces and penetrated into membranes. More significantly, membrane interfaces induced tau protein to partially adopt a more compact conformation with density similar to folded protein and ordered structure characteristic of beta-sheet formation. This suggests possible membrane-based mechanisms of tau aggregation. Membrane morphological changes were seen using fluorescence microscopy, and X-ray scattering techniques showed tau completely disrupts anionic membranes, suggesting an aggregate-based cytotoxicity mechanism. Further investigation of protein constructs and a "hyperphosphorylation" disease mimic helped

  1. Resveratrol induces membrane and DNA disruption via pro-oxidant activity against Salmonella typhimurium.

    Science.gov (United States)

    Lee, Wonjong; Lee, Dong Gun

    2017-07-22

    Resveratrol is a flavonoid found in various plants including grapes, which has been reported to be active against various pathogenic bacteria. However, antibacterial effects and mechanisms via pro-oxidant property of resveratrol remain unknown and speculative. This research investigated antibacterial mechanism of resveratrol against a food-borne human pathogen Salmonella typhimurium, and confirmed the cell death associated oxidative damage. Resveratrol increased outer membrane permeability and membrane depolarization. It also was observed DNA injury responses such as DNA fragmentation, increasing DNA contents and cell division inhibition. Intracellular ROS accumulation, GSH depletion and significant increased malondialdehyde levels were confirmed, which indicated pro-oxidant activity of resveratrol and oxidative stress. Furthermore, the observed lethal damages were reduced by antioxidant N-acetylcysteine treatment supported the view that resveratrol-induced oxidative stress stimulated S. typhimurium cell death. In conclusion, this study expands understanding on role of pro-oxidant property and insight into previously unrecognized oxygen-dependent anti-Salmonella mechanism on resveratrol. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Skin barrier disruption by acetone: observations in a hairless mouse skin model

    NARCIS (Netherlands)

    Rissmann, R.; Oudshoorn, M.H.M.; Hennink, W.E.; Ponec, M.; Bouwstra, J.A.

    2009-01-01

    To disrupt the barrier function of the skin, different in vivo methods have been established, e.g., by acetone wiping or tape-stripping. In this study, the acetone-induced barrier disruption of hairless mice was investigated in order to establish a reliable model to study beneficial, long-term effec

  3. Self-Segregation of Myelin Membrane Lipids in Model Membranes

    NARCIS (Netherlands)

    Yurlova, Larisa; Kahya, Nicoletta; Aggarwal, Shweta; Kaiser, Hermann-Josef; Chiantia, Salvatore; Bakhti, Mostafa; Pewzner-Jung, Yael; Ben-David, Oshrit; Futerman, Anthony H.; Bruegger, Britta; Simons, Mikael

    2011-01-01

    Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are multilamellar, lipid-rich membranes produced by oligodendrocytes in the central nervous system. To act as an insulator, myelin has to form a stable and firm membrane structure. In this study, we have analyzed t

  4. The polyene antimycotics nystatin and filipin disrupt the plasma membrane, whereas natamycin inhibits endocytosis in germinating conidia of Penicillium discolor

    NARCIS (Netherlands)

    Leeuwen, van M.R.; Golovina, E.A.; Dijksterhuis, J.

    2009-01-01

    To investigate the differences in membrane permeability and the effect on endocytosis of the polyene antimycotics nystatin, filipin and natamycin on germinating fungal conidia. Methods and Results: The model system was Penicillium discolor, a food spoilage fungus. Filipin resulted in permeabilizatio

  5. The polyene antimycotics nystatin and filipin disrupt the plasma membrane, whereas natamycin inhibits endocytosis in germinating conidia of Penicillium discolor

    NARCIS (Netherlands)

    Leeuwen, van M.R.; Golovina, E.A.; Dijksterhuis, J.

    2009-01-01

    To investigate the differences in membrane permeability and the effect on endocytosis of the polyene antimycotics nystatin, filipin and natamycin on germinating fungal conidia. Methods and Results: The model system was Penicillium discolor, a food spoilage fungus. Filipin resulted in permeabilizatio

  6. Disruption of the phagosomal membrane and egress of Legionella pneumophila into the cytoplasm during the last stages of intracellular infection of macrophages and Acanthamoeba polyphaga.

    Science.gov (United States)

    Molmeret, Maëlle; Bitar, Dina M; Han, Lihui; Kwaik, Yousef Abu

    2004-07-01

    Although the early stages of intracellular infection by Legionella pneumophila are well established at the ultrastructural level, a detailed ultrastructural analysis of late stages of intracellular replication has never been done. Here we show that the membrane of the L. pneumophila-containing phagosome (LCP) is intact for up to 8 h postinfection of macrophages and Acanthamoeba polyphaga. At 12 h, 71 and 74% of the LCPs are disrupted within macrophages and A. polyphaga, respectively, while the plasma membrane remains intact. At 18 and 24 h postinfection, cytoplasmic elements such as mitochondria, lysosomes, vesicles, and amorphous material are dispersed among the bacteria and these bacteria are considered cytoplasmic. At 18 h, 77% of infected macrophages and 32% of infected A. polyphaga amoebae harbor cytoplasmic bacteria. At 24 h, 99 and 78% of infected macrophages and amoebae, respectively, contain cytoplasmic bacteria. On the basis of lysosomal acid phosphatase staining of infected macrophages and A. polyphaga, the lysosomal enzyme is present among the bacteria when host vesicles are dispersed among bacteria. Our data indicate that bacterial replication proceeds despite physical disruption of the phagosomal membrane. We also show that an lspG mutant that is defective in the type II secretion system and therefore does not secrete the hydrolytic enzymes metalloprotease, p-nitrophenol phosphorylcholine hydrolase, lipase, phospholipase A, and lysophospholipase A is as efficient as the wild-type strain in disruption of the LCP. Therefore, L. pneumophila disrupts the phagosomal membrane and becomes cytoplasmic at the last stages of infection in both macrophages and A. polyphaga. Lysosomal elements, mitochondria, cytoplasmic vesicles, and amorphous material are all dispersed among the bacteria, after phagosomal disruption, within both human macrophages and A. polyphaga. The disruption of the LCP is independent of the hydrolytic enzymes exported by the type II secretion

  7. The model of stress distribution in polymer electrolyte membrane

    CERN Document Server

    Atrazhev, Vadim V; Dmitriev, Dmitry V; Erikhman, Nikolay S; Sultanov, Vadim I; Patterson, Timothy; Burlatsky, Sergei F

    2014-01-01

    An analytical model of mechanical stress in a polymer electrolyte membrane (PEM) of a hydrogen/air fuel cell with porous Water Transfer Plates (WTP) is developed in this work. The model considers a mechanical stress in the membrane is a result of the cell load cycling under constant oxygen utilization. The load cycling causes the cycling of the inlet gas flow rate, which results in the membrane hydration/dehydration close to the gas inlet. Hydration/dehydration of the membrane leads to membrane swelling/shrinking, which causes mechanical stress in the constrained membrane. Mechanical stress results in through-plane crack formation. Thereby, the mechanical stress in the membrane causes mechanical failure of the membrane, limiting fuel cell lifetime. The model predicts the stress in the membrane as a function of the cell geometry, membrane material properties and operation conditions. The model was applied for stress calculation in GORE-SELECT.

  8. Membrane Compartmentalization Reducing the Mobility of Lipids and Proteins within a Model Plasma Membrane.

    Science.gov (United States)

    Koldsø, Heidi; Reddy, Tyler; Fowler, Philip W; Duncan, Anna L; Sansom, Mark S P

    2016-09-01

    The cytoskeleton underlying cell membranes may influence the dynamic organization of proteins and lipids within the bilayer by immobilizing certain transmembrane (TM) proteins and forming corrals within the membrane. Here, we present coarse-grained resolution simulations of a biologically realistic membrane model of asymmetrically organized lipids and TM proteins. We determine the effects of a model of cytoskeletal immobilization of selected membrane proteins using long time scale coarse-grained molecular dynamics simulations. By introducing compartments with varying degrees of restraints within the membrane models, we are able to reveal how compartmentalization caused by cytoskeletal immobilization leads to reduced and anomalous diffusional mobility of both proteins and lipids. This in turn results in a reduced rate of protein dimerization within the membrane and of hopping of membrane proteins between compartments. These simulations provide a molecular realization of hierarchical models often invoked to explain single-molecule imaging studies of membrane proteins.

  9. Modeling of interactions between nanoparticles and cell membranes

    Science.gov (United States)

    Ban, Young-Min

    Rapid development of nanotechnology and ability to manufacture materials and devices with nanometer feature size leads to exciting innovations in many areas including the medical and electronic fields. However, the possible health and environmental impacts of manufactured nanomaterials are not fully known. Recent experimental reports suggest that some of the manufactured nanomaterials, such as fullerenes and carbon nanotubes, are highly toxic even in small concentrations. The goal of the current work is to understand the mechanisms responsible for the toxicity of nanomaterials. In the current study coarse-grained molecular dynamics simulations are employed to investigate the interactions between NPs and cellular membranes at a molecular level. One of the possible toxicity mechanisms of the nanomaterials is membrane disruption. Possibility of membrane disruption exposed to the manufactured nanomaterials are examined by considering chemical reactions and non-reactive physical interactions as chemical as well as physical mechanisms. Mechanisms of transport of carbon-based nanoparticles (fullerene and its derivative) across a phospholipid bilayer are investigated. The free energy profile is obtained using constrained simulations. It is shown that the considered nanoparticles are hydrophobic and therefore they tend to reside in the interior of the lipid bilayer. In addition, the dynamics of the membrane fluctuations is significantly affected by the nanoparticles at the bilayer-water interface. The hydrophobic interaction between the particles and membrane core induces the strong coupling between the nanoparticle motion and membrane deformation. It is observed that the considered nanoparticles affect several physical properties of the membrane. The nanoparticles embedded into the membrane interior lead to the membrane softening, which becomes more significant with increase in CNT length and concentration. The lateral pressure profile and membrane energy in the membrane

  10. Stability of Model Membranes in Extreme Environments

    Science.gov (United States)

    Namani, Trishool; Deamer, David W.

    2008-08-01

    The first forms of cellular life required a source of amphiphilic compounds capable of assembling into stable boundary structures. Membranes composed of fatty acids have been proposed as model systems of primitive membranes, but their bilayer structure is stable only within a narrow pH range and low ionic strength. They are particularly sensitive to aggregating effects of divalent cations (Mg+2, Ca+2, Fe+2) that would be present in Archaean sea water. Here we report that mixtures of alkyl amines and fatty acids form vesicles at strongly basic and acidic pH ranges which are resistant to the effects of divalent cations up to 0.1 M. Vesicles formed by mixtures of decylamine and decanoic acid (1:1 mole ratio) are relatively permeable to pyranine, a fluorescent anionic dye, but permeability could be reduced by adding 2 mol% of a polycyclic aromatic hydrocarbon such as pyrene. Permeability to the dye was also reduced by increasing the chain length of the amphiphiles. For instance, 1:1 mole ratio mixtures of dodecylamine and dodecanoic acid were able to retain pyranine dye during and following gel filtration. We conclude that primitive cell membranes were likely to be composed of mixtures of amphiphilic and hydrophobic molecules that manifested increased stability over pure fatty acid membranes.

  11. Alteration of cellular lipids and lipid metabolism markers in RTL-W1 cells exposed to model endocrine disrupters.

    Science.gov (United States)

    Dimastrogiovanni, Giorgio; Córdoba, Marlon; Navarro, Isabel; Jáuregui, Olga; Porte, Cinta

    2015-08-01

    This work investigates the suitability of the rainbow trout liver cell line (RTL-W1) as an in-vitro model to study the ability of model endocrine disrupters, namely TBT, TPT, 4-NP, BPA and DEHP, to act as metabolic disrupters by altering cellular lipids and markers of lipid metabolism. Among the tested compounds, BPA and DEHP significantly increased the intracellular accumulation of triacylglycerols (TAGs), while all the compounds -apart from TPT-, altered membrane lipids - phosphatidylcholines (PCs) and plasmalogen PCs - indicating a strong interaction of the toxicants with cell membranes and cell signaling. RTL-W1 expressed a number of genes involved in lipid metabolism that were modulated by exposure to BPA, TBT and TPT (up-regulation of FATP1 and FAS) and 4-NP and DEHP (down-regulation of FAS and LPL). Multiple and complex modes of action of these chemicals were observed in RTL-W1 cells, both in terms of expression of genes related to lipid metabolism and alteration of cellular lipids. Although further characterization is needed, this might be a useful model for the detection of chemicals leading to steatosis or other diseases associated with lipid metabolism in fish.

  12. Disrupted Junctional Membrane Complexes and Hyperactive Ryanodine Receptors Following Acute Junctophilin Knockdown in Mice

    Science.gov (United States)

    van Oort, Ralph J.; Garbino, Alejandro; Wang, Wei; Dixit, Sayali S.; Landstrom, Andrew P.; Gaur, Namit; De Almeida, Angela C.; Skapura, Darlene G.; Rudy, Yoram; Burns, Alan R.; Ackerman, Michael J.; Wehrens, Xander H.T.

    2011-01-01

    Background Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum (SR) within junctional membrane complexes (JMCs). Whereas previous studies revealed a loss of JMCs and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in JMC formation and the Ca2+-induced Ca2+ release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy. Methods and Results To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of JMCs and increased variability in the plasmalemma-SR distance. Conclusions Loss of JPH2 had profound effects on Ca2+ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca2+ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific shRNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca2+ release in the heart. PMID:21339484

  13. Workshop on Populations & Crowds: Dynamics, Disruptions and their Computational Models

    Science.gov (United States)

    2015-01-01

    behavior and, ultimately, what can be done to block contagion of hostile behavior in both population and crowd contexts. The workshop was organized at the...powerful in their ability to spread information and rapidly alter their collective behavior . Crowds can transition from loosely to tightly organized and...7 September, 2012 concentrating on organization , dynamics and disruption of populations and crowds. The purpose of this workshop was to bring

  14. Modelling the interaction of steroid receptors with endocrine disrupting chemicals.

    Science.gov (United States)

    D'Ursi, Pasqualina; Salvi, Erika; Fossa, Paola; Milanesi, Luciano; Rovida, Ermanna

    2005-12-01

    The organic polychlorinated compounds like dichlorodiphenyltrichloroethane with its metabolites and polychlorinated biphenyls are a class of highly persistent environmental contaminants. They have been recognized to have detrimental health effects both on wildlife and humans acting as endocrine disrupters due to their ability of mimicking the action of the steroid hormones, and thus interfering with hormone response. There are several experimental evidences that they bind and activate human steroid receptors. However, despite the growing concern about the toxicological activity of endocrine disrupters, molecular data of the interaction of these compounds with biological targets are still lacking. We have used a flexible docking approach to characterize the molecular interaction of seven endocrine disrupting chemicals with estrogen, progesterone and androgen receptors in the ligand-binding domain. All ligands docked in the buried hydrophobic cavity corresponding to the hormone steroid pocket. The interaction was characterized by multiple hydrophobic contacts involving a different number of residues facing the binding pocket, depending on ligands orientation. The EDC ligands did not display a unique binding mode, probably due to their lipophilicity and flexibility, which conferred them a great adaptability into the hydrophobic and large binding pocket of steroid receptors. Our results are in agreement with toxicological data on binding and allow to describe a pattern of interactions for a group of ECD to steroid receptors suggesting the requirement of a hydrophobic cavity to accommodate these chlorine carrying compounds. Although the affinity is lower than for hormones, their action can be brought about by a possible synergistic effect.

  15. Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture.

    Directory of Open Access Journals (Sweden)

    Ryan P O'Connell

    Full Text Available Epicardial adiposity and plasma levels of free fatty acids (FFAs are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown.To determine the mechanisms underlying electrophysiological effects of palmitic (PA, stearic (SA and oleic (OA FFAs on sheep atrial myocytes.We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min, short-term (4-6 hour or 24-hour application of individual FFAs (10 μM on isolated ovine left atrial myocytes (LAMs.Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs. 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05 action potential duration at 30% repolarization (APD30. APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05, and abbreviated APD at all values measured (p≤0.001. OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01 of the L-type calcium current (ICa-L and ~30% reduction (p<0.05 in the transient outward potassium current (ITO. A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001.SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis.

  16. A Double-Disruption Substorm Model - The Growth Phase

    Science.gov (United States)

    Sofko, G. J.; McWilliams, K. A.; Hussey, G. C.

    2014-12-01

    When the IMF turns from Bz- to Bz+, dayside merging forms open lobe field lines at low latitudes. These lobe lines are populated with shocked solar wind and dayside magnetospheric plasma from the reconnection inflow. As those lobe flux tubes pass tailward over the polar caps, they are also populated with outflow from the north and south polar cap ionospheres. As the lobe lines move tailward, they acquire a convex curvature that blocks the westward-flowing cross-tail current (XTJ). This constitutes the first stage of XTJ disruption, and it begins less than 10 min after the frontside merging.The disrupted XTJ closes dawn-to-dusk in the transition plasmasheet (TPS), where it produces a downward FAC to the ionosphere. This causes the proton arc, which is seen for the period from about 10 - 80 min after frontside merging begins at time t=0. The lobe lines eventually reconnect well downtail at about t=30 minutes. The middle section that closes the lobe lines has concave curvature and is called the Neutral Sheet (NSh). The resulting stretched field lines thus have a central NSh which separates the two convex-curvature regions to the north and south, regions which are called the Disruption Zones (DZs); the overall combination of the NDZ, NSh and SDZ is called the Stretched Plasmasheet (SPS). As the SPS continues to grow and the stretched lines are pulled earthward to relieve the magnetic tension, the filling of the NSh occurs both from the DTNL with the higher energy magnetospheric particle population on the lobe lines, but eventually also at about 25 earth radii when the polar cap ionospheric outflow (PCO) component finally reaches the NSh. A NSh FAC system forms, from which electrons flow down to the auroral ionosphere to create the pre-onset arc, starting at about t=65 min. At the same time, the Lyons-Speiser mechanism is initiated in the inner NSh, causing the PCO ions to become trapped and accelerated in the inner NSh region. Eventually, when the SPS grows earthward

  17. Putting theory to the test: modeling a multidimensional, developmentally-based approach to preschool disruptive behavior.

    Science.gov (United States)

    Wakschlag, Lauren S; Henry, David B; Tolan, Patrick H; Carter, Alice S; Burns, James L; Briggs-Gowan, Margaret J

    2012-06-01

    There is increasing emphasis on dimensional conceptualizations of psychopathology, but empirical evidence of their utility is just emerging. In particular, although a range of multidimensional models have been proposed, the relative fit of competing models has rarely been tested. Furthermore, developmental considerations have received scant attention. In this study, we tested a developmentally based, four-dimensional model of disruptive behavior theorized to represent the defining features of disruptive behavior at preschool age: Temper Loss, Noncompliance, Aggression, and Low Concern for Others. Model testing was conducted in two independent samples of preschoolers: Clinically Enriched Sample (n = 336) and Epidemiologic Sample (n = 532). The tau-equivalent confirmatory factor analyses were used to test the fit of the Developmental Model relative to three leading competing models (DSM opositional defiant disorder (ODD)/conduct disorder (CD) Model, "Callous" Model, and an "Irritable/Headstrong/Hurtful" Model). Reliability of the four dimensions was also tested. Validity of the dimensions was tested by predicting multi-informant, multi-method ratings of disruptive behavior and impairment, and incremental utility relative to DSM symptoms. In both samples, the Developmental Model demonstrated a superior fit compared with the competing models within the full sample, and across key demographic subgroups. Validity was also demonstrated, including incremental utility relative to DSM-IV disruptive behavior symptoms. Critical next steps for achieving scientific consensus about the optimal dimensional model of disruptive behavior and its clinical application are discussed. Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Disrupted plasma membrane localization and loss of function reveal regions of human equilibrative nucleoside transporter 1 involved in structural integrity and activity.

    Science.gov (United States)

    Nivillac, Nicole M I; Wasal, Karanvir; Villani, Daniela F; Naydenova, Zlatina; Hanna, W J Brad; Coe, Imogen R

    2009-10-01

    Human Equilibrative Nucleoside Transporter 1 (hENT1) is an integral membrane protein that transports nucleosides and analog drugs across cellular membranes. Very little is known about intracellular processing and localization of hENT1. Here we show that disruption of a highly conserved triplet (PWN) near the N-terminus, or the last eight C-terminal residues (two hydrophobic triplets separated by a positive arginine) result in loss of plasma membrane localization and/or transport function. To understand the role of specific residues within these regions, we studied the localization patterns of N- or C-terminal deletion and/or substitution mutants of GFP-hENT1 using confocal microscopy. Quantification of GFP-hENT1 (mutant and wildtype) protein at the plasma membrane was conducted using nitrobenzylthioinosine (NBTI) binding. Functionality of the GFP-hENT1 mutants was determined by heterologous expression in Xenopus laevis oocytes followed by measurement of uridine uptake. Mutation of the proline within the PWN motif disrupts plasma membrane localization. C-terminal mutations (primarily within the hydrophobic triplets) lead to hENT1 retention within the cell (e.g. in the ER). Some mutants still localize to the plasma membrane but show reduced transport activity. These data suggest that these two regions contribute to the structural integrity and thus correct processing and function of hENT1.

  19. Disruption of the mitochondria-associated ER membrane (MAM) plays a central role in palmitic acid-induced insulin resistance.

    Science.gov (United States)

    Shinjo, Satoko; Jiang, Shuying; Nameta, Masaaki; Suzuki, Tomohiro; Kanai, Mai; Nomura, Yuta; Goda, Nobuhito

    2017-10-01

    The mitochondria-associated ER membrane (MAM) is a specialized subdomain of ER that physically connects with mitochondria. Although disruption of inter-organellar crosstalk via the MAM impairs cellular homeostasis, its pathological significance in insulin resistance in type 2 diabetes mellitus remains unclear. Here, we reveal the importance of reduced MAM formation in the induction of fatty acid-evoked insulin resistance in hepatocytes. Palmitic acid (PA) repressed insulin-stimulated Akt phosphorylation in HepG2 cells within 12h. Treatment with an inhibitor of the ER stress response failed to restore PA-mediated suppression of Akt activation. Mitochondrial reactive oxygen species (ROS) production did not increase in PA-treated cells. Even short-term exposure (3h) to PA reduced the calcium flux from ER to mitochondria, followed by a significant decrease in MAM contact area, suggesting that PA suppressed the functional interaction between ER and mitochondria. Forced expression of mitofusin-2, a critical component of the MAM, partially restored MAM contact area and ameliorated the PA-elicited suppression of insulin sensitivity with Ser473 phosphorylation of Akt selectively improved. These results suggest that loss of proximity between ER and mitochondria, but not perturbation of homeostasis in the two organelles individually, plays crucial roles in PA-evoked Akt inactivation in hepatic insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Mitochondrial uncouplers act synergistically with the fumigant phosphine to disrupt mitochondrial membrane potential and cause cell death.

    Science.gov (United States)

    Valmas, Nicholas; Zuryn, Steven; Ebert, Paul R

    2008-10-30

    Phosphine is the most widely used fumigant for the protection of stored commodities against insect pests, especially food products such as grain. However, pest insects are developing resistance to phosphine and thereby threatening its future use. As phosphine inhibits cytochrome c oxidase (complex IV) of the mitochondrial respiratory chain and reduces the strength of the mitochondrial membrane potential (DeltaPsi(m)), we reasoned that mitochondrial uncouplers should act synergistically with phosphine. The mitochondrial uncouplers FCCP and PCP caused complete mortality in populations of both wild-type and phosphine-resistant lines of Caenorhabditis elegans simultaneously exposed to uncoupler and phosphine at concentrations that were individually nonlethal. Strong synergism was also observed with a third uncoupler DNP. We have also tested an alternative complex IV inhibitor, azide, with FCCP and found that this also caused a synergistic enhancement of toxicity in C. elegans. To investigate potential causes of the synergism, we measured DeltaPsi(m), ATP content, and oxidative damage (lipid hydroperoxides) in nematodes subjected to phosphine-FCCP treatment and found that neither an observed 50% depletion in ATP nor oxidative stress accounted for the synergistic effect. Instead, a synergistic reduction in DeltaPsi(m) was observed upon phosphine-FCCP co-treatment suggesting that this is directly responsible for the subsequent mortality. These results support the hypothesis that phosphine-induced mortality results from the in vivo disruption of normal mitochondrial activity. Furthermore, we have identified a novel pathway that can be targeted to overcome genetic resistance to phosphine.

  1. Biophysical studies of cholesterol in unsaturated phospholipid model membranes

    Science.gov (United States)

    Williams, Justin Adam

    PUFAs can incorporate into lipid rafts, which are domains enriched in SM and chol in the plasma membrane, and potentially disrupt the activity of signaling proteins that reside therein. DHA, furthermore, may be the more potent component of fish oil. PUFA-chol interactions were also examined through affinity measurements. A novel method utilizing electron paramagnetic resonance (EPR) was developed, to monitor the partitioning of a spin-labeled analog of chol, 3beta-doxyl-5alpha-cholestane (chlstn), between large unilamellar vesicles (LUVs) and methyl-beta-cyclodextrin (mbetaCD). The EPR spectra for chlstn in the two environments are distinguishable due to the substantial differences in tumbling rates, allowing the population distribution ratio to be determined by spectral simulation. Advantages of this approach include speed of implementation and avoidance of potential artifacts associated with physical separation of LUV and mbetaCD. Additionally, in a check of the method, the relative partition coefficients between lipids measured for the spin label analog agree with values obtained for chol by isothermal titration calorimetry (ITC). Results from LUV with different composition confirmed a hierarchy of decreased sterol affinity for phospholipids with increasing acyl chain unsaturation, PDPC possessing half the affinity of the corresponding monounsaturated phospholipid. Taken together, the results of these studies on model membranes demonstrate the potential for PUFA-driven alteration of the architecture of biomembranes, a mechanism through which human health may be impacted.

  2. A Disruption-Tolerant Model for Building a Mobile Application Using Web Service

    Directory of Open Access Journals (Sweden)

    Maryati M. Yusof

    2010-01-01

    Full Text Available Problem statement: The emerging technology in broadband telecommunication and mobile devices has increased the use of mobile applications. However, the use of mobile application is affected with low bandwidth or disrupted broadband telecommunication due to building blockage or out of coverage area. Approach: We proposed a Disruption-Tolerant Mobile Application Model (DTMA that enables remote data access and overcomes constraint due to dysfunctional telecommunication. The interview process of Educational Service Officer at the Malaysian Educational Service Commissioner (MESC is selected as the case study. Design of the mobile application is based on the Smart Client and wireless Internet application concepts. The main components of the model are mobile devices with its own processing power, data storage, business logic and Web service. These features enable the application to become disruption-tolerant, which can be run even when communication line is not available or disrupted. In order to prove that the proposed model is effective, a prototype based on the DTMA model is developed and evaluated. Results: The prototype is known as Mobile Interview Information System (MIIS and it was developed using Visual Basic and .Net’s programming language in .NET Framework. Visual Studio is used as the platform. Users have performed MIIS testing and DTMA usability assessment in a real environment. The test showed that MIIS based on the DTMA model is disruption-tolerant. MIIS enables information to be accessed and updated even in a disrupted network. MIIS also enables information to be accessed and transmitted from or to the MESC’s headquarter via mobile devices. Further, MIIS enables the interview process to be implemented in a more efficient manner without any disruption. Conclusion: Mobile application developed based on the proposed DTMA model was proved to be disruption tolerant. Such application can save time, operational cost and

  3. A general model for membrane-based separation processes

    DEFF Research Database (Denmark)

    Soni, Vipasha; Abildskov, Jens; Jonsson, Gunnar Eigil;

    2009-01-01

    behaviour will play an important role. In this paper, modelling of membrane-based processes for separation of gas and liquid mixtures are considered. Two general models, one for membrane-based liquid separation processes (with phase change) and another for membrane-based gas separation are presented...

  4. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression.

    Science.gov (United States)

    Santoro, Stephen P; Kim, Soorin; Motz, Gregory T; Alatzoglou, Dimitrios; Li, Chunsheng; Irving, Melita; Powell, Daniel J; Coukos, George

    2015-01-01

    Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of protumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here, we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA(+) endothelial targets in vitro, regardless of the signaling domain. T cells bearing the third-generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA(+) vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide a strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA. Cancer Immunol Res; 3(1); 68-84. ©2014 AACR. ©2014 American Association for Cancer Research.

  5. Toxicity of perfluorooctane sulfonate and perfluorooctanoic acid to Escherichia coli: Membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death.

    Science.gov (United States)

    Liu, Gesheng; Zhang, Shuai; Yang, Kun; Zhu, Lizhong; Lin, Daohui

    2016-07-01

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two widely used polyfluorinated compounds (PFCs) and are persistent in the environment. This study for the first time systematically investigated their toxicities and the underlying mechanisms to Escherichia coli. Much higher toxicity was observed for PFOA than PFOS, with the 3 h half growth inhibition concentrations (IC50) determined to be 10.6 ± 1.0 and 374 ± 3 mg L(-1), respectively, while the bacterial accumulation of PFOS was much greater than that of PFOA. The PFC exposures disrupted cell membranes as evidenced by the dose-dependent variations of cell structures (by transmission electron microscopy observations), surface properties (electronegativity, hydrophobicity, and membrane fluidity), and membrane compositions (by gas chromatogram and Fourier transform infrared spectroscopy analyses). The increases in the contents of intracellular reactive oxygen species (ROS) and malondialdehyde and the activity of superoxide dismutase indicated the increment of oxidative stress induced by the PFCs in the bacterial cells. The fact that the cell growth inhibition was mitigated by the addition of ROS scavenger (N-acetyl cysteine) further evidenced the important role of oxidative damage in the toxicities of PFOS and PFOA. Eighteen genes involved in cell division, membrane instability, oxidative stress, and DNA damage of the exposed cells were up or down expressed, indicating the DNA damage by the PFCs. The toxicities of PFOS and PFOA to E. coli were therefore ascribed to the membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death. The difference in the bactericidal effect between PFOS and PFOA was supposed to be related to their different dominating toxicity mechanisms, i.e., membrane disruption and oxidative damage, respectively. The outcomes will shed new light on the assessment of ecological effects of PFCs.

  6. A Recovery Model for Production Scheduling: Combination of Disruption Management and Internet of Things

    Directory of Open Access Journals (Sweden)

    Yang Jiang

    2016-01-01

    Full Text Available It is difficult to generate the new schedule effectively for minimizing the negative impact when an unanticipated disruption occurs after a subset of tasks has been finished in production scheduling. In such cases, continuing with the original schedule may not be optimal or feasible. Based on disruption management and Internet of things (IoT, this study designs a real-time status analyzer to identify the disruption and propose a recovery model to deal with the disruption. The computational result proves that our algorithm is competitive with the existing heuristics. Furthermore, due to the tradeoff between all participators (mainly including customers, managers of production enterprise, and workers involved in production scheduling, our model is more effective than the total rescheduling and right-shift rescheduling.

  7. Modeling of membrane processes for air revitalization and water recovery

    Science.gov (United States)

    Lange, Kevin E.; Foerg, Sandra L.; Dall-Bauman, Liese A.

    1992-01-01

    Gas-separation and reverse-osmosis membrane models are being developed in conjunction with membrane testing at NASA JSC. The completed gas-separation membrane model extracts effective component permeabilities from multicomponent test data, and predicts the effects of flow configuration, operating conditions, and membrane dimensions on module performance. Variable feed- and permeate-side pressures are considered. The model has been applied to test data for hollow-fiber membrane modules with simulated cabin-air feeds. Results are presented for a membrane designed for air drying applications. Extracted permeabilities are used to predict the effect of operating conditions on water enrichment in the permeate. A first-order reverse-osmosis model has been applied to test data for spiral wound membrane modules with a simulated hygiene water feed. The model estimates an effective local component rejection coefficient under pseudosteady-state conditions. Results are used to define requirements for a detailed reverse-osmosis model.

  8. Disruption management in the airline industry-Concepts, models and methods

    DEFF Research Database (Denmark)

    Clausen, Jens; Larsen, Allan; Larsen, Jesper

    2010-01-01

    This paper provides a thorough review of the current state-of-the-art within airline disruption management of resources, including aircraft, crew, passenger and integrated recovery. An overview of model formulations of the aircraft and crew scheduling problems is presented in order to emphasize...... similarities between solution approaches applied to the planning and recovery problems. A brief overview of research within schedule robustness in airline scheduling is included in the review, since this proactive measure is a natural complement to disruption management....

  9. Disruption management in the airline industry-Concepts, models and methods

    DEFF Research Database (Denmark)

    Clausen, Jens; Larsen, Allan; Larsen, Jesper

    2010-01-01

    This paper provides a thorough review of the current state-of-the-art within airline disruption management of resources, including aircraft, crew, passenger and integrated recovery. An overview of model formulations of the aircraft and crew scheduling problems is presented in order to emphasize...... similarities between solution approaches applied to the planning and recovery problems. A brief overview of research within schedule robustness in airline scheduling is included in the review, since this proactive measure is a natural complement to disruption management....

  10. Business Model as an Inducer of Disruptive Innovations: The Case of Gol Airlines

    Directory of Open Access Journals (Sweden)

    Sirlei de Almeida Pereira

    2015-10-01

    Full Text Available This study was undertaken to investigate the premises that the success of disruptive innovation is related to the business model adopted by organizations. An analysis of five business models from the literature review - Bovet and Martha (2000, Applegate (2001, Chesbrough and Rosenbloom (2002, Osterwalder and Pigneur (2010, and Rodrigues, Maccari and Lenzi (2012 – was conducted based on the case of the Brazilian Gol Airlines who is recognized as a success business that promoted a disruptive innovation. The results suggest that the assertive choice of the business model can leverage innovation processes, and two of the models listed are adherence to the case studied. Keywords: Disruptive Innovation; Business Model; Innovation Elements; Strategy; Gol Airlines.

  11. Modeling The Optical Emission Of Tidal Disruption Events

    Science.gov (United States)

    Lodato, Giuseppe; Bonnerot, C.; Rossi, E.; Franchini, A.

    2016-10-01

    In this talk, i will present some new advances in the theory of Tidal Disruption Events (TDE). TDEs occur when a star approaches a SMBH close enough to be torn apart by the black hole tidal field. The rapid accretion of the stellar debris produce a luminous, possibly super-Eddington flare, lighting up an otherwise quiescent black hole. In this talk, I will present some recent results concerning the formation and early evolution of an accretion disc formed by the stellar debris. The structure of the disc is strongly dependent on the thermal state of the gas, with efficient or inefficient cooling giving rise to either a thin disc or an extended torus/envelope surrounding the black hole. I will present the results of numerical simulations confirming this picture and including relativistic effects, which are essential for the formation of the disc. Finally, I will discuss the possible development of quasi periodic signals arising from Lense-Thirring precession around a spinning black hole.

  12. Family Disruptions

    Science.gov (United States)

    ... stay angry, or avoid fights altogether? Your children model themselves on you. Departures and Returns Do you or your spouse frequently travel on business? These can be disruptive times for your child and for the family ...

  13. Atomic force microscopy of model lipid membranes.

    Science.gov (United States)

    Morandat, Sandrine; Azouzi, Slim; Beauvais, Estelle; Mastouri, Amira; El Kirat, Karim

    2013-02-01

    Supported lipid bilayers (SLBs) are biomimetic model systems that are now widely used to address the biophysical and biochemical properties of biological membranes. Two main methods are usually employed to form SLBs: the transfer of two successive monolayers by Langmuir-Blodgett or Langmuir-Schaefer techniques, and the fusion of preformed lipid vesicles. The transfer of lipid films on flat solid substrates offers the possibility to apply a wide range of surface analytical techniques that are very sensitive. Among them, atomic force microscopy (AFM) has opened new opportunities for determining the nanoscale organization of SLBs under physiological conditions. In this review, we first focus on the different protocols generally employed to prepare SLBs. Then, we describe AFM studies on the nanoscale lateral organization and mechanical properties of SLBs. Lastly, we survey recent developments in the AFM monitoring of bilayer alteration, remodeling, or digestion, by incubation with exogenous agents such as drugs, proteins, peptides, and nanoparticles.

  14. Simulation modeling of the probability of magmatic disruption of the potential Yucca Mountain Site

    Energy Technology Data Exchange (ETDEWEB)

    Crowe, B.M.; Perry, F.V.; Valentine, G.A. [Los Alamos National Lab., NM (United States); Wallmann, P.C.; Kossik, R. [Golder Associates, Inc., Redmond, WA (United States)

    1993-11-01

    The first phase of risk simulation modeling was completed for the probability of magmatic disruption of a potential repository at Yucca Mountain. E1, the recurrence rate of volcanic events, is modeled using bounds from active basaltic volcanic fields and midpoint estimates of E1. The cumulative probability curves for El are generated by simulation modeling using a form of a triangular distribution. The 50% estimates are about 5 to 8 {times} 10{sup 8} events yr{sup {minus}1}. The simulation modeling shows that the cumulative probability distribution for E1 is more sensitive to the probability bounds then the midpoint estimates. The E2 (disruption probability) is modeled through risk simulation using a normal distribution and midpoint estimates from multiple alternative stochastic and structural models. The 50% estimate of E2 is 4.3 {times} 10{sup {minus}3} The probability of magmatic disruption of the potential Yucca Mountain site is 2.5 {times} 10{sup {minus}8} yr{sup {minus}1}. This median estimate decreases to 9.6 {times} 10{sup {minus}9} yr{sup {minus}1} if E1 is modified for the structural models used to define E2. The Repository Integration Program was tested to compare releases of a simulated repository (without volcanic events) to releases from time histories which may include volcanic disruptive events. Results show that the performance modeling can be used for sensitivity studies of volcanic effects.

  15. Optimization model for Green Vendor Managed Inventory under disruptions

    OpenAIRE

    Baruah, Swapnali

    2015-01-01

    Purpose: This dissertation reviews the literature in the field of Vehicle Routing Problem to analyze gaps in the literature of Green Vehicle Routing Problem and proposes a model in this field. This model bridges one such gap in literature to find optimal routes to a set of customers minimizing the total cost and taking carbon emission into consideration. There is no model in literature that caters to these objectives all at the same time. Methodology: Previous research has mostly focused o...

  16. COMPUTATION MODELING OF TCDD DISRUPTION OF B CELL TERMINAL DIFFERENTIATION

    Science.gov (United States)

    In this study, we established a computational model describing the molecular circuit underlying B cell terminal differentiation and how TCDD may affect this process by impinging upon various molecular targets.

  17. β2 and γ3 laminins are critical cortical basement membrane components: ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia.

    Science.gov (United States)

    Radner, Stephanie; Banos, Charles; Bachay, Galina; Li, Yong N; Hunter, Dale D; Brunken, William J; Yee, Kathleen T

    2013-03-01

    Cortical development is dependent on the timely production and migration of neurons from neurogenic sites to their mature positions. Mutations in several receptors for extracellular matrix (ECM) molecules and their downstream signaling cascades produce dysplasia in brain. Although mutation of a critical binding site in the gene that encodes the ECM molecule laminin γ1 (Lamc1) disrupts cortical lamination, the ECM ligand(s) for many ECM receptors have not been demonstrated directly in the cortex. Several isoforms of the heterotrimeric laminins, all containing the β2 and γ3 chain, have been isolated from the brain, suggesting they are important for CNS function. Here, we report that mice homozygous null for the laminin β2 and γ3 chains exhibit cortical laminar disorganization. Mice lacking both of these laminin chains exhibit hallmarks of human cobblestone lissencephaly (type II, nonclassical): they demonstrate severe laminar disruption; midline fusion; perturbation of Cajal-Retzius cell distribution; altered radial glial cell morphology; and ectopic germinal zones. Surprisingly, heterozygous mice also exhibit laminar disruption of cortical neurons, albeit with lesser severity. In compound null mice, the pial basement membrane is fractured, and the distribution of a key laminin receptor, dystroglycan, is altered. These data suggest that β2 and γ3-containing laminins play an important dose-dependent role in development of the cortical pial basement membrane, which serves as an attachment site for Cajal-Retzius and radial glial cells, thereby guiding neural development.

  18. A stochastic inventory management model for a dual sourcing supply chain with disruptions

    Science.gov (United States)

    Iakovou, Eleftherios; Vlachos, Dimitrios; Xanthopoulos, Anastasios

    2010-03-01

    As companies continue to globalise their operations and outsource significant portion of their value chain activities, they often end up relying heavily on order replenishments from distant suppliers. The explosion in long-distance sourcing is exposing supply chains and shareholder value at ever increasing operational and disruption risks. It is well established, both in academia and in real-world business environments, that resource flexibility is an effective method for hedging against supply chain disruption risks. In this contextual framework, we propose a single period stochastic inventory decision-making model that could be employed for capturing the trade-off between inventory policies and disruption risks for an unreliable dual sourcing supply network for both the capacitated and uncapacitated cases. Through the developed model, we obtain some important managerial insights and evaluate the merit of contingency strategies in managing uncertain supply chains.

  19. Ultrasonic disruption of Pseudomonas putida for the release of arginine deiminase: Kinetics and predictive models.

    Science.gov (United States)

    Patil, Mahesh D; Dev, Manoj J; Tangadpalliwar, Sujit; Patel, Gopal; Garg, Prabha; Chisti, Yusuf; Banerjee, Uttam Chand

    2017-06-01

    The responses of the ultrasound-mediated disruption of Pseudomonas putida KT2440 were modelled as the function of biomass concentration in the cell suspension; the treatment time of sonication; the duty cycle and the acoustic power of the sonicator. For the experimental data, the response surface (RSM), the artificial neural network (ANN) and the support vector machine (SVM) models were compared for their ability to predict the performance parameters. The satisfactory prediction of the unseen data of the responses implied the proficient generalization capabilities of ANN. The extent of the cell disruption was mainly dependent on the acoustic power and the biomass concentration. The cellmass concentration in the slurry most strongly influenced the ADI and total protein release. Nearly 28U/mL ADI was released when a biomass concentration of 300g/L was sonicated for 6min with an acoustic power of 187.5W at 40% duty cycle. Cell disruption obeyed first-order kinetics.

  20. Modeling the pharmacodynamics of passive membrane permeability

    Science.gov (United States)

    Swift, Robert V.; Amaro, Rommie E.

    2011-11-01

    Small molecule permeability through cellular membranes is critical to a better understanding of pharmacodynamics and the drug discovery endeavor. Such permeability may be estimated as a function of the free energy change of barrier crossing by invoking the barrier domain model, which posits that permeation is limited by passage through a single "barrier domain" and assumes diffusivity differences among compounds of similar structure are negligible. Inspired by the work of Rezai and co-workers (JACS 128:14073-14080, 2006), we estimate this free energy change as the difference in implicit solvation free energies in chloroform and water, but extend their model to include solute conformational affects. Using a set of eleven structurally diverse FDA approved compounds and a set of thirteen congeneric molecules, we show that the solvation free energies are dominated by the global minima, which allows solute conformational distributions to be effectively neglected. For the set of tested compounds, the best correlation with experiment is obtained when the implicit chloroform global minimum is used to evaluate the solvation free energy difference.

  1. T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling.

    Science.gov (United States)

    Nivala, Michael; Song, Zhen; Weiss, James N; Qu, Zhilin

    2015-02-01

    In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF.

  2. The lognormal perfusion model for disruption replenishment measurements of blood flow: in vivo validation.

    Science.gov (United States)

    Hudson, John M; Leung, Kogee; Burns, Peter N

    2011-10-01

    Dynamic contrast enhanced ultrasound (DCE-US) is evolving as a promising tool to noninvasively quantify relative tissue perfusion in organs and solid tumours. Quantification using the method of disruption replenishment is best performed using a model that accurately describes the replenishment of microbubble contrast agents through the ultrasound imaging plane. In this study, the lognormal perfusion model was validated using an exposed in vivo rabbit kidney model. Compared against an implanted transit time flow meter, longitudinal relative flow measurement was (×3) less variable and correlated better when quantification was performed with the lognormal perfusion model (Spearman r = 0.90, 95% confidence interval [CI] = 0.05) vs. the prevailing mono-exponential model (Spearman r = 0.54, 95% CI = 0.18). Disruption-replenishment measurements using the lognormal perfusion model were reproducible in vivo to within 12%.

  3. Advanced Nuclear Fuel Cycle Transitions: Optimization, Modeling Choices, and Disruptions

    Science.gov (United States)

    Carlsen, Robert W.

    Many nuclear fuel cycle simulators have evolved over time to help understan the nuclear industry/ecosystem at a macroscopic level. Cyclus is one of th first fuel cycle simulators to accommodate larger-scale analysis with it liberal open-source licensing and first-class Linux support. Cyclus also ha features that uniquely enable investigating the effects of modeling choices o fuel cycle simulators and scenarios. This work is divided into thre experiments focusing on optimization, effects of modeling choices, and fue cycle uncertainty. Effective optimization techniques are developed for automatically determinin desirable facility deployment schedules with Cyclus. A novel method fo mapping optimization variables to deployment schedules is developed. Thi allows relationships between reactor types and scenario constraints to b represented implicitly in the variable definitions enabling the usage o optimizers lacking constraint support. It also prevents wasting computationa resources evaluating infeasible deployment schedules. Deployed power capacit over time and deployment of non-reactor facilities are also included a optimization variables There are many fuel cycle simulators built with different combinations o modeling choices. Comparing results between them is often difficult. Cyclus flexibility allows comparing effects of many such modeling choices. Reacto refueling cycle synchronization and inter-facility competition among othe effects are compared in four cases each using combinations of fleet of individually modeled reactors with 1-month or 3-month time steps. There are noticeable differences in results for the different cases. The larges differences occur during periods of constrained reactor fuel availability This and similar work can help improve the quality of fuel cycle analysi generally There is significant uncertainty associated deploying new nuclear technologie such as time-frames for technology availability and the cost of buildin advanced reactors

  4. A theoretical model to address organizational human conflict and disruptive behavior in health care organizations.

    Science.gov (United States)

    Piper, Llewellyn E

    2006-01-01

    This article proposes a theoretical model for leaders to use to address organizational human conflict and disruptive behavior in health care organizations. Leadership is needed to improve interpersonal relationships within the workforce. A workforce with a culture of internal conflict will be unable to achieve its full potential to delivery quality patient care.

  5. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    Science.gov (United States)

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component…

  6. Modeling resilience, friability, and cost of an airport affected by the large-scale disruptive event

    NARCIS (Netherlands)

    Janic, M.

    2013-01-01

    This paper deals with modeling resilience, friability, and cost of an airport affected by the largescale disruptive event. These events affecting the airport's operations individually or in combination can be bad weather, failures of particular crucial aiiport and ATC (Air Traffic Control) component

  7. Exploring the Utility of Self-Modeling in Decreasing Disruptive Behavior in Students with Intellectual Disability

    Science.gov (United States)

    Bilias-Lolis, Evelyn; Chafouleas, Sandra M.; Kehle, Thomas J.; Bray, Melissa A.

    2012-01-01

    Students with intellectual disabilities can exhibit a wide array of challenging behaviors in the classroom that pose disruptions to the learning milieu and management problems for those involved in their education. Self-modeling, a behavioral intervention that involves viewing edited videotapes of oneself depicting exemplary behavior, has had…

  8. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    Science.gov (United States)

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component…

  9. Exploring the Utility of Self-Modeling in Decreasing Disruptive Behavior in Students with Intellectual Disability

    Science.gov (United States)

    Bilias-Lolis, Evelyn; Chafouleas, Sandra M.; Kehle, Thomas J.; Bray, Melissa A.

    2012-01-01

    Students with intellectual disabilities can exhibit a wide array of challenging behaviors in the classroom that pose disruptions to the learning milieu and management problems for those involved in their education. Self-modeling, a behavioral intervention that involves viewing edited videotapes of oneself depicting exemplary behavior, has had…

  10. QSAR models for reproductive toxicity and endocrine disruption in regulatory use - a preliminary investigation

    DEFF Research Database (Denmark)

    Jensen, Gunde Egeskov; Niemela, J.R.; Wedebye, Eva Bay

    2008-01-01

    the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data...... for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption....

  11. Retinal ectopias and mechanically weakened basement membrane in a mouse model of muscle-eye-brain (MEB) disease congenital muscular dystrophy.

    Science.gov (United States)

    Hu, Huaiyu; Candiello, Joseph; Zhang, Peng; Ball, Sherry L; Cameron, David A; Halfter, Willi

    2010-07-28

    Some forms of congenital muscular dystrophy are associated with cortical and retinal dysplasias. Protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice, one of the mouse models of muscular dystrophy, exhibit a thinner retina with reduced density of retinal ganglion cells. This study is aimed to further characterize the knockout retina, with special emphasis on the inner limiting membrane, the basement membrane of the retina. Immunofluorescence staining and transmission electron microscopy were used to analyze the retinas. Atomic force microscopy was performed on the inner limiting membrane preparations to examine their mechanical properties. The inner limiting membrane of the knockout mice exhibited frequent breaks with protrusions of the Müller glial processes and ectopic placement of retinal ganglion cells into the vitreous humor. Disruptions in inner limiting membrane integrity developmentally precede the cellular abnormalities. Regions of disrupted inner limiting membrane were also associated with molecular abnormalities of Müller glia that included diminished presence of the integral membrane proteins Kir4.1 (an inwardly rectifying potassium channel) and aquaporin-4. When measured with atomic force microscopy, the POMGnT1 knockout mouse inner limiting membrane (ILM) exhibited significantly reduced Young's modulus and is therefore mechanically weaker than the ILM from controls. Deficiency of POMGnT1-mediated glycosylation of dystroglycan is implicated in reduced stiffness of the ILM. The weakened ILM results in the disruption of the membrane and subsequent reduction in retinal integrity.

  12. Partitioning, diffusion, and ligand binding of raft lipid analogs in model and cellular plasma membranes.

    Science.gov (United States)

    Sezgin, Erdinc; Levental, Ilya; Grzybek, Michal; Schwarzmann, Günter; Mueller, Veronika; Honigmann, Alf; Belov, Vladimir N; Eggeling, Christian; Coskun, Unal; Simons, Kai; Schwille, Petra

    2012-07-01

    Several simplified membrane models featuring coexisting liquid disordered (Ld) and ordered (Lo) lipid phases have been developed to mimic the heterogeneous organization of cellular membranes, and thus, aid our understanding of the nature and functional role of ordered lipid-protein nanodomains, termed "rafts". In spite of their greatly reduced complexity, quantitative characterization of local lipid environments using model membranes is not trivial, and the parallels that can be drawn to cellular membranes are not always evident. Similarly, various fluorescently labeled lipid analogs have been used to study membrane organization and function in vitro, although the biological activity of these probes in relation to their native counterparts often remains uncharacterized. This is particularly true for raft-preferring lipids ("raft lipids", e.g. sphingolipids and sterols), whose domain preference is a strict function of their molecular architecture, and is thus susceptible to disruption by fluorescence labeling. Here, we analyze the phase partitioning of a multitude of fluorescent raft lipid analogs in synthetic Giant Unilamellar Vesicles (GUVs) and cell-derived Giant Plasma Membrane Vesicles (GPMVs). We observe complex partitioning behavior dependent on label size, polarity, charge and position, lipid headgroup, and membrane composition. Several of the raft lipid analogs partitioned into the ordered phase in GPMVs, in contrast to fully synthetic GUVs, in which most raft lipid analogs mis-partitioned to the disordered phase. This behavior correlates with the greatly enhanced order difference between coexisting phases in the synthetic system. In addition, not only partitioning, but also ligand binding of the lipids is perturbed upon labeling: while cholera toxin B binds unlabeled GM1 in the Lo phase, it binds fluorescently labeled GMI exclusively in the Ld phase. Fluorescence correlation spectroscopy (FCS) by stimulated emission depletion (STED) nanoscopy on intact

  13. Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.

    Directory of Open Access Journals (Sweden)

    Georg Sebastian Nübling

    Full Text Available BACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn, implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. METHODS: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. RESULTS: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+ induced asyn129E oligomers and markedly reduced in Al(3+ induced oligomers. CONCLUSION: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.

  14. Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.

    Directory of Open Access Journals (Sweden)

    Tadakazu Okoshi

    Full Text Available Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid

  15. Membranous nephropathy: from models to man

    Science.gov (United States)

    Beck, Laurence H.; Salant, David J.

    2014-01-01

    As recently as 2002, most cases of primary membranous nephropathy (MN), a relatively common cause of nephrotic syndrome in adults, were considered idiopathic. We now recognize that MN is an organ-specific autoimmune disease in which circulating autoantibodies bind to an intrinsic antigen on glomerular podocytes and form deposits of immune complexes in situ in the glomerular capillary walls. Here we define the clinical and pathological features of MN and describe the experimental models that enabled the discovery of the major target antigen, the M-type phospholipase A2 receptor 1 (PLA2R). We review the pathophysiology of experimental MN and compare and contrast it with the human disease. We discuss the diagnostic value of serological testing for anti-PLA2R and tissue staining for the redistributed antigen, and their utility for differentiating between primary and secondary MN, and between recurrent MN after kidney transplant and de novo MN. We end with consideration of how knowledge of the antigen might direct future therapeutic strategies. PMID:24892704

  16. A model for technology assessment and commercialization for innovative disruptive technologies

    Energy Technology Data Exchange (ETDEWEB)

    KASSICIEH, SULEIMAN K.; WALSH, STEVE; MCWHORTER,PAUL J.; CUMMINGS JR.,JOHN C.; WILLIAMS,W. DAVID; ROMIG JR.,ALTON D.

    2000-05-17

    Disruptive technologies are scientific discoveries that break through the usual product technology capabilities and provide a basis for a new competitive paradigm as described by Anderson and Tushman [1990], Tushman and Rosenkopf [1992], and Bower and Christensen [1995]. Discontinuous innovations are products/processes/services that provide exponential improvements in the value received by the customer much in the same vein as Walsh [1996], Lynn, Morone and Paulson [1996], and Veryzer [1998]. For more on definitions of disruptive technologies and discontinuous innovations, see Walsh and Linton [1999] who provide a number of definitions for disruptive technologies and discontinuous innovations. Disruptive technologies and discontinuous innovations present a unique challenge and opportunity for R and D organizations seeking to build their commercialization efforts and to reinvent the corporation. These technologies do not have a proven path from scientific discovery to mass production and therefore require novel approaches. These critically important technologies are the wellspring of wealth creation and new competency generation but are not readily accepted by the corporate community. They are alternatively embraced and eschewed by the commercial community. They are finally accepted when the technology has already affected the industry or when the technological horse has already flown out of the hanger. Many firms, especially larger firms, seem reluctant to familiarize themselves with these technologies quickly. The trend seems to be that these firms prefer to react to a proven disruptive technology that has changed the product market paradigm. If true, then there is cause for concern. This paper will review the literature on disruptive technologies presenting a model of the progression from scientific idea to mass production for disruptive technologies contrasted to the more copious incremental technologies. The paper will then describe Sandia National Laboratories

  17. Dispersion of atmospheric fine particulate matters in simulated lung fluid and their effects on model cell membranes.

    Science.gov (United States)

    Zhou, Qiuhua; Wang, Lixin; Cao, Zhaoyu; Zhou, Xuehua; Yang, Fan; Fu, Pingqing; Wang, Zhenhua; Hu, Jingtian; Ding, Lei; Jiang, Wei

    2016-01-15

    Atmospheric fine particulate matter (PM2.5) was collected to investigate its dispersion in simulated lung fluid (SLF) and its interaction with model cell membranes. Organic acids, NH4(+), SO4(2-) and NO3(-) were detected in PM2.5 soluble fraction, and heavy metals were detected from the total mass. The insoluble fraction contained kaolinite, CaCO3, aliphatic carbons, aromatic rings, carboxyl and hydroxyl groups reflected by the infrared spectra. Proteins dispersed PM2.5 in SLF, resulted in smaller hydrodynamic diameter (dH) and slower sedimentation rate. Conversely, phospholipids increased dH value and accelerated sedimentation rate. Giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) were used as model cell membranes. PM2.5 adhered on and disrupted the membrane containing positively-charged lipids but not the membrane containing neutrally- and negatively-charged lipids, which was monitored by microscopy and a quartz crystal microbalance with dissipation (QCM-D). The cationic sites on membrane were necessary for PM2.5 adhesion, but membrane should be disrupted by the combined action of electrostatic forces and hydrogen bonds between PM2.5 oxygen containing groups and the lipid phosphate groups. Our results specified the roles of proteins and phospholipids in PM2.5 dispersion and transport, highly suggested that the health hazard of PM2.5 was related to the biomolecules in the lung fluid and the particle surface groups.

  18. Informed Principal Model and Contract in Supply Chain with Demand Disruption Asymmetric Information

    Directory of Open Access Journals (Sweden)

    Huan Zhang

    2016-01-01

    Full Text Available Because of the frequency and disastrous influence, the supply chain disruption has caused extensive concern both in the industry and in the academia. In a supply chain with one manufacturer and one retailer, the demand of the retailer is uncertain and meanwhile may suffer disruption with a probability. Taking the demand disruption probability as the retailer’s asymmetric information, an informed principal model with the retailer as the principal is explored to make the contract. The retailer can show its information to the manufacturer through the contract. It is found out that the high-risk retailer intends to pretend to be the low-risk one. So the separating contract is given through the low-information-intensity allocation, in which the order quantity and the transferring payment for the low-risk retailer distort upwards, but those of high-risk retailer do not distort. In order to reduce the signaling cost which the low-risk retailer pays, the interim efficient model is introduced, which ends up with the order quantity and transferring payment distorting upwards again but less than before. In the numerical examples, with two different mutation probabilities, the informed principal contracts show the application of the informed principal model in the supply chain with demand disruption.

  19. Evaluation of membrane models and their composition for islet amyloid polypeptide-membrane aggregation.

    Science.gov (United States)

    Caillon, Lucie; Lequin, Olivier; Khemtémourian, Lucie

    2013-09-01

    Human islet amyloid polypeptide (IAPP) forms amyloid fibrils in the pancreatic islets of patients suffering from type 2 diabetes mellitus (T2DM). The formation of IAPP fibrils has been shown to cause membrane damage which most likely is responsible for the death of pancreatic islet β-cells during the pathogenesis of T2DM. Several studies have demonstrated a clear interaction between IAPP and lipid membranes. However the effect of different lipid compositions and of various membrane mimetics (including micelles, bicelles, SUV and LUV) on fibril formation kinetics and fibril morphology has not yet systematically been analysed. Here we report that the interaction of IAPP with various membrane models promoted different processes of fibril formation. Our data reveal that in SDS and DPC micelles, IAPP adopts a stable α-helical structure for several days, suggesting that the micelle models may stabilize monomeric or small oligomeric species of IAPP. In contrast, zwitterionic DMPC/DHPC bicelles and DOPC SUV accelerate the fibril formation compared to zwitterionic DOPC LUV, indicating that the size of the membrane model and its curvature influence the fibrillation process. Negatively charged membranes decrease the lag-time of the fibril formation kinetics while phosphatidylethanolamine and cholesterol have an opposite effect, probably due to the modulation of the physical properties of the membrane and/or due to direct interactions with IAPP within the membrane core. Finally, our results show that the modulation of lipid composition influences not only the growth of fibrils at the membrane surface but also the interactions of β-sheet oligomers with membranes.

  20. Spatiotemporal Organization of Spin-Coated Supported Model Membranes

    Science.gov (United States)

    Simonsen, Adam Cohen

    All cells of living organisms are separated from their surroundings and organized internally by means of flexible lipid membranes. In fact, there is consensus that the minimal requirements for self-replicating life processes include the following three features: (1) information carriers (DNA, RNA), (2) a metabolic system, and (3) encapsulation in a container structure [1]. Therefore, encapsulation can be regarded as an essential part of life itself. In nature, membranes are highly diverse interfacial structures that compartmentalize cells [2]. While prokaryotic cells only have an outer plasma membrane and a less-well-developed internal membrane structure, eukaryotic cells have a number of internal membranes associated with the organelles and the nucleus. Many of these membrane structures, including the plasma membrane, are complex layered systems, but with the basic structure of a lipid bilayer. Biomembranes contain hundreds of different lipid species in addition to embedded or peripherally associated membrane proteins and connections to scaffolds such as the cytoskeleton. In vitro, lipid bilayers are spontaneously self-organized structures formed by a large group of amphiphilic lipid molecules in aqueous suspensions. Bilayer formation is driven by the entropic properties of the hydrogen bond network in water in combination with the amphiphilic nature of the lipids. The molecular shapes of the lipid constituents play a crucial role in bilayer formation, and only lipids with approximately cylindrical shapes are able to form extended bilayers. The bilayer structure of biomembranes was discovered by Gorter and Grendel in 1925 [3] using monolayer studies of lipid extracts from red blood cells. Later, a number of conceptual models were developed to rationalize the organization of lipids and proteins in biological membranes. One of the most celebrated is the fluid-mosaic model by Singer and Nicolson (1972) [4]. According to this model, the lipid bilayer component of

  1. Performance modeling of direct contact membrane distillation (DCMD) seawater desalination process using a commercial composite membrane

    KAUST Repository

    Lee, Junggil

    2015-01-10

    This paper presents the development of a rigorous theoretical model to predict the transmembrane flux of a flat sheet hydrophobic composite membrane, comprising both an active layer of polytetrafluoroethylene and a scrim-backing support layer of polypropylene, in the direct contact membrane distillation (DCMD) process. An integrated model includes the mass, momentum, species and energy balances for both retentate and permeate flows, coupled with the mass transfer of water vapor through the composite membrane and the heat transfer across the membrane and through the boundary layers adjacent to the membrane surfaces. Experimental results and model predictions for permeate flux and performance ratio are compared and shown to be in good agreement. The permeate flux through the composite layer can be ignored in the consideration of mass transfer pathways at the composite membrane. The effect of the surface porosity and the thickness of active and support layers on the process performance of composite membrane has also been studied. Among these parameters, surface porosity is identified to be the main factor significantly influencing the permeate flux and performance ratio, while the relative influence of the surface porosity on the performance ratio is less than that on flux.

  2. CHARMM-GUI HMMM Builder for Membrane Simulations with the Highly Mobile Membrane-Mimetic Model.

    Science.gov (United States)

    Qi, Yifei; Cheng, Xi; Lee, Jumin; Vermaas, Josh V; Pogorelov, Taras V; Tajkhorshid, Emad; Park, Soohyung; Klauda, Jeffery B; Im, Wonpil

    2015-11-17

    Slow diffusion of the lipids in conventional all-atom simulations of membrane systems makes it difficult to sample large rearrangements of lipids and protein-lipid interactions. Recently, Tajkhorshid and co-workers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules. The HMMM model provides accelerated lipid diffusion by one to two orders of magnitude, and is particularly useful in studying membrane-protein associations. However, building an HMMM simulation system is not easy, as it requires sophisticated treatment of the lipid tails. In this study, we have developed CHARMM-GUI HMMM Builder (http://www.charmm-gui.org/input/hmmm) to provide users with ready-to-go input files for simulating HMMM membrane systems with/without proteins. Various lipid-only and protein-lipid systems are simulated to validate the qualities of the systems generated by HMMM Builder with focus on the basic properties and advantages of the HMMM model. HMMM Builder supports all lipid types available in CHARMM-GUI and also provides a module to convert back and forth between an HMMM membrane and a full-length membrane. We expect HMMM Builder to be a useful tool in studying membrane systems with enhanced lipid diffusion.

  3. Mathematical modelling of dextran filtration through hollow fibre membranes

    DEFF Research Database (Denmark)

    Vinther, Frank; Pinelo, Manuel; Brøns, Morten

    2014-01-01

    In this paper we present a mathematical model of an ultrafiltration process. The results of the model are produced using standard numerical techniques with Comsol Multiphysics. The model describes the fluid flow and separation in hollow fibre membranes. The flow of solute and solvent within...... of the solute permeability the concentration dependent viscosity decreases the volumetric flux through the membrane at high pressures. This effect is due to a very high concentration at the membrane surface. The model is related to experimental data. There is a good qualitative and a reasonable quantitative...

  4. An Integrated Framework Advancing Membrane Protein Modeling and Design.

    Directory of Open Access Journals (Sweden)

    Rebecca F Alford

    2015-09-01

    Full Text Available Membrane proteins are critical functional molecules in the human body, constituting more than 30% of open reading frames in the human genome. Unfortunately, a myriad of difficulties in overexpression and reconstitution into membrane mimetics severely limit our ability to determine their structures. Computational tools are therefore instrumental to membrane protein structure prediction, consequently increasing our understanding of membrane protein function and their role in disease. Here, we describe a general framework facilitating membrane protein modeling and design that combines the scientific principles for membrane protein modeling with the flexible software architecture of Rosetta3. This new framework, called RosettaMP, provides a general membrane representation that interfaces with scoring, conformational sampling, and mutation routines that can be easily combined to create new protocols. To demonstrate the capabilities of this implementation, we developed four proof-of-concept applications for (1 prediction of free energy changes upon mutation; (2 high-resolution structural refinement; (3 protein-protein docking; and (4 assembly of symmetric protein complexes, all in the membrane environment. Preliminary data show that these algorithms can produce meaningful scores and structures. The data also suggest needed improvements to both sampling routines and score functions. Importantly, the applications collectively demonstrate the potential of combining the flexible nature of RosettaMP with the power of Rosetta algorithms to facilitate membrane protein modeling and design.

  5. Action spectrum for photochemical retinal pigment epithelium (RPE) disruption in an in vivo monkey model

    Science.gov (United States)

    Zhang, Jie; Sabarinathan, Ranjani; Bubel, Tracy; Williams, David R.; Hunter, Jennifer J.

    2016-03-01

    Observations of RPE disruption and autofluorescence (AF) photobleaching at light levels below the ANSI photochemical maximum permissible exposure (MPE) (Morgan et al., 2008) indicates a demand to modify future light safety standards to protect the retina from harm. To establish safe light exposures, we measured the visible light action spectrum for RPE disruption in an in vivo monkey model with fluorescence adaptive optics retinal imaging. Using this high resolution imaging modality can provide insight into the consequences of light on a cellular level and allow for longitudinal monitoring of retinal changes. The threshold retinal radiant exposures (RRE) for RPE disruption were determined for 4 wavelengths (460, 488, 544, and 594 nm). The anaesthetized macaque retina was exposed to a uniform 0.5° × 0.5° field of view (FOV). Imaging within a 2° × 2° FOV was performed before, immediately after and at 2 week intervals for 10 weeks. At each wavelength, multiple RREs were tested with 4 repetitions each to determine the threshold for RPE disruption. For qualitative analysis, RPE disruption is defined as any detectable change from the pre exposure condition in the cell mosaic in the exposed region relative to the corresponding mosaic in the immediately surrounding area. We have tested several metrics to evaluate the RPE images obtained before and after exposure. The measured action spectrum for photochemical RPE disruption has a shallower slope than the current ANSI photochemical MPE for the same conditions and suggests that longer wavelength light is more hazardous than other measurements would suggest.

  6. Metabolic disruption identified in the Huntington’s disease transgenic sheep model

    OpenAIRE

    Handley, Renee. R.; Reid, Suzanne J; Stefano Patassini; Rudiger, Skye R.; Vladimir Obolonkin; McLaughlan, Clive J.; Jacobsen, Jessie C.; Gusella, James F.; MacDonald, Marcy E.; Waldvogel, Henry J.; C Simon Bawden; Faull, Richard L. M.; Snell, Russell G.

    2016-01-01

    Huntington’s disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of ...

  7. Business Model as an Inducer of Disruptive Innovations: The Case of Gol Airlines

    OpenAIRE

    Sirlei de Almeida Pereira; Fabricio Garcia Imbrizi; Alessandra Demite Goncalves de Freitas; Marcelo Aparecido Alvarenga

    2015-01-01

    This study was undertaken to investigate the premises that the success of disruptive innovation is related to the business model adopted by organizations. An analysis of five business models from the literature review - Bovet and Martha (2000), Applegate (2001), Chesbrough and Rosenbloom (2002), Osterwalder and Pigneur (2010), and Rodrigues, Maccari and Lenzi (2012) – was conducted based on the case of the Brazilian Gol Airlines who is recognized as a success business that promoted a disrupti...

  8. A Sharp Boundary Model of Nonaxisymmetric Vertical Disruption Events in Tokamaks

    Science.gov (United States)

    Fitzpatrick, Richard

    2010-11-01

    A semi-analytic sharp boundary model of a nonaxisymmetric vertical disruption event (VDE) in a vertically elongated tokamak plasma is developed. The model is used to simulate nonaxisymmetric VDEs with a wide range of different plasma equilibrium and vacuum vessel parameters. These simulations yield poloidal halo current fractions and toroidal peaking factors that are similar to those seen in experiments. The simulations also reproduce the experimentally observed inverse scaling between the current fraction and the peaking factor. The peak poloidal halo current density is found to correlate strongly with the reciprocal of the minimum edge safety-factor attained during the disruption. The peak vertical force per unit area acting on the vacuum vessel is observed to have a strong correlation with the equilibrium toroidal plasma current at the onset of the disruption, but is also seen to increase with increasing vacuum vessel conductivity relative to the SOL plasma. Finally, the peak horizontal force is found to be largely determined by the plasma beta prior to the disruption.

  9. Membrane Tolerance to Ethanol is Rapidly Lost after Withdrawal: A Model for Studies of Membrane Adaptation

    Science.gov (United States)

    Taraschi, Theodore F.; Ellingson, John S.; Wu, Alice; Zimmerman, Robert; Rubin, Emanuel

    1986-06-01

    The structural properties of liver microsomes and erythrocytes obtained from rats that had been chronically administered ethanol were examined by electron spin resonance (ESR) following ethanol withdrawal for 1-10 days. Membranes obtained from control animals exhibited considerable molecular disordering upon the addition of ethanol in vitro (50-100 mM). Conversely, microsomal and erythrocyte membranes from alcoholic animals were resistant to this disordering by ethanol (membrane tolerance). These membrane properties were also apparent in lipid bilayers comprised of either total lipids or phospholipids isolated from the control and alcoholic animals. While several weeks of ethanol administration were required for both erythrocytes and microsomes to develop membrane tolerance, erythrocytes from alcoholic animals were disordered by ethanol in vitro after the animals had been withdrawn from ethanol for only 1 day. The same rapid loss of tolerance was observed in microsomes after 2 days of withdrawal. The same time course for the loss of tolerance was observed in lipid bilayers prepared from the total lipid and phospholipid extracts. No significant differences in the cholesterol/phospholipid ratio were observed between the microsomal or erythrocyte membranes isolated before and after withdrawal. Thus, alterations in the microsomal and erythrocyte phospholipids, and not cholesterol content, were responsible for conveying membrane tolerance. Membrane structural properties can be rapidly adjusted in a mammalian system in response to the withdrawal of the external membrane perturbant ethanol. The withdrawal model, which begins with established membrane tolerance and leads to rapid and complete loss of tolerance, provides a model to analyze the compositional changes responsible for this tolerance to disordering by ethanol.

  10. A reliable facility location design model with site-dependent disruption in the imperfect information context.

    Science.gov (United States)

    Yun, Lifen; Wang, Xifu; Fan, Hongqiang; Li, Xiaopeng

    2017-01-01

    This paper proposes a reliable facility location design model under imperfect information with site-dependent disruptions; i.e., each facility is subject to a unique disruption probability that varies across the space. In the imperfect information contexts, customers adopt a realistic "trial-and-error" strategy to visit facilities; i.e., they visit a number of pre-assigned facilities sequentially until they arrive at the first operational facility or give up looking for the service. This proposed model aims to balance initial facility investment and expected long-term operational cost by finding the optimal facility locations. A nonlinear integer programming model is proposed to describe this problem. We apply a linearization technique to reduce the difficulty of solving the proposed model. A number of problem instances are studied to illustrate the performance of the proposed model. The results indicate that our proposed model can reveal a number of interesting insights into the facility location design with site-dependent disruptions, including the benefit of backup facilities and system robustness against variation of the loss-of-service penalty.

  11. SPH calculations of asteroid disruptions: The role of pressure dependent failure models

    CERN Document Server

    Jutzi, Martin

    2015-01-01

    We present recent improvements of the modeling of the disruption of strength dominated bodies using the Smooth Particle Hydrodynamics (SPH) technique. The improvements include an updated strength model and a friction model, which are successfully tested by a comparison with laboratory experiments. In the modeling of catastrophic disruptions of asteroids, a comparison between old and new strength models shows no significant deviation in the case of targets which are initially non-porous, fully intact and have a homogeneous structure (such as the targets used in the study by Benz&Asphaug (1999). However, for many cases (e.g. initially partly or fully damaged targets, rubble-pile structures, etc.) we find that it is crucial that friction is taken into account and the material has a pressure dependent shear strength. Our investigations of the catastrophic disruption threshold $Q^*_{D}$ as a function of target properties and target sizes up to a few 100 km show that a fully damaged target modeled without frict...

  12. Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role in β-Cell Death in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Lucie Khemtémourian

    2008-01-01

    Full Text Available The presence of fibrillar protein deposits (amyloid of human islet amyloid polypeptide (hIAPP in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2. The mechanism of hIAPP-induced β-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of β-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer’s disease, Parkinson’s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to β-cell death in DM2.

  13. Biophysical investigation of the membrane-disrupting mechanism of the antimicrobial and amyloid-like peptide dermaseptin S9.

    Directory of Open Access Journals (Sweden)

    Lucie Caillon

    Full Text Available Dermaseptin S9 (Drs S9 is an atypical cationic antimicrobial peptide with a long hydrophobic core and with a propensity to form amyloid-like fibrils. Here we investigated its membrane interaction using a variety of biophysical techniques. Rather surprisingly, we found that Drs S9 induces efficient permeabilisation in zwitterionic phosphatidylcholine (PC vesicles, but not in anionic phosphatidylglycerol (PG vesicles. We also found that the peptide inserts more efficiently in PC than in PG monolayers. Therefore, electrostatic interactions between the cationic Drs S9 and anionic membranes cannot explain the selectivity of the peptide towards bacterial membranes. CD spectroscopy, electron microscopy and ThT fluorescence experiments showed that the peptide adopts slightly more β-sheet and has a higher tendency to form amyloid-like fibrils in the presence of PC membranes as compared to PG membranes. Thus, induction of leakage may be related to peptide aggregation. The use of a pre-incorporation protocol to reduce peptide/peptide interactions characteristic of aggregates in solution resulted in more α-helix formation and a more pronounced effect on the cooperativity of the gel-fluid lipid phase transition in all lipid systems tested. Calorimetric data together with (2H- and (31P-NMR experiments indicated that the peptide has a significant impact on the dynamic organization of lipid bilayers, albeit slightly less for zwitterionic than for anionic membranes. Taken together, our data suggest that in particular in membranes of zwitterionic lipids the peptide binds in an aggregated state resulting in membrane leakage. We propose that also the antimicrobial activity of Drs S9 may be a result of binding of the peptide in an aggregated state, but that specific binding and aggregation to bacterial membranes is regulated not by anionic lipids but by as yet unknown factors.

  14. Numerical Poisson-Boltzmann Model for Continuum Membrane Systems.

    Science.gov (United States)

    Botello-Smith, Wesley M; Liu, Xingping; Cai, Qin; Li, Zhilin; Zhao, Hongkai; Luo, Ray

    2013-01-01

    Membrane protein systems are important computational research topics due to their roles in rational drug design. In this study, we developed a continuum membrane model utilizing a level set formulation under the numerical Poisson-Boltzmann framework within the AMBER molecular mechanics suite for applications such as protein-ligand binding affinity and docking pose predictions. Two numerical solvers were adapted for periodic systems to alleviate possible edge effects. Validation on systems ranging from organic molecules to membrane proteins up to 200 residues, demonstrated good numerical properties. This lays foundations for sophisticated models with variable dielectric treatments and second-order accurate modeling of solvation interactions.

  15. Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology.

    Science.gov (United States)

    Fleet, Tiffany; Stashi, Erin; Zhu, Bokai; Rajapakshe, Kimal; Marcelo, Kathrina L; Kettner, Nicole M; Gorman, Blythe K; Coarfa, Cristian; Fu, Loning; O'Malley, Bert W; York, Brian

    2016-10-01

    Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver.

  16. Simplified model for fouling of a pleated membrane filter

    Science.gov (United States)

    Sanaei, Pejman; Cummings, Linda

    2014-11-01

    Pleated filter cartridge are widely used to remove undesired impurities from a fluid. A filter membrane is sandwiched between porous support layers, then pleated and packed in to an annular cylindrical cartridge. Although this arrangement offers a high ratio of surface filtration area to volume, the filter performance (measured, e.g., by graph of total flux versus throughput for a given pressure drop), is not as good as a flat filter membrane. The reasons for this difference in performance are currently unclear, but likely factors include the additional resistance of the porous support layers upstream and downstream of the membrane, the pleat packing density (PPD) and possible damage to the membrane during the pleating process. To investigate this, we propose a simplified mathematical model of the filtration within a single pleat. We consider the fluid dynamics through the membrane and support layers, and propose a model by which the pores of the membrane become fouled (i) by particles smaller than the membrane pore size; and (ii) by particles larger than the pores.We present some simulations of our model, investigating how flow and fouling differ between not only flat and pleated membranes, but also for support layers of different permeability profiles. NSF DMS-1261596.

  17. Transferable coarse-grained model for perfluorosulfonic acid polymer membranes

    Science.gov (United States)

    Kuo, An-Tsung; Okazaki, Susumu; Shinoda, Wataru

    2017-09-01

    Perfluorosulfonic acid (PFSA) polymer membranes are widely used as proton exchange membranes. Because the structure of the aqueous domain within the PFSA membrane is expected to directly influence proton conductance, many coarse-grained (CG) simulation studies have been performed to investigate the membrane morphology; these studies mostly used phenomenological models, such as dissipative particle dynamics. However, a chemically accurate CG model is required to investigate the morphology in realistic membranes and to provide a concrete molecular design. Here, we attempt to construct a predictive CG model for the structure and morphology of PFSA membranes that is compatible with the Sinoda-DeVane-Klein (SDK) CG water model [Shinoda et al., Mol. Simul. 33, 27 (2007)]. First, we extended the parameter set for the SDK CG force field to examine a hydrated PFSA membrane based on thermodynamic and structural data from experiments and all-atom (AA) molecular dynamics (MD) simulations. However, a noticeable degradation of the morphology motivated us to improve the structural properties by using the iterative Boltzmann inversion (IBI) approach. Thus, we explored a possible combination of the SDK and IBI approaches to describe the nonbonded interaction. The hybrid SDK/IBI model improved the structural issues of SDK, showing a better agreement with AA-MD in the radial distribution functions. The hybrid SDK/IBI model was determined to reasonably reproduce both the thermodynamic and structural properties of the PFSA membrane for all examined water contents. In addition, the model demonstrated good transferability and has considerable potential for application to realistic long-chained PFSA membranes.

  18. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    OpenAIRE

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component hypotheses were that (a) maladaptive traits would increase risk for inattention/hyperactivity, (b) inattention/hyperactivity would increase risk for disrupti...

  19. There Is No Simple Model of the Plasma Membrane Organization

    Science.gov (United States)

    Bernardino de la Serna, Jorge; Schütz, Gerhard J.; Eggeling, Christian; Cebecauer, Marek

    2016-01-01

    Ever since technologies enabled the characterization of eukaryotic plasma membranes, heterogeneities in the distributions of its constituents were observed. Over the years this led to the proposal of various models describing the plasma membrane organization such as lipid shells, picket-and-fences, lipid rafts, or protein islands, as addressed in numerous publications and reviews. Instead of emphasizing on one model we in this review give a brief overview over current models and highlight how current experimental work in one or the other way do not support the existence of a single overarching model. Instead, we highlight the vast variety of membrane properties and components, their influences and impacts. We believe that highlighting such controversial discoveries will stimulate unbiased research on plasma membrane organization and functionality, leading to a better understanding of this essential cellular structure. PMID:27747212

  20. There is no simple model of the plasma membrane organisation

    Directory of Open Access Journals (Sweden)

    Jorge Bernardino De La Serna

    2016-09-01

    Full Text Available Ever since technologies enabled the characterisation of eukaryotic plasma membranes, heterogeneities in the distributions of its constituents were observed. Over the years this led to the proposal of various models describing the plasma membrane organisation such as lipid shells, picket-and-fences, lipid rafts, or protein islands, as addressed in numerous publications and reviews. Instead of emphasising on one model we in this review give a brief overview over current models and highlight how current experimental work in one or the other way do not support the existence of a single overarching model. Instead, we highlight the vast variety of membrane properties and components, their influences and impacts. We believe that highlighting such controversial discoveries will stimulate unbiased research on plasma membrane organisation and functionality, leading to a better understanding of this essential cellular structure.

  1. Dynamic modeling of ultrafiltration membranes for whey separation processes

    NARCIS (Netherlands)

    Saltık, M.B.; Özkan, Leyla; Jacobs, Marc; Padt, van der Albert

    2017-01-01

    In this paper, we present a control relevant rigorous dynamic model for an ultrafiltration membrane unit in a whey separation process. The model consists of a set of differential algebraic equations and is developed for online model based applications such as model based control and process monitori

  2. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease.

    Science.gov (United States)

    Holland, Philip R; Searcy, James L; Salvadores, Natalia; Scullion, Gillian; Chen, Guiquan; Lawson, Greig; Scott, Fiona; Bastin, Mark E; Ihara, Masafumi; Kalaria, Rajesh; Wood, Emma R; Smith, Colin; Wardlaw, Joanna M; Horsburgh, Karen

    2015-06-01

    Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood-brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies.

  3. Interactions between model bacterial membranes and synthetic antimicrobials.

    Science.gov (United States)

    Yang, Lihua; Mishra, Abhijit; Som, Abhigyan; Tew, Gregory N.; Wong, Gerard C. L.

    2006-03-01

    Antimicrobial peptides comprise a key component of innate immunity for a wide range of multicellular organisms. It has been shown that natural antimicrobial peptides and their analogs can permeate bacterial membranes selectively. There are a number of proposed models for this action, but the detailed molecular mechanism of the induced membrane permeation remains unclear. We investigate interactions between model bacterial membranes and a prototypical family of phenylene ethynylene-based antimicrobials with controllable hydrophilic and hydrophobic volume fractions, controllable charge placement. Preliminary results from synchrotron small angle x-ray scattering (SAXS) results will be presented.

  4. Breaches of the pial basement membrane are associated with defective dentate gyrus development in mouse models of congenital muscular dystrophies.

    Science.gov (United States)

    Li, Jing; Yu, Miao; Feng, Gang; Hu, Huaiyu; Li, Xiaofeng

    2011-11-07

    A subset of congenital muscular dystrophies (CMDs) has central nervous system manifestations. There are good mouse models for these CMDs that include POMGnT1 knockout, POMT2 knockout and Large(myd) mice with all exhibiting defects in dentate gyrus. It is not known how the abnormal dentate gyrus is formed during the development. In this study, we conducted a detailed morphological examination of the dentate gyrus in adult and newborn POMGnT1 knockout, POMT2 knockout, and Large(myd) mice by immunofluorescence staining and electron microscopic analyses. We observed that the pial basement membrane overlying the dentate gyrus was disrupted and there was ectopia of granule cell precursors through the breached pial basement membrane. Besides these, the knockout dentate gyrus exhibited reactive gliosis in these mouse models. Thus, breaches in the pial basement membrane are associated with defective dentate gyrus development in mouse models of congenital muscular dystrophies.

  5. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  6. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  7. Development of a cost-effective vaccine candidate with outer membrane vesicles of a tolA-disrupted Shigella boydii strain.

    Science.gov (United States)

    Mitra, Soma; Sinha, Ritam; Mitobe, Jiro; Koley, Hemanta

    2016-04-04

    Our previous studies on outer membrane vesicles based vaccine development against shigellosis, revealed the inability of Shigella to release significant amount of vesicles naturally, during growth. Disruption of tolA, one of the genes of the Tol-Pal system of Gram negative bacterial membrane, has increased the vesicle release rate of a Shigella boydii type 4 strain to approximately 60% higher. We also noticed the vesicles, released from tolA-disrupted strain captured more OmpA protein and lipopolysaccharide, compared to the vesicles released from its wild type prototype. Six to seven weeks old BALB/c mice, immunized with 25 μg of three oral doses of the vesicles, released by tolA mutant, conferred 100% protection against lethal homologous challenge through nasal route, compared to only 60% protection after the same dose of wild type immunogen. Mice, immunized with the vesicles from tolA-mutant, manifested significant secretion of mucosal IgG and IgA. A sharp and significant response of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ) were also observed in the lung lavage of these groups of mice, within 6h post challenge; but at 24h, these inflammatory cytokines showed the sign of subsidence and the system was taken over by the release of anti-inflammatory cytokines (IL-4 and IL-10). Studies with naïve peritoneal macrophages, proved further, the potency of these vesicles to stimulate nitric oxide and TNF-α, IL-12p70, IL-6 and IL-10 productions in-vitro. The ability of these vesicles to trigger polarization of CD4(+) T cells toward Th1 adaptive immune response, had also been observed along with the presence of anti-inflammatory cytokines in the system. Our study demonstrated, the vesicles from tolA-disrupted Shigella were able to suppress Shigella-mediated inflammation in the host and could balance between inflammation and anti-inflammation, promoting better survival and health of the infected mice. Outer membrane vesicles from tolA-mutant, could be a potential

  8. Modelling inter-supply chain competition with resource limitation and demand disruption

    Science.gov (United States)

    Chen, Zhaobo; Teng, Chunxian; Zhang, Ding; Sun, Jiayi

    2016-05-01

    This paper proposes a comprehensive model for studying supply chain versus supply chain competition with resource limitation and demand disruption. We assume that there are supply chains with heterogeneous supply network structures that compete at multiple demand markets. Each supply chain is comprised of internal and external firms. The internal firms are coordinated in production and distribution and share some common but limited resources within the supply chain, whereas the external firms are independent and do not share the internal resources. The supply chain managers strive to develop optimal strategies in terms of production level and resource allocation in maximising their profit while facing competition at the end market. The Cournot-Nash equilibrium of this inter-supply chain competition is formulated as a variational inequality problem. We further study the case when there is demand disruption in the plan-execution phase. In such a case, the managers need to revise their planned strategy in order to maximise their profit with the new demand under disruption and minimise the cost of change. We present a bi-criteria decision-making model for supply chain managers and develop the optimal conditions in equilibrium, which again can be formulated by another variational inequality problem. Numerical examples are presented for illustrative purpose.

  9. Determining the prediction limits of models and classifiers with applications for disruption prediction in JET

    Science.gov (United States)

    Murari, A.; Peluso, E.; Vega, J.; Gelfusa, M.; Lungaroni, M.; Gaudio, P.; Martínez, F. J.; Contributors, JET

    2017-01-01

    Understanding the many aspects of tokamak physics requires the development of quite sophisticated models. Moreover, in the operation of the devices, prediction of the future evolution of discharges can be of crucial importance, particularly in the case of the prediction of disruptions, which can cause serious damage to various parts of the machine. The determination of the limits of predictability is therefore an important issue for modelling, classifying and forecasting. In all these cases, once a certain level of performance has been reached, the question typically arises as to whether all the information available in the data has been exploited, or whether there are still margins for improvement of the tools being developed. In this paper, a theoretical information approach is proposed to address this issue. The excellent properties of the developed indicator, called the prediction factor (PF), have been proved with the help of a series of numerical tests. Its application to some typical behaviour relating to macroscopic instabilities in tokamaks has shown very positive results. The prediction factor has also been used to assess the performance of disruption predictors running in real time in the JET system, including the one systematically deployed in the feedback loop for mitigation purposes. The main conclusion is that the most advanced predictors basically exploit all the information contained in the locked mode signal on which they are based. Therefore, qualitative improvements in disruption prediction performance in JET would need the processing of additional signals, probably profiles.

  10. Disrupted Cortical Connectivity as an Explanatory Model for Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Jenniefer Drude Borup

    2014-02-01

    Full Text Available The aim of this article is to explain the theory of Disrupted Cortical Connectivity and discuss whether or not it can integrate the following three theories: Theory of Mind, Executive Functioning, and Weak Central Coherence that dominate the field of autism spectrum disorder research. Due to a lack of existing literature discussing this potential integration, we have consequentially undertaken such an endeavour. In our opinion, integration appears to be possible since this explanatory model can account for difficulties in both social cognition and executive functioning commonly found in autism spectrum disorder. Moreover, the theory of Disrupted Cortical Connectivity could be described as an extension of the theory of Weak Central Coherence.

  11. Formation and disruption of tonotopy in a large-scale model of the auditory cortex.

    Science.gov (United States)

    Tomková, Markéta; Tomek, Jakub; Novák, Ondřej; Zelenka, Ondřej; Syka, Josef; Brom, Cyril

    2015-10-01

    There is ample experimental evidence describing changes of tonotopic organisation in the auditory cortex due to environmental factors. In order to uncover the underlying mechanisms, we designed a large-scale computational model of the auditory cortex. The model has up to 100 000 Izhikevich's spiking neurons of 17 different types, almost 21 million synapses, which are evolved according to Spike-Timing-Dependent Plasticity (STDP) and have an architecture akin to existing observations. Validation of the model revealed alternating synchronised/desynchronised states and different modes of oscillatory activity. We provide insight into these phenomena via analysing the activity of neuronal subtypes and testing different causal interventions into the simulation. Our model is able to produce experimental predictions on a cell type basis. To study the influence of environmental factors on the tonotopy, different types of auditory stimulations during the evolution of the network were modelled and compared. We found that strong white noise resulted in completely disrupted tonotopy, which is consistent with in vivo experimental observations. Stimulation with pure tones or spontaneous activity led to a similar degree of tonotopy as in the initial state of the network. Interestingly, weak white noise led to a substantial increase in tonotopy. As the STDP was the only mechanism of plasticity in our model, our results suggest that STDP is a sufficient condition for the emergence and disruption of tonotopy under various types of stimuli. The presented large-scale model of the auditory cortex and the core simulator, SUSNOIMAC, have been made publicly available.

  12. Dose-Dependent Thresholds of 10-ns Electric Pulse Induced Plasma Membrane Disruption and Cytotoxicity in Multiple Cell Lines

    Science.gov (United States)

    2011-01-01

    SJ, Fox PM, Rec LJ, Somers K, Stark RH, et al. (2002) Nanosecond Pulsed Electric Field (nsPEF) Effects on Cells and Tissues: Apoptosis Induction and...and a case report of intense nanosecond pulsed electric field as a local therapy for human malignancies. Int J Cancer 121: 675–682. 22. Nuccitelli R...Chen X, Pakhomov AG, Baldwin WH, Sheikh S, et al. (2009) A new pulsed electric field therapy for melanoma disrupts the tumor’s blood supply and causes

  13. Membraner

    DEFF Research Database (Denmark)

    Bach, Finn

    2009-01-01

    Notatet giver en kort introduktion til den statiske virkemåde af membraner og membrankonstruktioner......Notatet giver en kort introduktion til den statiske virkemåde af membraner og membrankonstruktioner...

  14. Sleep Disruption Medical Intervention Forecasting (SDMIF) Module for the Integrated Medical Model

    Science.gov (United States)

    Lewandowski, Beth; Brooker, John; Mallis, Melissa; Hursh, Steve; Caldwell, Lynn; Myers, Jerry

    2011-01-01

    The NASA Integrated Medical Model (IMM) assesses the risk, including likelihood and impact of occurrence, of all credible in-flight medical conditions. Fatigue due to sleep disruption is a condition that could lead to operational errors, potentially resulting in loss of mission or crew. Pharmacological consumables are mitigation strategies used to manage the risks associated with sleep deficits. The likelihood of medical intervention due to sleep disruption was estimated with a well validated sleep model and a Monte Carlo computer simulation in an effort to optimize the quantity of consumables. METHODS: The key components of the model are the mission parameter program, the calculation of sleep intensity and the diagnosis and decision module. The mission parameter program was used to create simulated daily sleep/wake schedules for an ISS increment. The hypothetical schedules included critical events such as dockings and extravehicular activities and included actual sleep time and sleep quality. The schedules were used as inputs to the Sleep, Activity, Fatigue and Task Effectiveness (SAFTE) Model (IBR Inc., Baltimore MD), which calculated sleep intensity. Sleep data from an ISS study was used to relate calculated sleep intensity to the probability of sleep medication use, using a generalized linear model for binomial regression. A human yes/no decision process using a binomial random number was also factored into sleep medication use probability. RESULTS: These probability calculations were repeated 5000 times resulting in an estimate of the most likely amount of sleep aids used during an ISS mission and a 95% confidence interval. CONCLUSIONS: These results were transferred to the parent IMM for further weighting and integration with other medical conditions, to help inform operational decisions. This model is a potential planning tool for ensuring adequate sleep during sleep disrupted periods of a mission.

  15. Interplay of electrostatics and lipid packing determines the binding of charged polymer coated nanoparticles to model membranes.

    Science.gov (United States)

    Biswas, Nupur; Bhattacharya, Rupak; Saha, Arindam; Jana, Nikhil R; Basu, Jaydeep K

    2015-10-07

    Understanding of nanoparticle-membrane interactions is useful for various applications of nanoparticles like drug delivery and imaging. Here we report on the studies of interaction between hydrophilic charged polymer coated semiconductor quantum dot nanoparticles with model lipid membranes. Atomic force microscopy and X-ray reflectivity measurements suggest that cationic nanoparticles bind and penetrate bilayers of zwitterionic lipids. Penetration and binding depend on the extent of lipid packing and result in the disruption of the lipid bilayer accompanied by enhanced lipid diffusion. On the other hand, anionic nanoparticles show minimal membrane binding although, curiously, their interaction leads to reduction in lipid diffusivity. It is suggested that the enhanced binding of cationic QDs at higher lipid packing can be understood in terms of the effective surface potential of the bilayers which is tunable through membrane lipid packing. Our results bring forth the subtle interplay of membrane lipid packing and electrostatics which determine nanoparticle binding and penetration of model membranes with further implications for real cell membranes.

  16. Modeling and vibration control of an active membrane mirror

    Science.gov (United States)

    Ruggiero, Eric J.; Inman, Daniel J.

    2009-09-01

    The future of space satellite technology lies in ultra-large mirrors and radar apertures for significant improvements in imaging and communication bandwidths. The availability of optical-quality membranes drives a parallel effort for structural models that can capture the dominant dynamics of large, ultra-flexible satellite payloads. Unfortunately, the inherent flexibility of membrane mirrors wreaks havoc with the payload's on-orbit stability and maneuverability. One possible means of controlling these undesirable dynamics is by embedding active piezoelectric ceramics near the boundary of the membrane mirror. In doing so, active feedback control can be used to eliminate detrimental vibration, perform static shape control, and evaluate the health of the structure. The overall motivation of the present work is to design a control system using distributed bimorph actuators to eliminate any detrimental vibration of the membrane mirror. As a basis for this study, a piezoceramic wafer was attached in a bimorph configuration near the boundary of a tensioned rectangular membrane sample. A finite element model of the system was developed to capture the relevant system dynamics from 0 to 300 Hz. The finite element model was compared against experimental results, and fair agreement found. Using the validated finite element models, structural control using linear quadratic regulator control techniques was then used to numerically demonstrate effective vibration control. Typical results show that less than 12 V of actuation voltage is required to eliminate detrimental vibration of the membrane samples in less than 15 ms. The functional gains of the active system are also derived and presented. These spatially descriptive control terms dictate favorable regions within the membrane domain for placing sensors and can be used as a design guideline for structural control applications. The results of the present work demonstrate that thin plate theory is an appropriate modeling

  17. Proton exchange membrane fuel cells modeling

    CERN Document Server

    Gao, Fengge; Miraoui, Abdellatif

    2013-01-01

    The fuel cell is a potential candidate for energy storage and conversion in our future energy mix. It is able to directly convert the chemical energy stored in fuel (e.g. hydrogen) into electricity, without undergoing different intermediary conversion steps. In the field of mobile and stationary applications, it is considered to be one of the future energy solutions.Among the different fuel cell types, the proton exchange membrane (PEM) fuel cell has shown great potential in mobile applications, due to its low operating temperature, solid-state electrolyte and compactness.This book pre

  18. Modeling the Elastic Properties of Lipid Bilayer Membranes

    Science.gov (United States)

    Barry, Edward; Gibaud, Thomas; Zakhary, Mark; Dogic, Zvonimir

    2011-03-01

    Model membranes such as lipid bilayers have been indispensable tools for our understanding of the elastic properties of biological membranes. In this talk, I will introduce a colloidal model for membranes and demonstrate that the physical properties of these colloidal membranes are identical to lipid bilayers. The model system is unique in that the constituent molecules are homogenous and non-amphiphilic, yet their self-assembly into membranes and other hierarchical assemblages, such as a lamellar type phases and chiral ribbons, proceeds spontaneously in solution. Owing to the large size of the constituent molecules, individual molecules can be directly visualized and simultaneous observations at the continuum and molecular lengthscales are used to characterize the behavior of model membranes with unprecedented detail. Moreover, once assembled in solution, molecular interactions can be controlled in situ. In particular, the strength of chiral interactions can be varied, leading to fascinating transitions in behavior that resembles the formation of starfish vesicles. These observations point towards the important role of line tension, and have potential implications for phase separated lipid mixtures or lipid rafts.

  19. Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.

    Science.gov (United States)

    Podechard, Normand; Chevanne, Martine; Fernier, Morgane; Tête, Arnaud; Collin, Aurore; Cassio, Doris; Kah, Olivier; Lagadic-Gossmann, Dominique; Sergent, Odile

    2016-11-28

    The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Stability and rupture of archaebacterial cell membrane: a model study.

    Science.gov (United States)

    Li, Shuangyang; Zheng, Fengxian; Zhang, Xianren; Wang, Wenchuan

    2009-01-29

    It is known that the thermoacidophilic archaebacterium Sulfolobus acidocaldarius can grow in hot springs at 65-80 degrees C and live in acidic environments (pH 2-3); however, the origin of its unusual thermal stability remains unclear. In this work, using a vesicle as a model, we study the thermal stability and rupture of archaebacterial cell membrane. We perform a simulation investigation of the structure-property relationship of monolayer membrane formed by bolaform lipids and compare it with that of bilayer membrane formed by monopolar lipids. The origin of the unusually thermal stability of archaebacterial cell and the mechanism for its rupture are presented in molecular details.

  1. Bound simian virus 40 translocates to caveolin-enriched membrane domains, and its entry is inhibited by drugs that selectively disrupt caveolae.

    Science.gov (United States)

    Anderson, H A; Chen, Y; Norkin, L C

    1996-11-01

    Simian virus 40 (SV40) entry leading to infection occurred only after the virus was at the cell surface for 1.5 to 2 h. SV40 infectious entry was not sensitive to cytosol acidification, a treatment that blocks endocytosis via clathrin-coated vesicles. Instead, SV40 infectious entry was blocked by treating cells with the phorbol ester PMA or nystatin, which selectively disrupts caveolae. In control experiments, transferrin internalization was sensitive to cytosol acidification but was not sensitive to PMA or nystatin. Also, absorbed transferrin entered cells within minutes. Finally, bound SV40 translocated to caveolin-enriched membrane complexes isolated by a Triton X-100 insolubility protocol. Treatment with nystatin did not impair SV40 binding but did block the partitioning of virus into the caveolin-enriched complexes.

  2. Selecting the right bird model in experimental studies on endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Veerle L.B. Jaspers

    2015-05-01

    Full Text Available Birds have been used as model species in ecotoxicological research for decades but have only recently been included in toxicity testing schemes. However, the avian fauna is very diverse. Given this diversity the ecology, behavior and reproduction should be considered when selecting the appropriate bird model in ecotoxicological studies. This article focusses on choosing the right bird model species for experimental studies with endocrine disrupting chemicals (EDCs. EDCs have been associated with adverse effects on the reproduction and development in birds and other wildlife. In addition, new EDCs continue to emerge and the concern for potential effects in humans and wildlife is calling for increased toxicity testing and hence appropriate model species. Common bird model species used in ecotoxicological studies investigating EDCs will be reviewed. In addition, considerations for selecting the right bird model, along with potential drawbacks and restrictions on the use of certain species will be discussed.

  3. Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.

    Science.gov (United States)

    Odermatt, Alex; Strajhar, Petra; Engeli, Roger T

    2016-04-01

    In the modern world, humans are exposed during their whole life to a large number of synthetic chemicals. Some of these chemicals have the potential to disrupt endocrine functions and contribute to the development and/or progression of major diseases. Every year approximately 1000 novel chemicals, used in industrial production, agriculture, consumer products or as pharmaceuticals, are reaching the market, often with limited safety assessment regarding potential endocrine activities. Steroids are essential endocrine hormones, and the importance of the steroidogenesis pathway as a target for endocrine disrupting chemicals (EDCs) has been recognized by leading scientists and authorities. Cell lines have a prominent role in the initial stages of toxicity assessment, i.e. for mechanistic investigations and for the medium to high throughput analysis of chemicals for potential steroidogenesis disrupting activities. Nevertheless, the users have to be aware of the limitations of the existing cell models in order to apply them properly, and there is a great demand for improved cell-based testing systems and protocols. This review intends to provide an overview of the available cell lines for studying effects of chemicals on gonadal and adrenal steroidogenesis, their use and limitations, as well as the need for future improvements of cell-based testing systems and protocols.

  4. STARD4 knockdown in HepG2 cells disrupts cholesterol trafficking associated with the plasma membrane, ER, and ERC

    DEFF Research Database (Denmark)

    Garbarino, J.; Pan, M. H.; Chin, H. F.

    2012-01-01

    STARD4, a member of the evolutionarily conserved START gene family, has been implicated in the non-vesicular intracellular transport of cholesterol. However, the direction of transport and the membranes with which this protein interacts are not clear. We present studies of STARD4 function using...... small hairpin RNA knockdown technology to reduce STARD4 expression in HepG2 cells. In a cholesterol-poor environment, we found that a reduction in STARD4 expression leads to retention of cholesterol at the plasma membrane, reduction of endoplasmic reticulum-associated cholesterol, and decreased ACAT...... synthesized cholesteryl esters. Furthermore, D4 KD cells exhibited a reduced rate of sterol transport to the endocytic recycling compartment after cholesterol repletion. Although these cells displayed normal endocytic trafficking in cholesterol-poor and replete conditions, cell surface low density lipoprotein...

  5. Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

    Science.gov (United States)

    Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

  6. Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

    Science.gov (United States)

    Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

  7. Critical Review of Membrane Bioreactor Models

    DEFF Research Database (Denmark)

    Naessens, W.; Maere, T.; Ratkovich, Nicolas Rios;

    2012-01-01

    modelling. In this paper, the vast literature on hydrodynamic and integrated modelling in MBR is critically reviewed. Hydrodynamic models are used at different scales and focus mainly on fouling and only little on system design/optimisation. Integrated models also focus on fouling although the ones...

  8. QSAR classification models for the screening of the endocrine-disrupting activity of perfluorinated compounds.

    Science.gov (United States)

    Kovarich, S; Papa, E; Li, J; Gramatica, P

    2012-01-01

    Perfluorinated compounds (PFCs) are a class of emerging pollutants still widely used in different materials as non-adhesives, waterproof fabrics, fire-fighting foams, etc. Their toxic effects include potential for endocrine-disrupting activity, but the amount of experimental data available for these pollutants is limited. The use of predictive strategies such as quantitative structure-activity relationships (QSARs) is recommended under the REACH regulation, to fill data gaps and to screen and prioritize chemicals for further experimentation, with a consequent reduction of costs and number of tested animals. In this study, local classification models for PFCs were developed to predict their T4-TTR (thyroxin-transthyretin) competing potency. The best models were selected by maximizing the sensitivity and external predictive ability. These models, characterized by robustness, good predictive power and a defined applicability domain, were applied to predict the activity of 33 other PFCs of environmental concern. Finally, classification models recently published by our research group for T4-TTR binding of brominated flame retardants and for estrogenic and anti-androgenic activity were applied to the studied perfluorinated chemicals to compare results and to further evaluate the potential for these PFCs to cause endocrine disruption.

  9. Modeling Of Proton Exchange Membrane Fuel Cell Systems

    DEFF Research Database (Denmark)

    Nielsen, Mads Pagh

    The objective of this doctoral thesis was to develop reliable steady-state and transient component models suitable to asses-, develop- and optimize proton exchange membrane (PEM) fuel cell systems. Several components in PEM fuel cell systems were characterized and modeled. The developed component...

  10. Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance.

    Science.gov (United States)

    Rieusset, Jennifer; Fauconnier, Jeremy; Paillard, Melanie; Belaidi, Elise; Tubbs, Emily; Chauvin, Marie-Agnès; Durand, Annie; Bravard, Amélie; Teixeira, Geoffrey; Bartosch, Birke; Michelet, Maud; Theurey, Pierre; Vial, Guillaume; Demion, Marie; Blond, Emilie; Zoulim, Fabien; Gomez, Ludovic; Vidal, Hubert; Lacampagne, Alain; Ovize, Michel

    2016-03-01

    Mitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca(2+)) transfer between both organelles through the complex formed between the voltage-dependent anion channel, glucose-regulated protein 75 and inositol 1,4,5-triphosphate receptor (IP3R). We recently identified cyclophilin D (CYPD) as a new partner of this complex and demonstrated a new role for MAMs in the control of insulin's action in the liver. Here, we report on the mechanisms by which disruption of MAM integrity induces hepatic insulin resistance in CypD (also known as Ppif)-knockout (KO) mice. We used either in vitro pharmacological and genetic inhibition of CYPD in HuH7 cells or in vivo loss of CYPD in mice to investigate ER-mitochondria interactions, inter-organelle Ca(2+) exchange, organelle homeostasis and insulin action. Pharmacological and genetic inhibition of CYPD concomitantly reduced ER-mitochondria interactions, inhibited inter-organelle Ca(2+) exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histamine-stimulated Ca(2+) transfer from ER to mitochondria was blunted in isolated hepatocytes of CypD-KO mice and this was associated with an increase in ER calcium store. Interestingly, disruption of inter-organelle Ca(2+) transfer was associated with ER stress, mitochondrial dysfunction, lipid accumulation, activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)ε and insulin resistance in liver of CypD-KO mice. Finally, CYPD-related alterations of insulin signalling were mediated by activation of PKCε rather than JNK in HuH7 cells. Disruption of IP3R-mediated Ca(2+) signalling in the liver of CypD-KO mice leads to hepatic insulin resistance through disruption of organelle interaction and function, increase in lipid accumulation and activation of PKCε. Modulation of ER-mitochondria Ca(2+) exchange may thus provide an exciting new avenue for

  11. Carbon dioxide (hydrogen sulfide) membrane separations and WGS membrane reactor modeling for fuel cells

    Science.gov (United States)

    Huang, Jin

    Acid-gas removal is of great importance in many environmental or energy-related processes. Compared to current commercial technologies, membrane-based CO2 and H2S capture has the advantages of low energy consumption, low weight and space requirement, simplicity of installation/operation, and high process flexibility. However, the large-scale application of the membrane separation technology is limited by the relatively low transport properties. In this study, CO2 (H2S)-selective polymeric membranes with high permeability and high selectivity have been studied based on the facilitated transport mechanism. The membrane showed facilitated effect for both CO2 and H2S. A CO2 permeability of above 2000 Barrers, a CO2/H2 selectivity of greater than 40, and a CO2/N2 selectivity of greater than 200 at 100--150°C were observed. As a result of higher reaction rate and smaller diffusing compound, the H2S permeability and H2S/H2 selectivity were about three times higher than those properties for CO2. The novel CO2-selective membrane has been applied to capture CO 2 from flue gas and natural gas. In the CO2 capture experiments from a gas mixture with N2 and H2, a permeate CO 2 dry concentration of greater than 98% was obtained by using steam as the sweep gas. In CO2/CH4 separation, decent CO 2 transport properties were obtained with a feed pressure up to 500 psia. With the thin-film composite membrane structure, significant increase on the CO2 flux was achieved with the decrease of the selective layer thickness. With the continuous removal of CO2, CO2-selective water-gas-shift (WGS) membrane reactor is a promising approach to enhance CO conversion and increase the purity of H2 at process pressure under relatively low temperature. The simultaneous reaction and transport process in the countercurrent WGS membrane reactor was simulated by using a one-dimensional non-isothermal model. The modeling results show that a CO concentration of less than 10 ppm and a H2 recovery of greater

  12. A Simple Ideal MHD Model of Vertical Disruption Events in Tokamaks

    Science.gov (United States)

    Fitzpatrick, Richard

    2008-11-01

    A simple model of axisymmetric vertical disruption events (VDEs) in tokamaks is presented in which the halo current force exerted on the vacuum vessel is calculated directly from linear, marginally stable, ideal-magnetohydrodynamical (MHD) stability analysis. The basic premise of the model is that the halo current force modifies pressure balance at the edge of the plasma, and therefore also modifies ideal-MHD plasma stability. In order to prevent the ideal vertical instability, responsible for the VDE, from growing on the very short Alfv'en time- scale, the halo current force must adjust itself such that the instability is rendered marginally stable. The model predicts halo currents which are similar in magnitude to those observed experimentally. An approximate non-axisymmetric version of the model is developed in order to calculate the toroidal peaking factor of the halo current force.

  13. A simple ideal magnetohydrodynamical model of vertical disruption events in tokamaks

    Science.gov (United States)

    Fitzpatrick, R.

    2009-01-01

    A simple model of axisymmetric vertical disruption events (VDEs) in tokamaks is presented in which the halo current force exerted on the vacuum vessel is calculated directly from linear, marginally stable, ideal-magnetohydrodynamical (MHD) stability analysis. The basic premise of the model is that the halo current force modifies pressure balance at the edge of the plasma, and therefore also modifies ideal-MHD plasma stability. In order to prevent the ideal vertical instability, responsible for the VDE, from growing on the very short Alfvén time scale, the halo current force must adjust itself such that the instability is rendered marginally stable. The model predicts halo currents which are similar in magnitude to those observed experimentally. An approximate nonaxisymmetric version of the model is developed in order to calculate the toroidal peaking factor for the halo current force.

  14. Membrane Modeling, Simulation and Optimization for Propylene/Propane Separation

    KAUST Repository

    Alshehri, Ali

    2015-06-01

    Energy efficiency is critical for sustainable industrial growth and the reduction of environmental impacts. Energy consumption by the industrial sector accounts for more than half of the total global energy usage and, therefore, greater attention is focused on enhancing this sector’s energy efficiency. It is predicted that by 2020, more than 20% of today’s energy consumption can be avoided in countries that have effectively implemented an action plan towards efficient energy utilization. Breakthroughs in material synthesis of high selective membranes have enabled the technology to be more energy efficient. Hence, high selective membranes are increasingly replacing conventional energy intensive separation processes, such as distillation and adsorption units. Moreover, the technology offers more special features (which are essential for special applications) and its small footprint makes membrane technology suitable for platform operations (e.g., nitrogen enrichment for oil and gas offshore sites). In addition, its low maintenance characteristics allow the technology to be applied to remote operations. For these reasons, amongst other, the membrane technology market is forecast to reach $16 billion by 2017. This thesis is concerned with the engineering aspects of membrane technology and covers modeling, simulation and optimization of membranes as a stand-alone process or as a unit operation within a hybrid system. Incorporating the membrane model into a process modeling software simplifies the simulation and optimization of the different membrane processes and hybrid configurations, since all other unit operations are pre-configured. Various parametric analyses demonstrated that only the membrane selectivity and transmembrane pressure ratio parameters define a membrane’s ability to accomplish a certain separation task. Moreover, it was found that both membrane selectivity and pressure ratio exhibit a minimum value that is only defined by the feed composition

  15. Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators

    Directory of Open Access Journals (Sweden)

    Arthur Dyer

    2017-03-01

    Full Text Available Enadenotucirev (EnAd is a chimeric group B adenovirus isolated by bioselection from a library of adenovirus serotypes. It replicates selectively in and kills a diverse range of carcinoma cells, shows effective anticancer activity in preclinical systems, and is currently undergoing phase I/II clinical trials. EnAd kills cells more quickly than type 5 adenovirus, and speed of cytotoxicity is dose dependent. The EnAd death pathway does not involve p53, is predominantly caspase independent, and appears to involve a rapid fall in cellular ATP. Infected cells show early loss of membrane integrity; increased exposure of calreticulin; extracellular release of ATP, HSP70, and HMGB1; and influx of calcium. The virus also causes an obvious single membrane blister reminiscent of ischemic cell death by oncosis. In human tumor biopsies maintained in ex vivo culture, EnAd mediated release of pro-inflammatory mediators such as TNF-α, IL-6, and HMGB1. In accordance with this, EnAd-infected tumor cells showed potent stimulation of dendritic cells and CD4+ T cells in a mixed tumor-leukocyte reaction in vitro. Whereas many viruses have evolved for efficient propagation with minimal inflammation, bioselection of EnAd for rapid killing has yielded a virus with a short life cycle that combines potent cytotoxicity with a proinflammatory mechanism of cell death.

  16. A Dry Membrane Protection Technique to Allow Surface Acoustic Wave Biosensor Measurements of Biological Model Membrane Approaches

    Directory of Open Access Journals (Sweden)

    Marius Enachescu

    2013-09-01

    Full Text Available Model membrane approaches have attracted much attention in biomedical sciences to investigate and simulate biological processes. The application of model membrane systems for biosensor measurements is partly restricted by the fact that the integrity of membranes critically depends on the maintenance of an aqueous surrounding, while various biosensors require a preconditioning of dry sensors. This is for example true for the well-established surface acoustic wave (SAW biosensor SAM®5 blue. Here, a simple drying procedure of sensor-supported model membranes is introduced using the protective disaccharide trehalose. Highly reproducible model membranes were prepared by the Langmuir-Blodgett technique, transferred to SAW sensors and supplemented with a trehalose solution. Membrane rehydration after dry incorporation into the SAW device becomes immediately evident by phase changes. Reconstituted model membranes maintain their full functionality, as indicated by biotin/avidin binding experiments. Atomic force microscopy confirmed the morphological invariability of dried and rehydrated membranes. Approximating to more physiological recognition phenomena, the site-directed immobilization of the integrin VLA-4 into the reconstituted model membrane and subsequent VCAM-1 ligand binding with nanomolar affinity were illustrated. This simple drying procedure is a novel way to combine the model membrane generation by Langmuir-Blodgett technique with SAW biosensor measurements, which extends the applicability of SAM®5 blue in biomedical sciences.

  17. Disruption of visual circuit formation and refinement in a mouse model of autism.

    Science.gov (United States)

    Cheng, Ning; Khanbabaei, Maryam; Murari, Kartikeya; Rho, Jong M

    2017-02-01

    Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi- and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower-level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2017, 10: 212-223. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

  18. Tidal Downsizing model. I. Numerical methods: saving giant planets from tidal disruptions

    CERN Document Server

    Nayakshin, Sergei

    2014-01-01

    Tidal Downsizing (TD) is a recently developed planet formation theory that supplements the classical Gravitational disc Instability (GI) model with planet migration inward and tidal disruptions of GI fragments in the inner regions of the disc. Numerical methods for a detailed population synthesis of TD planets are presented here. As an example application, the conditions under which GI fragments collapse faster than they migrate into the inner $a\\sim$ few AU disc are considered. It is found that most gas fragments are tidally or thermally disrupted unless (a) their opacity is $\\sim 3$ orders of magnitude less than the interstellar dust opacity at metallicities typical of the observed giant planets, or (b) the opacity is high but the fragments accrete large dust grains (pebbles) from the disc. Case (a) models produce very low mass solid cores ($M_{\\rm core} < 0.1$ Earth masses) and follow a negative correlation of giant planet frequency with host star metallicity. In contrast, case (b) models produce massiv...

  19. Market disruption, cascading effects, and economic recovery:a life-cycle hypothesis model.

    Energy Technology Data Exchange (ETDEWEB)

    Sprigg, James A.

    2004-11-01

    This paper builds upon previous work [Sprigg and Ehlen, 2004] by introducing a bond market into a model of production and employment. The previous paper described an economy in which households choose whether to enter the labor and product markets based on wages and prices. Firms experiment with prices and employment levels to maximize their profits. We developed agent-based simulations using Aspen, a powerful economic modeling tool developed at Sandia, to demonstrate that multiple-firm economies converge toward the competitive equilibria typified by lower prices and higher output and employment, but also suffer from market noise stemming from consumer churn. In this paper we introduce a bond market as a mechanism for household savings. We simulate an economy of continuous overlapping generations in which each household grows older in the course of the simulation and continually revises its target level of savings according to a life-cycle hypothesis. Households can seek employment, earn income, purchase goods, and contribute to savings until they reach the mandatory retirement age; upon retirement households must draw from savings in order to purchase goods. This paper demonstrates the simultaneous convergence of product, labor, and savings markets to their calculated equilibria, and simulates how a disruption to a productive sector will create cascading effects in all markets. Subsequent work will use similar models to simulate how disruptions, such as terrorist attacks, would interplay with consumer confidence to affect financial markets and the broader economy.

  20. Continuous Modeling of Calcium Transport Through Biological Membranes

    Science.gov (United States)

    Jasielec, J. J.; Filipek, R.; Szyszkiewicz, K.; Sokalski, T.; Lewenstam, A.

    2016-08-01

    In this work an approach to the modeling of the biological membranes where a membrane is treated as a continuous medium is presented. The Nernst-Planck-Poisson model including Poisson equation for electric potential is used to describe transport of ions in the mitochondrial membrane—the interface which joins mitochondrial matrix with cellular cytosis. The transport of calcium ions is considered. Concentration of calcium inside the mitochondrion is not known accurately because different analytical methods give dramatically different results. We explain mathematically these differences assuming the complexing reaction inside mitochondrion and the existence of the calcium set-point (concentration of calcium in cytosis below which calcium stops entering the mitochondrion).

  1. Insights into thermophilic archaebacterial membrane stability from simplified models of lipid membranes

    Science.gov (United States)

    Davis, Charles H.; Nie, Huifen; Dokholyan, Nikolay V.

    2007-05-01

    Lipid aggregation into fluid bilayers is an essential process for sustaining life. Simplified models of lipid structure, which allow for long time scales or large length scales not obtainable with all-atom simulations, have recently been developed and show promise for describing lipid dynamics in biological systems. Here, we describe two simplified models, a reduced-lipid model and a bola-lipid model for thermophilic bacterial membranes, developed for use with the rapid discrete molecular dynamics simulation method. In the reduced-lipid model, we represent the lipid chain by a series of three beads interacting through pairwise discrete potentials that model hydrophobic attractions between hydrocarbon tails in implicit solvent. Our phase diagram recapitulates those produced by continuous potential models with similar coarse-grained lipid representations. We also find that phase transition temperatures for our reduced-lipid model are dependent upon the flexibility of the lipid chain, giving an insight into archaebacterial membrane stability and prompting development of a bola-lipid model specific for archaebacteria lipids. With both the reduced-lipid and bola-lipid model, we find that the reduced flexibility inherent in archaebacteria lipids yields more stable bilayers as manifested by increased phase transition temperatures. The results of these studies provide a simulation methodology for lipid molecules in biological systems and show that discrete molecular dynamics is applicable to lipid aggregation and dynamics.

  2. Stability properties of elementary dynamic models of membrane transport.

    Science.gov (United States)

    Hernández, Julio A

    2003-01-01

    Living cells are characterized by their capacity to maintain a stable steady state. For instance, cells are able to conserve their volume, internal ionic composition and electrical potential difference across the plasma membrane within values compatible with the overall cell functions. The dynamics of these cellular variables is described by complex integrated models of membrane transport. Some clues for the understanding of the processes involved in global cellular homeostasis may be obtained by the study of the local stability properties of some partial cellular processes. As an example of this approach, I perform, in this study, the neighborhood stability analysis of some elementary integrated models of membrane transport. In essence, the models describe the rate of change of the intracellular concentration of a ligand subject to active and passive transport across the plasma membrane of an ideal cell. The ligand can be ionic or nonionic, and it can affect the cell volume or the plasma membrane potential. The fundamental finding of this study is that, within the physiological range, the steady states are asymptotically stable. This basic property is a necessary consequence of the general forms of the expressions employed to describe the active and passive fluxes of the transported ligand.

  3. Membrane Phospholipid Redistribution in Cytokinesis: A Theoretical Model

    Institute of Scientific and Technical Information of China (English)

    Mei-Wen AN; Wen-Zhou WU; Wei-Yi CHEN

    2005-01-01

    In cell mitosis, cytokinesis is a major deformation process, during which the site of the contractile ring is determined by the biochemical stimulus from asters of the mitotic apparatus, actin and myosin assembly is related to the motion of membrane phospholipids, and local distribution and arrangement of the microfilament cytoskeleton are different at different cytokinesis stages. Based on the Zinemanas-Nir model, a new model is proposed in this study to simulate the entire process by coupling the biochemical stimulus with the mechanical actions. There were three assumptions in this model: the movements of phospholipid proteins are driven by gradients of biochemical stimulus on the membrane surface; the local assembly of actin and myosin filament depends on the amount of phospholipid proteins at the same location;and the surface tension includes membrane tensions due to both the passive deformation of the membrane and the active contraction of actin filament, which is determined by microfilament redistribution and rearrangement. This model could explain the dynamic movement of microfilaments during cytokinesis and predict cell deformation. The calculated results from this model demonstrated that the reorientation of phospholipid proteins and the redistribution and reorientation of microfilaments may play a crucial role in cell division. This model may better represent the cytokinesis process by the introduction of biochemical stimulus.

  4. Disrupted cortical connectivity theory as an explanatory model for autism spectrum disorders

    Science.gov (United States)

    Kana, Rajesh K.; Libero, Lauren E.; Moore, Marie S.

    2011-12-01

    such as Theory-of-Mind, cognitive flexibility, and information processing; and 2) how connection abnormalities relate to, and may determine, behavioral symptoms hallmarked by the triad of Impairments in ASD. Furthermore, we will relate the disrupted cortical connectivity model to existing cognitive and neural models of ASD.

  5. Disrupted cortical connectivity theory as an explanatory model for autism spectrum disorders.

    Science.gov (United States)

    Kana, Rajesh K; Libero, Lauren E; Moore, Marie S

    2011-12-01

    as Theory-of-Mind, cognitive flexibility, and information processing; and 2) how connection abnormalities relate to, and may determine, behavioral symptoms hallmarked by the triad of Impairments in ASD. Furthermore, we will relate the disrupted cortical connectivity model to existing cognitive and neural models of ASD.

  6. Minimally Disruptive Medicine: A Pragmatically Comprehensive Model for Delivering Care to Patients with Multiple Chronic Conditions

    Directory of Open Access Journals (Sweden)

    Aaron L. Leppin

    2015-01-01

    Full Text Available An increasing proportion of healthcare resources in the United States are directed toward an expanding group of complex and multimorbid patients. Federal stakeholders have called for new models of care to meet the needs of these patients. Minimally Disruptive Medicine (MDM is a theory-based, patient-centered, and context-sensitive approach to care that focuses on achieving patient goals for life and health while imposing the smallest possible treatment burden on patients’ lives. The MDM Care Model is designed to be pragmatically comprehensive, meaning that it aims to address any and all factors that impact the implementation and effectiveness of care for patients with multiple chronic conditions. It comprises core activities that map to an underlying and testable theoretical framework. This encourages refinement and future study. Here, we present the conceptual rationale for and a practical approach to minimally disruptive care for patients with multiple chronic conditions. We introduce some of the specific tools and strategies that can be used to identify the right care for these patients and to put it into practice.

  7. Interpretation of machine-learning-based disruption models for plasma control

    Science.gov (United States)

    Parsons, Matthew S.

    2017-08-01

    While machine learning techniques have been applied within the context of fusion for predicting plasma disruptions in tokamaks, they are typically interpreted with a simple ‘yes/no’ prediction or perhaps a probability forecast. These techniques take input signals, which could be real-time signals from machine diagnostics, to make a prediction of whether a transient event will occur. A major criticism of these methods is that, due to the nature of machine learning, there is no clear correlation between the input signals and the output prediction result. Here is proposed a simple method that could be applied to any existing prediction model to determine how sensitive the state of a plasma is at any given time with respect to the input signals. This is accomplished by computing the gradient of the decision function, which effectively identifies the quickest path away from a disruption as a function of the input signals and therefore could be used in a plasma control setting to avoid them. A numerical example is provided for illustration based on a support vector machine model, and the application to real data is left as an open opportunity.

  8. Minimally Disruptive Medicine: A Pragmatically Comprehensive Model for Delivering Care to Patients with Multiple Chronic Conditions.

    Science.gov (United States)

    Leppin, Aaron L; Montori, Victor M; Gionfriddo, Michael R

    2015-01-29

    An increasing proportion of healthcare resources in the United States are directed toward an expanding group of complex and multimorbid patients. Federal stakeholders have called for new models of care to meet the needs of these patients. Minimally Disruptive Medicine (MDM) is a theory-based, patient-centered, and context-sensitive approach to care that focuses on achieving patient goals for life and health while imposing the smallest possible treatment burden on patients' lives. The MDM Care Model is designed to be pragmatically comprehensive, meaning that it aims to address any and all factors that impact the implementation and effectiveness of care for patients with multiple chronic conditions. It comprises core activities that map to an underlying and testable theoretical framework. This encourages refinement and future study. Here, we present the conceptual rationale for and a practical approach to minimally disruptive care for patients with multiple chronic conditions. We introduce some of the specific tools and strategies that can be used to identify the right care for these patients and to put it into practice.

  9. Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease.

    Science.gov (United States)

    Wilke, Scott A; Raam, Tara; Antonios, Joseph K; Bushong, Eric A; Koo, Edward H; Ellisman, Mark H; Ghosh, Anirvan

    2014-01-01

    The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control - they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease.

  10. Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Scott A Wilke

    Full Text Available The earliest stages of Alzheimer's disease (AD are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF synapse between dentate gyrus (DG and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD. FAD mutant MF terminal complexes were severely disrupted compared to control - they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease.

  11. [Membrane model of the cupula of the vestibular semicircular canals].

    Science.gov (United States)

    Kondrachuk, A V; Shipov, A A; Sirenko, S P

    1987-01-01

    A mathematical model of the time-course variations of the cupula of the semicircular canals of the vestibular apparatus is presented. The model is found to be in good agreement with experimental data which suggests that the cupular matter has viscosity-elasticity properties. Their role in the functioning of the vestibular apparatus is discussed in qualitative terms. The applicability of the membrane model to the description of the time-course variations of the cupula is considered.

  12. Modeling and Simulation for Fuel Cell Polymer Electrolyte Membrane

    Directory of Open Access Journals (Sweden)

    Takahiro Hayashi

    2013-01-01

    Full Text Available We have established methods to evaluate key properties that are needed to commercialize polyelectrolyte membranes for fuel cell electric vehicles such as water diffusion, gas permeability, and mechanical strength. These methods are based on coarse-graining models. For calculating water diffusion and gas permeability through the membranes, the dissipative particle dynamics–Monte Carlo approach was applied, while mechanical strength of the hydrated membrane was simulated by coarse-grained molecular dynamics. As a result of our systematic search and analysis, we can now grasp the direction necessary to improve water diffusion, gas permeability, and mechanical strength. For water diffusion, a map that reveals the relationship between many kinds of molecular structures and diffusion constants was obtained, in which the direction to enhance the diffusivity by improving membrane structure can be clearly seen. In order to achieve high mechanical strength, the molecular structure should be such that the hydrated membrane contains narrow water channels, but these might decrease the proton conductivity. Therefore, an optimal design of the polymer structure is needed, and the developed models reviewed here make it possible to optimize these molecular structures.

  13. Interactions of biocidal guanidine hydrochloride polymer analogs with model membranes: a comparative biophysical study

    Institute of Scientific and Technical Information of China (English)

    Zhongxin Zhou; Anna Zheng; Jianjiang Zhong

    2011-01-01

    Four synthesized biocidal guanidine hydrochloride polymers with different alkyl chain length,including polyhexamethylene guanidine hydrochloride and its three new analogs,were used to investigate their interactions with phospholipids vesicles mimicking bacterial membrane.Characterization was conducted by using fluorescence dye leakage,isothermal titration calorimetry,and differential scanning calorimetry.The results showed that the gradually lengthened alkyl chain of the polymer increased the biocidal activity,accompanied with the increased dye leakage rate and the increased binding constant and energy change value of polymer-membrane interaction.The polymer-membrane interaction induced the change of pretransition and main phase transition (decreased temperature and increased width) of phospholipids vesicles,suggesting the conformational change in the phospholipids headgroups and disordering in the hydrophobic regions of lipid membranes.The above information revealed that the membrane disruption actions of guanidine hydrochloride polymers are the results of the polymer's strong binding to the phospholipids membrane and the subsequent perturbations of the polar headgroups and hydrophobic core region of the phospholipids membrane.The alkyl chain structure significantly affects the binding constant and energy change value of the polymer-membrane interactions and the perturbation extent of the phospholipids membrane,which lead to the different biocidal activity of the polymer analogs.This work provides important information about the membrane disruption action mechanism of biocidal guanidine hydrochloride polymers.

  14. Ultrafast spectroscopy of model biological membranes

    NARCIS (Netherlands)

    Ghosh, Avishek

    2009-01-01

    In this PhD thesis, I have described the novel time-resolved sum-frequency generation (TR-SFG) spectroscopic technique that I developed during the course of my PhD research and used it study the ultrafast vibrational, structural and orientational dynamics of water molecules at model biological membr

  15. Aluminium and Acrylamide Disrupt Cerebellum Redox States, Cholinergic Function and Membrane-Bound ATPase in Adult Rats and Their Offspring.

    Science.gov (United States)

    Ghorbel, Imen; Amara, Ibtissem Ben; Ktari, Naourez; Elwej, Awatef; Boudawara, Ons; Boudawara, Tahia; Zeghal, Najiba

    2016-12-01

    Accumulation of aluminium and acrylamide in food is a major source of human exposure. Their adverse effects are well documented, but there is no information about the health problems arising from their combined exposure. The aim of the present study was to examine the possible neurotoxic effects after co-exposure of pregnant and lactating rats to aluminium and acrylamide in order to evaluate redox state, cholinergic function and membrane-bound ATPases in the cerebellum of adult rats and their progeny. Pregnant female rats have received aluminium (50 mg/kg body weight) via drinking water and acrylamide (20 mg/kg body weight) by gavage, either individually or in combination from the 14th day of pregnancy until day 14 after delivery. Exposure to these toxicants provoked an increase in malondialdehyde (MDA) and advanced oxidation protein product (AOPP) levels and a decrease in SOD, CAT, GPx, Na(+)K(+)-ATPase, Mg(2+)-ATPase and AChE activities in the cerebellum of mothers and their suckling pups. A reduction in GSH, NPSH and vitamin C levels was also observed. These changes were confirmed by histological results. Interestingly, co-exposure to these toxicants exhibited synergism based on physical and biochemical variables in the cerebellum of mothers and their progeny.

  16. Concanavalin A/IFN-gamma triggers autophagy-related necrotic hepatocyte death through IRGM1-mediated lysosomal membrane disruption.

    Directory of Open Access Journals (Sweden)

    Chih-Peng Chang

    Full Text Available Interferon-gamma (IFN-γ, a potent Th1 cytokine with multiple biological functions, can induce autophagy to enhance the clearance of the invading microorganism or cause cell death. We have reported that Concanavalin A (Con A can cause autophagic cell death in hepatocytes and induce both T cell-dependent and -independent acute hepatitis in immunocompetent and immunodeficient mice, respectively. Although IFN-γ is known to enhance liver injury in Con A-induced hepatitis, its role in autophagy-related hepatocyte death is not clear. In this study we report that IFN-γ can enhance Con A-induced autophagic flux and cell death in hepatoma cell lines. A necrotic cell death with increased lysosomal membrane permeabilization (LMP is observed in Con A-treated hepatoma cells in the presence of IFN-γ. Cathepsin B and L were released from lysosomes to cause cell death. Furthermore, IFN-γ induces immunity related GTPase family M member 1(IRGM1 translocation to lysosomes and prolongs its activity in Con A-treated hepatoma cells. Knockdown of IRGM1 inhibits the IFN-γ/Con A-induced LMP change and cell death. Furthermore, IFN-γ(-/- mice are resistant to Con A-induced autophagy-associated necrotic hepatocyte death. We conclude that IFN-γ enhances Con A-induced autophagic flux and causes an IRGM1-dependent lysosome-mediated necrotic cell death in hepatocytes.

  17. Interaction of Cytotoxic and Cytoprotective Bile Acids with Model Membranes: Influence of the Membrane Composition.

    Science.gov (United States)

    Esteves, M; Ferreira, M J; Kozica, A; Fernandes, A C; Gonçalves da Silva, A; Saramago, B

    2015-08-18

    To understand the role of bile acids (BAs) in cell function, many authors have investigated their effect on biomembrane models which are less complex systems, but there are still many open questions. The present study aims to contribute for the deepening of the knowledge of the interaction between BAs and model membranes, in particular, focusing on the effect of BA mixtures. The cytotoxic deoxycholic acid (DCA), the cytoprotective ursodeoxycholic acid (UDCA), and the equimolar mixture (DCA + UDCA) were investigated. Monolayers and liposomes were taken as model membranes with two lipid compositions: an equimolar mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sphingomyelin (SM), and cholesterol (Chol)) traditionally associated with the formation of lipid rafts and an equimolar POPC/SM binary mixture. The obtained results showed that DCA causes the fluidization of monolayers and bilayers, leading to the eventual rupture of POPC/SM liposomes at high concentration. UDCA may provide a stabilization of POPC/SM membranes but has a negligible effect on the Chol-containing liposomes. In the case of equimolar mixture DCA/UDCA, the interactions depend not only on the lipid composition but also on the design of the experiment. The BA mixture has a greater impact on the monolayers than do pure BAs, suggesting a cooperative DCA-UDCA interaction that enhances the penetration of UDCA in both POPC/SM and POPC/SM/Chol monolayers. For the bilayers, the presence of UDCA in the mixture decreases the disturbing effect of DCA.

  18. A Novel Multiobjective Programming Model for Coping with Supplier Selection Disruption Risks under Mixed Uncertainties

    Directory of Open Access Journals (Sweden)

    Ying Li

    2016-01-01

    Full Text Available Supply chain has become more and more vulnerable to disruption since it is suffering widespread risk issues from inside or outside. Higher uncertainties in the supplier selection problem have gone beyond the traditional cost minimization concern. These uncertainties are related to an ever increasing product variety, more demanding customers, and a highly interconnected distribution network. This paper focuses on the supplier selection problem with disruption risks and mixed uncertainties. A novel multiobjective optimization model with mixed uncertain coefficients is developed, which maximizes the total profits and minimizes the percentage of items delivered late, percentage of items rejected, and total loss cost due to supplier dysfunction. Meanwhile, we also consider the customer demand to be a random fuzzy variable and the unit purchase cost to be a fuzzy variable. By examining a numerical example, we found that the confidence level and demand of customers have impact on the quantities purchased by customers from suppliers although the distribution of suppliers will not change. The cost, quality, and service also influence the selection of suppliers. The superevents have little influence on the distribution of supplier selection; however, when unique event occurs, the distribution of supplier selection will change.

  19. Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork.

    Directory of Open Access Journals (Sweden)

    Johanna L Barclay

    Full Text Available Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.

  20. A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Hayashi, Akane; Matsunaga, Naoya; Okazaki, Hiroyuki; Kakimoto, Keisuke; Kimura, Yoshinori; Azuma, Hiroki; Ikeda, Eriko; Shiba, Takeshi; Yamato, Mayumi; Yamada, Ken-Ichi; Koyanagi, Satoru; Ohdo, Shigehiro

    2013-06-01

    Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP(+)) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP(+)-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

  1. A Mathematical Model for Predicting the Life of PEM Fuel Cell Membranes Subjected to Hydration Cycling

    CERN Document Server

    Burlatsky, S F; O'Neill, J; Atrazhev, V V; Varyukhin, A N; Dmitriev, D V; Erikhman, N S

    2013-01-01

    Under typical PEM fuel cell operating conditions, part of membrane electrode assembly is subjected to humidity cycling due to variation of inlet gas RH and/or flow rate. Cyclic membrane hydration/dehydration would cause cyclic swelling/shrinking of the unconstrained membrane. In a constrained membrane, it causes cyclic stress resulting in mechanical failure in the area adjacent to the gas inlet. A mathematical modeling framework for prediction of the lifetime of a PEM FC membrane subjected to hydration cycling is developed in this paper. The model predicts membrane lifetime as a function of RH cycling amplitude and membrane mechanical properties. The modeling framework consists of three model components: a fuel cell RH distribution model, a hydration/dehydration induced stress model that predicts stress distribution in the membrane, and a damage accrual model that predicts membrane life-time. Short descriptions of the model components along with overall framework are presented in the paper. The model was used...

  2. New hybrid model of proton exchange membrane fuel cell

    Institute of Scientific and Technical Information of China (English)

    WANG Rui-min; CAO Guang-yi; ZHU Xin-jian

    2007-01-01

    Model and simulation are good tools for design optimization of fuel cell systems. This paper proposes a new hybrid model of proton exchange membrane fuel cell (PEMFC). The hybrid model includes physical component and black-box component. The physical component represents the well-known part of PEMFC, while artificial neural network (ANN) component estimates the poorly known part of PEMFC. The ANN model can compensate the performance of the physical model. This hybrid model is implemented on Matlab/Simulink software. The hybrid model shows better accuracy than that of the physical model and ANN model. Simulation results suggest that the hybrid model can be used as a suitable and accurate model for PEMFC.

  3. Kinetic modelling of coupled transport across biological membranes.

    Science.gov (United States)

    Korla, Kalyani; Mitra, Chanchal K

    2014-04-01

    In this report, we have modelled a secondary active co-transporter (symport and antiport), based on the classical kinetics model. Michaelis-Menten model of enzyme kinetics for a single substrate, single intermediate enzyme catalyzed reaction was proposed more than a hundred years ago. However, no single model for the kinetics of co-transport of molecules across a membrane is available in the literature We have made several simplifying assumptions and have followed the basic Michaelis-Menten approach. The results have been simulated using GNU Octave. The results will be useful in general kinetic simulations and modelling.

  4. Understanding Peptide Dendrimer Interactions with Model Cell Membrane Mimics

    DEFF Research Database (Denmark)

    Lind, Tania Kjellerup

    membranes or highly conserved motifs, effectively making resistance due to mutations less likely to develop and spread. For this we studied the conditions to form supported lipid bilayers with basic systems and further established a protocol for producing biomimetic bacterial model membranes via the vesicle...... fusion method, which presents improved means for studying drug-membrane interactions in the future. The interaction mechanism of a family of dendrimers was examined and in particular one dendrimer (BALY) was extensively studied by the combined use of quartz crystal microbalance, atomic force microscopy...... and neutron reection. The application of several complementary surface-sensitive techniques allowed for systematically addressing the interface-related processes and gain insights into different aspects of the interaction. BALY was found to interact via a uidity-dependent mechanism. It inserted into the outer...

  5. Phase behaviors and membrane properties of model liposomes: Temperature effect

    Science.gov (United States)

    Wu, Hsing-Lun; Sheng, Yu-Jane; Tsao, Heng-Kwong

    2014-09-01

    The phase behaviors and membrane properties of small unilamellar vesicles have been explored at different temperatures by dissipative particle dynamics simulations. The vesicles spontaneously formed by model lipids exhibit pre-transition from gel to ripple phase and main transition from ripple to liquid phase. The vesicle shape exhibits the faceted feature at low temperature, becomes more sphere-like with increasing temperature, but loses its sphericity at high temperature. As the temperature rises, the vesicle size grows but the membrane thickness declines. The main transition (Tm) can be identified by the inflection point. The membrane structural characteristics are analyzed. The inner and outer leaflets are asymmetric. The length of the lipid tail and area density of the lipid head in both leaflets decrease with increasing temperature. However, the mean lipid volume grows at low temperature but declines at high temperature. The membrane mechanical properties are also investigated. The water permeability grows exponentially with increasing T but the membrane tension peaks at Tm. Both the bending and stretching moduli have their minima near Tm. Those results are consistent with the experimental observations, indicating that the main signatures associated with phase transition are clearly observed in small unilamellar vesicles.

  6. A minimally disruptive model and three-dimensional evaluation of Lisfranc joint diastasis.

    Science.gov (United States)

    Panchbhavi, Vinod K; Andersen, Clark R; Vallurupalli, Santaram; Yang, Jinping

    2008-12-01

    There is no model that can reproduce the diastasis at the Lisfranc joint after isolated transection of the Lisfranc ligament. Prior models required extensive sectioning of ligaments in the midfoot and represent injuries that cause extensive tarsometatarsal fracture-dislocations. They do not represent a subset of injuries that cause subtle or limited disruption at the Lisfranc joint. The purpose of this study was to create a model with the minimum amount of ligamentous disruption and loading necessary to consistently observe diastasis at the Lisfranc joint. Fourteen fresh-frozen paired cadaver feet were dissected to expose the dorsum. Three screws were inserted into each first cuneiform and second metatarsal to create a pair of registration triads. A digitizer was utilized to record the three-dimensional positions of the screws and their displacement under loaded and unloaded conditions before and after the Lisfranc ligament was cut (intact and cut conditions). The first and second cuneiforms and their metatarsals were removed, and the attachment sites of the dorsal and the Lisfranc ligament were digitized. The three-dimensional positions of the bones and ligament displacement were determined. The significance of differences between conditions was tested with analysis of variance, and linear regression analysis was used to test the correlation between dorsal and plantar displacements. There was a significant difference, of 1.3 mm, in the mean displacement between the cut loaded and intact loaded conditions (p < 0.0001). A modest correlation (r(2) = 0.60) was found between dorsal displacement and displacement at the site of the Lisfranc ligament, possibly attributable to rotations between the first cuneiform and second metatarsal. Isolated sectioning of the Lisfranc ligament is sufficient to consistently create diastasis at the Lisfranc joint. Dorsal displacements between the first cuneiform and second metatarsal are a modest predictor of plantar displacements.

  7. An in vitro model of the glomerular capillary wall using electrospun collagen nanofibres in a bioartificial composite basement membrane.

    Directory of Open Access Journals (Sweden)

    Sadie C Slater

    Full Text Available The filtering unit of the kidney, the glomerulus, contains capillaries whose walls function as a biological sieve, the glomerular filtration barrier. This comprises layers of two specialised cells, glomerular endothelial cells (GEnC and podocytes, separated by a basement membrane. Glomerular filtration barrier function, and dysfunction in disease, remains incompletely understood, partly due to difficulties in studying the relevant cell types in vitro. We have addressed this by generation of unique conditionally immortalised human GEnC and podocytes. However, because the glomerular filtration barrier functions as a whole, it is necessary to develop three dimensional co-culture models to maximise the benefit of the availability of these cells. Here we have developed the first two tri-layer models of the glomerular capillary wall. The first is based on tissue culture inserts and provides evidence of cell-cell interaction via soluble mediators. In the second model the synthetic support of the tissue culture insert is replaced with a novel composite bioartificial membrane. This consists of a nanofibre membrane containing collagen I, electrospun directly onto a micro-photoelectroformed fine nickel supporting mesh. GEnC and podocytes grew in monolayers on either side of the insert support or the novel membrane to form a tri-layer model recapitulating the human glomerular capillary in vitro. These models will advance the study of both the physiology of normal glomerular filtration and of its disruption in glomerular disease.

  8. Mathematical and Computational Modeling of Polymer Exchange Membrane Fuel Cells

    Science.gov (United States)

    Ulusoy, Sehribani

    In this thesis a comprehensive review of fuel cell modeling has been given and based on the review, a general mathematical fuel cell model has been developed in order to understand the physical phenomena governing the fuel cell behavior and in order to contribute to the efforts investigating the optimum performance at different operating conditions as well as with different physical parameters. The steady state, isothermal model presented here accounts for the combined effects of mass and species transfer, momentum conservation, electrical current distribution through the gas channels, the electrodes and the membrane, and the electrochemical kinetics of the reactions in the anode and cathode catalyst layers. One of the important features of the model is that it proposes a simpler modified pseudo-homogeneous/agglomerate catalyst layer model which takes the advantage of the simplicity of pseudo-homogenous modeling while taking into account the effects of the agglomerates in the catalyst layer by using experimental geometric parameters published. The computation of the general mathematical model can be accomplished in 3D, 2D and 1D with the proper assumptions. Mainly, there are two computational domains considered in this thesis. The first modeling domain is a 2D Membrane Electrode Assembly (MEA) model including the modified agglomerate/pseudo-homogeneous catalyst layer modeling with consistent treatment of water transport in the MEA while the second domain presents a 3D model with different flow filed designs: straight, stepped and tapered. COMSOL Multiphysics along with Batteries and Fuel Cell Module have been used for 2D & 3D model computations while ANSYS FLUENT PEMFC Module has been used for only 3D two-phase computation. Both models have been validated with experimental data. With 2D MEA model, the effects of temperature and water content of the membrane as well as the equivalent weight of the membrane on the performance have been addressed. 3D COMSOL simulation

  9. Percolative model of proton conductivity of Nafion {sup registered} membranes

    Energy Technology Data Exchange (ETDEWEB)

    Costamagna, Paola; Grosso, Simone; Di Felice, Renzo [DICheP, Department of Chemical and Process Engineering ' G.B. Bonino' , University of Genoa, Via Opera Pia 15, 16145 Genoa (Italy)

    2008-04-01

    A model is proposed for the simulation of Nafion {sup registered} proton conductivity, where it is assumed that proton conduction occurs only in the water present in the membrane pores. Water is considered to be present in the pores due to two different phenomena: adsorption and capillary condensation. In the latter case, the pore is flooded and proton conduction occurs throughout the whole pore section. The conditions under which capillary condensation occurs are simulated in the model through the Kelvin-Cohan equation for condensation. The Kelvin-Cohan equation is a function of RH, temperature and the pore radius; the larger the pore, the higher the RH for which capillary condensation takes place. If the conditions for capillary condensation are not satisfied, then water is present in the pore due to adsorption under the form of a water layer which covers the pore walls and provides a path for proton conduction. In this case, the modified Brunauer-Emmet-Teller (BET) equation has been used in the model to simulate the thickness of the water layer. In both cases of capillary condensation and adsorption, the conductance g of a pore has then been calculated through the formula g = {kappa}S/l, where {kappa} is the proton conductivity of water, S the cross-section of the pore volume which is occupied by water, and l is the pore length. Pores of different size are present in the membrane (data of pore size distribution have been extracted from the literature); connectivity of the water layers present in the different pores is necessary in order to achieve a continuous path of proton conduction through the membrane, which is a percolation problem. To this end, the structure of the membrane pores has been simulated in the model through the effective medium approximation (EMA). The simulation results of proton conductivity of the membrane show good agreement with literature experimental data, even when varying the RH operating conditions. (author)

  10. A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals.

    Science.gov (United States)

    Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Gong, Ping; Xiao, Wenming; Tong, Weida

    2016-03-25

    Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold² software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

  11. A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals

    Directory of Open Access Journals (Sweden)

    Huixiao Hong

    2016-03-01

    Full Text Available Endocrine disruptors such as polychlorinated biphenyls (PCBs, diethylstilbestrol (DES and dichlorodiphenyltrichloroethane (DDT are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest and the molecular descriptors calculated from two-dimensional structures by Mold2 software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69% and external validations using 22 chemicals (balanced accuracy of 71%. Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

  12. Antibacterial Activity and Membrane-Disruptive Mechanism of 3-p-trans-Coumaroyl-2-hydroxyquinic Acid, a Novel Phenolic Compound from Pine Needles of Cedrus deodara, against Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Yanping Wu

    2016-08-01

    Full Text Available Recently, we reported that a novel phenolic compound isolated from Cedrus deodara, 3-p-trans-coumaroyl-2-hydroxyquinic acid (CHQA, exhibits a potent antioxidant activity. The present study aimed to evaluate the antibacterial activity of CHQA against eleven food-borne pathogens and to elucidate its mechanism of action against Staphylococcus aureus. The results from minimum inhibitory concentration (MIC determinations showed that CHQA exhibited moderate inhibitory effects on all of the tested pathogens with MIC values ranging from 2.5–10 mg/mL. Membrane potential measurements and flow cytometric analysis demonstrated that CHQA damaged the cytoplasmic membrane of S. aureus, causing a significant membrane hyperpolarization with a loss of membrane integrity. Moreover, CHQA induced an increase in membrane fluidity and conformational changes in membrane protein of S. aureus, suggesting that CHQA probably acts on the cell membrane by interactions with membrane lipid and protein. Transmission electron microscopic observations further confirmed that CHQA disrupted the cell membrane of S. aureus and caused severe morphological changes, which even led to leakage of intracellular constituents. These findings indicated that CHQA could have the potential to serve as a natural antibacterial agent to control and prevent the growth of pathogens in food and in food-processing environments.

  13. Effects of sphingomyelin/ceramide ratio on the permeability and microstructure of model stratum corneum lipid membranes.

    Science.gov (United States)

    Pullmannová, Petra; Staňková, Klára; Pospíšilová, Markéta; Skolová, Barbora; Zbytovská, Jarmila; Vávrová, Kateřina

    2014-08-01

    The conversion of sphingomyelin (SM) to a ceramide (Cer) by acid sphingomyelinase (aSMase) is an important event in skin barrier development. A deficiency in aSMase in diseases such as Niemann-Pick disease and atopic dermatitis coincides with impaired skin barrier recovery after disruption. We studied how an increased SM/Cer ratio influences the barrier function and microstructure of model stratum corneum (SC) lipid membranes. In the membranes composed of isolated human SC Cer (hCer)/cholesterol/free fatty acids/cholesteryl sulfate, partial or full replacement of hCer by SM increased water loss. Partial replacement of 25% and 50% of hCer by SM also increased the membrane permeability to theophylline and alternating electric current, while a higher SM content either did not alter or even decreased the membrane permeability. In contrast, in a simple membrane model with only one type of Cer (nonhydroxyacyl sphingosine, CerNS), an increased SM/Cer ratio provided a similar or better barrier against the permeation of various markers. X-ray powder diffraction revealed that the replacement of hCer by SM interferes with the formation of the long periodicity lamellar phase with a repeat distance of d=12.7nm. Our results suggest that SM-to-Cer processing in the human epidermis is essential for preventing excessive water loss, while the permeability barrier to exogenous compounds is less sensitive to the presence of sphingomyelin. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. An Approach to Modeling Complex Socio-Economic Impacts and Responses to Climate Disruption

    Science.gov (United States)

    Pikas, C. K.; Nix, M.; Ihde, A. G.; Weiss, M.; Simpkins, S.; Fountain, G. H.; Paxton, L. J.

    2011-12-01

    In this paper we describe the application of a proven methodology for modeling the complex social and economic interactions of a system under stress to the issues that are arising and will arise from global climate disruption. There is a long history in the Defense community of using what are known as strategic simulations or "wargames" to model the complex interactions between the environment, people, resources, infrastructure and the economy in a competitive environment. We describe in this paper, work that we have done on understanding how this heritage can be repurposed to help us explore how the complex interplay between climate disruption and our socio/political and economic structures will affect our future. These strategic simulations would be done under the auspices of the GAIA project (http://gaia.jhuapl.edu). While these simulations cannot definitively predict what will happen, they do illuminate non-linear feedbacks between human choices and the environment. These simulations can be focused on the global, regional, or local environment and capture the various actors (governments, agencies, resources, industries, religious/political groups, etc.) that compete to achieve their particular goals. We note that these simulations are not "zero sum" games - there need not be a winner and a loser. They are, however, competitive influence games: they represent the tools that a nation, state, faction or group has at its disposal to influence policy (diplomacy), finances, industry (economy), infrastructure, information, etc to achieve their particular goals. In the simulation, humans play various roles and understand that not everyone shares the same definition of a successful or favorable outcome. Rigorous post-analysis is used to illuminate where decisions were made that enabled or prevented a particular outcome from occurring. In addition, the simulations allow us to investigate how effective "technology injects" can be in achieving a particular, desired end

  15. Geochemistry of polymict ureilite EET83309, and a partially-disruptive impact model for ureilite origin

    Science.gov (United States)

    Warren, Paul H.; Kallemeyn, Gregory W.

    1989-01-01

    Bulk-compositional data for the EET83309 polymict ureilite were obtained using INAA and radiochemistry procedures and electron probe analysis. It was found that the EET83309 has a bulk composition indistinguishable from ordinary ('monomict') ureilites for all elements except light-middle REEs (which are present in much higher concentrations), suggesting that polymict ureilites are mixtures of ordinary ureilites which were mixed on a very small number of parent bodies. Despite the light-REE enrichments, polymict ureilites are nearly devoid of basaltic (Al-rich) material. It is suggested that the missing basalt may have been blown off the parent body by a partially disruptive collision with a large C-rich projectile. This impact model of ureilite origin reconciles many paradoxical aspects of ureilite composition.

  16. A multi-objective reliable programming model for disruption in supply chain

    Directory of Open Access Journals (Sweden)

    Emran Mohammadi

    2013-05-01

    Full Text Available One of the primary concerns on supply chain management is to handle risk components, properly. There are various reasons for having risk in supply chain such as natural disasters, unexpected incidents, etc. When a series of facilities are built and deployed, one or a number of them could probably fail at any time due to bad weather conditions, labor strikes, economic crises, sabotage or terrorist attacks and changes in ownership of the system. The objective of risk management is to reduce the effects of different domains to an acceptable level. To overcome the risk, we propose a reliable capacitated supply chain network design (RSCND model by considering random disruptions risk in both distribution centers and suppliers. The proposed study of this paper considers three objective functions and the implementation is verified using some instance.

  17. Mixtures of endocrine disrupting contaminants modelled on human high end exposures

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Kortenkamp, A.; Petersen, Marta Axelstad

    2012-01-01

    in vivo endocrine disrupting effects and information about human exposures was available, including phthalates, pesticides, UV‐filters, bisphenol A, parabens and the drug paracetamol. The mixture ratio was chosen to reflect high end human intakes. To make decisions about the dose levels for studies...... though each individual chemical is present at low, ineffective doses, but the effects of mixtures modelled based on human intakes have not previously been investigated. To address this issue for the first time, we selected 13 chemicals for a developmental mixture toxicity study in rats where data about...... in the rat, we employed the point of departure index (PODI) approach, which sums up ratios between estimated exposure levels and no‐observed‐adverse‐effect‐level (NOAEL) values of individual substances. For high end human exposures to the 13 selected chemicals, we calculated a PODI of 0.016. As only a PODI...

  18. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

    Science.gov (United States)

    Griesi-Oliveira, K; Acab, A; Gupta, A R; Sunaga, D Y; Chailangkarn, T; Nicol, X; Nunez, Y; Walker, M F; Murdoch, J D; Sanders, S J; Fernandez, T V; Ji, W; Lifton, R P; Vadasz, E; Dietrich, A; Pradhan, D; Song, H; Ming, G-L; Gu, X; Haddad, G; Marchetto, M C N; Spitzer, N; Passos-Bueno, M R; State, M W; Muotri, A R

    2015-11-01

    An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

  19. Modeled Microgravity Disrupts Collagen I/Integrin Signaling During Osteoblastic Differentiation of Human Mesenchymal Stem Cells

    Science.gov (United States)

    Meyers, Valerie E.; Zayzafoon, Majd; Gonda, Steven R.; Gathings, William E.; McDonald, Jay M.

    2004-01-01

    Spaceflight leads to reduced bone mineral density in weight bearing bones that is primarily attributed to a reduction in bone formation. We have previously demonstrated severely reduced osteoblastogenesis of human mesenchymal stem cells (hMSC) following seven days culture in modeled microgravity. One potential mechanism for reduced osteoblastic differentiation is disruption of type I collagen-integrin interactions and reduced integrin signaling. Integrins are heterodimeric transmembrane receptors that bind extracellular matrix proteins and produce signals essential for proper cellular function, survival, and differentiation. Therefore, we investigated the effects of modeled microgravity on integrin expression and function in hMSC. We demonstrate that seven days of culture in modeled microgravity leads to reduced expression of the extracellular matrix protein, type I collagen (Col I). Conversely, modeled microgravity consistently increases Col I-specific alpha2 and beta1 integrin protein expression. Despite this increase in integrin sub-unit expression, autophosphorylation of adhesion-dependent kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), is significantly reduced. Activation of Akt is unaffected by the reduction in FAK activation. However, reduced downstream signaling via the Ras-MAPK pathway is evidenced by a reduction in Ras and ERK activation. Taken together, our findings indicate that modeled microgravity decreases integrin/MAPK signaling, which likely contributes to the observed reduction in osteoblastogenesis.

  20. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

    Science.gov (United States)

    Griesi-Oliveira, Karina; Acab, Allan; Gupta, Abha R.; Sunaga, Daniele Yumi; Chailangkarn, Thanathom; Nicol, Xavier; Nunez, Yanelli; Walker, Michael F.; Murdoch, John D.; Sanders, Stephan J.; Fernandez, Thomas V.; Ji, Weizhen; Lifton, Richard P.; Vadasz, Estevão; Dietrich, Alexander; Pradhan, Dennis; Song, Hongjun; Ming, Guo-li; Guoe, Xiang; Haddad, Gabriel; Marchetto, Maria C. N.; Spitzer, Nicholas; Passos-Bueno, Maria Rita; State, Matthew W.; Muotri, Alysson R.

    2014-01-01

    An increasing number of genetic variants have been implicated in autism spectrum disorders (ASD), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, iPSC-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology, and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with IGF1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway might benefit from these drugs. We also demonstrate that MeCP2 levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells. PMID:25385366

  1. Early neural disruption and auditory processing outcomes in rodent models: Implications for developmental language disability

    Directory of Open Access Journals (Sweden)

    Roslyn Holly Fitch

    2013-10-01

    Full Text Available Most researchers in the field of neural plasticity are familiar with the Kennard Principle," which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood. As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand. These tasks were created to model (in rodents aspects of human sensory processing that may correlate – both developmentally and functionally – with typical and atypical language. We found that bilateral focal lesions to the cortical plate in rats during active neuronal migration led to worse auditory outcomes than comparable lesions induced after cortical migration was complete. Conversely, unilateral hypoxic-ischemic injuries (similar to those seen in premature infants and term infants with birth complications led to permanent auditory processing deficits when induced at a neurodevelopmental point comparable to human "term," but only transient deficits (undetectable in adulthood when induced in a "preterm" window. Convergent evidence suggests that regardless of when or how disruption of early neural development occurs, the consequences may be particularly deleterious to rapid auditory processing outcomes when they trigger developmental alterations that extend into subcortical structures (i.e., lower sensory processing stations. Collective findings hold implications for the study of behavioral outcomes following early brain injury as well as genetic/environmental disruption, and are relevant to our understanding of the neurologic risk factors underlying developmental language disability in

  2. Modeling Of Proton Exchange Membrane Fuel Cell Systems

    DEFF Research Database (Denmark)

    Nielsen, Mads Pagh

    The objective of this doctoral thesis was to develop reliable steady-state and transient component models suitable to asses-, develop- and optimize proton exchange membrane (PEM) fuel cell systems. Several components in PEM fuel cell systems were characterized and modeled. The developed component...... cell systems. Consequences of indirectly fueling PEM stacks with hydrocarbons using reforming technology were investigated using a PEM stack model including CO poisoning kinetics and a transient Simulink steam reforming system model. Aspects regarding the optimization of PEM fuel cell systems...

  3. Computational model for amoeboid motion: Coupling membrane and cytosol dynamics.

    Science.gov (United States)

    Moure, Adrian; Gomez, Hector

    2016-10-01

    A distinguishing feature of amoeboid motion is that the migrating cell undergoes large deformations, caused by the emergence and retraction of actin-rich protrusions, called pseudopods. Here, we propose a cell motility model that represents pseudopod dynamics, as well as its interaction with membrane signaling molecules. The model accounts for internal and external forces, such as protrusion, contraction, adhesion, surface tension, or those arising from cell-obstacle contacts. By coupling the membrane and cytosol interactions we are able to reproduce a realistic picture of amoeboid motion. The model results are in quantitative agreement with experiments and show how cells may take advantage of the geometry of their microenvironment to migrate more efficiently.

  4. Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Z.; Peldszus, S.; Huck, P.M. [University of Waterloo, Waterloo, ON (Canada). NSERC Chair in Water Treatment

    2009-03-01

    The adsorption of two representative pharmaceutically active compounds (PhACs) naproxen and carbamazepine and one endocrine disrupting compound (EDC) nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. The GAC adsorbents were coal-based Calgon Filtrasorb 400 and coconut shell-based PICA CTIF TE. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surface diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol. 25 refs., 4 figs., 1 tab.

  5. QSAR classification models for the prediction of endocrine disrupting activity of brominated flame retardants.

    Science.gov (United States)

    Kovarich, Simona; Papa, Ester; Gramatica, Paola

    2011-06-15

    The identification of potential endocrine disrupting (ED) chemicals is an important task for the scientific community due to their diffusion in the environment; the production and use of such compounds will be strictly regulated through the authorization process of the REACH regulation. To overcome the problem of insufficient experimental data, the quantitative structure-activity relationship (QSAR) approach is applied to predict the ED activity of new chemicals. In the present study QSAR classification models are developed, according to the OECD principles, to predict the ED potency for a class of emerging ubiquitary pollutants, viz. brominated flame retardants (BFRs). Different endpoints related to ED activity (i.e. aryl hydrocarbon receptor agonism and antagonism, estrogen receptor agonism and antagonism, androgen and progesterone receptor antagonism, T4-TTR competition, E2SULT inhibition) are modeled using the k-NN classification method. The best models are selected by maximizing the sensitivity and external predictive ability. We propose simple QSARs (based on few descriptors) characterized by internal stability, good predictive power and with a verified applicability domain. These models are simple tools that are applicable to screen BFRs in relation to their ED activity, and also to design safer alternatives, in agreement with the requirements of REACH regulation at the authorization step. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Novel Design of Heptad Amphiphiles To Enhance Cell Selectivity, Salt Resistance, Antibiofilm Properties and Their Membrane-Disruptive Mechanism.

    Science.gov (United States)

    Dou, Xiujing; Zhu, Xin; Wang, Jiajun; Dong, Na; Shan, Anshan

    2017-03-23

    Coiled-coil, a basic folding pattern of native proteins, was previously demonstrated to be associated with the specific spatial recognition, association, and dissociation of proteins and can be used to perfect engineering peptide model. Thus, in this study, a series of amphiphiles composed of heptads repeats with coiled-coil structures was constructed, and the designed peptides exhibited a broad spectrum of antimicrobial activities. Circular dichroism and biological assays showed that the heptad repeats and length of the linker between the heptads largely influenced the amphiphile's helical propensity and cell selectivity. The engineered amphiphiles were also found to efficiently reduce sessile P. aeruginosa biofilm biomass, neutralize endotoxins, inhibit the inflammatory response, and remain active under physiological salt concentrations. In summary, these findings are helpful for short AMP design with a highly therapeutic index to treat bacteria-induced infection.

  7. Towards improved animal models for evaluating social cognition and its disruption in schizophrenia: the CNTRICS initiative.

    Science.gov (United States)

    Millan, Mark J; Bales, Karen L

    2013-11-01

    Social cognition refers to processes used to monitor and interpret social signals from others, to decipher their state of mind, emotional status and intentions, and select appropriate social behaviour. Social cognition is sophisticated in humans, being embedded with verbal language and enacted in a complex cultural environment. Its disruption characterises the entire course of schizophrenia and is correlated with poor functional outcome. Further, deficits in social cognition are related to impairment in other cognitive domains, positive symptoms (paranoia and delusions) and negative symptoms (social withdrawal and reduced motivation). In light of the significance and inadequate management of social cognition deficits, there is a need for translatable experimental procedures for their study, and identification of effective pharmacotherapy. No single paradigm captures the multi-dimensional nature of social cognition, and procedures for assessing ability to infer mental states are not well-developed for experimental therapeutic settings. Accordingly, a recent CNTRICS meeting prioritised procedures for measuring a specific construct: "acquisition and recognition of affective (emotional) states", coupled to individual recognition. Two complementary paradigms for refinement were identified: social recognition/preference in rodents, and visual tracking of social scenes in non-human primates (NHPs). Social recognition is disrupted in genetic, developmental or pharmacological disease models for schizophrenia, and performance in both procedures is improved by the neuropeptide oxytocin. The present article surveys a broad range of procedures for studying social cognition in rodents and NHPs, discusses advantages and drawbacks, and focuses on development of social recognition/preference and gaze-following paradigms for improved study of social cognition deficits in schizophrenia and their potential treatment.

  8. Helfrich model of membrane bending: from Gibbs theory of liquid interfaces to membranes as thick anisotropic elastic layers.

    Science.gov (United States)

    Campelo, Felix; Arnarez, Clement; Marrink, Siewert J; Kozlov, Michael M

    2014-06-01

    Helfrich model of membrane bending elasticity has been most influential in establishment and development of Soft-Matter Physics of lipid bilayers and biological membranes. Recently, Helfrich theory has been extensively used in Cell Biology to understand the phenomena of shaping, fusion and fission of cellular membranes. The general background of Helfrich theory on the one hand, and the ways of specifying the model parameters on the other, are important for quantitative treatment of particular biologically relevant membrane phenomena. Here we present the origin of Helfrich model within the context of the general Gibbs theory of capillary interfaces, and review the strategies of computing the membrane elastic moduli based on considering a lipid monolayer as a three-dimensional thick layer characterized by trans-monolayer profiles of elastic parameters. We present the results of original computations of these profiles by a state-of-the-art numerical approach.

  9. A model for a liquid membrane separation stage

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-02-01

    The coupled mixer-settlers having a common settling zone suggested for use to extract fission products from a conversion reactor blanket are analogues of membrane apparatuses and at a first glance in terms of hydrodynamics do not differ from conventional mixer-settlers. However, the common settling zone complicates both the design solutions and their modelling. For example, different emulsion types can result in mixers and it is not known how this fact will affect phenomena such as separation rates, disperse phase entrainment under conditions close to flooding. For initial studies of the feasibility of the process in principle and the primary optimization of the structure of the transfer scheme one needs to have a model and a program to calculate the statics of a multistage membrane facility of this type.

  10. Interaction of tea tree oil with model and cellular membranes.

    Science.gov (United States)

    Giordani, Cristiano; Molinari, Agnese; Toccacieli, Laura; Calcabrini, Annarica; Stringaro, Annarita; Chistolini, Pietro; Arancia, Giuseppe; Diociaiuti, Marco

    2006-07-27

    Tea tree oil (TTO) is the essential oil steam-distilled from Melaleuca alternifolia, a species of northern New South Wales, Australia. It exhibits a broad-spectrum antimicrobial activity and an antifungal activity. Only recently has TTO been shown to inhibit the in vitro growth of multidrug resistant (MDR) human melanoma cells. It has been suggested that the effect of TTO on tumor cells could be mediated by its interaction with the plasma membrane, most likely by inducing a reorganization of lipid architecture. In this paper we report biophysical and structural results obtained using simplified planar model membranes (Langmuir films) mimicking lipid "rafts". We also used flow cytometry analysis (FCA) and freeze-fracturing transmission electron microscopy to investigate the effects of TTO on actual MDR melanoma cell membranes. Thermodynamic (compression isotherms and adsorption kinetics) and structural (Brewster angle microscopy) investigation of the lipid monolayers clearly indicates that TTO interacts preferentially with the less ordered DPPC "sea" and that it does not alter the more ordered lipid "rafts". Structural observations, performed by freeze fracturing, confirm that TTO interacts with the MDR melanoma cell plasma membrane. Moreover, experiments performed by FCA demonstrate that TTO does not interfere with the function of the MDR drug transporter P-gp. We therefore propose that the effect exerted on MDR melanoma cells is mediated by the interaction with the fluid DPPC phase, rather than with the more organized "rafts" and that this interaction preferentially influences the ATP-independent antiapoptotic activity of P-gp likely localized outside "rafts".

  11. Simulation modeling of supported lipid membranes - a review.

    Science.gov (United States)

    Hirtz, Michael; Kumar, Naresh; Chi, Lifeng

    2014-03-01

    Lipid membranes are of great importance for many biological systems and biotechnological applications. One method to gain a profound understanding of the dynamics in lipid membranes and their interaction with other system components is by modeling these systems by computer simulations. Many different approaches have been undertaken in this endeavor that have led to molecular level insights into the underlying mechanisms of several experimental observations and biological processes with an extremely high temporal resolution. As compared to the free-standing lipid bilayers, there are fewer simulation studies addressing the systems of supported lipid membranes. Nevertheless, these have significantly enhanced our understanding of the behavior of lipid layers employed in applications spanning from biosensors to drug delivery and for biological processes such as the breathing cycle of lung surfactants. In this review, we give an account of the state of the art of methods and applications of the simulations of supported lipid bilayers, interfacial membranes at the air/water interface and on solid surfaces.

  12. QSAR modeling and prediction of the endocrine-disrupting potencies of brominated flame retardants.

    Science.gov (United States)

    Papa, Ester; Kovarich, Simona; Gramatica, Paola

    2010-05-17

    In the European Union REACH regulation, the chemicals with particularly harmful behaviors, such as endocrine disruptors (EDs), are subject to authorization, and the identification of safer alternatives to these chemicals is required. In this context, the use of quantitative structure-activity relationships (QSAR) becomes particularly useful to fill the data gap due to the very small number of experimental data available to characterize the environmental and toxicological profiles of new and emerging pollutants with ED behavior such as brominated flame retardants (BFRs). In this study, different QSAR models were developed on different responses of endocrine disruption measured for several BFRs. The multiple linear regression approach was applied to a variety of theoretical molecular descriptors, and the best models, which were identified from all of the possible combinations of the structural variables, were internally validated for their performance using the leave-one-out (Q(LOO)(2) = 73-91%) procedure and scrambling of the responses. External validation was provided, when possible, by splitting the data sets in training and test sets (range of Q(EXT)(2) = 76-90%), which confirmed the predictive ability of the proposed equations. These models, which were developed according to the principles defined by the Organization for Economic Co-operation and Development to improve the regulatory acceptance of QSARs, represent a simple tool for the screening and characterization of BFRs.

  13. Child Disruptive Behavior and Parenting Efficacy: A Comparison of the Effects of Two Models of Insights

    Science.gov (United States)

    O'Connor, Erin; Rodriguez, Eileen; Cappella, Elise; Morris, Jordan; McClowry, Sandee

    2012-01-01

    In this article, we investigate the effectiveness of INSIGHTS into Children's Temperament (INSIGHTS), a temperament-based preventive intervention, in reducing the disruptive behavior problems of young children from low-income, urban families. Results indicate that children enrolled in INSIGHTS evidenced a decrease in disruptive behavior problems…

  14. Child Disruptive Behavior and Parenting Efficacy: A Comparison of the Effects of Two Models of Insights

    Science.gov (United States)

    O'Connor, Erin; Rodriguez, Eileen; Cappella, Elise; Morris, Jordan; McClowry, Sandee

    2012-01-01

    In this article, we investigate the effectiveness of INSIGHTS into Children's Temperament (INSIGHTS), a temperament-based preventive intervention, in reducing the disruptive behavior problems of young children from low-income, urban families. Results indicate that children enrolled in INSIGHTS evidenced a decrease in disruptive behavior problems…

  15. Ex vivo model for pre-clinical evaluation of dialyzers containing new membranes.

    Science.gov (United States)

    Mahiout, A; Meinhold, H; Jörres, A; Krieg, R; Kessel, M; Tretzel, J; Baurmeister, U

    1985-01-01

    The ex vivo model which reflects hemodialysis modulating factors during the first twenty minutes of blood membrane interaction, is applicable as a pre-clinical test for new membranes. The biocompatibility of a new cellulosic membrane (MC) proved to be superior to regenerated cellulose and comparable to synthetic membranes such as PAN regarding complement activation.

  16. Modeling and optimization of membrane lifetime in dead-end ultra filtration

    NARCIS (Netherlands)

    Zondervan, Edwin; Roffel, Brian

    2008-01-01

    In this paper, a membrane lifetime model is developed and experimentally validated. The lifetime model is based on the Weibull probability density function. The lifetime model can be used to determine an unambiguous characteristic membrane lifetime. Experimental results showed that membrane lifetime

  17. Resting state functional network disruptions in a kainic acid model of temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Ravnoor Singh Gill

    2017-01-01

    Full Text Available We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN. The limbic network includes the hippocampus, amygdala, piriform cortex, nucleus accumbens, and mediodorsal thalamus, whereas DMN involves the medial prefrontal cortex, anterior and posterior cingulate cortex, auditory and temporal association cortex, and posterior parietal cortex. The TLE model manifested a higher clustering coefficient, increased global and local efficiency, and increased small-worldness as compared to controls, despite having a similar characteristic path length. These results suggest extensive disruptions in the functional brain networks, which may be the basis of altered cognitive, emotional and psychiatric symptoms in TLE.

  18. Modeling uncertainties in workforce disruptions from influenza pandemics using dynamic input-output analysis.

    Science.gov (United States)

    El Haimar, Amine; Santos, Joost R

    2014-03-01

    Influenza pandemic is a serious disaster that can pose significant disruptions to the workforce and associated economic sectors. This article examines the impact of influenza pandemic on workforce availability within an interdependent set of economic sectors. We introduce a simulation model based on the dynamic input-output model to capture the propagation of pandemic consequences through the National Capital Region (NCR). The analysis conducted in this article is based on the 2009 H1N1 pandemic data. Two metrics were used to assess the impacts of the influenza pandemic on the economic sectors: (i) inoperability, which measures the percentage gap between the as-planned output and the actual output of a sector, and (ii) economic loss, which quantifies the associated monetary value of the degraded output. The inoperability and economic loss metrics generate two different rankings of the critical economic sectors. Results show that most of the critical sectors in terms of inoperability are sectors that are related to hospitals and health-care providers. On the other hand, most of the sectors that are critically ranked in terms of economic loss are sectors with significant total production outputs in the NCR such as federal government agencies. Therefore, policy recommendations relating to potential mitigation and recovery strategies should take into account the balance between the inoperability and economic loss metrics.

  19. The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Badea, Alexandra; Kane, Lauren; Anderson, Robert J; Qi, Yi; Foster, Mark; Cofer, Gary P; Medvitz, Neil; Buckley, Anne F; Badea, Andreas K; Wetsel, William C; Colton, Carol A

    2016-11-15

    Multivariate biomarkers are needed for detecting Alzheimer's disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination-through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy.

  20. Influence of the bilayer composition on the binding and membrane disrupting effect of Polybia-MP1, an antimicrobial mastoparan peptide with leukemic T-lymphocyte cell selectivity.

    Science.gov (United States)

    dos Santos Cabrera, Marcia Perez; Arcisio-Miranda, Manoel; Gorjão, Renata; Leite, Natália Bueno; de Souza, Bibiana Monson; Curi, Rui; Procopio, Joaquim; Ruggiero Neto, João; Palma, Mario Sérgio

    2012-06-19

    This study shows that MP-1, a peptide from the venom of the Polybia paulista wasp, is more toxic to human leukemic T-lymphocytes than to human primary lymphocytes. By using model membranes and electrophysiology measurements to investigate the molecular mechanisms underlying this selective action, the porelike activity of MP-1 was identified with several bilayer compositions. The highest average conductance was found in bilayers formed by phosphatidylcholine or a mixture of phosphatidylcholine and phosphatidylserine (70:30). The presence of cholesterol or cardiolipin substantially decreases the MP-1 pore activity, suggesting that the membrane fluidity influences the mechanism of selective toxicity. The determination of partition coefficients from the anisotropy of Trp indicated higher coefficients for the anionic bilayers. The partition coefficients were found to be 1 order of magnitude smaller when the bilayers contain cholesterol or a mixture of cholesterol and sphingomyelin. The blue shift fluorescence, anisotropy values, and Stern-Volmer constants are indications of a deeper penetration of MP-1 into anionic bilayers than into zwitterionic bilayers. Our results indicate that MP-1 prefers to target leukemic cell membranes, and its toxicity is probably related to the induction of necrosis and not to DNA fragmentation. This mode of action can be interpreted considering a number of bilayer properties like fluidity, lipid charge, and domain formation. Cholesterol-containing bilayers are less fluid and less charged and have a tendency to form domains. In comparison to healthy cells, leukemic T-lymphocyte membranes are deprived of this lipid, resulting in decreased peptide binding and lower conductance. We showed that the higher content of anionic lipids increases the level of binding of the peptide to bilayers. Additionally, the absence of cholesterol resulted in enhanced pore activity. These findings may drive the selective toxicity of MP-1 to Jurkat cells.

  1. A Theoretical Model of Flow Disruptions for the Anesthesia Team During Cardiovascular Surgery.

    Science.gov (United States)

    Boquet, Albert; Cohen, Tara; Diljohn, Fawaaz; Cabrera, Jennifer; Reeves, Scott; Shappell, Scott

    2017-07-03

    This investigation explores flow disruptions observed during cardiothoracic surgery and how they serve to disconnect anesthesia providers from their primary task. We can improve our understanding of this disengagement by exploring what we call the error space or the accumulated time required to resolve disruptions. Trained human factors students observed 10 cardiac procedures for disruptions impacting the anesthesia team and recorded the time required to resolve these events. Observations were classified using a human factors taxonomy. Of 301 disruptions observed, interruptions (e.g., those events related to alerts, distractions, searching activity, spilling/dropping, teaching moment, and task deviations) accounted for the greatest frequency of events (39.20%). The average amount of time needed for each disruption to be resolved was 48 seconds. Across 49.87 hours of observation, more than 4 hours were spent resolving disruptions to the anesthesia team's work flow. By defining a calculable error space associated with these disruptions, this research provides a conceptual metric that can serve in the identification and design of targeted interventions. This method serves as a proactive approach for recognizing systemic threats, affording healthcare workers the opportunity to mitigate the development and incidence of preventable errors precedently.

  2. AB159. Endocrine disrupting chemicals: toxicological risk assessment in vivo and in vitro models

    Science.gov (United States)

    Thuy, Vo Thi Bich; Nguyen Binh, Le Thi; Phuong Oanh, Kim Thi; Van Hai, Nong

    2015-01-01

    In several studies, scientists asserted that many of endocrine disruptors (EDs), which have been involved in developmental, reproductive, neural, immunological, and other problems in wildlife and laboratory animals. Some environmental EDs, such as di-(2-ethylhexyl) phthalate (DEHP), flutamide (Flu), parabens, are used in many products in life and environment. However, the adverse effects caused by EDs can be temporary or permanent and the mechanism(s) through which these chemicals elicit their effects on biological systems of human and animal health is not clearly understood. The specific aim of this study is to evaluate endocrine disrupting chemicals-induced impact on the male or female reproductive system. An attempt is also made to elucidate the impact of these EDs in an in vitro model, i.e., GH3 rat pituitary cell line. A great deal of work has been carried out on the toxicity of phthalate, Flu, parabens in vivo and in vitro models. In brief, studies have been indicated that long-term and short-term exposure to various endocrine disrupting compounds (i.e., DEHP, Flu, parabens) during development stage (i.e., gestation, neonatal, immature, peripubertal) were done to find alternative dysfunctions later in animal life. The development and function of male or female reproductive tract showed many abnormalities, e.g., menstrual cycle irregularities; impaired fertility, endometriosis, and polycystic ovarian syndrome in female or morphological and functional gonadal dysfunction, e.g., infertility and decreased libido, congenital malformations (altered embryonic and fetal intrauterine development) and testicular dysgenesis syndrome in male. In addition, the differential gene expression patterns by microarray analysis following EDs exposure were found, particularly in steroid hormone synthesis, androgen and/or estrogen synthesis, and sex determination-related gene. On the other hand, studies revealed that parabens, a weak estrogenic chemical, exerted their actions on

  3. Penetration of alkali atoms throughout a graphene membrane: theoretical modeling.

    Science.gov (United States)

    Boukhvalov, D W; Virojanadara, C

    2012-03-07

    Theoretical studies of penetration of various alkali atoms (Li, Na, Rb, Cs) throughout a graphene membrane grown on a silicon carbide substrate are reported and compared with recent experimental results. Results of first principles modeling demonstrate a rather low (about 0.8 eV) energy barrier for the formation of temporary defects in the carbon layer required for the penetration of Li at a high concentration of adatoms, a higher (about 2 eV) barrier for Na, and barriers above 4 eV for Rb and Cs. Experiments prove migration of lithium adatoms from the graphene surface to the buffer layer and SiC substrate at room temperature, sodium at 100 °C and impenetrability of the graphene membrane for Rb and Cs. Differences between epitaxial and free-standing graphene for the penetration of alkali ions are also discussed.

  4. Modeling Steroidogenesis Disruption Using High-Throughput In Vitro Screening Data (SOT)

    Science.gov (United States)

    Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on ...

  5. Disruptive Models in Primary Care: Caring for High-Needs, High-Cost Populations.

    Science.gov (United States)

    Hochman, Michael; Asch, Steven M

    2017-04-01

    Starfield and colleagues have suggested four overarching attributes of good primary care: "first-contact access for each need; long-term person- (not disease) focused care; comprehensive care for most health needs; and coordinated care when it must be sought elsewhere." As this series on reinventing primary care highlights, there is a compelling need for new care delivery models that would advance these objectives. This need is particularly urgent for high-needs, high-cost (HNHC) populations. By definition, HNHC patients require extensive attention and consume a disproportionate share of resources, and as a result they strain traditional office-based primary care practices. In this essay, we offer a clinical vignette highlighting the challenges of caring for HNHC populations. We then describe two categories of primary care-based approaches for managing HNHC populations: complex case management, and specialized clinics focused on HNHC patients. Although complex case management programs can be incorporated into or superimposed on the traditional primary care system, such efforts often fail to engage primary care clinicians and HNHC patients, and proven benefits have been modest to date. In contrast, specialized clinics for HNHC populations are more disruptive, as care for HNHC patients must be transferred to a multidisciplinary team that can offer enhanced care coordination and other support. Such specialized clinics may produce more substantial benefits, though rigorous evaluation of these programs is needed. We conclude by suggesting policy reforms to improve care for HNHC populations.

  6. Disrupted Glutamatergic Transmission in Prefrontal Cortex Contributes to Behavioral Abnormality in an Animal Model of ADHD.

    Science.gov (United States)

    Cheng, Jia; Liu, Aiyi; Shi, Michael Y; Yan, Zhen

    2017-03-22

    Spontaneously hypertensive rats (SHR) are the most widely used animal model for the study of attention deficit hyperactivity disorder (ADHD). Here we sought to reveal the neuronal circuits and molecular basis of ADHD and its potential treatment using SHR. Combined electrophysiological, biochemical, pharmacological, chemicogenetic, and behavioral approaches were utilized. We found that AMPAR-mediated synaptic transmission in pyramidal neurons of prefrontal cortex (PFC) was diminished in SHR, which was correlated with the decreased surface expression of AMPAR subunits. Administration of methylphenidate (a psychostimulant drug used to treat ADHD), which blocks dopamine transporters and norepinephrine transporters, ameliorated the behavioral deficits of adolescent SHR and restored AMPAR-mediated synaptic function. Activation of PFC pyramidal neurons with a CaMKII-driven Gq-coupled designer receptor exclusively activated by designer drug also led to the elevation of AMPAR function and the normalization of ADHD-like behaviors in SHR. These results suggest that the disrupted function of AMPARs in PFC may underlie the behavioral deficits in adolescent SHR and enhancing PFC activity could be a treatment strategy for ADHD.Neuropsychopharmacology advance online publication, 22 March 2017; doi:10.1038/npp.2017.30.

  7. Oscillations and multiple steady states in active membrane transport models.

    Science.gov (United States)

    Vieira, F M; Bisch, P M

    1994-01-01

    The dynamic behavior of some non-linear extensions of the six-state alternating access model for active membrane transport is investigated. We use stoichio-metric network analysis to study the stability of steady states. The bifurcation analysis has been done through standard numerical methods. For the usual six-state model we have proved that there is only one steady state, which is globally asymptotically stable. When we added an autocatalytic step we found self-oscillations. For the competition between a monomer cycle and a dimer cycle, with steps of dimer formation, we have also found self-oscillations. We have also studied models involving the formation of a complex with other molecules. The addition of two steps for formation of a complex of the monomer with another molecule does not alter either the number or the stability of steady states of the basic six-state model. The model which combines the formation of a complex with an autocatalytic step shows both self-oscillations and multiple steady states. The results lead us to conclude that oscillations could be produced by active membrane transport systems if the transport cycle contains a sufficiently large number of steps (six in the present case) and is coupled to at least one autocatalytic reaction,. Oscillations are also predicted when the monomer cycle is coupled to a dimer cycle. In fact, the autocatalytic reaction can be seen as a simplification of the model involving competition between monomer and dimer cycles, which seems to be a more realistic description of biological systems. A self-regulation mechanism of the pumps, related to the multiple stationary states, is expected only for a combined effect of autocatalysis and formation of complexes with other molecules. Within the six-state model this model also leads to oscillation.

  8. Membrane dynamics

    DEFF Research Database (Denmark)

    Bendix, Pól Martin

    2015-01-01

    Current topics include membrane-protein interactions with regard to membrane deformation or curvature sensing by BAR domains. Also, we study the dynamics of membrane tubes of both cells and simple model membrane tubes. Finally, we study membrane phase behavior which has important implications...... for the lateral organization of membranes as wells as for physical properties like bending, permeability and elasticity...

  9. Modelling wastewater treatment in a submerged anaerobic membrane bioreactor.

    Science.gov (United States)

    Spagni, Alessandro; Ferraris, Marco; Casu, Stefania

    2015-01-01

    Mathematical modelling has been widely applied to membrane bioreactor (MBRs) processes. However, to date, very few studies have reported on the application of the anaerobic digestion model N.1 (ADM1) to anaerobic membrane processes. The aim of this study was to evaluate the applicability of the ADM1 to a submerged anaerobic MBR (SAMBR) treating simulated industrial wastewater composed of cheese whey and sucrose. This study demonstrated that the biological processes involved in SAMBRs can be modelled by using the ADM1. Moreover, the results showed that very few modifications of the parameters describing the ADM1 were required to reasonably fit the experimental data. In particular, adaptation to the specific conditions of the coefficients describing the wastewater characterisation and the reduction of the hydrolysis rate of particulate carbohydrate (khyd,ch) from 0.25 d(-1) (as suggested by the ADM1 for high-rate mesophilic reactors) to 0.13 d(-1) were required to fit the experimental data.

  10. Model for probing membrane-cortex adhesion by micropipette aspiration and fluctuation spectroscopy

    CERN Document Server

    Alert, Ricard; Brugués, Jan; Sens, Pierre

    2016-01-01

    We propose a model for membrane-cortex adhesion which couples membrane deformations, hydrodynamics and kinetics of membrane-cortex ligands. In its simplest form, the model gives explicit predictions for the critical pressure for membrane detachment and for the value of adhesion energy. We show that these quantities exhibit a significant dependence on the active acto-myosin stresses. The model provides a simple framework to access quantitative information on cortical activity by means of micropipette experiments. We also extend the model to incorporate fluctuations and show that detailed information on the stability of membrane-cortex coupling can be obtained by a combination of micropipette aspiration and fluctuation spectroscopy measurements.

  11. Time-dependent cell membrane damage under mechanical tension: Experiments and modeling

    OpenAIRE

    Lu, Bo; Chang, Jay Han-Chieh; Tai, Yu-Chong

    2011-01-01

    This paper reports a study of cancer cell membrane damage during filtration caused by cell membrane tension. The membrane tension was induced when cells were captured on a microfabricated parylene-C filter during the constant-pressure-driven filtration. This work includes both experiments and modeling to explore the underlying biomechanics of the cell membrane damage. The developed model not only agrees with our time-dependent cell damage data, but also fits well with previous results on red ...

  12. Unraveling the impact of hydroxylation on interactions of bile acid cationic lipids with model membranes by in-depth calorimetry studies.

    Science.gov (United States)

    Singh, Manish; Bajaj, Avinash

    2014-09-28

    We used eight bile acid cationic lipids differing in the number of hydroxyl groups and performed in-depth differential scanning calorimetry studies on model membranes doped with different percentages of these cationic bile acids. These studies revealed that the number and positioning of free hydroxyl groups on bile acids modulate the phase transition and co-operativity of membranes. Lithocholic acid based cationic lipids having no free hydroxyl groups gel well with dipalmitoylphosphatidylcholine (DPPC) membranes. Chenodeoxycholic acid lipids having one free hydroxyl group at the 7'-carbon position disrupt the membranes and lower their co-operativity. Deoxycholic acid and cholic acid based cationic lipids have free hydroxyl groups at the 12'-carbon position, and at 7'- and 12'-carbon positions respectively. Doping of these lipids at high concentrations increases the co-operativity of membranes suggesting that these lipids might induce self-assembly in DPPC membranes. These different modes of interactions between cationic lipids and model membranes would help in future for exploring their use in DNA/drug delivery.

  13. Fouling of a microfiltration membrane by humic-like substances: a mathematical approach to modelling permeate flux and membrane retention.

    Science.gov (United States)

    Poorasgari, Eskandar; Farsi, Ali; Christensen, Morten Lykkegaard

    2016-01-01

    Membrane retention of the humic-like substances present in a soluble microbial products (SMP) suspension was studied by using a dead-end filtration system. The SMP suspension was extracted from the sludge of an enhanced biological phosphorus removal-membrane bioreactor. Our results showed that both adsorption and steric retention of the humic-like substances governed their transport through the membrane during the filtration. The adsorption, which followed pseudo-first order kinetics, did not cause substantial decline of permeate flux. The steric retention, on the other hand, formed a gel layer, which in turn led to a major decrease in the flux. The reduction of permeate flux was well predicted by cake filtration theory. Based on the adsorption and the steric retention, a new model was developed for predicting the overall membrane retention of the humic-like substances. The general trend of the modelled overall retention was in partial agreement with the experimental results.

  14. Mathematical modelling of methane steam reforming in a membrane reactor: an isothermal model

    Energy Technology Data Exchange (ETDEWEB)

    Assaf, E.M. [Sao Paulo Univ., Sao Carlos, SP (Brazil). Dept. de Fisico-Quimica; Jesus, C.D.F.; Assaf, J.M. [Sao Carlos Univ., SP (Brazil). Dept. de Engenharia Quimica

    1998-06-01

    A mathematical modelling of one-dimensional, stationary and isothermic membrane reactor for methane steam reforming was developed to compare the maximum yield for methane conversion in this reactor with that in a conventional fixed-bed reactor. Fick`s first law was used to describe the mechanism of hydrogen permeation. The variables studied include: reaction temperature, hydrogen feed flow rate and membrane thickness. The results show that the membrane reactor presents a higher methane conversion yield than the conventional fixed-bed reactor. (author) 16 refs., 5 figs., 1 tab.; e-mail: eassaf at iqsc.sc.usp.br; mansur at power.ufscar.br

  15. MATHEMATICAL MODELLING OF METHANE STEAM REFORMING IN A MEMBRANE REACTOR: AN ISOTHERMIC MODEL

    Directory of Open Access Journals (Sweden)

    E.M. ASSAF

    1998-06-01

    Full Text Available A mathematical modelling of one-dimensional, stationary and isothermic membrane reactor for methane steam reforming was developed to compare the maximum yield for methane conversion in this reactor with that in a conventional fixed-bed reactor. Fick's first law was used to describe the mechanism of hydrogen permeation. The variables studied include: reaction temperature, hydrogen feed flow rate and membrane thickness. The results show that the membrane reactor presents a higher methane conversion yield than the conventional fixed-bed reactor.

  16. Recombinant Dengue virus protein NS2B alters membrane permeability in different membrane models

    OpenAIRE

    León-Juárez, Moisés; Martínez-Castillo, Macario; Shrivastava, Gaurav; García-Cordero, Julio; Villegas-Sepulveda, Nicolás; Mondragón-Castelán, Mónica; Mondragón-Flores, Ricardo; Cedillo-Barrón, Leticia

    2016-01-01

    Background One of the main phenomena occurring in cellular membranes during virus infection is a change in membrane permeability. It has been observed that numerous viral proteins can oligomerize and form structures known as viroporins that alter the permeability of membranes. Previous findings have identified such proteins in cells infected with Japanese encephalitis virus (JEV), a member of the same family that Dengue virus (DENV) belongs to (Flaviviridae). In the present work, we investiga...

  17. Isoeugenol has a non-Disruptive Detergent-like Mechanism of Action

    Directory of Open Access Journals (Sweden)

    Morten eHyldgaard

    2015-07-01

    Full Text Available Isoeugenol is an essential oil constituent of nutmeg, clove, and cinnamon. Despite isoeugenol’s promising antimicrobial activity, no studies have yet investigated its mode of antibacterial action at the molecular level. The aim of this study is to clarify isoeugenol’s antibacterial mode of action using the Gram-negative and Gram-positive model organisms Escherichia coli and Listeria innocua, respectively. We determined the antimicrobial activity of isoeugenol against the model organisms, and examined how isoeugenol affects cell morphology, cell membrane permeabilization, and how isoeugenol interacts with phospholipid membranes using vesicle and supported lipid bilayer models.Isoeugenol demonstrated a bactericidal activity against E. coli and L. innocua that did not affect cell morphology, although the cell membrane was permeabilized. We hypothesized that the cell membrane was the primary site of action, and studied this interaction in further detail using purified membrane model systems. Isoeugenol’s permeabilization of calcein-encapsulated vesicles was concentration dependent, and isoeugenol’s interaction with giant unilamellar vesicles indicated increased membrane fluidity and a non-disruptive permeabilization mechanism. This contradicted membrane fluidity measurements on supported lipid bilayers, which indicated decreased membrane fluidity. However, further investigations demonstrated that the interaction between isoeugenol and bilayers was reversible, and caused membranes to display heterogeneous topography, an increased mass, and a higher degree of hydration. In conclusion, we propose that isoeugenol interacts with membranes in a reversible non-disruptive detergent-like manner, which causes membrane destabilization. Furthermore, we argue that isoeugenol increases membrane fluidity.

  18. Regenerative response and endocrine disrupters in crinoid echinoderms: an old experimental model, a new ecotoxicological test.

    Science.gov (United States)

    Candia Carnevali, M D

    2005-01-01

    The regenerative phenomena that reproduce developmental processes in adult organisms and are regulated by endocrine and neurohumoral mechanisms can provide new sensitive tests for monitoring the effects of exposure to anthropogenic chemicals such as endocrine disrupter (ED) contaminants. These pollutants in fact can be bioaccumulated by the organisms, causing dysfunctions in steroid hormone production/metabolism and activities and inducing dramatic effects on reproductive competence, development and growth in many animals, man included. Current research is exploring the effects of exposure to different classes of compounds well known for their ED activity, such as polychlorinated biphenyls (PCBs), nonylphenols and organotins, on regenerative potential of echinoderms, a relatively unexplored and promising applied approach which offers the unique chance to study physiological developmental processes in adult animals. The selected test species is the crinoid Antedon mediterranea, which represents a valuable experimental model for investigation into the regenerative process from the macroscopic to the molecular level. The present study employs an integrated approach which combines exposure experiments, chemical analysis and biological analysis utilizing classical methods of light (LM) and electron (TEM and SEM) microscopy and immunocytochemistry. The experiments were carried out on experimentally induced arm regenerations in controlled conditions with exposure concentrations comparable to those of moderately polluted coastal zones in order to reproduce common conditions of exposure to environmental contaminants. The results of the exposure tests were analysed in terms of effects at the whole organism, at the tissue and cellular level, and possible sites of action of EDs. Our results show that prolonged exposure to these compounds significantly affects the regenerative mechanisms by inducing appreciable anomalies in terms of regeneration times, overall growth, general

  19. Mathematical Model of Natural Gas Desulfurization Based on Membrane Absorption

    Institute of Scientific and Technical Information of China (English)

    Wang Shuli; Ma Jun; Wang Ganyu; Zhou Heng

    2014-01-01

    Models of mass transfer kinetics combined with mass transfer differential equation and mass transfer resistance equation were established on the basis of double-iflm theory. Mass transfer process of H2S absorption by means of polypro-pylene hydrophobic microporous hollow ifber membrane contactor was simulated using MDEA (N-methyldiethanolamine) as the absorption liquid and corresponding experiments of natural gas desulfurization were performed. The simulation re-sults indicated that the removal rate of hydrogen sulifde showed positive dependence on the absorption liquid concentration and gas pressure. However, the desulfurization rate showed negative dependence on gas lfow. The simulated values were in good agreement with the experimental results. The in-tube concentration of hydrogen sulifde at the same point increased with increase in the gas velocity. Axial concentration of hydrogen sulifde decreased rapidly at the beginning, and the de-crease saw a slowdown during the latter half period. Hydrogen sulifde concentration dropped quickly in the radial direction, and the reduction in the radial direction was weakened with the increase of axial length due to the gradual reduction of hy-drogen sulifde concentration along the tube. The desulfurization rate under given operating conditions can be predicted by this model, and the theoretical basis for membrane module design can also be provided.

  20. Modeling impermeable membranes as acoustic filters for biomedical applications.

    Science.gov (United States)

    Goenaga, Miguel A; Juan, Eduardo J

    2006-01-01

    The main purpose of this research project was to explore a mathematical expression that could be used by medical device designers to appropriately select impermeable membranes to isolate acoustic transducers from water, dust, earwax or other foreign material. The sound transmission properties of various types of impermeable membranes were analytically evaluated and compared to experimental measurements. Computer simulations were also performed to estimate the effects of three key membrane parameters: thickness (h), density (p) and sound speed (c), on the membrane's overall acoustic response. Results indicated that membrane thickness and density affect sound transmission the most. Membrane sound speed had minimal effect on sound transmission.

  1. Computer-aided modeling framework – a generic modeling template for catalytic membrane fixed bed reactors

    DEFF Research Database (Denmark)

    Fedorova, Marina; Sin, Gürkan; Gani, Rafiqul

    2013-01-01

    This work focuses on development of computer-aided modeling framework. The framework is a knowledge-based system that is built on a generic modeling language and structured based on workflows for different general modeling tasks. The overall objective of this work is to support the model developers...... and users to generate and test models systematically, efficiently and reliably. In this way, development of products and processes can be faster, cheaper and very efficient. In this contribution, as part of the framework a generic modeling template for the systematic derivation of problem specific catalytic...... membrane fixed bed models is developed. The application of the modeling template is highlighted with a case study related to the modeling of a catalytic membrane reactor coupling dehydrogenation of ethylbenzene with hydrogenation of nitrobenzene....

  2. Pervaporation : membranes and models for the dehydration of ethanol

    NARCIS (Netherlands)

    Spitzen, Johannes Wilhelmus Franciscus

    1988-01-01

    In this thesis the dehydration of ethanol/water mixtures by pervaporation using homogeneous membranes is studied. Both the general transport mechanism as well as the development of highly selective membranes for ethanol/water separation are investigated.

  3. Disruption of an EAAT-Mediated Chloride Channel in a Drosophila Model of Ataxia.

    Science.gov (United States)

    Parinejad, Neda; Peco, Emilie; Ferreira, Tiago; Stacey, Stephanie M; van Meyel, Donald J

    2016-07-20

    Patients with Type 6 episodic ataxia (EA6) have mutations of the excitatory amino acid transporter EAAT1 (also known as GLAST), but the underlying pathophysiological mechanism for EA6 is not known. EAAT1 is a glutamate transporter expressed by astrocytes and other glia, and it serves dual function as an anion channel. One EA6-associated mutation is a P>R substitution (EAAT1(P>R)) that in transfected cells has a reduced rate of glutamate transport and an abnormal anion conductance. We expressed this EAAT1(P>R) mutation in glial cells of Drosophila larvae and found that these larvae exhibit episodic paralysis, and their astrocytes poorly infiltrate the CNS neuropil. These defects are not seen in Eaat1-null mutants, and so they cannot be explained by loss of glutamate transport. We instead explored the role of the abnormal anion conductance of the EAAT1(P>R) mutation, and to do this we expressed chloride cotransporters in astrocytes. Like the EAAT1(P>R) mutation, the chloride-extruding K(+)-Cl(-) cotransporter KccB also caused astroglial malformation and paralysis, supporting the idea that the EAAT1(P>R) mutation causes abnormal chloride flow from CNS glia. In contrast, the Na(+)-K(+)-Cl(-) cotransporter Ncc69, which normally allows chloride into cells, rescued the effects of the EAAT1(P>R) mutation. Together, our results indicate that the cytopathology and episodic paralysis in our Drosophila EA6 model stem from a gain-of-function chloride channelopathy of glial cells. We studied a mutation found in episodic ataxia of the dual-function glutamate transporter/anion channel EAAT1, and discovered it caused malformation of astrocytes and episodes of paralysis in a Drosophila model. These effects were mimicked by a chloride-extruding cotransporter and were rescued by restoring chloride homeostasis to glial cells with a Na(+)-K(+)-2Cl(-) cotransporter. Our findings reveal a new pathophysiological mechanism in which astrocyte cytopathology and neural circuit dysfunction

  4. Model Checking the Biological Model of Membrane Computing with Probabilistic Symbolic Model Checker by Using Two Biological Systems

    Directory of Open Access Journals (Sweden)

    Ravie c. Muniyandi

    2010-01-01

    Full Text Available Problem statement: Membrane computing formalism has provided better modeling capabilities for biological systems in comparison to conventional mathematical models. Model checking could be used to reason about the biological system in detail and with precision by verifying formally whether membrane computing model meets the properties of the system. Approach: This study was carried to investigate the preservation of properties of two biological systems that had been modeled and simulated in membrane computing by a method of model checking using PRISM. The two biological systems were prey-predator population and signal processing in the legend-receptor networks of protein TGF-ß. Results: The model checking of membrane computing model of the biological systems with five different properties showed that the properties of the biological systems could be preserved in the membrane computing model. Conclusion: Membrane computing model not only provides a better approach in representing and simulating a biological system but also able to sustain the basic properties of the system.

  5. Testing the effects of safety climate and disruptive children behavior on school bus drivers performance: A multilevel model.

    Science.gov (United States)

    Zohar, Dov; Lee, Jin

    2016-10-01

    The study was designed to test a multilevel path model whose variables exert opposing effects on school bus drivers' performance. Whereas departmental safety climate was expected to improve driving safety, the opposite was true for in-vehicle disruptive children behavior. The driving safety path in this model consists of increasing risk-taking practices starting with safety shortcuts leading to rule violations and to near-miss events. The study used a sample of 474 school bus drivers in rural areas, driving children to school and school-related activities. Newly developed scales for measuring predictor, mediator and outcome variables were validated with video data taken from inner and outer cameras, which were installed in 29 buses. Results partially supported the model by indicating that group-level safety climate and individual-level children distraction exerted opposite effects on the driving safety path. Furthermore, as hypothesized, children disruption moderated the strength of the safety rule violation-near miss relationship, resulting in greater strength under high disruptiveness. At the same time, the hypothesized interaction between the two predictor variables was not supported. Theoretical and practical implications for studying safety climate in general and distracted driving in particular for professional drivers are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. The origin of gender dimorphism in animal-dispersed plants: disruptive selection in a model of social evolution.

    Science.gov (United States)

    Biernaskie, Jay M

    2010-06-01

    Dioecy (separate sexes) in plants is associated with animal fruit dispersal, but hypotheses for a role of dispersal in the origin of gender dimorphism have received little support. Here, I present a patch-structured model to explore the conditions that favor dimorphism when dispersal is coupled with sex allocation. The model shows that if the proportion of fruits dispersed from a cosexual plant increases with its allocation to fruits (causing accelerating fitness returns from dispersed fruits), disruptive selection can arise when the cost of dispersal is minimal and the correlation among patchmates (i.e., relatedness) is high. In reality, however, the proportion of fruits dispersed from a plant's patch may decline with further allocation to fruits. Even in this case, novel contexts that lead to disruptive selection on sex allocation are discovered, occurring when dispersal costs are high and relatedness is low, which causes accelerating returns from nondispersed fruits. Hence, surprisingly, gender dimorphism can evolve because female specialists are better able to escape local competition or to succeed in it. Building on the few existing models of disruptive selection on social traits, the mechanisms here show that selection for relaxed local competition (cooperation) can sometimes facilitate diversification and sometimes prevent it.

  7. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes.

    Science.gov (United States)

    Mason, R Preston; Jacob, Robert F; Shrivastava, Sandeep; Sherratt, Samuel C R; Chattopadhyay, Amitabha

    2016-12-01

    Cholesterol crystalline domains characterize atherosclerotic membranes, altering vascular signaling and function. Omega-3 fatty acids reduce membrane lipid peroxidation and subsequent cholesterol domain formation. We evaluated non-peroxidation-mediated effects of eicosapentaenoic acid (EPA), other TG-lowering agents, docosahexaenoic acid (DHA), and other long-chain fatty acids on membrane fluidity, bilayer width, and cholesterol domain formation in model membranes. In membranes prepared at 1.5:1 cholesterol-to-phospholipid (C/P) mole ratio (creating pre-existing domains), EPA, glycyrrhizin, arachidonic acid, and alpha linolenic acid promoted the greatest reductions in cholesterol domains (by 65.5%, 54.9%, 46.8%, and 45.2%, respectively) compared to controls; other treatments had modest effects. EPA effects on cholesterol domain formation were dose-dependent. In membranes with 1:1 C/P (predisposing domain formation), DHA, but not EPA, dose-dependently increased membrane fluidity. DHA also induced cholesterol domain formation without affecting temperature-induced changes in-bilayer unit cell periodicity relative to controls (d-space; 57Å-55Å over 15-30°C). Together, these data suggest simultaneous formation of distinct cholesterol-rich ordered domains and cholesterol-poor disordered domains in the presence of DHA. By contrast, EPA had no effect on cholesterol domain formation and produced larger d-space values relative to controls (60Å-57Å; pmembrane bilayer width, membrane fluidity, and cholesterol crystalline domain formation; suggesting omega-3 fatty acids with differing chain length or unsaturation may differentially influence membrane lipid dynamics and structural organization as a result of distinct phospholipid/sterol interactions.

  8. Development of a Computational Model for Female Fathead Minnows exposed to Two Endocrine Disrupting Chemicals

    Science.gov (United States)

    Endocrine disrupting chemicals (e.g., estrogens and androgens) are known to affect reproductive functions in fish. A synthetic estrogen used in birth control pills, 17á-ethynylestradiol (EE2), is discharged from wastewater treatment plants into water bodies throughout the United ...

  9. Development of a Computational Model for Female Fathead Minnows exposed to Two Endocrine Disrupting Chemicals

    Science.gov (United States)

    Endocrine disrupting chemicals (e.g., estrogens and androgens) are known to affect reproductive functions in fish. A synthetic estrogen used in birth control pills, 17á-ethynylestradiol (EE2), is discharged from wastewater treatment plants into water bodies throughout the United ...

  10. A Developmental Model of Maternal and Child Contributions to Disruptive Conduct: The First Six Years

    Science.gov (United States)

    Kochanska, Grazyna; Barry, Robin A.; Aksan, Nazan; Boldt, Lea J.

    2008-01-01

    Background: The parent-child relationship is considered important for children's future conscience, and conscience is seen as protecting them from disruptive behavior problems, but specific mechanisms of this developmental process are rarely studied. Methods: This multi-trait multi-method study examined, in a longitudinal design, paths linking…

  11. Handling Disruptions in Supply Chains: An Integrated Framework and an Agent-based Model

    NARCIS (Netherlands)

    Behdani, B.

    2013-01-01

    The degree of supply chain risk faced by many companies has risen dramatically and the impact of disruptions can cascade easily across companies’ and countries’ borders. To handle this increased vulnerability, systematic approaches and decision making tools are needed to provide support in managing

  12. Derivation of adsorption parameters for nanofiltration membranes using a 1-pK Basic Stern model

    NARCIS (Netherlands)

    de Lint, W.B.S.; Benes, Nieck Edwin; Higler, A.P.; Verweij, H.

    2002-01-01

    The ion retention and flux of nanofiltration (NF) membranes are to a large extent determined by the membrane surface charge. This surface charge is in turn strongly influenced by adsorption of ions from the solution onto the membrane material. A 1-pK adsorption model with a Basic Stern electrostatic

  13. Polymer Electrolyte Membrane (PEM) Fuel Cells Modeling and Optimization

    Science.gov (United States)

    Zhang, Zhuqian; Wang, Xia; Shi, Zhongying; Zhang, Xinxin; Yu, Fan

    2006-11-01

    Performance of polymer electrolyte membrane (PEM) fuel cells is dependent on operating parameters and designing parameters. Operating parameters mainly include temperature, pressure, humidity and the flow rate of the inlet reactants. Designing parameters include reactants distributor patterns and dimensions, electrodes dimensions, and electrodes properties such as porosity, permeability and so on. This work aims to investigate the effects of various designing parameters on the performance of PEM fuel cells, and the optimum values will be determined under a given operating condition.A three-dimensional steady-state electrochemical mathematical model was established where the mass, fluid and thermal transport processes are considered as well as the electrochemical reaction. A Powell multivariable optimization algorithm will be applied to investigate the optimum values of designing parameters. The objective function is defined as the maximum potential of the electrolyte fluid phase at the membrane/cathode interface at a typical value of the cell voltage. The robustness of the optimum design of the fuel cell under different cell potentials will be investigated using a statistical sensitivity analysis. By comparing with the reference case, the results obtained here provide useful tools for a better design of fuel cells.

  14. Modelling and Fabrication of Micro-SOFC Membrane Structure

    Directory of Open Access Journals (Sweden)

    Brigita ABAKEVIČIENĖ

    2014-06-01

    Full Text Available Fabrication process of micro-SOFC membrane structure using the bulk micromachining of silicon technique with SiO2 and Si3N4 sacrificial layers is presented in this study. The process involves back side photolithography, magnetron sputtering of platinum thin films, thermal evaporation of YSZ electrolyte, deep reactive ion etching of silicon, and, finally, release of free-standing membrane using CF4/O2 plasma etching.X-ray analysis shows the cubic phase of YSZ electrolyte and platinum electrodes. Modelling of normal stress distribution in the micro-SOFC structure with the Si3N4 sacrificial layer shows that at high temperatures the substrate expands less than the coating, causing tensile stresses in the substrate area next to the coating and compressive stresses in the coating, as the substrate material has a lower coefficient of thermal expansion than the layered Pt/YSZ/Pt coating. DOI: http://dx.doi.org/10.5755/j01.ms.20.2.5585

  15. Modelling and Fabrication of Micro-SOFC Membrane Structure

    Directory of Open Access Journals (Sweden)

    Brigita ABAKEVIČIENĖ

    2014-06-01

    Full Text Available Fabrication process of micro-SOFC membrane structure using the bulk micromachining of silicon technique with SiO2 and Si3N4 sacrificial layers is presented in this study. The process involves back side photolithography, magnetron sputtering of platinum thin films, thermal evaporation of YSZ electrolyte, deep reactive ion etching of silicon, and, finally, release of free-standing membrane using CF4/O2 plasma etching.X-ray analysis shows the cubic phase of YSZ electrolyte and platinum electrodes. Modelling of normal stress distribution in the micro-SOFC structure with the Si3N4 sacrificial layer shows that at high temperatures the substrate expands less than the coating, causing tensile stresses in the substrate area next to the coating and compressive stresses in the coating, as the substrate material has a lower coefficient of thermal expansion than the layered Pt/YSZ/Pt coating. DOI: http://dx.doi.org/10.5755/j01.ms.20.2.5585

  16. Membrane trafficking in the yeast Saccharomyces cerevisiae model.

    Science.gov (United States)

    Feyder, Serge; De Craene, Johan-Owen; Bär, Séverine; Bertazzi, Dimitri L; Friant, Sylvie

    2015-01-09

    The yeast Saccharomyces cerevisiae is one of the best characterized eukaryotic models. The secretory pathway was the first trafficking pathway clearly understood mainly thanks to the work done in the laboratory of Randy Schekman in the 1980s. They have isolated yeast sec mutants unable to secrete an extracellular enzyme and these SEC genes were identified as encoding key effectors of the secretory machinery. For this work, the 2013 Nobel Prize in Physiology and Medicine has been awarded to Randy Schekman; the prize is shared with James Rothman and Thomas Südhof. Here, we present the different trafficking pathways of yeast S. cerevisiae. At the Golgi apparatus newly synthesized proteins are sorted between those transported to the plasma membrane (PM), or the external medium, via the exocytosis or secretory pathway (SEC), and those targeted to the vacuole either through endosomes (vacuolar protein sorting or VPS pathway) or directly (alkaline phosphatase or ALP pathway). Plasma membrane proteins can be internalized by endocytosis (END) and transported to endosomes where they are sorted between those targeted for vacuolar degradation and those redirected to the Golgi (recycling or RCY pathway). Studies in yeast S. cerevisiae allowed the identification of most of the known effectors, protein complexes, and trafficking pathways in eukaryotic cells, and most of them are conserved among eukaryotes.

  17. Membrane Trafficking in the Yeast Saccharomyces cerevisiae Model

    Directory of Open Access Journals (Sweden)

    Serge Feyder

    2015-01-01

    Full Text Available The yeast Saccharomyces cerevisiae is one of the best characterized eukaryotic models. The secretory pathway was the first trafficking pathway clearly understood mainly thanks to the work done in the laboratory of Randy Schekman in the 1980s. They have isolated yeast sec mutants unable to secrete an extracellular enzyme and these SEC genes were identified as encoding key effectors of the secretory machinery. For this work, the 2013 Nobel Prize in Physiology and Medicine has been awarded to Randy Schekman; the prize is shared with James Rothman and Thomas Südhof. Here, we present the different trafficking pathways of yeast S. cerevisiae. At the Golgi apparatus newly synthesized proteins are sorted between those transported to the plasma membrane (PM, or the external medium, via the exocytosis or secretory pathway (SEC, and those targeted to the vacuole either through endosomes (vacuolar protein sorting or VPS pathway or directly (alkaline phosphatase or ALP pathway. Plasma membrane proteins can be internalized by endocytosis (END and transported to endosomes where they are sorted between those targeted for vacuolar degradation and those redirected to the Golgi (recycling or RCY pathway. Studies in yeast S. cerevisiae allowed the identification of most of the known effectors, protein complexes, and trafficking pathways in eukaryotic cells, and most of them are conserved among eukaryotes.

  18. Acidic phospholipid bicelles: a versatile model membrane system.

    Science.gov (United States)

    Struppe, J; Whiles, J A; Vold, R R

    2000-01-01

    With the aim of establishing acidic bicellar solutions as a useful membrane model system, we have used deuterium NMR spectroscopy to investigate the properties of dimyristoyl/dihexanoylphosphatidylcholine (DMPC/DHPC) bicelles containing 25% (w/w in H(2)O) of either dimyristoylphosphatidylserine (DMPS) or dimyristoylphosphatidylglycerol (DMPG). The addition of the acidic lipid component to this lyotropic liquid crystalline system reduces its range of stability because of poor miscibility of the two dimyristoylated phospholipids. Compared to the neutral bicelles, which are stable at pH 4 to pH 7, acidic bicelles are stable only from pH 5.5 to pH 7. Solid-state deuterium NMR analysis of d(54)-DMPC showed similar ordering in neutral and acidic bicelles. Fully deuterated DMPS or DMPG is ordered in a way similar to that of DMPC. Study of the binding of the myristoylated N-terminal 14-residue peptide mu-GSSKSKPKDPSQRR from pp60(nu-src) to both neutral and acidic bicelles shows the utility of these novel membrane mimetics. PMID:10620292

  19. Defective membrane remodeling in neuromuscular diseases: insights from animal models.

    Directory of Open Access Journals (Sweden)

    Belinda S Cowling

    Full Text Available Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1, and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1 a common molecular pathway underlying these different neuromuscular diseases, and (2 tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.

  20. Temperature Driven Annealing of Perforations in Bicellar Model Membranes

    Energy Technology Data Exchange (ETDEWEB)

    Nieh, Mu-Ping [University of Connecticut, Storrs; Raghunathan, V.A. [Raman Research Institute, India; Pabst, Georg [Austrian Academy of Sciences, Graz, Austria; Harroun, Thad [Brock University, St. Catharines, ON, Canada; Nagashima, K [University of Toronto, Mississauga, ON, Canada; Morales, H [University of Toronto, Mississauga, ON, Canada; Katsaras, John [ORNL; Macdonald, P [University of Toronto, Mississauga, ON, Canada

    2011-01-01

    Bicellar model membranes composed of 1,2-dimyristoylphosphatidylcholine (DMPC) and 1,2-dihexanoylphosphatidylcholine (DHPC), with a DMPC/DHPC molar ratio of 5, and doped with the negatively charged lipid 1,2-dimyristoylphosphatidylglycerol (DMPG), at DMPG/DMPC molar ratios of 0.02 or 0.1, were examined using small angle neutron scattering (SANS), {sup 31}P NMR, and {sup 1}H pulsed field gradient (PFG) diffusion NMR with the goal of understanding temperature effects on the DHPC-dependent perforations in these self-assembled membrane mimetics. Over the temperature range studied via SANS (300-330 K), these bicellar lipid mixtures exhibited a well-ordered lamellar phase. The interlamellar spacing d increased with increasing temperature, in direct contrast to the decrease in d observed upon increasing temperature with otherwise identical lipid mixtures lacking DHPC. {sup 31}P NMR measurements on magnetically aligned bicellar mixtures of identical composition indicated a progressive migration of DHPC from regions of high curvature into planar regions with increasing temperature, and in accord with the 'mixed bicelle model' (Triba, M. N.; Warschawski, D. E.; Devaux, P. E. Biophys. J.2005, 88, 1887-1901). Parallel PFG diffusion NMR measurements of transbilayer water diffusion, where the observed diffusion is dependent on the fractional surface area of lamellar perforations, showed that transbilayer water diffusion decreased with increasing temperature. A model is proposed consistent with the SANS, {sup 31}P NMR, and PFG diffusion NMR data, wherein increasing temperature drives the progressive migration of DHPC out of high-curvature regions, consequently decreasing the fractional volume of lamellar perforations, so that water occupying these perforations redistributes into the interlamellar volume, thereby increasing the interlamellar spacing.

  1. Temperature driven annealing of perforations in bicellar model membranes.

    Science.gov (United States)

    Nieh, Mu-Ping; Raghunathan, V A; Pabst, Georg; Harroun, Thad; Nagashima, Kazuomi; Morales, Hannah; Katsaras, John; Macdonald, Peter

    2011-04-19

    Bicellar model membranes composed of 1,2-dimyristoylphosphatidylcholine (DMPC) and 1,2-dihexanoylphosphatidylcholine (DHPC), with a DMPC/DHPC molar ratio of 5, and doped with the negatively charged lipid 1,2-dimyristoylphosphatidylglycerol (DMPG), at DMPG/DMPC molar ratios of 0.02 or 0.1, were examined using small angle neutron scattering (SANS), (31)P NMR, and (1)H pulsed field gradient (PFG) diffusion NMR with the goal of understanding temperature effects on the DHPC-dependent perforations in these self-assembled membrane mimetics. Over the temperature range studied via SANS (300-330 K), these bicellar lipid mixtures exhibited a well-ordered lamellar phase. The interlamellar spacing d increased with increasing temperature, in direct contrast to the decrease in d observed upon increasing temperature with otherwise identical lipid mixtures lacking DHPC. (31)P NMR measurements on magnetically aligned bicellar mixtures of identical composition indicated a progressive migration of DHPC from regions of high curvature into planar regions with increasing temperature, and in accord with the "mixed bicelle model" (Triba, M. N.; Warschawski, D. E.; Devaux, P. E. Biophys. J.2005, 88, 1887-1901). Parallel PFG diffusion NMR measurements of transbilayer water diffusion, where the observed diffusion is dependent on the fractional surface area of lamellar perforations, showed that transbilayer water diffusion decreased with increasing temperature. A model is proposed consistent with the SANS, (31)P NMR, and PFG diffusion NMR data, wherein increasing temperature drives the progressive migration of DHPC out of high-curvature regions, consequently decreasing the fractional volume of lamellar perforations, so that water occupying these perforations redistributes into the interlamellar volume, thereby increasing the interlamellar spacing.

  2. Multiscale modeling of droplet interface bilayer membrane networks.

    Science.gov (United States)

    Freeman, Eric C; Farimani, Amir B; Aluru, Narayana R; Philen, Michael K

    2015-11-01

    Droplet interface bilayer (DIB) networks are considered for the development of stimuli-responsive membrane-based materials inspired by cellular mechanics. These DIB networks are often modeled as combinations of electrical circuit analogues, creating complex networks of capacitors and resistors that mimic the biomolecular structures. These empirical models are capable of replicating data from electrophysiology experiments, but these models do not accurately capture the underlying physical phenomena and consequently do not allow for simulations of material functionalities beyond the voltage-clamp or current-clamp conditions. The work presented here provides a more robust description of DIB network behavior through the development of a hierarchical multiscale model, recognizing that the macroscopic network properties are functions of their underlying molecular structure. The result of this research is a modeling methodology based on controlled exchanges across the interfaces of neighboring droplets. This methodology is validated against experimental data, and an extension case is provided to demonstrate possible future applications of droplet interface bilayer networks.

  3. Characterisation of the effects of caffeine on sleep in the rat: a potential model of sleep disruption.

    Science.gov (United States)

    Paterson, L M; Wilson, S J; Nutt, D J; Hutson, P H; Ivarsson, M

    2009-07-01

    Caffeine is known to disrupt sleep and its administration to human subjects has been used to model sleep disruption. We previously showed that its effects on sleep onset latency are comparable between rats and humans. This study evaluated the potential use of caffeine as a model of sleep disruption in the rat, by assessing its effects on sleep architecture and electroencephalogram (EEG) frequency spectrum, and using sleep-promoting drugs to reverse these effects. Rats were implanted with radiotelemetry devices for body temperature, EEG, electromyogram and locomotor activity. Following recovery, animals were dosed with caffeine (10 mg/kg) alone or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg). Sleep was scored for the subsequent 12 h using automated analysis software. Caffeine dose-dependently disrupted sleep: it increased WAKE time, decreased NREM (non-REM) sleep time and NREM bout duration (but not bout number), and decreased delta activity in NREM sleep. It also dose-dependently increased locomotor activity and body temperature. When given alone, zolpidem suppressed REM whilst trazodone increased NREM sleep time at the expense of WAKE, increased NREM bout duration, increased delta activity in NREM sleep and reduced body temperature. In combination, zolpidem attenuated caffeine's effects on WAKE, whilst trazodone attenuated its effects on NREM sleep, NREM bout duration, delta activity, body temperature and locomotor activity. Caffeine administration produced many of the signs of insomnia that were improved by two of its most successful current treatments. This model may therefore be useful in the study of new drugs for the treatment of sleep disturbance.

  4. Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer.

    Science.gov (United States)

    Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J; Zhao, Mei; Pickering, Curtis R; Zhou, Ge; Sandulache, Vlad C; Wheeler, David A; Gibbs, Richard A; Caulin, Carlos; Myers, Jeffrey N

    2011-11-01

    To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings. Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared. These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations. HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. ©2011 AACR

  5. Advanced Wastewater Treatment Engineering—Investigating Membrane Fouling in both Rotational and Static Membrane Bioreactor Systems Using Empirical Modelling

    Directory of Open Access Journals (Sweden)

    Parneet Paul

    2016-01-01

    Full Text Available Advanced wastewater treatment using membranes are popular environmental system processes since they allow reuse and recycling. However, fouling is a key limiting factor and so proprietary systems such as Avanti’s RPU-185 Flexidisks membrane bioreactor (MBR use novel rotating membranes to assist in ameliorating it. In earlier research, this rotating process was studied by creating a simulation model based on first principles and traditional fouling mechanisms. In order to directly compare the potential benefits of this rotational system, this follow-up study was carried out using Avanti’s newly developed static (non-rotating Flexidisks MBR system. The results from operating the static pilot unit were simulated and modelled using the rotational fouling model developed earlier however with rotational switching functions turned off and rotational parameters set to a static mode. The study concluded that a rotating MBR system could increase flux throughput when compared against a similar static system. It is thought that although the slowly rotating spindle induces a weak crossflow shear, it is still able to even out cake build up across the membrane surface, thus reducing the likelihood of localised critical flux being exceeded at the micro level and lessening the potential of rapid trans-membrane pressure increases at the macro level.

  6. Advanced Wastewater Treatment Engineering-Investigating Membrane Fouling in both Rotational and Static Membrane Bioreactor Systems Using Empirical Modelling.

    Science.gov (United States)

    Paul, Parneet; Jones, Franck Anderson

    2016-01-05

    Advanced wastewater treatment using membranes are popular environmental system processes since they allow reuse and recycling. However, fouling is a key limiting factor and so proprietary systems such as Avanti's RPU-185 Flexidisks membrane bioreactor (MBR) use novel rotating membranes to assist in ameliorating it. In earlier research, this rotating process was studied by creating a simulation model based on first principles and traditional fouling mechanisms. In order to directly compare the potential benefits of this rotational system, this follow-up study was carried out using Avanti's newly developed static (non-rotating) Flexidisks MBR system. The results from operating the static pilot unit were simulated and modelled using the rotational fouling model developed earlier however with rotational switching functions turned off and rotational parameters set to a static mode. The study concluded that a rotating MBR system could increase flux throughput when compared against a similar static system. It is thought that although the slowly rotating spindle induces a weak crossflow shear, it is still able to even out cake build up across the membrane surface, thus reducing the likelihood of localised critical flux being exceeded at the micro level and lessening the potential of rapid trans-membrane pressure increases at the macro level.

  7. Bilayer Thickness Mismatch Controls Domain Size in Model Membranes

    Energy Technology Data Exchange (ETDEWEB)

    Heberle, Frederick A [ORNL; Petruzielo, Robin S [ORNL; Pan, Jianjun [ORNL; Drazba, Paul [ORNL; Kucerka, Norbert [Canadian Neutron Beam Centre and Comelius University (Slovakia); Feigenson, Gerald [Cornell University; Katsaras, John [ORNL

    2013-01-01

    The observation of lateral phase separation in lipid bilayers has received considerable attention, especially in connection to lipid raft phenomena in cells. It is widely accepted that rafts play a central role in cellular processes, notably signal transduction. While micrometer-sized domains are observed with some model membrane mixtures, rafts much smaller than 100 nm beyond the reach of optical microscopy are now thought to exist, both in vitro and in vivo. We have used small-angle neutron scattering, a probe free technique, to measure the size of nanoscopic membrane domains in unilamellar vesicles with unprecedented accuracy. These experiments were performed using a four-component model system containing fixed proportions of cholesterol and the saturated phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), mixed with varying amounts of the unsaturated phospholipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dioleoylsn- glycero-3-phosphocholine (DOPC). We find that liquid domain size increases with the extent of acyl chain unsaturation (DOPC:POPC ratio). Furthermore, we find a direct correlation between domain size and the mismatch in bilayer thickness of the coexisting liquid-ordered and liquid-disordered phases, suggesting a dominant role for line tension in controlling domain size. While this result is expected from line tension theories, we provide the first experimental verification in free-floating bilayers. Importantly, we also find that changes in bilayer thickness, which accompany changes in the degree of lipid chain unsaturation, are entirely confined to the disordered phase. Together, these results suggest how the size of functional domains in homeothermic cells may be regulated through changes in lipid composition.

  8. Network modeling of membrane-based artificial cellular systems

    Science.gov (United States)

    Freeman, Eric C.; Philen, Michael K.; Leo, Donald J.

    2013-04-01

    Computational models are derived for predicting the behavior of artificial cellular networks for engineering applications. The systems simulated involve the use of a biomolecular unit cell, a multiphase material that incorporates a lipid bilayer between two hydrophilic compartments. These unit cells may be considered building blocks that enable the fabrication of complex electrochemical networks. These networks can incorporate a variety of stimuli-responsive biomolecules to enable a diverse range of multifunctional behavior. Through the collective properties of these biomolecules, the system demonstrates abilities that recreate natural cellular phenomena such as mechanotransduction, optoelectronic response, and response to chemical gradients. A crucial step to increase the utility of these biomolecular networks is to develop mathematical models of their stimuli-responsive behavior. While models have been constructed deriving from the classical Hodgkin-Huxley model focusing on describing the system as a combination of traditional electrical components (capacitors and resistors), these electrical elements do not sufficiently describe the phenomena seen in experiment as they are not linked to the molecular scale processes. From this realization an advanced model is proposed that links the traditional unit cell parameters such as conductance and capacitance to the molecular structure of the system. Rather than approaching the membrane as an isolated parallel plate capacitor, the model seeks to link the electrical properties to the underlying chemical characteristics. This model is then applied towards experimental cases in order that a more complete picture of the underlying phenomena responsible for the desired sensing mechanisms may be constructed. In this way the stimuli-responsive characteristics may be understood and optimized.

  9. A new method for modeling rough membrane surface and calculation of interfacial interactions.

    Science.gov (United States)

    Zhao, Leihong; Zhang, Meijia; He, Yiming; Chen, Jianrong; Hong, Huachang; Liao, Bao-Qiang; Lin, Hongjun

    2016-01-01

    Membrane fouling control necessitates the establishment of an effective method to assess interfacial interactions between foulants and rough surface membrane. This study proposed a new method which includes a rigorous mathematical equation for modeling membrane surface morphology, and combination of surface element integration (SEI) method and the composite Simpson's approach for assessment of interfacial interactions. The new method provides a complete solution to quantitatively calculate interfacial interactions between foulants and rough surface membrane. Application of this method in a membrane bioreactor (MBR) showed that, high calculation accuracy could be achieved by setting high segment number, and moreover, the strength of three energy components and energy barrier was remarkably impaired by the existence of roughness on the membrane surface, indicating that membrane surface morphology exerted profound effects on membrane fouling in the MBR. Good agreement between calculation prediction and fouling phenomena was found, suggesting the feasibility of this method.

  10. Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ghribi Othman

    2008-04-01

    Full Text Available Abstract High levels of serum cholesterol and disruptions of the blood brain barrier (BBB have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease.

  11. Random walk model of subdiffusion in a system with a thin membrane.

    Science.gov (United States)

    Kosztołowicz, Tadeusz

    2015-02-01

    We consider in this paper subdiffusion in a system with a thin membrane. The subdiffusion parameters are the same in both parts of the system separated by the membrane. Using the random walk model with discrete time and space variables the probabilities (Green's functions) P(x,t) describing a particle's random walk are found. The membrane, which can be asymmetrical, is characterized by the two probabilities of stopping a random walker by the membrane when it tries to pass through the membrane in both opposite directions. Green's functions are transformed to the system in which the variables are continuous, and then the membrane permeability coefficients are given by special formulas which involve the probabilities mentioned above. From the obtained Green's functions, we derive boundary conditions at the membrane. One of the conditions demands the continuity of a flux at the membrane, but the other one is rather unexpected and contains the Riemann-Liouville fractional time derivative P(x(N)(-),t)=λ(1)P(x(N)(+),t)+λ(2)∂(α/2)P(x(N)(+),t)/∂t(α/2), where λ(1),λ(2) depending on membrane permeability coefficients (λ(1)=1 for a symmetrical membrane), α is a subdiffusion parameter, and x(N) is the position of the membrane. This boundary condition shows that the additional "memory effect," represented by the fractional derivative, is created by the membrane. This effect is also created by the membrane for a normal diffusion case in which α=1.

  12. Experimental and Modeling Studies of the Methane Steam Reforming Reaction at High Pressure in a Ceramic Membrane Reactor

    OpenAIRE

    Hacarlioglu, Pelin

    2007-01-01

    This dissertation describes the preparation of a novel inorganic membrane for hydrogen permeation and its application in a membrane reactor for the study of the methane steam reforming reaction. The investigations include both experimental studies of the membrane permeation mechanism and theoretical modeling of mass transfer through the membrane and simulation of the membrane reactor with 1-D and 2-D models. A hydrothermally stable and hydrogen selective membrane composed of silica and a...

  13. The Fluid-Mosaic Model of Membrane Structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years.

    Science.gov (United States)

    Nicolson, Garth L

    2014-06-01

    In 1972 the Fluid-Mosaic Membrane Model of membrane structure was proposed based on thermodynamic principals of organization of membrane lipids and proteins and available evidence of asymmetry and lateral mobility within the membrane matrix [S. J. Singer and G. L. Nicolson, Science 175 (1972) 720-731]. After over 40years, this basic model of the cell membrane remains relevant for describing the basic nano-structures of a variety of intracellular and cellular membranes of plant and animal cells and lower forms of life. In the intervening years, however, new information has documented the importance and roles of specialized membrane domains, such as lipid rafts and protein/glycoprotein complexes, in describing the macrostructure, dynamics and functions of cellular membranes as well as the roles of membrane-associated cytoskeletal fences and extracellular matrix structures in limiting the lateral diffusion and range of motion of membrane components. These newer data build on the foundation of the original model and add new layers of complexity and hierarchy, but the concepts described in the original model are still applicable today. In updated versions of the model more emphasis has been placed on the mosaic nature of the macrostructure of cellular membranes where many protein and lipid components are limited in their rotational and lateral motilities in the membrane plane, especially in their natural states where lipid-lipid, protein-protein and lipid-protein interactions as well as cell-matrix, cell-cell and intracellular membrane-associated protein and cytoskeletal interactions are important in restraining the lateral motility and range of motion of particular membrane components. The formation of specialized membrane domains and the presence of tightly packed integral membrane protein complexes due to membrane-associated fences, fenceposts and other structures are considered very important in describing membrane dynamics and architecture. These structures along

  14. Petri Net-Based Model of Helicobacter pylori Mediated Disruption of Tight Junction Proteins in Stomach Lining during Gastric Carcinoma

    Directory of Open Access Journals (Sweden)

    Anam Naz

    2017-09-01

    Full Text Available Tight junctions help prevent the passage of digestive enzymes and microorganisms through the space between adjacent epithelial cells lining. However, Helicobacter pylori encoded virulence factors negatively regulate these tight junctions and contribute to dysfunction of gastric mucosa. Here, we have predicted the regulation of important tight junction proteins, such as Zonula occludens-1, Claudin-2 and Connexin32 in the presence of pathogenic proteins. Molecular events such as post translational modifications and crosstalk between phosphorylation, O-glycosylation, palmitoylation and methylation are explored which may compromise the integrity of these tight junction proteins. Furthermore, the signaling pathways disrupted by dysregulated kinases, proteins and post-translational modifications are reviewed to design an abstracted computational model showing the situation-dependent dynamic behaviors of these biological processes and entities. A qualitative hybrid Petri Net model is therefore constructed showing the altered host pathways in the presence of virulence factor cytotoxin-associated gene A, leading to the disruption of tight junction proteins. The model is qualitative logic-based, which does not depend on any kinetic parameter and quantitative data and depends on knowledge derived from experiments. The designed model provides insights into the tight junction disruption and disease progression. Model is then verified by the available experimental data, nevertheless formal in vitro experimentation is a promising way to ensure its validation. The major findings propose that H. pylori activated kinases are responsible to trigger specific post translational modifications within tight junction proteins, at specific sites. These modifications may favor alterations in gastric barrier and provide a route to bacterial invasion into host cells.

  15. Protein-lipid interactions in bilayer membranes: a lattice model.

    Science.gov (United States)

    Pink, D A; Chapman, D

    1979-04-01

    A lattice model has been developed to study the effects of intrinsic membrane proteins upon the thermodynamic properties of a lipid bilayer membrane. We assume that only nearest-neighbor van der Waals and steric interactions are important and that the polar group interactions can be represented by effective pressure-area terms. Phase diagrams, the temperature T(0), which locates the gel-fluid melting, the transition enthalpy, and correlations were calculated by mean field and cluster approximations. Average lipid chain areas and chain areas when the lipid is in a given protein environment were obtained. Proteins that have a "smooth" homogeneous surface ("cholesterol-like") and those that have inhomogeneous surfaces or that bind lipids specifically were considered. We find that T(0) can vary depending upon the interactions and that another peak can appear upon the shoulder of the main peak which reflects the melting of a eutectic mixture. The transition enthalpy decreases generally, as was found before, but when a second peak appears departures from this behavior reflect aspects of the eutectic mixture. We find that proteins have significant nonzero probabilities for being adjacent to one another so that no unbroken "annulus" of lipid necessarily exists around a protein. If T(0) does not increase much, or decreases, with increasing c, then lipids adjacent to a protein cannot all be all-trans on the time scale (10(-7) sec) of our system. Around a protein the lipid correlation depth is about one lipid layer, and this increases with c. Possible consequences of ignoring changes in polar group interactions due to clustering of proteins are discussed.

  16. Opioids Inhibit Angiogenesis in a Chorioallantoic Membrane Model.

    Science.gov (United States)

    Karaman, Haktan; Tufek, Adnan; Karaman, Evren; Tokgoz, Orhan

    2017-02-01

    Angiogenesis is an important characteristic of cancer. Switching from the avascular phase to the vascular phase is a necessary process for tumor growth. Therefore, research in cancer treatment has focused on angiogenesis as a drug target. Despite the widespread use of opioids to treat pain in patients with cancer, little is known about the effect of these drugs on vascular endothelium and angiogenesis. We aimed to investigate the efficacies of morphine, codeine, and tramadol in 3 different concentrations on angiogenesis in hens' eggs. This is a prospective, observational, controlled, in-vivo animal study. Single academic medical center. This study was conducted on the chorioallantoic membrane (CAM) of fertilized hens' eggs. The efficacies of morphine, codeine, and tramadol in 3 different concentrations were evaluated on angiogenesis in a total of 165 hens' eggs. Statistically significant differences were found between drug-free agarose used as a negative control and concentrations of morphine of 10 µM and 1 µM, a concentration of tramadol of 10 µM, and concentrations of codeine of 10 µM and 1 µM. Concentrations of morphine of 10 µM and 1 µM showed strong antiangiogenic effects. While codeine had strong antiangiogenic effects at high concentrations, at 0.1 µM it was shown to have weak antiangiogenic effects. However, tramadol at a concentration of 10 µM had only weak antiangiogenic effects. This is just a CAM model study. In this study, we tested the effects of 3 different opioid drugs on angiogenesis in 3 different concentrations, and we observed that morphine was a good anti-angiogenic agent, but tramadol and codeine only had anti-angiogenic effects at high doses.Key Words: Morphine, codeine, tramadol, opioid, bevacizumab, chorioallantoic membrane (CAM), angiogenesis.

  17. Resveratrol induces chain interdigitation in DPPC cell membrane model systems.

    Science.gov (United States)

    Longo, Elena; Ciuchi, Federica; Guzzi, Rita; Rizzuti, Bruno; Bartucci, Rosa

    2016-12-01

    Resveratrol is a natural polyphenol found in various plants with potential therapeutic activity as anti-oxidant, anti-inflammatory, cardioprotective and anti-tumoral. Lipid membranes are among cellular components that are targets of its action. In this work ESR of chain labeled lipids, calorimetry, X-ray diffraction and molecular docking are used to study the interaction of resveratrol with membrane model systems of dipalmitoylphosphatidylcholine (DPPC) as a function of resveratrol concentration (0-30 mol% of the lipid) and temperature (10-50°C). Resveratrol incorporated in DPPC bilayers induces considerable motional restriction at the lipid tail termini, removing the gradient of increasing mobility along the chain found in DPPC bilayers in the gel phase. In contrast, it leaves unperturbed the DPPC chain flexibility profile in the liquid-crystalline phase. At low concentration, resveratrol progressively reduces the pre-transition temperature and eliminates the pre-transition for content ≥5mol%. A reduced cooperativity and a downshift of the main transition temperature are observed, especially at high content. The typical diffraction pattern of DPPC multibilayers in the Lβ' phase is converted to a lamellar pattern with reduced d-spacing of untilted lipid chain in a hexagonal packing at 30 mol% of resveratrol. Molecular docking indicates that the energetically favoured anchoring site is the polar headgroup region, where resveratrol acts as a spacer. The overall results are consistent with the formation in DPPC of an interdigitated Lβi gel phase induced by 30 mol% resveratrol. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Molecular Modeling of Interfacial Proton Transport in Polymer Electrolyte Membranes

    OpenAIRE

    2014-01-01

    The proton conductivity of polymer electrolyte membranes (PEMs) plays a crucial role for the performance of polymer electrolyte fuel cells (PEFCs). High hydration of Nafion-like membranes is crucial to high proton conduction across the PEM, which limits the operation temperature of PEFCs to <100o C. At elevated temperatures (>100o C) and minimal hydration, interfacial proton transport becomes vital for membrane operation. Along with fuel cell systems, interfacial proton conduction is of...

  19. Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Beverly A. Karpinski

    2014-02-01

    Full Text Available We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS, a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V, glossopharyngeal (IX or vagus (X cranial nerves (CNs that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

  20. Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11) deletion syndrome.

    Science.gov (United States)

    Karpinski, Beverly A; Maynard, Thomas M; Fralish, Matthew S; Nuwayhid, Samer; Zohn, Irene E; Moody, Sally A; LaMantia, Anthony-S

    2014-02-01

    We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia--debilitating feeding, swallowing and nutrition difficulties from birth onward--within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

  1. Simulation Modeling for Analysis of a (Q, r Inventory System under Supply Disruption and Customer Differentiation with Partial Backordering

    Directory of Open Access Journals (Sweden)

    Parham Azimi

    2012-01-01

    Full Text Available We have modeled a new (Q, r inventory system which involves a single product, a supplier, and a retailer with customer differentiation under continuous review inventory policy. The supplier provides the retailer with all requirements, and the retailer sells products to the customers. The supplying process is randomly subject to disruptions. Partial backordering is applied when a stock out occurs, and customer can select either to leave the system without purchasing or to backorder products. The customers are categorized into two main classes regarding to their backordering probabilities. The main contribution of this paper is including the customer differentiation in the inventory model. We used simulation technique to verify the impact of supply disruptions and customer differentiation and carried out sensitivity analysis. To test the performance of the model, we have compared our model to one from the latest related research. As the results show, the average of total annual cost of the (Q, r inventory system is lower than that of the previously developed models such as (r, T inventory systems.

  2. Aroma Stripping under various Forms of Membrane Distillation Processes: Experiments and modeling

    DEFF Research Database (Denmark)

    Jonsson, Gunnar Eigil

    of MD configurations: Vacuum Membrane Distillation , Sweeping Gas Membrane Distillation , Direct Contact Membrane Distillation and Osmotic Membrane Distillation. The influence of feed temperature and feed flow rate on the permeate flux and concentration factor for different types of aroma compounds have...... been measured for these MD configurations. A general transport model for the flux of water and aroma compounds have been derived and compared with the experimental data. A reasonable agreement between the modelling and the experiments could be obtained. From the modelling it was possible to explain...

  3. Burnout Disrupts Anxiety Buffer Functioning Among Nurses: A Three-Way Interaction Model

    Science.gov (United States)

    Trifiletti, Elena; Pedrazza, Monica; Berlanda, Sabrina; Pyszczynski, Tom

    2017-01-01

    Over the last 40 years, job burnout has attracted a great deal of attention among researchers and practitioners and, after decades of research and interventions, it is still regarded as an important issue. With the aim of extending the Anxiety Buffer Disruption Theory (ABDT), in this paper we argue that high levels of burnout may disrupt the anxiety buffer functioning that protects people from death concerns. ABDT was developed from Terror Management Theory (TMT). According to TMT, reminders of one’s mortality are an essential part of humans’ daily experience and have the potential to awake paralyzing fear and anxiety. In order to cope with death concerns, people typically activate an anxiety-buffering system centered on their cultural worldview and self-esteem. Recent ABDT research shows that individuals with post-traumatic stress disorder are unable to activate such anxiety buffering defenses. In line with these results, we hypothesized that the burnout syndrome may have similar effects, and that individuals with higher levels of burnout will be less likely to activate an anxiety buffering response when their mortality is made salient. Participants were 418 nurses, who completed a questionnaire including: a mortality salience (MS) manipulation, a delay manipulation, and measures of burnout, work-related self-efficacy, and representation of oneself as a valuable caregiver. Nurses are daily exposed both to the risk of burnout and to mortality reminders, and thus constituted an ideal population for this study. In line with an anxiety buffer disruption hypothesis, we found a significant three-way interaction between burnout, MS and delay. Participants with lower levels of burnout reported higher levels of self-efficacy and a more positive representation as caregivers in the MS condition compared to the control condition, when there was a delay between MS manipulation and the assessment of the dependent measures. The difference was non-significant for participants

  4. Burnout Disrupts Anxiety Buffer Functioning Among Nurses: A Three-Way Interaction Model.

    Science.gov (United States)

    Trifiletti, Elena; Pedrazza, Monica; Berlanda, Sabrina; Pyszczynski, Tom

    2017-01-01

    Over the last 40 years, job burnout has attracted a great deal of attention among researchers and practitioners and, after decades of research and interventions, it is still regarded as an important issue. With the aim of extending the Anxiety Buffer Disruption Theory (ABDT), in this paper we argue that high levels of burnout may disrupt the anxiety buffer functioning that protects people from death concerns. ABDT was developed from Terror Management Theory (TMT). According to TMT, reminders of one's mortality are an essential part of humans' daily experience and have the potential to awake paralyzing fear and anxiety. In order to cope with death concerns, people typically activate an anxiety-buffering system centered on their cultural worldview and self-esteem. Recent ABDT research shows that individuals with post-traumatic stress disorder are unable to activate such anxiety buffering defenses. In line with these results, we hypothesized that the burnout syndrome may have similar effects, and that individuals with higher levels of burnout will be less likely to activate an anxiety buffering response when their mortality is made salient. Participants were 418 nurses, who completed a questionnaire including: a mortality salience (MS) manipulation, a delay manipulation, and measures of burnout, work-related self-efficacy, and representation of oneself as a valuable caregiver. Nurses are daily exposed both to the risk of burnout and to mortality reminders, and thus constituted an ideal population for this study. In line with an anxiety buffer disruption hypothesis, we found a significant three-way interaction between burnout, MS and delay. Participants with lower levels of burnout reported higher levels of self-efficacy and a more positive representation as caregivers in the MS condition compared to the control condition, when there was a delay between MS manipulation and the assessment of the dependent measures. The difference was non-significant for participants

  5. Development of predictive models for predicting binding affinity of endocrine disrupting chemicals to fish sex hormone-binding globulin.

    Science.gov (United States)

    Liu, Huihui; Yang, Xianhai; Yin, Cen; Wei, Mengbi; He, Xiao

    2017-02-01

    Disturbing the transport process is a crucial pathway for endocrine disrupting chemicals (EDCs) exerting disrupting endocrine function. However, this mechanism has not received enough attention compared with that of hormones receptors and synthetase. Recently, we have explored the interaction between EDCs and sex hormone-binding globulin of human (hSHBG). In this study, interactions between EDCs and sex hormone-binding globulin of eight fish species (fSHBG) were investigated by employing classification methods and quantitative structure-activity relationships (QSAR). In the modeling, the relative binding affinity (RBA) of a chemical with 17β-estradiol binding to fSHBG was selected as the endpoint. Classification models were developed for two fish species, while QSAR models were established for the other six fish species. Statistical results indicated that the models had satisfactory goodness of fit, robustness and predictive ability, and that application domain covered a large number of endogenous and exogenous steroidal and non-steroidal chemicals. Additionally, by comparing the log RBA values, it was found that the same chemical may have different affinities for fSHBG from different fish species, thus species diversity should be taken into account. However, the affinity of fSHBG showed a high correlation for fishes within the same Order (i.e., Salmoniformes, Cypriniformes, Perciformes and Siluriformes), thus the fSHBG binding data for one fish species could be used to extrapolate other fish species in the same Order.

  6. Investigating cellular electroporation using planar membrane models and miniaturized devices

    NARCIS (Netherlands)

    Uitert, van Iris

    2010-01-01

    This thesis focuses on increasing our understanding of the electroporation process. Electroporation is a technique employed to introduce foreign molecules into cells that can normally not pass the cell membrane. By applying a short but high electric field, pores appear in the membrane through which

  7. The Matrix protein M1 from influenza C virus induces tubular membrane invaginations in an in vitro cell membrane model

    Science.gov (United States)

    Saletti, David; Radzimanowski, Jens; Effantin, Gregory; Midtvedt, Daniel; Mangenot, Stéphanie; Weissenhorn, Winfried; Bassereau, Patricia; Bally, Marta

    2017-01-01

    Matrix proteins from enveloped viruses play an important role in budding and stabilizing virus particles. In order to assess the role of the matrix protein M1 from influenza C virus (M1-C) in plasma membrane deformation, we have combined structural and in vitro reconstitution experiments with model membranes. We present the crystal structure of the N-terminal domain of M1-C and show by Small Angle X-Ray Scattering analysis that full-length M1-C folds into an elongated structure that associates laterally into ring-like or filamentous polymers. Using negatively charged giant unilamellar vesicles (GUVs), we demonstrate that M1-C full-length binds to and induces inward budding of membrane tubules with diameters that resemble the diameter of viruses. Membrane tubule formation requires the C-terminal domain of M1-C, corroborating its essential role for M1-C polymerization. Our results indicate that M1-C assembly on membranes constitutes the driving force for budding and suggest that M1-C plays a key role in facilitating viral egress. PMID:28120862

  8. Disruption of lolCDE, Encoding an ATP-Binding Cassette Transporter, Is Lethal for Escherichia coli and Prevents Release of Lipoproteins from the Inner Membrane

    OpenAIRE

    Narita, Shin-ichiro; Tanaka, Kimie; Matsuyama, Shin-ichi; Tokuda, Hajime

    2002-01-01

    ATP-binding cassette transporter LolCDE was previously identified, by using reconstituted proteoliposomes, as an apparatus catalyzing the release of outer membrane-specific lipoproteins from the inner membrane of Escherichia coli. Mutations resulting in defective LolD were previously shown to be lethal for E. coli. The amino acid sequences of LolC and LolE are similar to each other, but the necessity of both proteins for lipoprotein release has not been proved. Moreover, previous reconstituti...

  9. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  10. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

    Science.gov (United States)

    Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

    2016-02-16

    Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

  11. Politisk disruption

    DEFF Research Database (Denmark)

    Tække, Jesper

    2017-01-01

    Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på.......Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på....

  12. A Coarse Grained Model for a Lipid Membrane with Physiological Composition and Leaflet Asymmetry.

    Directory of Open Access Journals (Sweden)

    Satyan Sharma

    Full Text Available The resemblance of lipid membrane models to physiological membranes determines how well molecular dynamics (MD simulations imitate the dynamic behavior of cell membranes and membrane proteins. Physiological lipid membranes are composed of multiple types of phospholipids, and the leaflet compositions are generally asymmetric. Here we describe an approach for self-assembly of a Coarse-Grained (CG membrane model with physiological composition and leaflet asymmetry using the MARTINI force field. An initial set-up of two boxes with different types of lipids according to the leaflet asymmetry of mammalian cell membranes stacked with 0.5 nm overlap, reliably resulted in the self-assembly of bilayer membranes with leaflet asymmetry resembling that of physiological mammalian cell membranes. Self-assembly in the presence of a fragment of the plasma membrane protein syntaxin 1A led to spontaneous specific positioning of phosphatidylionositol(4,5bisphosphate at a positively charged stretch of syntaxin consistent with experimental data. An analogous approach choosing an initial set-up with two concentric shells filled with different lipid types results in successful assembly of a spherical vesicle with asymmetric leaflet composition. Self-assembly of the vesicle in the presence of the synaptic vesicle protein synaptobrevin 2 revealed the correct position of the synaptobrevin transmembrane domain. This is the first CG MD method to form a membrane with physiological lipid composition as well as leaflet asymmetry by self-assembly and will enable unbiased studies of the incorporation and dynamics of membrane proteins in more realistic CG membrane models.

  13. Atomic-level description of protein-lipid interactions using an accelerated membrane model.

    Science.gov (United States)

    Baylon, Javier L; Vermaas, Josh V; Muller, Melanie P; Arcario, Mark J; Pogorelov, Taras V; Tajkhorshid, Emad

    2016-07-01

    Peripheral membrane proteins are structurally diverse proteins that are involved in fundamental cellular processes. Their activity of these proteins is frequently modulated through their interaction with cellular membranes, and as a result techniques to study the interfacial interaction between peripheral proteins and the membrane are in high demand. Due to the fluid nature of the membrane and the reversibility of protein-membrane interactions, the experimental study of these systems remains a challenging task. Molecular dynamics simulations offer a suitable approach to study protein-lipid interactions; however, the slow dynamics of the lipids often prevents sufficient sampling of specific membrane-protein interactions in atomistic simulations. To increase lipid dynamics while preserving the atomistic detail of protein-lipid interactions, in the highly mobile membrane-mimetic (HMMM) model the membrane core is replaced by an organic solvent, while short-tailed lipids provide a nearly complete representation of natural lipids at the organic solvent/water interface. Here, we present a brief introduction and a summary of recent applications of the HMMM to study different membrane proteins, complementing the experimental characterization of the presented systems, and we offer a perspective of future applications of the HMMM to study other classes of membrane proteins. This article is part of a Special Issue entitled: Membrane proteins edited by J.C. Gumbart and Sergei Noskov.

  14. Study of Raft Domains in Model Membrane of DPPC/PE/Cholesterol

    Science.gov (United States)

    Lor, Chai; Hirst, Linda

    2010-10-01

    Raft domains in bilayer membrane are thought to play an important role in many cell functions such as cell signaling or trans-membrane protein activation. Here we use a model membrane consisting of DPPC/PE/cholesterol to examine the structure of membrane rafts and phase interactions. In particular we are interested in lipids containing the highly polyunsaturated fatty acid DHA. We use both atomic force microscopy (AFM) and fluorescence microscopy to obtain information on the structural properties of raft regions and track cholesterol. As expected, we find phase separation of raft regions between saturated and unsaturated lipids. Moreover, we find that the roughness of the domains change with varying cholesterol concentration possibly due to overpacking. This model study provides further understanding of the role of cholesterol in bilayer membrane leading towards a better knowledge of cell membranes.

  15. Immunology of membranous nephropathy: from animal models to humans.

    Science.gov (United States)

    Sinico, R A; Mezzina, N; Trezzi, B; Ghiggeri, G M; Radice, A

    2016-02-01

    Membranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits that consist mainly of immunoglobulin (Ig)G and complement. Most of the cases are primary or idiopathic (iMN), while only approximately 25% of the cases are secondary to some known disease such as systemic lupus erythematosus, hepatitis B, drugs and malignancies. Most of our knowledge on the pathogenesis of iMN has relied upon old experimental models (i.e. Heymann nephritis) that have shown that immune deposits are formed in situ by the reaction of autoantibodies against the respective podocyte antigen. Recent findings indicate that podocyte proteins also act as an autoantigen in human iMN. The M-type phospholipase A2 receptor (PLA2R) has been identified as the main target antigen, as it can be found in approximately 70% of iMN patients but only rarely in other glomerulonephritides. Podocytes damage in the experimental model of Heymann nephritis is complement-mediated. In humans, the presence of complement within the subepithelial deposits is well established, but IgG4, which does not activate complement by classical or alternative pathways, represents the predominant subclass of IgG anti-PLA2R. Some evidence suggests that IgG4 anti-PLA2R autoantibodies can bind mannan-binding lectin (MBL) and activate the lectin complement pathway. A genetic background for iMN has been demonstrated by genome-wide association studies that have shown highly significant associations of the PLA2R1 and the human leucocyte antigen (HLA)-DQA1 loci with iMN. In addition to their diagnostic value, anti-PLA2R antibodies may be useful to monitor disease activity and predict response to treatment.

  16. Theoretical modeling and experimental validation of transport and separation properties of carbon nanotube electrospun membrane distillation

    KAUST Repository

    Lee, Jung-Gil

    2016-12-27

    Developing a high flux and selective membrane is required to make membrane distillation (MD) a more attractive desalination process. Amongst other characteristics membrane hydrophobicity is significantly important to get high vapor transport and low wettability. In this study, a laboratory fabricated carbon nanotubes (CNTs) composite electrospun (E-CNT) membrane was tested and has showed a higher permeate flux compared to poly(vinylidene fluoride-co-hexafluoropropylene) (PH) electrospun membrane (E-PH membrane) in a direct contact MD (DCMD) configuration. Only 1% and 2% of CNTs incorporation resulted in an enhanced permeate flux with lower sensitivity to feed salinity while treating a 35 and 70 g/L NaCl solutions. Experimental results and the mechanisms of E-CNT membrane were validated by a proposed new step-modeling approach. The increased vapor transport in E-CNT membranes could not be elucidated by an enhancement of mass transfer only at a given physico-chemical properties. However, the theoretical modeling approach considering the heat and mass transfers simultaneously enabled to explain successfully the enhanced flux in the DCMD process using E-CNT membranes. This indicates that both mass and heat transfers improved by CNTs are attributed to the enhanced vapor transport in the E-CNT membrane.

  17. Relating rejection of trace organic contaminants to membrane properties in forward osmosis: measurements, modelling and implications.

    Science.gov (United States)

    Xie, Ming; Nghiem, Long D; Price, William E; Elimelech, Menachem

    2014-02-01

    This study elucidates the relationship between membrane properties and the rejection of trace organic contaminants (TrOCs) in forward osmosis (FO). An asymmetric cellulose triacetate (CTA) and a thin-film composite (TFC) polyamide FO membrane were used for this investigation. The effective average pore radius (rp), selective barrier thickness over porosity parameter (l/ε), surface charge, support layer structural parameter (S), pure water permeability coefficient (A) and salt (NaCl) permeability coefficient (B) of the two membranes were systematically characterised. Results show that measured rejection of TrOCs as a function of permeate water flux can be well described by the pore hindrance transport model. This observation represents the first successful application of this model, which was developed for pressure-driven nanofiltration, to an osmotically-driven membrane process. The rejection of charged TrOCs by the CTA and TFC membranes was high and was governed by both electrostatic repulsion and steric hindrance. The TFC membrane exhibited higher rejection of neutral TrOCs with low molecular weight than the CTA membrane, although the estimated pore size of the TFC membrane (0.42 nm) was slightly larger than that of the CTA membrane (0.37 nm). This higher rejection of neutral TrOCs by the TFC membrane is likely attributed to its active layer properties, namely a more effective active layer structure, as indicated by a larger l/ε parameter, and pore hydration induced by the negative surface charge.

  18. Solar photocatalytic degradation of resorcinol a model endocrine disrupter in water using zinc oxide

    Energy Technology Data Exchange (ETDEWEB)

    Pardeshi, S.K. [Department of Chemistry, University of Pune, Ganeshkhind, Pune 411007 (India)], E-mail: skpar@chem.unipune.ernet.in; Patil, A.B. [Department of Chemistry, University of Pune, Ganeshkhind, Pune 411007 (India)

    2009-04-15

    Photocatalytic degradation (PCD) of resorcinol a potent endocrine disrupting chemical in aqueous medium was investigated by ZnO under sunlight irradiation in a batch photoreactor. The influence of various parameters such as photocatalyst amount, initial concentration of resorcinol and pH was examined for maximum PCD of resorcinol. A considerable influence of pH upon the chemical oxygen demand (COD) disappearance was observed. In general, neutral or basic pH is favorable for COD removal of resorcinol. PCD intermediates were identified using FTIR and GC/MS. Two of the initial oxidation intermediates detected were 1,2,4-trihydroxy-benzene and 1,2,3-trihydroxy-benzene. FTIR studies revealed 1,2,4-trihydroxy-benzene as the major PCD intermediate. A working photodegradation mechanism is also suggested for PCD of resorcinol. This work envisages the great potential that sunlight mediated photocatalysis has in the removal of resorcinol from waste water.

  19. Three-dimensional non-linear magnetohydrodynamic modeling of massive gas injection triggered disruptions in JET

    Science.gov (United States)

    Fil, A.; Nardon, E.; Hoelzl, M.; Huijsmans, G. T. A.; Orain, F.; Becoulet, M.; Beyer, P.; Dif-Pradalier, G.; Guirlet, R.; Koslowski, H. R.; Lehnen, M.; Morales, J.; Pamela, S.; Passeron, C.; Reux, C.; Saint-Laurent, F.

    2015-06-01

    JOREK 3D non-linear MHD simulations of a D2 Massive Gas Injection (MGI) triggered disruption in JET are presented and compared in detail to experimental data. The MGI creates an overdensity that rapidly expands in the direction parallel to the magnetic field. It also causes the growth of magnetic islands ( m / n = 2 / 1 and 3/2 mainly) and seeds the 1/1 internal kink mode. O-points of all island chains (including 1/1) are located in front of the MGI, consistently with experimental observations. A burst of MHD activity and a peak in plasma current take place at the same time as in the experiment. However, the magnitude of these two effects is much smaller than in the experiment. The simulated radiation is also much below the experimental level. As a consequence, the thermal quench is not fully reproduced. Directions for progress are identified. Radiation from impurities is a good candidate.

  20. C. elegans as a model for membrane traffic.

    Science.gov (United States)

    Sato, Ken; Norris, Anne; Sato, Miyuki; Grant, Barth D

    2014-01-01

    The counterbalancing action of the endocytosis and secretory pathways maintains a dynamic equilibrium that regulates the composition of the plasma membrane, allowing it to maintain homeostasis and to change rapidly in response to alterations in the extracellular environment and/or intracellular metabolism. These pathways are intimately integrated with intercellular signaling systems and play critical roles in all cells. Studies in Caenorhabditis elegans have revealed diverse roles of membrane trafficking in physiology and development and have also provided molecular insight into the fundamental mechanisms that direct cargo sorting, vesicle budding, and membrane fisson and fusion. In this review, we summarize progress in understanding membrane trafficking mechanisms derived from work in C. elegans, focusing mainly on work done in non-neuronal cell-types, especially the germline, early embryo, coelomocytes, and intestine.

  1. The molecular face of lipid rafts in model membranes

    NARCIS (Netherlands)

    Risselada, H. Jelger; Marrink, Siewert J.

    2008-01-01

    Cell membranes contain a large number of different lipid species. Such a multicomponent mixture exhibits a complex phase behavior with regions of structural and compositional heterogeneity. Especially domains formed in ternary mixtures, composed of saturated and unsaturated lipids together with

  2. Bacoside-A, an anti-amyloid natural substance, inhibits membrane disruption by the amyloidogenic determinant of prion protein through accelerating fibril formation.

    Science.gov (United States)

    Malishev, Ravit; Nandi, Sukhendu; Kolusheva, Sofiya; Shaham-Niv, Shira; Gazit, Ehud; Jelinek, Raz

    2016-09-01

    Bacosides, class of compounds extracted from the Bacopa monniera plant, exhibit interesting therapeutic properties, particularly enhancing cognitive functions and putative anti-amyloid activity. We show that bacoside-A exerted significant effects upon fibrillation and membrane interactions of the amyloidogenic fragment of the prion protein [PrP(106-126)]. Specifically, when co-incubated with PrP(106-126), bacoside-A accelerated fibril formation in the presence of lipid bilayers and in parallel inhibited bilayer interactions of the peptide aggregates formed in solution. These interesting phenomena were studied by spectroscopic and microscopic techniques, which suggest that bacoside A-promoted fibrillation reduced the concentration of membrane-active pre-fibrillar species of the prion fragment. This study suggests that induction of fibril formation and corresponding inhibition of membrane interactions are likely the underlying factors for ameliorating amyloid protein toxicity by bacoside-A.

  3. Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal Models

    OpenAIRE

    Cowling, Belinda S; Anne Toussaint; Jean Muller; Jocelyn Laporte

    2012-01-01

    Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Too...

  4. Comparison of the Modeling Approach between Membrane Bioreactor and Conventional Activated Sludge Processes

    DEFF Research Database (Denmark)

    Jiang, Tao; Sin, Gürkan; Spanjers, Henri

    2009-01-01

    Activated sludge models (ASM) have been developed and largely applied in conventional activated sludge (CAS) systems. The applicability of ASM to model membrane bioreactors (MBR) and the differences in modeling approaches have not been studied in detail. A laboratory-scale MBR was modeled using ASM...... to the inhibition effect of soluble microbial products (SMP) at elevated concentration. Second, a greater biomass affinity to oxygen and ammonium was found, which was probably related to smaller MBR sludge flocs. Finally, the membrane throughput during membrane backwashing/relaxation can be normalized...

  5. Zonal rate model for stacked membrane chromatography part II: characterizing ion-exchange membrane chromatography under protein retention conditions.

    Science.gov (United States)

    Francis, Patrick; von Lieres, Eric; Haynes, Charles

    2012-03-01

    The Zonal Rate Model (ZRM) has previously been shown to accurately account for contributions to elution band broadening, including external flow nonidealities and radial concentration gradients, in ion-exchange membrane (IEXM) chromatography systems operated under nonbinding conditions. Here, we extend the ZRM to analyze and model the behavior of retained proteins by introducing terms for intra-column mass transfer resistances and intrinsic binding kinetics. Breakthrough curve (BTC) data from a scaled-down anion-exchange membrane chromatography module using ovalbumin as a model protein were collected at flow rates ranging from 1.5 to 20 mL min(-1). Through its careful accounting of transport nonidealities within and external to the membrane stack, the ZRM is shown to provide a useful framework for characterizing putative protein binding mechanisms and models, for predicting BTCs and complex elution behavior, including the common observation that the dynamic binding capacity can increase with linear velocity in IEXM systems, and for simulating and scaling separations using IEXM chromatography. Global fitting of model parameters is used to evaluate the performance of the Langmuir, bi-Langmuir, steric mass action (SMA), and spreading-type protein binding models in either correlating or fundamentally describing BTC data. When combined with the ZRM, the bi-Langmuir, and SMA models match the chromatography data, but require physically unrealistic regressed model parameters to do so. In contrast, for this system a spreading-type model is shown to accurately predict column performance while also providing a realistic fundamental explanation for observed trends, including an observed increase in dynamic binding capacity with flow rate.

  6. Pore-scale modeling and simulation of flow, transport, and adsorptive or osmotic effects in membranes: the influence of membrane microstructure

    KAUST Repository

    Calo, Victor M.

    2015-07-17

    The selection of an appropriate membrane for a particular application is a complex and expensive process. Computational modeling can significantly aid membrane researchers and manufacturers in this process. The membrane morphology is highly influential on its efficiency within several applications, but is often overlooked in simulation. Two such applications which are very important in the provision of clean water are forward osmosis and filtration using functionalized micro/ultra/nano-filtration membranes. Herein, we investigate the effect of the membrane morphology in these two applications. First we present results of the separation process using resolved finger- and sponge-like support layers. Second, we represent the functionalization of a typical microfiltration membrane using absorptive pore walls, and illustrate the effect of different microstructures on the reactive process. Such numerical modeling will aid manufacturers in optimizing operating conditions and designing efficient membranes.

  7. Ascending central canal dilation and progressive ependymal disruption in a contusion model of rodent chronic spinal cord injury

    Directory of Open Access Journals (Sweden)

    Keirstead Hans S

    2007-09-01

    Full Text Available Abstract Background Chronic spinal cord injury (SCI can lead to an insidious decline in motor and sensory function in individuals even years after the initial injury and is accompanied by a slow and progressive cytoarchitectural destruction. At present, no pathological mechanisms satisfactorily explain the ongoing degeneration. Methods Adult female Sprague-Dawley rats were anesthetized laminectomized at T10 and received spinal cord contusion injuries with a force of 250 kilodynes using an Infinite Horizon Impactor. Animals were randomly distributed into 5 groups and killed 1 (n = 4, 28 (n = 4, 120 (n = 4, 450 (n = 5, or 540 (n = 5 days after injury. Morphometric and immunohistochemical studies were then performed on 1 mm block sections, 6 mm cranial and 6 mm caudal to the lesion epicenter. The SPSS 11.5 t test was used to determine differences between quantitative measures. Results Here, we document the first report of an ascending central canal dilation and progressive ependymal disruption cranial to the epicenter of injury in a contusion model of chronic SCI, which was characterized by extensive dural fibrosis and intraparenchymal cystic cavitation. Expansion of the central canal lumen beyond a critical diameter corresponded with ependymal cell ciliary loss, an empirically predictable thinning of the ependymal region, and a decrease in cell proliferation in the ependymal region. Large, aneurysmal dilations of the central canal were accompanied by disruptions in the ependymal layer, periependymal edema and gliosis, and destruction of the adjacent neuropil. Conclusion Cells of the ependymal region play an important role in CSF homeostasis, cellular signaling and wound repair in the spinal cord. The possible effects of this ascending pathology on ependymal function are discussed. Our studies suggest central canal dilation and ependymal region disruption as steps in the pathogenesis of chronic SCI, identify central canal dilation as a marker of

  8. Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice.

    Science.gov (United States)

    Pilz, Luísa K; Trojan, Yasmine; Quiles, Caroline L; Benvenutti, Radharani; Melo, Gabriela; Levandovski, Rosa; Hidalgo, Maria Paz L; Elisabetsky, Elaine

    2015-03-01

    Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.

  9. Boric acid permeation in forward osmosis membrane processes: modeling, experiments, and implications.

    Science.gov (United States)

    Jin, Xue; Tang, Chuyang Y; Gu, Yangshuo; She, Qianhong; Qi, Saren

    2011-03-15

    Forward osmosis (FO) is attracting increasing interest for its potential applications in desalination. In FO, permeation of contaminants from feed solution into draw solution through the semipermeable membrane can take place simultaneously with water diffusion. Understanding the contaminants transport through and rejection by FO membrane has significant technical implications in the way to separate clean water from the diluted draw solution. In this study, a model was developed to predict boron flux in FO operation. A strong agreement between modeling results and experimental data indicates that the model developed in this study can accurately predict the boron transport through FO membranes. Furthermore, the model can guide the fabrication of improved FO membranes with decreased boron permeability and structural parameter to minimize boron flux. Both theoretical model and experimental results demonstrated that when membrane active layer was facing draw solution, boron flux was substantially greater compared to the other membrane orientation due to more severe internal concentration polarization. In this investigation, for the first time, rejection of contaminants was defined in FO processes. This is critical to compare the membrane performance between different membranes and experimental conditions.

  10. Studies on the interactions of bisphenols with anionic phospholipids of decomposer membranes in model systems.

    Science.gov (United States)

    Broniatowski, Marcin; Sobolewska, Katarzyna; Flasiński, Michał; Wydro, Paweł

    2016-04-01

    Bisphenol A (BPA) and other bisphenols constitute a class of organic pollutants, which because of their estrogenic properties, low dose activity and bioaccumulation pose considerable risk for public health as well as for the environment. Accumulated in the sediment bisphenols can endanger the decomposers' populations being incorporated into their cellular membranes; however, the mechanism of their membrane activity is unknown. Therefore, to study these phenomena we applied anionic phospholipid Langmuir monolayers as simple but versatile models of decomposers biomembranes. Phosphatidylglycerols and cardiolipins are not only the main components of bacterial membranes but also of crucial importance in mitochondrial and thylakoid membranes in eukaryotic cells. In our investigations we applied five compounds of the bisphenol class most commonly detected in the environment. To characterize the bisphenols-model membrane interactions we applied multiple mutually independent methods of physical chemistry; namely: the Langmuir monolayer technique, surface potential measurements, Brewster angle microscopy for the visualization of the monolayers' texture and grazing incidence X-ray diffraction for the discussion of the phospholipids packing within the monolayers. Our studies indicated that all the investigated bisphenols interact with the model membrane, but the strength of the interactions is dependent on the bisphenol structure and hydrophobicity and the fluidity of the model membranes. We proved that bisphenol S often treated as the least toxic BPA analog can also be incorporated to the model membranes changing their structure and fluidity.

  11. Membrane-elasticity model of Coatless vesicle budding induced by ESCRT complexes.

    Directory of Open Access Journals (Sweden)

    Bartosz Różycki

    Full Text Available The formation of vesicles is essential for many biological processes, in particular for the trafficking of membrane proteins within cells. The Endosomal Sorting Complex Required for Transport (ESCRT directs membrane budding away from the cytosol. Unlike other vesicle formation pathways, the ESCRT-mediated budding occurs without a protein coat. Here, we propose a minimal model of ESCRT-induced vesicle budding. Our model is based on recent experimental observations from direct fluorescence microscopy imaging that show ESCRT proteins colocalized only in the neck region of membrane buds. The model, cast in the framework of membrane elasticity theory, reproduces the experimentally observed vesicle morphologies with physically meaningful parameters. In this parameter range, the minimum energy configurations of the membrane are coatless buds with ESCRTs localized in the bud neck, consistent with experiment. The minimum energy configurations agree with those seen in the fluorescence images, with respect to both bud shapes and ESCRT protein localization. On the basis of our model, we identify distinct mechanistic pathways for the ESCRT-mediated budding process. The bud size is determined by membrane material parameters, explaining the narrow yet different bud size distributions in vitro and in vivo. Our membrane elasticity model thus sheds light on the energetics and possible mechanisms of ESCRT-induced membrane budding.

  12. Modeling of hydrodynamics in hollow fiber membrane bioreactor for mammalian cells cultivation

    Directory of Open Access Journals (Sweden)

    N. V. Menshutina

    2016-01-01

    Full Text Available The mathematical modelling in CFD-packages are powerfull instrument for design and calculation of any engineering tasks. CFD-package contains the set of programs that allow to model the different objects behavior based on the mathematical lows. ANSYS Fluent are widely used for modelling of biotechnological and chemical-technological processes. This package is convenient to describe their hydrodynamics. As cell cultivation is one of the actual scientific direction in modern biotechnology ANSYS Fluent was used to create the model of hollow fiber membrane bioreactor. The fibers are hollow cylindrical membrane to be used for cell cultivation. The criterion of process effectiveness for cell growth is full filling of the membrane surface by cells in the bioreactor. While the cell growth the fiber permeability is decreased which effects to feed flow through membrane pores. The specific feature of this process is to ensure such feed flow to deliver the optimal nutrition for the cells on the external membrane surface. The velocity distribution inside the fiber and in all bioreactor as a whole has been calculated based on mass an impulse conservation equations taking into account the mathematical model assumptions. The hydrodynamics analysis in hollow fiber membrane bioreactor is described by the three-dimensional model created in ANSYS Fluent. The specific features of one membrane model are considered and for whole bioreactor too.

  13. An Equivalent Electrical Circuit Model of Proton Exchange Membrane Fuel Cells Based on Mathematical Modelling

    Directory of Open Access Journals (Sweden)

    Dinh An Nguyen

    2012-07-01

    Full Text Available Many of the Proton Exchange Membrane Fuel Cell (PEMFC models proposed in the literature consist of mathematical equations. However, they are not adequately practical for simulating power systems. The proposed model takes into account phenomena such as activation polarization, ohmic polarization, double layer capacitance and mass transport effects present in a PEM fuel cell. Using electrical analogies and a mathematical modeling of PEMFC, the circuit model is established. To evaluate the effectiveness of the circuit model, its static and dynamic performances under load step changes are simulated and compared to the numerical results obtained by solving the mathematical model. Finally, the applicability of our model is demonstrated by simulating a practical system.

  14. Key factors regulating the mass delivery of macromolecules to model cell membranes

    DEFF Research Database (Denmark)

    Campbell, Richard A.; Watkins, Erik B.; Jagalski, Vivien

    2014-01-01

    We show that both gravity and electrostatics are key factors regulating interactions between model cell membranes and self-assembled liquid crystalline aggregates of dendrimers and phospholipids. The system is a proxy for the trafficking of reservoirs of therapeutic drugs to cell membranes for slow...... diffusion and continuous delivery. Neutron reflectometry measurements were carried out on supported lipid bilayers of varying charge and on hydrophilic silica surfaces. Translocation of the macromolecule across the membrane and adsorption of the lamellar aggregates occur only when the membrane (1...... of the aggregates to activate endocytosis pathways on specific cell types is discussed in the context of targeted drug delivery applications....

  15. Air gap membrane distillation. 2. Model validation and hollow fibre module performance analysis

    NARCIS (Netherlands)

    Guijt, C.M.; Meindersma, G.W.; Reith, T.; de Haan, A.B.

    2005-01-01

    In this paper the experimental results of counter current flow air gap membrane distillation experiments are presented and compared with predictive model calculations. Measurements were carried out with a cylindrical test module containing a single hollow fibre membrane in the centre and a

  16. Structural models of the membrane anchors of envelope glycoproteins E1 and E2 from pestiviruses

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jimin, E-mail: jimin.wang@yale.edu; Li, Yue; Modis, Yorgo, E-mail: yorgo.modis@yale.edu

    2014-04-15

    The membrane anchors of viral envelope proteins play essential roles in cell entry. Recent crystal structures of the ectodomain of envelope protein E2 from a pestivirus suggest that E2 belongs to a novel structural class of membrane fusion machinery. Based on geometric constraints from the E2 structures, we generated atomic models of the E1 and E2 membrane anchors using computational approaches. The E1 anchor contains two amphipathic perimembrane helices and one transmembrane helix; the E2 anchor contains a short helical hairpin stabilized in the membrane by an arginine residue, similar to flaviviruses. A pair of histidine residues in the E2 ectodomain may participate in pH sensing. The proposed atomic models point to Cys987 in E2 as the site of disulfide bond linkage with E1 to form E1–E2 heterodimers. The membrane anchor models provide structural constraints for the disulfide bonding pattern and overall backbone conformation of the E1 ectodomain. - Highlights: • Structures of pestivirus E2 proteins impose constraints on E1, E2 membrane anchors. • Atomic models of the E1 and E2 membrane anchors were generated in silico. • A “snorkeling” arginine completes the short helical hairpin in the E2 membrane anchor. • Roles in pH sensing and E1–E2 disulfide bond formation are proposed for E1 residues. • Implications for E1 ectodomain structure and disulfide bonding pattern are discussed.

  17. Statistical modelling of the interplay between solute shape and rejection in porous membranes

    DEFF Research Database (Denmark)

    Vinther, Frank; Pinelo, Manuel; Brøns, Morten

    2012-01-01

    membrane, it can be expected that the possibility for a solute particle to enter the membrane pore will only depend upon the relation between such molecular conformation and pore size. The objective of the present study is to use geometric and statistical modelling to determine the effect of particle elongation...

  18. Membrane Disordering by Eicosapentaenoic Acid in B Lymphomas Is Reduced by Elongation to Docosapentaenoic Acid as Revealed with Solid-State Nuclear Magnetic Resonance Spectroscopy of Model Membranes.

    Science.gov (United States)

    Harris, Mitchell; Kinnun, Jacob J; Kosaraju, Rasagna; Leng, Xiaoling; Wassall, Stephen R; Shaikh, Saame Raza

    2016-07-01

    Plasma membrane organization is a mechanistic target of n-3 (ω-3) polyunsaturated fatty acids. Previous studies show that eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) differentially disrupt plasma membrane molecular order to enhance the frequency and function of B lymphocytes. However, it is not known whether EPA and DHA affect the plasma membrane organization of B lymphomas differently to influence their function. We tested whether EPA and DHA had different effects on membrane order in B lymphomas and liposomes and studied their effects on B-lymphoma growth. B lymphomas were treated with 25 μmol EPA, DHA, or serum albumin control/L for 24 h. Membrane order was measured with fluorescence polarization, and cellular fatty acids (FAs) were analyzed with GC. Growth was quantified with a viability assay. (2)H nuclear magnetic resonance (NMR) studies were conducted on deuterated phospholipid bilayers. Treating Raji, Ramos, and RPMI lymphomas for 24 h with 25 μmol EPA or DHA/L lowered plasma membrane order by 10-40% relative to the control. There were no differences between EPA and DHA on membrane order for the 3 cell lines. FA analyses revealed complex changes in response to EPA or DHA treatment and a large fraction of EPA was converted to docosapentaenoic acid (DPA; 22:5n-3). NMR studies, which were used to understand why EPA and DHA had similiar membrane effects, showed that phospholipids containing DPA, similar to DHA, were more ordered than those containing EPA. Finally, treating B lymphomas with 25 μmol EPA or DHA/L did not increase the frequency of B lymphomas compared with controls. The results establish that 25 μmol EPA and DHA/L equally disrupt membrane order and do not promote B lymphoma growth. The data open a new area of investigation, which is how EPA's conversion to DPA substantially moderates its influence on membrane properties. © 2016 American Society for Nutrition.

  19. Reconstituting ring-rafts in bud-mimicking topography of model membranes

    Science.gov (United States)

    Ryu, Yong-Sang; Lee, In-Ho; Suh, Jeng-Hun; Park, Seung Chul; Oh, Soojung; Jordan, Luke R.; Wittenberg, Nathan J.; Oh, Sang-Hyun; Jeon, Noo Li; Lee, Byoungho; Parikh, Atul N.; Lee, Sin-Doo

    2014-07-01

    During vesicular trafficking and release of enveloped viruses, the budding and fission processes dynamically remodel the donor cell membrane in a protein- or a lipid-mediated manner. In all cases, in addition to the generation or relief of the curvature stress, the buds recruit specific lipids and proteins from the donor membrane through restricted diffusion for the development of a ring-type raft domain of closed topology. Here, by reconstituting the bud topography in a model membrane, we demonstrate the preferential localization of cholesterol- and sphingomyelin-enriched microdomains in the collar band of the bud-neck interfaced with the donor membrane. The geometrical approach to the recapitulation of the dynamic membrane reorganization, resulting from the local radii of curvatures from nanometre-to-micrometre scales, offers important clues for understanding the active roles of the bud topography in the sorting and migration machinery of key signalling proteins involved in membrane budding.

  20. Modelling Meso-Scale Diffusion Processes in Stochastic Fluid Bio-Membranes

    CERN Document Server

    Rafii-Tabar, H

    1999-01-01

    The space-time dynamics of rigid inhomogeneities (inclusions) free to move in a randomly fluctuating fluid bio-membrane is derived and numerically simulated as a function of the membrane shape changes. Both vertically placed (embedded) inclusions and horizontally placed (surface) inclusions are considered. The energetics of the membrane, as a two-dimensional (2D) meso-scale continuum sheet, is described by the Canham-Helfrich Hamiltonian, with the membrane height function treated as a stochastic process. The diffusion parameter of this process acts as the link coupling the membrane shape fluctuations to the kinematics of the inclusions. The latter is described via Ito stochastic differential equation. In addition to stochastic forces, the inclusions also experience membrane-induced deterministic forces. Our aim is to simulate the diffusion-driven aggregation of inclusions and show how the external inclusions arrive at the sites of the embedded inclusions. The model has potential use in such emerging fields as...

  1. Human intestinal cell monolayers are preferentially sensitive to disruption of barrier function from basolateral exposure to cholic acid: correlation with membrane transport and transepithelial secretion.

    Science.gov (United States)

    Lowes, S; Simmons, N L

    2001-11-01

    Unconjugated bile acids such as cholic acid cause diarrhoea, mucosal irritation and toxicity. We sought to define the mechanism of cholate permeation across intestinal mucosal cells to understand how cellular exposure and accumulation are deleterious to mucosal function. Human intestinal Caco-2 and T84 cell monolayers were prepared by high-density seeding and cultured for >14 days on permeable culture supports. Cholate transport and cellular accumulation were determined using [3H]cholic acid. Epithelial barrier function was assessed by measuring transepithelial electrical resistance (Rt) and [14C]mannitol fluxes. Exposure of Caco-2 epithelia to serosal cholate caused a dose- and time-dependent disruption of barrier function. Apical exposure was without disruptive effect. Similar responses were observed for T84 epithelia. Cholate was preferentially accumulated across the basolateral surfaces in both Caco-2 and T84 cells, but was subject to active transepithelial secretion in Caco-2 monolayers only. Net secretion was substantially reduced by ATP depletion, showed saturation kinetics, and was subject to competitive inhibition by other bile acids. Cholate secretion was also sensitive to inhibition by the leukotriene antagonist MK-571 but not by digoxin, suggesting that MRP2, not MDR1, was responsible. RT-PCR and Western blotting confirmed MRP2 expression in Caco-2 epithelia but indicated its apparent absence from T84 cells.

  2. Prenatal ethanol exposure disrupts intraneocortical circuitry, cortical gene expression, and behavior in a mouse model of FASD.

    Science.gov (United States)

    El Shawa, Hani; Abbott, Charles W; Huffman, Kelly J

    2013-11-27

    In utero ethanol exposure from a mother's consumption of alcoholic beverages impacts brain and cognitive development, creating a range of deficits in the child (Levitt, 1998; Lebel et al., 2012). Children diagnosed with fetal alcohol spectrum disorders (FASD) are often born with facial dysmorphology and may exhibit cognitive, behavioral, and motor deficits from ethanol-related neurobiological damage in early development. Prenatal ethanol exposure (PrEE) is the number one cause of preventable mental and intellectual dysfunction globally, therefore the neurobiological underpinnings warrant systematic research. We document novel anatomical and gene expression abnormalities in the neocortex of newborn mice exposed to ethanol in utero. This is the first study to demonstrate large-scale changes in intraneocortical connections and disruption of normal patterns of neocortical gene expression in any prenatal ethanol exposure animal model. Neuroanatomical defects and abnormal neocortical RZRβ, Id2, and Cadherin8 expression patterns are observed in PrEE newborns, and abnormal behavior is present in 20-d-old PrEE mice. The vast network of neocortical connections is responsible for high-level sensory and motor processing as well as complex cognitive thought and behavior in humans. Disruptions to this network from PrEE-related changes in gene expression may underlie some of the cognitive-behavioral phenotypes observed in children with FASD.

  3. A model for the multiwavelength radiation from tidal disruption event Swift J1644+57

    CERN Document Server

    Kumar, P; Bosnjak, Z; Piran, T

    2013-01-01

    Gamma-ray observations of a stellar tidal disruption event (TDE) detected by the Swift satellite and follow up observations in radio, mm, infrared and x-ray bands have provided a rich data set to study accretion onto massive blackholes, production of relativistic jets and their interaction with the surrounding medium. The radio and x-ray data for TDE Swift J1644+57 provide a conflicting picture regarding the energy in relativistic jet produced in this event: x-ray data suggest jet energy declining with time as t^{-5/3} whereas the nearly flat lightcurves in radio and mm bands lasting for about 100 days have been interpreted as evidence for the total energy output increasing with time. We show in this work that flat lightcurves don't require addition of energy to decelerating external shock (which produced radio and mm emission via synchrotron process), instead the flat behavior is due to inverse-Compton cooling of electrons by x-ray photons streaming through the external shock; the higher x-ray flux at earlie...

  4. Interactions of a Photochromic Spiropyran with Liposome Model Membranes

    KAUST Repository

    Jonsson, Fabian

    2013-02-19

    The interactions between anionic or zwitterionic liposomes and a water-soluble, DNA-binding photochromic spiropyran are studied using UV/vis absorption and linear dichroism (LD) spectroscopy. The spectral characteristics as well as the kinetics of the thermal isomerization process in the absence and presence of the two different liposome types provide information about the environment and whether or not the spiropyran resides in the liposome membrane. By measuring LD on liposomes deformed and aligned by shear flow, further insight is obtained about interaction and binding geometry of the spiropyran at the lipid membranes. We show that the membrane interactions differ between the two types of liposomes used as well as the isomeric forms of the spiropyran photoswitch. © 2013 American Chemical Society.

  5. [Membrane-based photochemical systems as models for photosynthetic cells

    Energy Technology Data Exchange (ETDEWEB)

    Hurst, J.K.

    1992-01-01

    The objectives of this research are to improve our conceptual view of the ways in which membranes and interfaces can be used to control chemical reactivity. We have focused on understanding three elementary processes that are central to developing membrane-based integrated chemical systems for water photolysis or related photoconversion/photostorage processes. Specifically, we have sought to identify: the influence of interfaces upon charge separation/recombination reactions, pathways for transmembrane charge separation across hydrocarbon bilayer membranes, and mechanisms of water oxidation catalyzed by transition metal coordination complexes. Historically, the chemical dynamics of each of these processes has been poorly understood, with numerous unresolved issues and conflicting viewpoints appearing in the literature. As described in this report our recent research has led to considerable clarification of the underlying reaction mechanisms.

  6. Disruption of Pseudomonas putida by high pressure homogenization: a comparison of the predictive capacity of three process models for the efficient release of arginine deiminase.

    Science.gov (United States)

    Patil, Mahesh D; Patel, Gopal; Surywanshi, Balaji; Shaikh, Naeem; Garg, Prabha; Chisti, Yusuf; Banerjee, Uttam Chand

    2016-12-01

    Disruption of Pseudomonas putida KT2440 by high-pressure homogenization in a French press is discussed for the release of arginine deiminase (ADI). The enzyme release response of the disruption process was modelled for the experimental factors of biomass concentration in the broth being disrupted, the homogenization pressure and the number of passes of the cell slurry through the homogenizer. For the same data, the response surface method (RSM), the artificial neural network (ANN) and the support vector machine (SVM) models were compared for their ability to predict the performance parameters of the cell disruption. The ANN model proved to be best for predicting the ADI release. The fractional disruption of the cells was best modelled by the RSM. The fraction of the cells disrupted depended mainly on the operating pressure of the homogenizer. The concentration of the biomass in the slurry was the most influential factor in determining the total protein release. Nearly 27 U/mL of ADI was released within a single pass from slurry with a biomass concentration of 260 g/L at an operating pressure of 510 bar. Using a biomass concentration of 100 g/L, the ADI release by French press was 2.7-fold greater than in a conventional high-speed bead mill. In the French press, the total protein release was 5.8-fold more than in the bead mill. The statistical analysis of the completely unseen data exhibited ANN and SVM modelling as proficient alternatives to RSM for the prediction and generalization of the cell disruption process in French press.

  7. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; Werthner, H.; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  8. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; H. Werthner; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  9. Lipid-packing perturbation of model membranes by pH-responsive antimicrobial peptides.

    Science.gov (United States)

    Alvares, Dayane S; Viegas, Taisa Giordano; Ruggiero Neto, João

    2017-08-29

    The indiscriminate use of conventional antibiotics is leading to an increase in the number of resistant bacterial strains, motivating the search for new compounds to overcome this challenging problem. Antimicrobial peptides, acting only in the lipid phase of membranes without requiring specific membrane receptors as do conventional antibiotics, have shown great potential as possible substituents of these drugs. These peptides are in general rich in basic and hydrophobic residues forming an amphipathic structure when in contact with membranes. The outer leaflet of the prokaryotic cell membrane is rich in anionic lipids, while the surface of the eukaryotic cell is zwitterionic. Due to their positive net charge, many of these peptides are selective to the prokaryotic membrane. Notwithstanding this preference for anionic membranes, some of them can also act on neutral ones, hampering their therapeutic use. In addition to the electrostatic interaction driving peptide adsorption by the membrane, the ability of the peptide to perturb lipid packing is of paramount importance in their capacity to induce cell lysis, which is strongly dependent on electrostatic and hydrophobic interactions. In the present research, we revised the adsorption of antimicrobial peptides by model membranes as well as the perturbation that they induce in lipid packing. In particular, we focused on some peptides that have simultaneously acidic and basic residues. The net charges of these peptides are modulated by pH changes and the lipid composition of model membranes. We discuss the experimental approaches used to explore these aspects of lipid membranes using lipid vesicles and lipid monolayer as model membranes.

  10. Analysis of mass transfer characteristics in a tubular membrane using CFD modeling.

    Science.gov (United States)

    Yang, Jixiang; Vedantam, Sreepriya; Spanjers, Henri; Nopens, Ingmar; van Lier, Jules B

    2012-10-01

    In contrast to the large amount of research into aerobic membrane bioreactors, little work has been reported on anaerobic membrane bioreactors (AMBRs). As to the application of membrane bioreactors, membrane fouling is a key issue. Membrane fouling generally occurs more seriously in AMBRs than in aerobic membrane bioreactors. However, membrane fouling could be managed through the application of suitable shear stress that can be introduced by the application of a two-phase flow. When the two-phase flow is applied in AMBRs, little is known about the mass transfer characteristics, which is of particular importance, in tubular membranes of AMBRs. In our present work, we have employed fluid dynamic modeling to analyze the mass transfer characteristics in the tubular membrane of a side stream AMBR in which, gas-lift two-phase flow was applied. The modeling indicated that the mass transfer capacity at the membrane surface at the noses of gas bubbles was higher than the mass transfer capacity at the tails of the bubbles, which is in contrast to the results when water instead of sludge is applied. At the given mass transfer rate, the filterability of the sludge was found to have a strong influence on the transmembrane pressure at a steady flux. In addition, the model also showed that the shear stress in the internal space of the tubular membrane was mainly around 20 Pa but could be as high as about 40 Pa due to gas bubble movements. Nonetheless, at these shear stresses a stable particle size distribution was found for sludge particles.

  11. Modeling the improvement of ultrafiltration membrane mass transfer when using biofiltration pretreatment in surface water applications.

    Science.gov (United States)

    Netcher, Andrea C; Duranceau, Steven J

    2016-03-01

    In surface water treatment, ultrafiltration (UF) membranes are widely used because of their ability to supply safe drinking water. Although UF membranes produce high-quality water, their efficiency is limited by fouling. Improving UF filtrate productivity is economically desirable and has been attempted by incorporating sustainable biofiltration processes as pretreatment to UF with varying success. The availability of models that can be applied to describe the effectiveness of biofiltration on membrane mass transfer are lacking. In this work, UF water productivity was empirically modeled as a function of biofilter feed water quality using either a quadratic or Gaussian relationship. UF membrane mass transfer variability was found to be governed by the dimensionless mass ratio between the alkalinity (ALK) and dissolved organic carbon (DOC). UF membrane productivity was optimized when the biofilter feed water ALK to DOC ratio fell between 10 and 14. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Ice Formation in Model Biological Membranes in the Presence of Cryoprotectors

    CERN Document Server

    Kiselev, M A; Kisselev, A M; Ollivon, M

    2000-01-01

    Ice formation in model biological membranes is studied by SAXS and WAXS in the presence of cryoprotectors: dimethyl sulfoxide and glycerol. Three types of phospholipid membranes: DPPC, DMPC, DSPC are chosen for the investigation as well-studied model biological membranes. A special cryostat is used for sample cooling from 14.1C to -55.4C. The ice formation is only detected by WAXS in binary phospholipid/water and ternary phospholipid/cryoprotector/water systems in the condition of excess solvent. Ice formation in a binary phospholipid/water system creates an abrupt decrease of the membrane repeat distance by delta-d, so-called ice-induced dehydration of intermembrane space. The value of delta-d decreases as the cryoprotector concentration increases. The formation of ice does not influence the membrane structure (delta-d = 0) for cryoprotector mole fractions higher than 0.05.

  13. Free energy difference in indolicidin attraction to eukaryotic and prokaryotic model cell membranes.

    Science.gov (United States)

    Yeh, In-Chul; Ripoll, Daniel R; Wallqvist, Anders

    2012-03-15

    We analyzed the thermodynamic and structural determinants of indolicidin interactions with eukaryotic and prokaryotic cell membranes using a series of atomistically detailed molecular dynamics simulations. We used quartz-supported bilayers with two different compositions of zwitterionic and anionic phospholipids as model eukaryotic and prokaryotic cell membranes. Indolicidin was preferentially attracted to the model prokaryotic cell membrane in contrast to the weak adsorption on the eukaryotic membrane. The nature of the indolicidin surface adsorption depended on an electrostatic guiding component, an attractive enthalpic component derived from van der Waals interactions, and a balance between entropic factors related to peptide confinement at the interface and counterion release from the bilayer surface. Thus, whereas we attributed the specificity of the indolicidin/membrane interaction to electrostatics, these interactions were not the sole contributors to the free energy of adsorption. Instead, a balance between an attractive van der Waals enthalpic component and a repulsive entropic component determined the overall strength of indolicidin adsorption.

  14. Models of natural computation : gene assembly and membrane systems

    NARCIS (Netherlands)

    Brijder, Robert

    2008-01-01

    This thesis is concerned with two research areas in natural computing: the computational nature of gene assembly and membrane computing. Gene assembly is a process occurring in unicellular organisms called ciliates. During this process genes are transformed through cut-and-paste operations. We

  15. Trafficking of Intracellular Membranes: Mass action model of virus fusion

    NARCIS (Netherlands)

    Nir, Shlomo; Duzgunes, Nejat; Hoekstra, Dick; Ramalho-Santos, Joao; Pedroso de Lima, Maria C

    1995-01-01

    :Shlomo Nir, Nejat Düzgüneş, Dick Hoekstra, João Ramalho-Santos, Maria C. Pedroso de Lima The purpose of this presentation is to describe procedures of analysis of final extents and kinetics of virus fusion with target membranes. The presentation of results will focus on deductions from studies of f

  16. Partitioning of Lipids at Domain Boundaries in Model Membranes

    NARCIS (Netherlands)

    Schafer, Lars V.; Marrink, Siewert J.

    2010-01-01

    Line-active molecules ("linactants") that bind to the boundary interface between different fluid lipid domains in membranes have a strong potential as regulators of the lateral heterogeneity that is important for many biological processes. Here, we use molecular dynamics simulations in combination w

  17. Models of natural computation : gene assembly and membrane systems

    NARCIS (Netherlands)

    Brijder, Robert

    2008-01-01

    This thesis is concerned with two research areas in natural computing: the computational nature of gene assembly and membrane computing. Gene assembly is a process occurring in unicellular organisms called ciliates. During this process genes are transformed through cut-and-paste operations. We stud

  18. Liposomal nanocontainers as models for viral infection: monitoring viral genomic RNA transfer through lipid membranes.

    Science.gov (United States)

    Bilek, Gerhard; Matscheko, Nena M; Pickl-Herk, Angela; Weiss, Victor U; Subirats, Xavier; Kenndler, Ernst; Blaas, Dieter

    2011-08-01

    After uptake into target cells, many nonenveloped viruses undergo conformational changes in the low-pH environment of the endocytic compartment. This results in exposure of amphipathic viral peptides and/or hydrophobic protein domains that are inserted into and either disrupt or perforate the vesicular membranes. The viral nucleic acids thereby gain access to the cytosol and initiate replication. We here demonstrate the in vitro transfer of the single-stranded positive-sense RNA genome of human rhinovirus 2 into liposomes decorated with recombinant very-low-density lipoprotein receptor fragments. Membrane-attached virions were exposed to pH 5.4, mimicking the in vivo pH environment of late endosomes. This triggered the release of the RNA whose arrival in the liposomal lumen was detected via in situ cDNA synthesis by encapsulated reverse transcriptase. Subsequently, cDNA was PCR amplified. At a low ratio between virions and lipids, RNA transfer was positively correlated with virus concentration. However, membranes became leaky at higher virus concentrations, which resulted in decreased cDNA synthesis. In accordance with earlier in vivo data, the RNA passes through the lipid membrane without causing gross damage to vesicles at physiologically relevant virus concentrations.

  19. Mathematical model analysis on the enhancement of aeration efficiency using ladder-type flat membrane module forms in the Submerged Membrane Bio-reactor(SMBR)

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The cross-flow shearing action produced from the inferior aeration in the Submerged Membrane Bio-reactor(SMBR) is an effective way to further improve anti-fouling effects of membrane modules.Based on the widely-applied vertical structure of flat membrane modules,improvements are made that ladder-type flat membrane structure is designed with a certain inclined angle θ so that the cross-flow velocity of bubble near the membrane surface can be held,and the intensity and times of elastic colli-sion between bubbles and membrane surface can be increased.This can improve scouring action of membrane surface on aeration and reduce energy consumption of strong aeration in SMBR.By de-ducing and improving the mathematics model of collision between bubble and vertical flat put forward by Vries,the relatively suitable incline angle θ under certain aeration place and in certain size rang of bubble can be obtained with the computer iterative calculation technology.Finally,for many groups of ladder-type flat membrane in parallel placement in the practical application of SMBR,some sugges-tions are offered:the interval distance of membrane modules is 8―15 mm,and aeration should be op-erated at 5―7 mm among membrane modules,and the optimal design angle of trapeziform membrane is 1.7°―2.5°.

  20. The Classroom Check-up: A Classwide Teacher Consultation Model for Increasing Praise and Decreasing Disruptive Behavior.

    Science.gov (United States)

    Reinke, Wendy M; Lewis-Palmer, Teri; Merrell, Kenneth

    2008-01-01

    School-based consultation typically focuses on individual student problems and on a small number of students rather than on changing the classroom system. The Classroom Check-up (CCU) was developed as a classwide consultation model to address the need for classroom level support while minimizing treatment integrity problems common to school-based consultation. The purpose of the study was to evaluate the effects of the CCU and Visual Performance Feedback on teacher and student behavior. Results indicated that implementation of the CCU plus Visual Performance Feedback increased teacher implementation of classroom management strategies, including increased use of praise, use of behavior specific praise, and decreased use of reprimands. Further, these changes in teacher behavior contributed to decreases in classroom disruptive behavior. The results are encouraging because they suggest that consultation at the classroom level can create meaningful teacher and student behavior change.

  1. Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

    Directory of Open Access Journals (Sweden)

    Morris Brian J

    2011-05-01

    Full Text Available Abstract Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. Results We present and justify a new technique for comparing pairs of networks--in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD, which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA receptor antagonist phencyclidine (PCP. This provides us with a means to quantify which predefined metabolic pathways (Kyoto

  2. A stochastic mathematical model to locate field hospitals under disruption uncertainty for large-scale disaster preparedness

    Directory of Open Access Journals (Sweden)

    Nezir Aydin

    2016-03-01

    Full Text Available In this study, we consider field hospital location decisions for emergency treatment points in response to large scale disasters. Specifically, we developed a two-stage stochastic model that determines the number and locations of field hospitals and the allocation of injured victims to these field hospitals. Our model considers the locations as well as the failings of the existing public hospitals while deciding on the location of field hospitals that are anticipated to be opened. The model that we developed is a variant of the P-median location model and it integrates capacity restrictions both on field hospitals that are planned to be opened and the disruptions that occur in existing public hospitals. We conducted experiments to demonstrate how the proposed model can be utilized in practice in a real life problem case scenario. Results show the effects of the failings of existing hospitals, the level of failure probability and the capacity of projected field hospitals to deal with the assessment of any given emergency treatment system’s performance. Crucially, it also specifically provides an assessment on the average distance within which a victim needs to be transferred in order to be treated properly and then from this assessment, the proportion of total satisfied demand is then calculated.

  3. Establishment of the model of vascular endothelial cell membrane chromatography and its preliminary application

    Institute of Scientific and Technical Information of China (English)

    LI YiPing; HE LangChong

    2007-01-01

    A model of vascular endothelial cell membrane chromatography was established by using an ECV304 cell membrane stationary phase (ECV304 CMSP) prepared by immobilizing the ECV304 cell membrane onto the surface of silica carrier. The surface and chromatographic characteristics of ECV304 CMSP were studied. The active component from Caulophyllum robustum was screened by using the model of vascular endothelial cell membrane chromatography. The interaction between the active component and membrane receptor was determined by using a replace experiments. The effect of the active component was tested by using tube formation of ECV304 cell. The results indicated that the model of ECV304 cell membrane chromatograph (ECV304 CMC) can stimulate the interaction between drug and receptor in vitro and the retention characteristics of taspine as active component was similar to that of model molecule in the model of ECV304 CMC. And therefore, taspine acted on VEGFR2 and inhibited the tube formation of ECV304 cell induced by VEGF. This model can be used to screen definite active component as a screening model.

  4. Mathematical model using non-uniform flow distribution for dynamic protein breakthrough with membrane adsorption media.

    Science.gov (United States)

    Schneiderman, Steven; Varadaraju, Hemanthram; Zhang, Lifeng; Fong, Hao; Menkhaus, Todd J

    2011-12-23

    A mathematical model has been investigated to predict protein breakthrough during membrane adsorption/chromatography operations. The new model incorporates a non-uniform boundary condition at the column inlet to help describe the deviation from plug flow within real membrane adsorption devices. The model provides estimated breakthrough profiles of a binding protein while explicitly accounting for non-uniform flow at the inlet of the separation operation by modeling the flow distribution by a polynomial. We have explored experimental breakthrough curves produced using commercial membrane adsorption devices, as well as novel adsorption media of nanolayered nanofiber membranes, and compare them to model predictions. Further, the impact of using various simplifying assumptions is considered, which can have a dramatic effect on the accuracy and predictive ability of the proposed models. The new model, using only simple batch equilibrium and kinetic uptake rate data, along with membrane properties, is able to accurately predict the non-uniform and unsymmetrical shape for protein breakthrough during operation of membrane adsorption/chromatography devices. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Exploring large-scale phenomena in composite membranes through an efficient implicit-solvent model

    Science.gov (United States)

    Laradji, Mohamed; Kumar, P. B. Sunil; Spangler, Eric J.

    2016-07-01

    Several microscopic and mesoscale models have been introduced in the past to investigate various phenomena in lipid membranes. Most of these models account for the solvent explicitly. Since in a typical molecular dynamics simulation, the majority of particles belong to the solvent, much of the computational effort in these simulations is devoted for calculating forces between solvent particles. To overcome this problem, several implicit-solvent mesoscale models for lipid membranes have been proposed during the last few years. In the present article, we review an efficient coarse-grained implicit-solvent model we introduced earlier for studies of lipid membranes. In this model, lipid molecules are coarse-grained into short semi-flexible chains of beads with soft interactions. Through molecular dynamics simulations, the model is used to investigate the thermal, structural and elastic properties of lipid membranes. We will also review here few studies, based on this model, of the phase behavior of nanoscale liposomes, cytoskeleton-induced blebbing in lipid membranes, as well as nanoparticles wrapping and endocytosis by tensionless lipid membranes. Topical Review article submitted to the Journal of Physics D: Applied Physics, May 9, 2016

  6. Sleep-like behavior and 24-h rhythm disruption in the Tc1 mouse model of Down syndrome.

    Science.gov (United States)

    Heise, I; Fisher, S P; Banks, G T; Wells, S; Peirson, S N; Foster, R G; Nolan, P M

    2015-02-01

    Down syndrome is a common disorder associated with intellectual disability in humans. Among a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24-h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans-species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterized in Tc1 mice. Using both circadian wheel-running analysis and video-based sleep scoring, we showed that these mice exhibited fragmented patterns of sleep-like behaviour during the light phase of a 12:12-h light/dark (LD) cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night-time was less effective in inducing sleep-like behaviour in Tc1 animals than in wild-type controls. In wheel-running analysis, free running in constant light (LL) or constant darkness (DD) showed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in LD and in DD. Our data confirm that Tc1 mice express sleep-related phenotypes that are comparable with those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes, while circadian period under constant lighting conditions is essentially unaffected. © 2015 Medical Research Council. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

  7. A Complete Transport Validated Model on a Zeolite Membrane for Carbon Dioxide Permeance and Capture

    CERN Document Server

    Gkanas, Evangelos I; Stubos, Athanasios K; Makridis, Sofoklis S

    2013-01-01

    The CO2 emissions from major industries cause serious global environment problems and their mitigation is urgently needed. The use of zeolite membranes is a very efficient way in order to capture CO2 from some flue gases. The dominant transport mechanism at low temperature andor high pressure is the diffusion through the membrane. This procedure can be divided in three steps: Adsorption of the molecules of the species in the surface of the membrane, then a driving force gives a path where the species follow inside the membrane and finally the species desorbed from the surface of the membrane. The current work is aimed at developing a simulation model for the CO2 transport through a zeolite membrane and estimate the diffusion phenomenon through a very thin membrane of 150 nm in a Wicke-Kallenbach cell. The cell is cylindrical in shape with diameter of 19 mm and consists of a retentate gas chamber, a permeate gas chamber which are separated by a cylindrical zeolite membrane. This apparatus have been modeled wit...

  8. Viroporins, Examples of the Two-Stage Membrane Protein Folding Model

    Directory of Open Access Journals (Sweden)

    Luis Martinez-Gil

    2015-06-01

    Full Text Available Viroporins are small, α-helical, hydrophobic virus encoded proteins, engineered to form homo-oligomeric hydrophilic pores in the host membrane. Viroporins participate in multiple steps of the viral life cycle, from entry to budding. As any other membrane protein, viroporins have to find the way to bury their hydrophobic regions into the lipid bilayer. Once within the membrane, the hydrophobic helices of viroporins interact with each other to form higher ordered structures required to correctly perform their porating activities. This two-step process resembles the two-stage model proposed for membrane protein folding by Engelman and Poppot. In this review we use the membrane protein folding model as a leading thread to analyze the mechanism and forces behind the membrane insertion and folding of viroporins. We start by describing the transmembrane segment architecture of viroporins, including the number and sequence characteristics of their membrane-spanning domains. Next, we connect the differences found among viroporin families to their viral genome organization, and finalize focusing on the pathways used by viroporins in their way to the membrane and on the transmembrane helix-helix interactions required to achieve proper folding and assembly.

  9. Modeling of Pervaporation Separation Benzene from Dilute Aqueous Solutions Through Polydimethylsiloxane Membranes

    Institute of Scientific and Technical Information of China (English)

    彭福兵; 姜忠义

    2005-01-01

    A modified solution-diffusion model was established based on Flory-Huggins thermodynamic theory and Fujita's free volume theory. This model was used for description of the mass transfer of removal benzene from dilute aqueous solutions through polydimethylsiloxane (PDMS) membranes. The effect of component concentration on the interaction parameter between components, that of the polymer membrane on the selectivity to benzene, and that of feed concentration and temperature on the permeation flux and separation factor of benzene/water through PDMS membranes were investigated. Calculated pervaporation fluxes of benzene and water were compared with the experimental results and were in good agreement with the experimental data.

  10. The absence of p53 during Human Cytomegalovirus infection leads to decreased UL53 expression, disrupting UL50 localization to the inner nuclear membrane, and thereby inhibiting capsid nuclear egress.

    Science.gov (United States)

    Kuan, Man I; O'Dowd, John M; Fortunato, Elizabeth A

    2016-10-01

    Our electron microscopy study (Kuan et al., 2016) found HCMV nuclear capsid egress was significantly reduced in p53 knockout cells (p53KOs), correlating with inhibited formation of infoldings of the inner nuclear membrane (IINMs). Molecular examination of these phenomena has found p53KOs expressed UL97 and phosphorylated lamins, however the lamina failed to remodel. The nuclear egress complex (NEC) protein UL50 was expressed in almost all cells. UL50 re-localized to the inner nuclear membrane (INM) in ~90% of wt cells, but only ~35% of p53KOs. UL53 expression was significantly reduced in p53KOs, and cells lacking UL50 nuclear staining, expressed no UL53. Re-introduction of p53 into p53KOs largely recovered UL53 positivity and UL50 nuclear re-localization. Nuclear rim located UL50/53 puncta, which co-localized with the major capsid protein, were largely absent in p53KOs. We believe these puncta were IINMs. In the absence of p53, UL53 expression was inhibited, disrupting formation of the NEC/IINMs, and reducing functional virion secretion.

  11. A Mathematical Model for Diffusion-Controlled Monolithic Matrix Coated with outer Membrane System

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A release model for diffusion-controlled monolithic matrix coated with outer membrane system is proposed and solved by using the refined double integral method. The calculated results are in satisfactory agreement with the experimental release data. The present model can be well used to describe the release process for all cd/cs values. In addition, the release effects of the monolithic matrix coated with outer membrane system are discussed theoretically.

  12. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    While projects of governance by transparency have become widespread over the past decades, theyare usually investigated and theorized in isolation from the wider field of visibility and surveillancein which they are embedded. Building on theories of governance, visibility and surveillance...... appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...... of surveillance produce new forms of governing, potentiallywidening the space of manoeuvring for corporations....

  13. A macroscopic model of proton transport through the membrane-ionomer interface of a polymer electrolyte membrane fuel cell

    Science.gov (United States)

    Kumar, Milan; Edwards, Brian J.; Paddison, Stephen J.

    2013-02-01

    The membrane-ionomer interface is the critical interlink of the electrodes and catalyst to the polymer electrolyte membrane (PEM); together forming the membrane electrode assembly in current state-of-the-art PEM fuel cells. In this paper, proton conduction through the interface is investigated to understand its effect on the performance of a PEM fuel cell. The water containing domains at this interface were modeled as cylindrical pores/channels with the anionic groups (i.e., -SO3-) assumed to be fixed on the pore wall. The interactions of each species with all other species and an applied external field were examined. Molecular-based interaction potential energies were computed in a small test element of the pore and were scaled up in terms of macroscopic variables. Evolution equations of the density and momentum of the species (water molecules and hydronium ions) were derived within a framework of nonequilibrium thermodynamics. The resulting evolution equations for the species were solved analytically using an order-of-magnitude analysis to obtain an expression for the proton conductivity. Results show that the conductivity increases with increasing water content and pore radius, and strongly depends on the separation distance between the sulfonate groups and their distribution on the pore wall. It was also determined that the conductivity of two similar pores of different radii in series is limited by the pore with the smaller radius.

  14. Unmasking the soil cover's disruption by use of a dynamic model of measurement aerospace parameters of ground vegetation

    Directory of Open Access Journals (Sweden)

    E. V. Vysotskaya

    2016-03-01

    Full Text Available The "Introduction" describes topicality and importance of revealing the soil cover's disruption for a wide range of fields. It was shown that spectral brightness and colorimetric parameters of ground vegetation can be used for this task. However, a traditional scheme of data processing for remote sensing requires a long-term observations and can not always be applied, if quick decision-making is necessary or there is lack of information. Such cases require the use of special methods, one of which is a dynamic model developed with authors' participation based on the following basic relationships: (+,- (-, - (+, 0, (-, 0 (0,0. The section "Brief description of a dynamic model" describes the basic principles of dynamic systems used to solve the problem. Using above-mentioned relationships, the dynamics of a system consisting of several components is constructed and its main properties are listed. The main feature of this model is that the identification of structure and parameters of the dynamic system does not required sequential order of observations (as for models based on time series. This feature of the model enables for identifying the system's parameters of dynamics of the natural system to use information from a single picture taken from the spacecraft rather than long-term observations. The section "Materials and Methods" describes specific colorimetric parameters used to analyze the vegetation cover. The section "Obtained results" contains an example of the model's application to a satellite image for detecting the differences in two sites of a field with vegetation. One site is a recultivated area near the liquidated gas-oil well, another site is non-recultivated area at a considerable distance from the well (500-1000 m. The simulation results are described by eight signed graphs (4 graphs for each sites, whose structure allows to identify the system differences between the two cases. The section "Conclusions" summarizes the results of

  15. Modeling and Design Optimization of Multifunctional Membrane Reactors for Direct Methane Aromatization.

    Science.gov (United States)

    Fouty, Nicholas J; Carrasco, Juan C; Lima, Fernando V

    2017-08-29

    Due to the recent increase of natural gas production in the U.S., utilizing natural gas for higher-value chemicals has become imperative. Direct methane aromatization (DMA) is a promising process used to convert methane to benzene, but it is limited by low conversion of methane and rapid catalyst deactivation by coking. Past work has shown that membrane separation of the hydrogen produced in the DMA reactions can dramatically increase the methane conversion by shifting the equilibrium toward the products, but it also increases coke production. Oxygen introduction into the system has been shown to inhibit this coke production while not inhibiting the benzene production. This paper introduces a novel mathematical model and design to employ both methods in a multifunctional membrane reactor to push the DMA process into further viability. Multifunctional membrane reactors, in this case, are reactors where two different separations occur using two differently selective membranes, on which no systems studies have been found. The proposed multifunctional membrane design incorporates a hydrogen-selective membrane on the outer wall of the reaction zone, and an inner tube filled with airflow surrounded by an oxygen-selective membrane in the middle of the reactor. The design is shown to increase conversion via hydrogen removal by around 100%, and decrease coke production via oxygen addition by 10% when compared to a tubular reactor without any membranes. Optimization studies are performed to determine the best reactor design based on methane conversion, along with coke and benzene production. The obtained optimal design considers a small reactor (length = 25 cm, diameter of reaction tube = 0.7 cm) to subvert coke production and consumption of the product benzene as well as a high permeance (0.01 mol/s·m²·atm(1/4)) through the hydrogen-permeable membrane. This modeling and design approach sets the stage for guiding further development of multifunctional membrane reactor

  16. A bilayer-couple model of bacterial outer membrane vesicle biogenesis.

    Science.gov (United States)

    Schertzer, Jeffrey W; Whiteley, Marvin

    2012-01-01

    Gram-negative bacteria naturally produce outer membrane vesicles (OMVs) that arise through bulging and pinching off of the outer membrane. OMVs have several biological functions for bacteria, most notably as trafficking vehicles for toxins, antimicrobials, and signaling molecules. While their biological roles are now appreciated, the mechanism of OMV formation has not been fully elucidated. We recently demonstrated that the signaling molecule 2-heptyl-3-hydroxy-4-quinolone (PQS) is required for OMV biogenesis in P. aeruginosa. We hypothesized that PQS stimulates OMV formation through direct interaction with the outer leaflet of the outer membrane. To test this hypothesis, we employed a red blood cell (RBC) model that has been used extensively to study small-molecule-membrane interactions. Our results revealed that addition of PQS to RBCs induced membrane curvature, resulting in the formation of membrane spicules (spikes), consistent with small molecules that are inserted stably into the outer leaflet of the membrane. Radiotracer experiments demonstrated that sufficient PQS was inserted into the membrane to account for this curvature and that curvature induction was specific to PQS structure. These data suggest that a low rate of interleaflet flip-flop forces PQS to accumulate in and expand the outer leaflet relative to the inner leaflet, thus inducing membrane curvature. In support of PQS-mediated outer leaflet expansion, the PQS effect was antagonized by chlorpromazine, a molecule known to be preferentially inserted into the inner leaflet. Based on these data, we propose a bilayer-couple model to describe P. aeruginosa OMV biogenesis and suggest that this is a general mechanism for bacterial OMV formation. Despite the ubiquity and importance of outer membrane vesicle (OMV) production in Gram-negative bacteria, the molecular details of OMV biogenesis are not fully understood. Early experiments showed that 2-heptyl-3-hydroxy-4-quinolone (PQS) induces OMV formation

  17. Anisotropic viscoelastic models in large deformation for architectured membranes

    Science.gov (United States)

    Rebouah, Marie; Chagnon, Gregory; Heuillet, Patrick

    2016-08-01

    Due to the industrial elaboration process, membranes can have an in-plane anisotropic mechanical behaviour. In this paper, anisotropic membranes elaborated with two different materials were developed either by calendering or by inducing a force in one direction during the process. Experimental tests are developed to measure the differences of mechanical behaviour for both materials in different in-plane properties: stiffness, viscoelasticity and stress-softening. A uniaxial formulation is developed, and a homogenisation by means of a sphere unit approach is used to propose a three-dimensional formulation to represent the materials behaviour. An evolution of the mechanical parameters, depending on the direction, is imposed to reproduce the anisotropic behaviour of the materials. Comparison with experimental data highlights very promising results.

  18. Putting Theory to the Test: Modeling a Multidimensional, Developmentally-Based Approach to Preschool Disruptive Behavior

    Science.gov (United States)

    Wakschlag, Lauren S.; Henry, David B.; Tolan, Patrick H.; Carter, Alice S.; Burns, James L.; Briggs-Gowan, Margaret J.

    2012-01-01

    Objective: There is increasing emphasis on dimensional conceptualizations of psychopathology, but empirical evidence of their utility is just emerging. In particular, although a range of multidimensional models have been proposed, the relative fit of competing models has rarely been tested. Furthermore, developmental considerations have received…

  19. Putting Theory to the Test: Modeling a Multidimensional, Developmentally-Based Approach to Preschool Disruptive Behavior

    Science.gov (United States)

    Wakschlag, Lauren S.; Henry, David B.; Tolan, Patrick H.; Carter, Alice S.; Burns, James L.; Briggs-Gowan, Margaret J.

    2012-01-01

    Objective: There is increasing emphasis on dimensional conceptualizations of psychopathology, but empirical evidence of their utility is just emerging. In particular, although a range of multidimensional models have been proposed, the relative fit of competing models has rarely been tested. Furthermore, developmental considerations have received…

  20. Analyzing development of working models for disrupted attachments: the case of hidden family violence.

    Science.gov (United States)

    Ayoub, Catherine C; Fischer, Kurt W; O'Connor, Erin E

    2003-06-01

    This article offers a developmental model of attachment theory rooted in dynamic skill theory. Dynamic skill theory is based on the assumption that people do not have integrated, fundamentally logical minds, but instead develop along naturally fractionated strands of a web. Contrary to traditional interpretations of attachment theory, dynamic skill theory proposes that individuals continue to modify their working models of attachments throughout the lifespan. In particular, working models of close relationships develop systematically through a series of skill levels such that the skills vary across strands in the web and will not automatically form a unified whole. The continual modification of working models is particularly pertinent for the consequences of hidden family violence for individuals' development. Dynamic skill theory shows how trauma can produce not developmental delay or fixation, as has been proposed previously, but instead the construction of advanced, complex working models.

  1. Enhancement of the Computational Efficiency of Membrane Computing Models

    Science.gov (United States)

    2007-04-01

    molecular inhibition of dopamine (e.g., a neurotransmitter ) transporter has been linked to the euphoria and the reinforcing properties of psycho...stimulants like cocaine and amphetamines . Also, major classes of antidepressants act by inhibiting norepinepherine and/or serotonin (other two...their intracellular contents after they are placed in a hypotonic media. These membranes reseal themselves by an unknown mechanism , yielding a closed

  2. Nanobiohybrids: New Model Systems for Membranes and Sensors

    Science.gov (United States)

    2005-06-01

    15358, 2004 137. S.R. Scully, M.T. Lloyd, R. Herrera, E.P. Giannelis and G.G. Malliaras, "Dye Sensitized Solar Cells Employing a Highly Conductive and...evaluate the sensing capability of our bioinspired membranes, films were formed on interdigitated electrodes (Figure 16) by solvent casting a...SEM picture of the sensor, the response of our sensor to glucose and sucrose microfabricated interdigitated was investigated. No significant

  3. Models and Simulations of C60-Fullerene Plasma Jets for Disruption Mitigation and Magneto-Inertial Fusion

    Science.gov (United States)

    Bogatu, Ioan-Niculae; Galkin, Sergei A.; Kim, Jin-Soo

    2009-11-01

    We present the models and simulation results of C60-fullerene plasma jets proposed to be used for the disruption mitigation on ITER and for magneto-inertial fusion (MIF). The model describing the fast production of a large mass of C60 molecular gas in the pulsed power source by explosive sublimation of C60 micro-grains is detailed. Several aspects of the magnetic ``piston'' model and the 2D interchange (magnetic Rayleigh-Taylor) instability in the rail gun arc dynamics are described. A plasma jet adiabatic expansion model is used to investigate the in-flight three-body recombination during jet transport to the plasma boundary. Our LSP PIC code 3D simulations show that heavy C60 plasmoid penetrates deeply through a transverse magnetic barrier demonstrating self-polarization and magnetic field expulsion effects. The LSP code 3D simulation of two plasma jets head-on injection along a magnetic field lines for MIF are also discussed.

  4. Assessment of the endocrine-disrupting effects of short-chain chlorinated paraffins in in vitro models.

    Science.gov (United States)

    Zhang, Quan; Wang, Jinghua; Zhu, Jianqiang; Liu, Jing; Zhang, Jianyun; Zhao, Meirong

    2016-09-01

    Short-chain chlorinated paraffins (SCCPs), which are candidate persistent organic pollutants (POPs) according to the Stockholm Convention, are of great concern because of their persistent bioaccumulation, long-range transport and potential adverse health effects. However, data on the endocrine-disrupting effects of SCCPs remain scarce. In this study, we first adopted two in vitro models (reporter gene assays and H295R cell line) to investigate the endocrine-disrupting effects of three SCCPs (C10-40.40%, C10-66.10% and C11-43.20%) via receptor mediated and non-receptor mediated pathway. The dual-luciferase reporter gene assay revealed that all test chemicals significantly induced estrogenic effects, which were mediated by estrogen receptor α (ERα), in the following order: C11-43.20%>C10-66.10%>C10-40.40%. Notably, C10-40.40% and C10-66.10% also demonstrated remarkable anti-estrogenic activities. Only C11-43.20% showed glucocorticoid receptor-mediated (GR) antagonistic activity, with a RIC20 value of 2.6×10(-8)mol/L. None of the SCCPs showed any agonistic or antagonistic activities against thyroid receptor β (TRβ). Meanwhile, all test SCCPs stimulated the secretion of 17β-estradiol (E2). Both C10-66.10% and C11-43.20% increased the production of cortisol at a high level in H295R cell lines. In order to explore the possible mechanism underlying the endocrine-disrupting effects of SCCPs through the non-receptor pathway, the mRNA levels of 9 steroidogenic genes were measured by real-time polymerase chain reaction (RT-PCR). StAR, 17βHSD, CYP11A1, CYP11B1, CYP19 and CYP21 were upregulated in a concentration-dependent manner by all chemicals. The data provided here emphasized that comprehensive assessments of the health and ecological risks of emerging contaminants, such as SCCPs, are of great concern and should be investigated further.

  5. Time resolved multiphoton excited fluorescence probes in model membranes

    CERN Document Server

    Bai, Y

    2000-01-01

    Using the time-correlated single-photon counting technique, this thesis reports on a time-resolved fluorescence study of several fluorescent probes successfully employed in membrane research. Concentration and temperature effects on fluorescence anisotropy parameters are demonstrated by DPH, p-terphenyl, alpha-NPO and PPO in DPPC lipid bilayers. Fluorescence anisotropy has shown that trans-stilbene and Rhd 800 have a two-site location in membranes. Multiphoton induced fluorescence of DPH, p-terphenyl, alpha-NPO and v-biphenyl in liposomes was measured using 800nm excitation with a femtosecond Ti:Sapphire laser. P-terphenyl, alpha-NPO and v-biphenyl are new probes for membranes. Comparison of one and multiphoton excitation results has demonstrated higher initial anisotropy with multiphoton excitation than with one-photon excitation. The rotational times were identical for one and multiphoton excitation, indicating the absence of significant local heating or sample perturbation. Excimer formation of alpha-NPO w...

  6. Modelling the Bioelectronic Interface in Engineered Tethered Membranes: From Biosensing to Electroporation.

    Science.gov (United States)

    Hoiles, William; Krishnamurthy, Vikram; Cornell, Bruce

    2015-06-01

    This paper studies the construction and predictive models of three novel measurement platforms: (i) a Pore Formation Measurement Platform (PFMP) for detecting the presence of pore forming proteins and peptides, (ii) the Ion Channel Switch (ICS) biosensor for detecting the presence of analyte molecules in a fluid chamber, and (iii) an Electroporation Measurement Platform (EMP) that provides reliable measurements of the electroporation phenomenon. Common to all three measurement platforms is that they are comprised of an engineered tethered membrane that is formed via a rapid solvent exchange technique allowing the platform to have a lifetime of several months. The membrane is tethered to a gold electrode bioelectronic interface that includes an ionic reservoir separating the membrane and gold surface, allowing the membrane to mimic the physiological response of natural cell membranes. The electrical response of the PFMP, ICS, and EMP are predicted using continuum theories for electrodiffusive flow coupled with boundary conditions for modelling chemical reactions and electrical double layers present at the bioelectronic interface. Experimental measurements are used to validate the predictive accuracy of the dynamic models. These include using the PFMP for measuring the pore formation dynamics of the antimicrobial peptide PGLa and the protein toxin Staphylococcal α-Hemolysin; the ICS biosensor for measuring nano-molar concentrations of streptavidin, ferritin, thyroid stimulating hormone (TSH), and human chorionic gonadotropin (pregnancy hormone hCG); and the EMP for measuring electroporation of membranes with different tethering densities, and membrane compositions.

  7. Multiscale modeling of tumor growth induced by circadian rhythm disruption in epithelial tissue.

    Science.gov (United States)

    Bratsun, D A; Merkuriev, D V; Zakharov, A P; Pismen, L M

    2016-01-01

    We propose a multiscale chemo-mechanical model of cancer tumor development in epithelial tissue. The model is based on the transformation of normal cells into a cancerous state triggered by a local failure of spatial synchronization of the circadian rhythm. The model includes mechanical interactions and a chemical signal exchange between neighboring cells, as well as a division of cells and intercalation that allows for modification of the respective parameters following transformation into the cancerous state. The numerical simulations reproduce different dephasing patterns--spiral waves and quasistationary clustering, with the latter being conducive to cancer formation. Modification of mechanical properties reproduces a distinct behavior of invasive and localized carcinoma.

  8. Modeling and parametric analysis of hollow fiber membrane system for carbon capture from multicomponent flue gas

    KAUST Repository

    Khalilpour, Rajab

    2011-08-12

    The modeling and optimal design/operation of gas membranes for postcombustion carbon capture (PCC) is presented. A systematic methodology is presented for analysis of membrane systems considering multicomponent flue gas with CO 2 as target component. Simplifying assumptions is avoided by namely multicomponent flue gas represented by CO 2/N 2 binary mixture or considering the co/countercurrent flow pattern of hollow-fiber membrane system as mixed flow. Optimal regions of flue gas pressures and membrane area were found within which a technoeconomical process system design could be carried out. High selectivity was found to not necessarily have notable impact on PCC membrane performance, rather, a medium selectivity combined with medium or high permeance could be more advantageous. © 2011 American Institute of Chemical Engineers (AIChE).

  9. Modeling hydrogen starvation conditions in proton-exchange membrane fuel cells

    Science.gov (United States)

    Ohs, Jan Hendrik; Sauter, Ulrich; Maass, Sebastian; Stolten, Detlef

    In this study, a steady state and isothermal 2D-PEM fuel cell model is presented. By simulation of a single cell along the channel and in through-plane direction, its behaviour under hydrogen starvation due to nitrogen dilution is analysed. Under these conditions, carbon corrosion and water electrolysis are observed on the cathode side. This phenomenon, causing severe cell degradation, is known as reverse current decay mechanism in literature. Butler-Volmer equations are used to model the electrochemical reactions. In addition, we account for permeation of gases through the membrane and for the local water content within the membrane. The results show that the membrane potential locally drops in areas starved from hydrogen. This leads to potential gradients >1.2 V between electrode and membrane on the cathode side resulting in significant carbon corrosion and electrolysis reaction rates. The model enables the analysis of sub-stoichiometric states occurring during anode gas recirculation or load transients.

  10. Modeling hydrogen starvation conditions in proton-exchange membrane fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Ohs, Jan Hendrik; Sauter, Ulrich; Maass, Sebastian [Robert Bosch GmbH, Robert-Bosch-Platz 1, 70839 Gerlingen-Schillerhoehe (Germany); Stolten, Detlef [Forschungszentrum Juelich GmbH, IEF-3: Fuel Cells, 52425 Juelich (Germany)

    2011-01-01

    In this study, a steady state and isothermal 2D-PEM fuel cell model is presented. By simulation of a single cell along the channel and in through-plane direction, its behaviour under hydrogen starvation due to nitrogen dilution is analysed. Under these conditions, carbon corrosion and water electrolysis are observed on the cathode side. This phenomenon, causing severe cell degradation, is known as reverse current decay mechanism in literature. Butler-Volmer equations are used to model the electrochemical reactions. In addition, we account for permeation of gases through the membrane and for the local water content within the membrane. The results show that the membrane potential locally drops in areas starved from hydrogen. This leads to potential gradients >1.2 V between electrode and membrane on the cathode side resulting in significant carbon corrosion and electrolysis reaction rates. The model enables the analysis of sub-stoichiometric states occurring during anode gas recirculation or load transients. (author)

  11. Spreading of a chain macromolecule onto a cell membrane by a computer simulation Model

    Science.gov (United States)

    Xie, Jun; Pandey, Ras

    2002-03-01

    Computer simulations are performed to study conformation and dynamics of a relatively large chain macromolecule at the surface of a model membrane - a preliminary attempt to ultimately realistic model for protein on a cell membrane. We use a discrete lattice of size Lx × L × L. The chain molecule of length Lc is modeled by consecutive nodes connected by bonds on the trail of a random walk with appropriate constraints such as excluded volume, energy dependent configurational bias, etc. Monte Carlo method is used to move chains via segmental dynamics, i.e., end-move, kink-jump, crank-shaft, reptation, etc. Membrane substrate is designed by a self-assemble biased short chains on a substrate. Large chain molecule is then driven toward the membrane by a field. We investigate the dynamics of chain macromolecule, spread of its density, and conformation.

  12. Mathematical modeling of liquid/liquid hollow fiber membrane contactor accounting for interfacial transport phenomena: Extraction of lanthanides as a surrogate for actinides

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, J.D.

    1994-08-04

    This report is divided into two parts. The second part is divided into the following sections: experimental protocol; modeling the hollow fiber extractor using film theory; Graetz model of the hollow fiber membrane process; fundamental diffusive-kinetic model; and diffusive liquid membrane device-a rigorous model. The first part is divided into: membrane and membrane process-a concept; metal extraction; kinetics of metal extraction; modeling the membrane contactor; and interfacial phenomenon-boundary conditions-applied to membrane transport.

  13. Modeling Yeast Organelle Membranes and How Lipid Diversity Influences Bilayer Properties.

    Science.gov (United States)

    Monje-Galvan, Viviana; Klauda, Jeffery B

    2015-11-17

    Membrane lipids are important for the health and proper function of cell membranes. We have improved computational membrane models for specific organelles in yeast Saccharomyces cerevisiae to study the effect of lipid diversity on membrane structure and dynamics. Previous molecular dynamics simulations were performed by Jo et al. [(2009) Biophys J. 97, 50-58] on yeast membrane models having six lipid types with compositions averaged between the endoplasmic reticulum (ER) and the plasma membrane (PM). We incorporated ergosterol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol lipids in our models to better describe the unique composition of the PM, ER, and trans-Golgi network (TGN) bilayers of yeast. Our results describe membrane structure based on order parameters (SCD), electron density profiles (EDPs), and lipid packing. The average surface area per lipid decreased from 63.8 ± 0.4 Å(2) in the ER to 47.1 ± 0.3 Å(2) in the PM, while the compressibility modulus (KA) varied in the opposite direction. The high SCD values for the PM lipids indicated a more ordered bilayer core, while the corresponding lipids in the ER and TGN models had lower parameters by a factor of at least 0.7. The hydrophobic core thickness (2DC) as estimated from EDPs is the thickest for PM, which is in agreement with estimates of hydrophobic regions of transmembrane proteins from the Orientation of Proteins in Membranes database. Our results show the importance of lipid diversity and composition on a bilayer's structural and mechanical properties, which in turn influences interactions with the proteins and membrane-bound molecules.

  14. Disruptive Models in Primary Care: Caring for High-Needs, High-Cost Populations

    National Research Council Canada - National Science Library

    Hochman, Michael; Asch, Steven M

    2017-01-01

    ...; and coordinated care when it must be sought elsewhere.” As this series on reinventing primary care highlights, there is a compelling need for new care delivery models that would advance these objectives...

  15. The Japanese Quail as an avian model for testing endocrine disrupting chemicals: endocrine and behavioral end points

    Science.gov (United States)

    Ottinger, M.A.; Abdelnabi, M.A.; Thompson, N.; Wu, J.; Henry, K.; Humphries, E.; Henry, P.F.P.

    2000-01-01

    Birds have extremely varied reproductive strategies. As such, the impact of endocrine disrupting chemicals (EDCs) can greatly differ across avian species. Precocial species, such as Japanese quail appear to be most sensitive to EDC effects during embryonic development, particularly sexual differentiation. A great deal is known about the ontogeny of Japanese quail (Coturnix japonica) relative to endocrine, neuro-endocrine, and behavioral components of reproduction. Therefore, this species provides an excellent model for understanding effects of EDCs on reproductive biology with exposure at specific stages of the life cycle. The purpose of these experiments was to conduct a 1- or 2- generation experiment with positive or negative control chemicals and to determine changes in selected end points. Japanese quail embryos were exposed to estradiol benzoate (EB; positive control) in a 2-generation design or to fadrozole (FAD; negative control) in a 1-generation design. Embryonic EB treatment resulted in significant reductions (p< 0.5) in hen day production (90.2 vs 54.1; control vs EB, resp.) and fertility (85.3 vs 33.4%, control vs EB, resp.). Males showed sharply reduced courtship and mating behaviors as well as increased lag time (26 vs 148 sec; control vs EB) in behavioral tests. Fadrozole exposure resulted in reduced hatchability of fertile eggs, particularly at higher doses. There were no significant effects on courtship and mating behavior of males although males showed an increased lag time in their responses, nally, a behavioral test for studying motor and fear responses in young chicks was used; chicks exposed to an estrogenic pesticide (methoxychlor) showed some deficits. In summary, the use of appropriate and reliable end points that are responsive to endocrine disruption are critical for assessment of EDCs. Supported in part by EPA grant R826134.

  16. Mathematical model analysis on the enhancement of aeration efficiency using ladder-type flat membrane module forms in the Submerged Membrane Bio-reactor (SMBR)

    Institute of Scientific and Technical Information of China (English)

    LI Bo; YE MaoSheng; YANG FengLin; MA Hui

    2009-01-01

    The cross-flow shearing action produced from the inferior aeration in the Submerged Membrane Bio-reactor (SMBR) Is an effective way to further improve anti-fouling effects of membrane modules.Based on the widely-applied vertical structure of flat membrane modules, improvements are made that ladder-type flat membrane structure is designed with a certain inclined angle θ so that the cross-flow velocity of bubble near the membrane surface can be held, and the intensity and times of elastic colli-sion between bubbles and membrane surface can be increased. This can improve scouring action ofmembrane surface on aeration and reduce energy consumption of strong aeration in SMBR. By de-ducing and improving the mathematics model of collision between bubble and vertical flat put forward by Vries, the relatively suitable Incline angle θ under certain aeration place and in certain size rang ofbubble can be obtained with the computer iterative calculation technology. Finally, for many groups of ladder-type flat membrane in parallel placement in the practical application of SMBR, some sugges-tions are offered: the interval distance of membrane modules is 8--15 mm, and aeration should be op-erated at 5--7 mm among membrane modules, and the optimal design angle of trapeziform membrane is 1.7°--2.5°.

  17. A study of the isobutane dehydrogenation in a porous membrane catalytic reactor: design, use and modelling

    Energy Technology Data Exchange (ETDEWEB)

    Casanave, D.

    1996-01-26

    The aim of this study was to set up and model a catalytic fixed-bed membrane reactor for the isobutane dehydrogenation. The catalyst, developed at Catalysis Research Institute (IRC), was a silicalite-supported Pt-based catalyst. Their catalytic performances (activity, selectivity, stability) where found better adapted to the membrane reactor, when compared with commercial Pt or Cr based catalysts. The kinetic study of the reaction has been performed in a differential reactor and led to the determination of a kinetic law, suitable when the catalyst is used near thermodynamic equilibrium. The mass transfer mechanisms were determined in meso-porous and microporous membranes through both permeability and gas mixtures (iC{sub 4}/H{sub 2}/N{sub 2}) separation measurements. For the meso-porous {gamma}-alumina, the mass transfer is ensured by a Knudsen diffusion mechanism which can compete with surface diffusion for condensable gas like isobutane. The resulting permselectivity H{sub 2}/iC4 of this membrane is low ({approx} 4). For the microporous zeolite membrane, molecular sieving occurs due to steric hindrance, leading to higher permselectivity {approx}14. Catalyst/membrane associations were compared in terms of isobutane dehydrogenation performances, for both types of membranes (meso-porous and microporous) and for two different reactor configurations (co-current and counter-current sweep gas flow). The best experimental results were obtained with the zeolite membrane, when sweeping the outer compartment in a co-current flow. The equilibrium displacement observed with the {gamma}-alumina membrane was lower and mainly due to a dilution effect of the reaction mixture by the sweep gas. A mathematical model was developed, which correctly describes all the experimental results obtained with the zeolite membrane, when the co-current mode is used. (Abstract Truncated)

  18. Performances of nanofiltration and low pressure reverse osmosis membranes for desalination: characterization and modelling

    Science.gov (United States)

    Boussouga, Y. A.; Lhassani, A.

    2017-03-01

    The nanofiltration and the reverse osmosis processes are the most common techniques for the desalination of water contaminated by an excess of salts. In this present study, we were interested in the characterization of commercial, composite and asymmetric membranes of nanofiltration (NF90, NF270) and low pressure reverse osmosis (BW30LE). The two types of characterization that we opted for our study: (i) characterization of electrical proprieties, in terms of the surface charge of various membranes studied by the measurement of the streaming potential, (ii) hydrodynamic characterization in terms of hydraulic permeability with pure water, mass transfer and phenomenological parameters for each system membrane/salt using hydrodynamic approaches. The irreversible thermodynamics allowed us to model the observed retention Robs of salts (NaCl and Na2SO4) for the different membranes studied, to understand and to predict a good filtration with a membrane. A study was conducted on the type of mass transfer for each system membrane/salt: convection and diffusion. The results showed that all tested membranes are negatively charged for the solutions at neutral pH, this is explained by their material composition. The results also showed competitiveness between the different types of membranes. In view of that the NF remains effective in terms of selective retention with less energy consumption than LPRO.

  19. Salt transport properties of model reverse osmosis membranes using electrochemical impedance spectroscopy

    Science.gov (United States)

    Feldman, Kathleen; Chan, Edwin; Stafford, Gery; Stafford, Christopher

    With the increasing shortage of clean water, efficient purification technologies including membrane separations are becoming critical. The main requirement of reverse osmosis in particular is to maximize water permeability while minimizing salt permeability. Such performance optimization has typically taken place through trial and error approaches. In this work, key salt transport metrics are instead measured in model reverse osmosis membranes using electrochemical impedance spectroscopy (EIS). As shown previously, EIS can provide both the membrane resistance Rm and membrane capacitance Cm, with Rm directly related to salt permeability. The membranes are fabricated in a molecular layer by layer approach, which allows for control over such parameters as thickness, surface and bulk chemistry, and network geometry/connectivity. Rm, and therefore salt permeability, follows the expected trends with thickness and membrane area but shows unusual behavior when the network geometry is systematically varied. By connecting intrinsic material properties such as the salt permeability with macroscopic performance measures we can begin to establish design rules for improving membrane efficiency and facilitate the creation of next-generation separation membranes.

  20. Disruption of prefrontal cortical-hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride.

    Science.gov (United States)

    Belujon, Pauline; Patton, Mary H; Grace, Anthony A

    2013-04-01

    The nucleus accumbens (NAc) receives converging inputs from the medial prefrontal cortex (mPFC) and the hippocampus which have competitive interactions in the NAc to influence motivational drive. We have previously shown altered synaptic plasticity in the hippocampal-NAc pathway in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in rodents that is dependent on cortical inputs. Thus, because mPFC-hippocampal balance is known to be partially altered in this model, we investigated potential pathological changes in the hippocampal influence over cortex-driven NAc spike activity. Here we show that the reciprocal interaction between the hippocampus and mPFC is absent in MAM animals but is able to be reinstated with administration of the antipsychotic drug, sulpiride. The lack of interaction between these structures in this model could explain the attentional deficits in schizophrenia patients and shed light onto their inability to focus on a single task.

  1. Two-dimensional modeling of a polymer electrolyte membrane fuel cell with long flow channel. Part I. Model development

    OpenAIRE

    2015-01-01

    A two-dimensional single-phase model is developed for the steady-state and transient analysis of polymer electrolyte membrane fuel cells (PEMFC). Based on diluted and concentrated solution theories, viscous flow is introduced into a phenomenological multi-component modeling framework in the membrane. Characteristic variables related to the water uptake are discussed. A ButlereVolmer formulation of the current-overpotential relationship is developed based on an elementary mechanism of elect...

  2. Social disruption alters pain and cognition in an animal model of multiple sclerosis.

    Science.gov (United States)

    Linsenbardt, H R; Cook, J L; Young, E E; Vichaya, E G; Young, C R; Reusser, N M; Storts, R; Welsh, C J; Meagher, M W

    2015-11-15

    Although pain and cognitive deficits are widespread and debilitating symptoms of multiple sclerosis (MS), they remain poorly understood. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS where disease course is exacerbated by prior stressors. Here chronic infection coupled with prior social stress increased pain behavior and impaired hippocampal-dependent memory consolidation during the demyelinating phase of disease in SJL mice. These results suggest that the TMEV model may be useful in investigating pain and cognitive impairments in MS. However, in contrast to prior Balb/cJ studies, stress failed to consistently alter behavioral and physiological indicators of disease course.

  3. Parameter estimation in neuronal stochastic differential equation models from intracellular recordings of membrane potentials in single neurons

    DEFF Research Database (Denmark)

    Ditlevsen, Susanne; Samson, Adeline

    2016-01-01

    evolution. One-dimensional models are the stochastic integrate-and-fire neuronal diffusion models. Biophysical neuronal models take into account the dynamics of ion channels or synaptic activity, leading to multidimensional diffusion models. Since only the membrane potential can be measured......Dynamics of the membrane potential in a single neuron can be studied by estimating biophysical parameters from intracellular recordings. Diffusion processes, given as continuous solutions to stochastic differential equations, are widely applied as models for the neuronal membrane potential...

  4. Buffers affect the bending rigidity of model lipid membranes.

    Science.gov (United States)

    Bouvrais, Hélène; Duelund, Lars; Ipsen, John H

    2014-01-14

    In biophysical and biochemical studies of lipid bilayers the influence of the used buffer is often ignored or assumed to be negligible on membrane structure, elasticity, or physical properties. However, we here present experimental evidence, through bending rigidity measurements performed on giant vesicles, of a more complex behavior, where the buffering molecules may considerably affect the bending rigidity of phosphatidylcholine bilayers. Furthermore, a synergistic effect on the bending modulus is observed in the presence of both salt and buffer molecules, which serves as a warning to experimentalists in the data interpretation of their studies, since typical lipid bilayer studies contain buffer and ion molecules.

  5. REM sleep deprivation generates cognitive and neurochemical disruptions in the intranigral rotenone model of Parkinson's disease.

    Science.gov (United States)

    Dos Santos, Ana Carolina D; Castro, Marcela Alexandra V; Jose, Elis Angela K; Delattre, Ana Márcia; Dombrowski, Patrícia A; Da Cunha, Claudio; Ferraz, Anete C; Lima, Marcelo M S

    2013-11-01

    The recently described intranigral rotenone model of Parkinson's disease (PD) in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. The relevance of this model remains unexplored with regard to sleep disorders that occur in PD. On this basis, the construction of a PD model depicting several behavioral and neurochemical alterations related to sleep would be helpful in understanding the association between PD and sleep regulation. We performed bilateral intranigral injections of rotenone (12 μg) on day 0 and the open-field test initially on day 20 after rotenone. Acquisition phase of the object-recognition test, executed also during day 20, was followed by an exact period of 24 hr of rapid eye movement (REM) sleep deprivation (REMSD; day 21). In the subsequent day (22), the rats were re-exposed to the open-field test and to the object-recognition test (choice phase). After the last session of behavioral tests, the rat brains were immediately dissected, and their striata were collected for neurochemical purposes. We observed that a brief exposure to REMSD was able to impair drastically the object-recognition test, similarly to a nigrostriatal lesion promoted by intranigral rotenone. However, the combination of REMSD and rotenone surprisingly did not inflict memory impairment, concomitant with a moderate compensatory mechanism mediated by striatal dopamine release. In addition, we demonstrated the existence of changes in serotonin and noradrenaline neurotransmissions within the striatum mostly as a function of REMSD and REMSD plus rotenone, respectively.

  6. Fisetin inhibits growth, induces G₂ /M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation.

    Science.gov (United States)

    Pal, Harish C; Sharma, Samriti; Elmets, Craig A; Athar, Mohammad; Afaq, Farrukh

    2013-07-01

    Non-melanoma skin cancers (NMSCs), one of the most common neoplasms, cause serious morbidity and mortality. Therefore, identification of non-toxic phytochemicals for prevention/treatment of NMSCs is highly desirable. Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid, present in fruits and vegetables possesses anti-oxidant and antiproliferative properties. The aim of this study was to investigate the chemotherapeutic potential of fisetin in cultured human epidermoid carcinoma A431 cells. Treatment of A431 cells with fisetin (5-80 μm) resulted in a significant decrease in cell viability in a dose- and time-dependent manner. Employing clonogenic assay, we found that fisetin treatment significantly reduced colony formation in A431 cells. Fisetin treatment of A431 cells resulted in G₂ /M arrest and induction of apoptosis. Furthermore, treatment of A431 cells with fisetin resulted in (i) decreased expression of anti-apoptotic proteins (Bcl2; Bcl-xL and Mcl-1); (ii) increased expression of pro-apoptotic proteins (Bax, Bak and Bad); (iii) disruption of mitochondrial potential; (iv) release of cytochrome c and Smac/DIABLO from mitochondria; (v) activation of caspases; and (vi) cleavage of Poly(ADP-ribose) polymerase (PARP) protein. Pretreatment of A431 cells with the pan-caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced cleavage of caspases and PARP. Taken together, these data provide evidence that fisetin possesses chemotherapeutic potential against human epidermoid carcinoma A431 cells. Overall, these results suggest that fisetin could be developed as a novel therapeutic agent for the management of NMSCs. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Fisetin inhibits growth, induces G2/M arrest and apoptosis of human epidermoid carcinoma A431 cells: Role of mitochondrial membrane potential disruption and consequent caspases activation

    Science.gov (United States)

    Pal, Harish C.; Sharma, Samriti; Elmets, Craig A.; Athar, Mohammad; Afaq, Farrukh

    2013-01-01

    Non-melanoma skin cancers (NMSCs) one of the most common neoplasms causes serious morbidity and mortality. Therefore, identification of non-toxic phytochemicals for prevention/treatment of NMSCs is highly desirable. Fisetin (3,3′,4′,7-tetrahydroxyflavone), a dietary flavonoid, present in fruits and vegetables possesses anti-oxidant and anti-proliferative properties. The aim of this study was to investigate the chemotherapeutic potential of fisetin in cultured human epidermoid carcinoma A431 cells. Treatment of A431 cells with fistein (5-80 μM) resulted in a significant decrease in cell viability in a dose- and time-dependent manner. Employing clonogenic assay, we found that fisetin treatment significantly reduced colony formation in A431 cells. Fisetin treatment of A431 cells resulted in G2/M arrest and induction of apoptosis. Furthermore, treatment of A431 cells with fisetin resulted in (i) decreased expression of anti-apoptotic proteins (Bcl2, Bcl-xL and Mcl-1), (ii) increased expression of pro-apoptotic proteins (Bax, Bak and Bad), (iii) disruption of mitochondrial potential, (iv) release of cytchrome c and Smac/DIABLO from mitochondria, (v) activation of caspases, and (vi) cleavage of PARP protein. Pretreatment of A431 cells with the pan-caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced cleavage of caspases and PARP. Taken together, these data provide evidence that fisetin possesses chemotherapeutic potential against human epidermoid carcinoma A431 cells. Overall, these results suggest that fisetin could be developed as a novel therapeutic agent for the management of NMSCs. PMID:23800058

  8. Molecular dynamics study of lipid bilayers modeling the plasma membranes of mouse hepatocytes and hepatomas

    Science.gov (United States)

    Andoh, Yoshimichi; Aoki, Noriyuki; Okazaki, Susumu

    2016-02-01

    Molecular dynamics (MD) calculations of lipid bilayers modeling the plasma membranes of normal mouse hepatocytes and hepatomas in water have been performed under physiological isothermal-isobaric conditions (310.15 K and 1 atm). The changes in the membrane properties induced by hepatic canceration were investigated and were compared with previous MD calculations included in our previous study of the changes in membrane properties induced by murine thymic canceration. The calculated model membranes for normal hepatocytes and hepatomas comprised 23 and 24 kinds of lipids, respectively. These included phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, lysophospholipids, and cholesterol. We referred to previously published experimental values for the mole fraction of the lipids adopted in the present calculations. The calculated structural and dynamic properties of the membranes such as lateral structure, order parameters, lateral self-diffusion constants, and rotational correlation times all showed that hepatic canceration causes plasma membranes to become more ordered laterally and less fluid. Interestingly, this finding contrasts with the less ordered structure and increased fluidity of plasma membranes induced by thymic canceration observed in our previous MD study.

  9. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development...... invested in the issue of sustainable business development, in particular the leaders and employees of SMEs, but also to design education seeking new ways to consciously handle and teach the complexity inherent in sustainable transformation. Findings indicate that the SD design thinking approach contributes....... The tools have been applied in practice in collaboration with 11 small and medium sized companies (SMEs). The study investigates these approaches to further understand how design thinking can contribute to sustainable transition in a business context. The study and the findings are relevant to organizations...

  10. Fatty acid membrane assembly on coacervate microdroplets as a step towards a hybrid protocell model

    Science.gov (United States)

    Dora Tang, T.-Y.; Rohaida Che Hak, C.; Thompson, Alexander J.; Kuimova, Marina K.; Williams, D. S.; Perriman, Adam W.; Mann, Stephen

    2014-06-01

    Mechanisms of prebiotic compartmentalization are central to providing insights into how protocellular systems emerged on the early Earth. Protocell models are based predominantly on the membrane self-assembly of fatty-acid vesicles, although membrane-free scenarios that involve liquid-liquid microphase separation (coacervation) have also been considered. Here we integrate these alternative models of prebiotic compartmentalization and develop a hybrid protocell model based on the spontaneous self-assembly of a continuous fatty-acid membrane at the surface of preformed coacervate microdroplets prepared from cationic peptides/polyelectrolytes and adenosine triphosphate or oligo/polyribonucleotides. We show that the coacervate-supported membrane is multilamellar, and mediates the selective uptake or exclusion of small and large molecules. The coacervate interior can be disassembled without loss of membrane integrity, and fusion and growth of the hybrid protocells can be induced under conditions of high ionic strength. Our results highlight how notions of membrane-mediated compartmentalization, chemical enrichment and internalized structuration can be integrated in protocell models via simple chemical and physical processes.

  11. Antimicrobial mechanism of flavonoids against Escherichia coli ATCC 25922 by model membrane study

    Energy Technology Data Exchange (ETDEWEB)

    He, Mengying; Wu, Ting; Pan, Siyi; Xu, Xiaoyun, E-mail: xiaoyunxu88@gmail.com

    2014-06-01

    Antimicrobial mechanism of four flavonoids (kaempferol, hesperitin, (+)-catechin hydrate, biochanin A) against Escherichia coli ATCC 25922 was investigated through cell membranes and a liposome model. The release of bacterial protein and images from transmission electron microscopy demonstrated damage to the E. coli ATCC 25922 membrane. A liposome model with dipalmitoylphosphatidylethanolamine (DPPE) (0.6 molar ratio) and dipalmitoylphosphatidylglycerol (DPPG) (0.4 molar ratio), representative of the phospholipid membrane of E. coli ATCC 25922, was used to specify the mode of action of four selected flavonoids through Raman spectroscopy and differential scanning calorimetry. It is suggested that for flavonoids, to be effective antimicrobials, interaction with the polar head-group of the model membrane followed by penetration into the hydrophobic regions must occur. The antimicrobial efficacies of the flavonoids were consistent with liposome interaction activities, kaempferol > hesperitin > (+)-catechin hydrate > biochanin A. This study provides a liposome model capable of mimicking the cell membrane of E. coli ATCC 25922. The findings are important in understanding the antibacterial mechanism on cell membranes.

  12. Modeling of air-gap membrane distillation process: A theoretical and experimental study

    KAUST Repository

    Alsaadi, Ahmad Salem

    2013-06-03

    A one dimensional (1-D) air gap membrane distillation (AGMD) model for flat sheet type modules has been developed. This model is based on mathematical equations that describe the heat and mass transfer mechanisms of a single-stage AGMD process. It can simulate AGMD modules in both co-current and counter-current flow regimes. The theoretical model was validated using AGMD experimental data obtained under different operating conditions and parameters. The predicted water vapor flux was compared to the flux measured at five different feed water temperatures, two different feed water salinities, three different air gap widths and two MD membranes with different average pore sizes. This comparison showed that the model flux predictions are strongly correlated with the experimental data, with model predictions being within +10% of the experimentally determined values. The model was then used to study and analyze the parameters that have significant effect on scaling-up the AGMD process such as the effect of increasing the membrane length, and feed and coolant flow rates. The model was also used to analyze the maximum thermal efficiency of the AGMD process by tracing changes in water production rate and the heat input to the process along the membrane length. This was used to understand the gain in both process production and thermal efficiency for different membrane surface areas and the resultant increases in process capital and water unit cost. © 2013 Elsevier B.V.

  13. Electrical Thermal Network for Direct Contact Membrane Distillation Modeling and Analysis

    KAUST Repository

    Karam, Ayman M.

    2015-02-04

    Membrane distillation is an emerging water distillation technology that offers several advantages compared to conventional water desalination processes. Although progress has been made to model and understand the physics of the process, many studies are based on steady-state assumptions or are computationally not appropriate for real time control. This paper presents the derivation of a novel dynamical model, based on analogy between electrical and thermal systems, for direct contact membrane distillation (DCMD). The proposed model captures the dynamics of temperature distribution and distilled water flux. To demonstrate the adequacy of the proposed model, validation with transient and steady-state experimental data is presented.

  14. Modelling membrane hydration and water balance of a pem fuel cell

    DEFF Research Database (Denmark)

    Liso, Vincenzo; Nielsen, Mads Pagh

    2015-01-01

    propose a novel mathematical zero-dimensional model for water mass balance of a polymer electrolyte membrane. Physical and electrochemical processes occurring in the membrane electrolyte are included; water adsorption/desorption phenomena are also considered. The effect of diffusivity, surface roughness...... and water content driving force is considered. We validate the model against experimental data. The water balance calculated by this model shows better fit with experimental data-points compared to other models such as the one by Springer et al.. We conclude that this discrepancy is due a different rate...

  15. An Agent-Based Modeling Approach to Integrate Tsunami Science, Human Behavior, and Unplanned Network Disruptions for Nearfield Tsunami Evacuation

    Science.gov (United States)

    Cox, D. T.; Wang, H.; Cramer, L.; Mostafizi, A.; Park, H.

    2016-12-01

    For the Cascadia Subduction Zone (CSZ) and other extreme near-field tsunami hazards, coastal residents and tourist must evacuate within 15 to 30 minutes immediately following intense ground-shaking and will be confronted with an array of choices: Should I evacuate on foot or by car? Alone, or find friends and family first? Head for high ground far away, or seek shelter a nearby building? How will the roads and bridges be affected by the preceding earthquake? In this project, we integrate the disciplines of tsunami inundation science, sociology, and civil engineering to investigate how decision-making by individual evacuees with respect to milling time, mode choice, and destination affects their life safety. We use an Agent-Based Model (ABM) to create credible scenarios for near-field tsunami evacuation. The ABM integrates (1) the time-dependent tsunami inundation computed separately using NOAA's ComMIT/MOST model, (2) population layers to account for variations in population density of residents and tourist, (3) evacuation route network including roads, bridges and foot paths for multi-modal transportation, and (4) evacuation destinations for horizontal and vertical evacuation. For this project, we apply the ABM at two locations: the city Seaside, OR, and South Beach State Park in Newport, OR. In the Seaside scenario, we show how unplanned network disruption - e.g. the partial or total failure of bridges due to the preceding earthquake - will affect life safety and show how the ABM can be used to provide retrofit strategies. For South Beach, we show how alternative routing can have a substantial impact on life safety. The ABM shows results that are initially counterintuitive. For the Seaside example, resource allocation for bridge retrofit favors investments in nodes and links not necessarily in close proximity to population centers. For the South Beach example, the routes which provide for the lowest risk (maximum life safety) are not always those with the

  16. Afterglow model for the radio emission from the jetted tidal disruption candidate Swift J1644+57

    Science.gov (United States)

    Metzger, Brian D.; Giannios, Dimitrios; Mimica, Petar

    2012-03-01

    The recent transient event Swift J1644+57 has been interpreted as emission from a collimated relativistic jet, powered by the sudden onset of accretion on to a supermassive black hole following the tidal disruption of a star. Here we model the radio-microwave emission as synchrotron radiation produced by the shock interaction between the jet and the gaseous circumnuclear medium (CNM). At early times after the onset of the jet (t≲ 5-10 d) a reverse shock propagates through and decelerates the ejecta, while at later times the outflow approaches the Blandford-McKee self-similar evolution (possibly modified by additional late energy injection). The achromatic break in the radio light curve of Swift J1644+57 is naturally explained as the transition between these phases. We show that the temporal indices of the pre- and post-break light curve are consistent with those predicted if the CNM has a wind-type radial density profile n∝r-2. The observed synchrotron frequencies and self-absorbed flux constrain the fraction of the post-shock thermal energy in relativistic electrons ɛe≈ 0.03-0.1, the CNM density at 1018 cm n18≈ 1-10 cm-3 and the initial Lorentz factor Γj≈ 10-20 and opening angle ? of the jet. Radio modelling thus provides robust independent evidence for a narrowly collimated outflow. Extending our model to the future evolution of Swift J1644+57, we predict that the radio flux at low frequencies (ν≲ few GHz) will begin to brighten more rapidly once the characteristic frequency νm crosses below the radio band after it decreases below the self-absorption frequency on a time-scale of months (indeed, such a transition may already have begun). Our results demonstrate that relativistic outflows from tidal disruption events provide a unique probe of the conditions in distant, previously inactive galactic nuclei, complementing studies of normal active galactic nuclei.

  17. Equilibrium microphase separation in the two-leaflet model of lipid membranes

    Science.gov (United States)

    Reigada, Ramon; Mikhailov, Alexander S.

    2016-01-01

    Because of the coupling between local lipid composition and the thickness of the membrane, microphase separation in two-component lipid membranes can take place; such effects may underlie the formation of equilibrium nanoscale rafts. Using a kinetic description, this phenomenon is analytically and numerically investigated. The phase diagram is constructed through the stability analysis for linearized kinetic equations, and conditions for microphase separation are discussed. Simulations of the full kinetic model reveal the development of equilibrium membrane nanostructures with various morphologies from the initial uniform state.

  18. Aroma Stripping under various Forms of Membrane Distillation Processes: Experiments and modeling

    DEFF Research Database (Denmark)

    Jonsson, Gunnar Eigil

    Concentration of fruit juices by membrane distillation is an interesting process as it can be done at low temperature giving a gentle concentration process with little deterioration of the juices. Since the juices contains many different aroma compounds with a wide range of chemical properties...... such as volatility, activity coefficient and vapor pressure, it is important to know how these aroma compounds will eventually pass through the membrane. Experiments have been made on an aroma model solution and on black currant juice in a lab scale membrane distillation set up which can be operated in various types...

  19. Nonlinear Dynamics of Ion Concentration Polarization in Porous Media: The Leaky Membrane Model

    CERN Document Server

    Dydek, E Victoria

    2013-01-01

    The conductivity of highly charged membranes is nearly constant, due to counter-ions screening pore surfaces. Weakly charged porous media, or "leaky membranes", also contain a significant concentration of co-ions, whose depletion at high current leads to ion concentration polarization and conductivity shock waves. To describe these nonlinear phenomena the absence of electro-osmotic flow, a simple Leaky Membrane Model is formulated, based on macroscopic electroneutrality and Nernst-Planck ionic fluxes. The model is solved in cases of unsupported binary electrolytes: steady conduction from a reservoir to a cation-selective surface, transient response to a current step, steady conduction to a flow-through porous electrode, and steady conduction between cation-selective surfaces in cross flow. The last problem is motivated by separations in leaky membranes, such as shock electrodialysis. The article begins with a tribute to Neal Amundson, whose pioneering work on shock waves in chromatography involved similar mat...

  20. Modeling the dynamic behavior of proton-exchange membrane fuel cell

    Energy Technology Data Exchange (ETDEWEB)

    Llapade, Peter O [Los Alamos National Laboratory; Mukundan, Rangachary [Los Alamos National Laboratory; Davey, John R [Los Alamos National Laboratory; Borup, Rodney L [Los Alamos National Laboratory; Meyers, Jeremy P [UNIV OF TEXAS-AUSTIN

    2010-01-01

    A two-phase transient model that incorporates the permanent hysteresis observed in the experimentally measured capillary pressure of GDL has been developed. The model provides explanation for the difference in time constant between membrane hydration and dehydration observed in the HFR experiment conducted at LANL. When there is liquid water at the cathode catalyst layer, time constant of the water content in the membrane is closely tied to that of liquid water saturation in the CCL, as the vapor is already saturated. The water content in the membrane will not reach steady state as long as the liquid water flow in the CCL is not at steady state. Also, Increased resistance to proton transport in the membrane is observed when the cell voltage is stepped down to a very low value.

  1. A Brownian Energy Depot Model of the Basilar Membrane Oscillation with a Braking Mechanism

    CERN Document Server

    Zhang, Yong; Lee, Kong-Ju-Bock; Park, Youngah

    2008-01-01

    High auditory sensitivity, sharp frequency selectivity, and otoacoustic emissions are signatures of active amplification of the cochlea. The human ear can also detect very large amplitude sound without being damaged as long as the exposed time is not too long. The outer hair cells are believed as the best candidate for the active force generator of the mammalian cochlea. In this paper, we propose a new model for the basilar membrane oscillation which successfully describes both the active and the protective mechanisms by employing an energy depot concept and a critical velocity of the basilar membrane. One of the main results is that thermal noise in the absence of external stimulation can be amplified leading to the spontaneous basilar membrane oscillation. The compressive response of the basilar membrane at the characteristic frequency and the dynamic response to the stimulation are consistent with the experimental results as expected. Our model also shows the nonlinear distortion of the response of the bas...

  2. Modeling of Fischer-Tropsch Synthesis in a Slurry Reactor with Water Permeable Membrane

    Institute of Scientific and Technical Information of China (English)

    Fabiano A. N. Fernandes

    2007-01-01

    Fischer-Tropsch synthesis is an important chemical process for the production of liquid fuels and olefins. In recent years, the abundant availability of natural gas and the increasing demand of olefins, diesel, and waxes have led to a high interest to further develop this process. A mathematical model of a slurry membrane reactor used for syngas polymerization was developed to simulate and compare the maximum yields and operating conditions in the reactor with that in a conventional slurry reactor.The carbon polymerization was studied from a modeling point of view in a slurry reactor with a water permeable membrane and a conventional slurry reactor. Simulation results show that different parameters affect syngas conversion and carbon product distribution, such as the hydrogen to carbon monoxide ratio,and the membrane parameters such as membrane permeance.

  3. Effects of oxyethylated glycerol cryoprotectants on phase transitions of DPPC model membranes

    Directory of Open Access Journals (Sweden)

    Kasian N. A.

    2015-04-01

    Full Text Available Aim. To determine the effect of the oxyethylated glycerol cryoprotectants (OEGn with polymerization degrees n = 5, 25, 30 on the phase states and phase transitions of dipalmitoylphosphatidylcholine (DPPC-based model membranes. Methods. Differential scanning calorimetry. Results. Model lipid membranes on water/OEGn and water/glycerol subphases with varying cryoprotectant concentrations from 0 to ~ 100 % w/w were studied. A significant raise in the pre-transition and main phase transition temperatures with increasing OEGn concentration was noted whereas the membrane melting peak persist to 100 % w/w OEGn. A sharp increase in the melting enthalpy was observed for OEGn = 5. Conclusions. The solvating ability of the subphase in DPPC membranes decreases in the order water > glycerol > OEGn = 5 > OEGn = 25 > OEGn = 30, which correlates with the relative number of groups effectively contributing to the solvation process.

  4. Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption

    OpenAIRE

    1997-01-01

    Genetic defects in a number of components of the dystrophin–glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Ev...

  5. Growth of the chorioallantoic membrane into a rapid-prototyped model pore system: experiments and mathematical model.

    Science.gov (United States)

    Lemon, Greg; Howard, Daniel; Yang, Hongyi; Ratchev, Svetan M; Segal, Joel I; Rose, Felicity R A J; Jensen, Oliver E; Waters, Sarah L; King, John R

    2011-07-01

    This paper presents a mathematical model to describe the growth of tissue into a rapid-prototyped porous scaffold when it is implanted onto the chorioallantoic membrane (CAM). The scaffold was designed to study the effects of the size and shape of pores on tissue growth into conventional tissue engineering scaffolds, and consists of an array of pores each having a pre-specified shape. The experimental observations revealed that the CAM grows through each pore as an intact layer of tissue, provided the width of the pore exceeds a threshold value. Based on these results a mathematical model is described to simulate the growth of the membrane, assuming that the growth is a function of the local isotropic membrane tension. The model predictions are compared against measurements of the extent of membrane growth through the pores as a function of time for pores with different dimensions.

  6. Modelling and sequential simulation of multi-tubular metallic membrane and techno-economics of a hydrogen production process employing thin-layer membrane reactor

    KAUST Repository

    Shafiee, Alireza

    2016-09-24

    A theoretical model for multi-tubular palladium-based membrane is proposed in this paper and validated against experimental data for two different sized membrane modules that operate at high temperatures. The model is used in a sequential simulation format to describe and analyse pure hydrogen and hydrogen binary mixture separations, and then extended to simulate an industrial scale membrane unit. This model is used as a sub-routine within an ASPEN Plus model to simulate a membrane reactor in a steam reforming hydrogen production plant. A techno-economic analysis is then conducted using the validated model for a plant producing 300 TPD of hydrogen. The plant utilises a thin (2.5 μm) defect-free and selective layer (Pd75Ag25 alloy) membrane reactor. The economic sensitivity analysis results show usefulness in finding the optimum operating condition that achieves minimum hydrogen production cost at break-even point. A hydrogen production cost of 1.98 $/kg is estimated while the cost of the thin-layer selective membrane is found to constitute 29% of total process capital cost. These results indicate the competiveness of this thin-layer membrane process against conventional methods of hydrogen production. © 2016 Hydrogen Energy Publications LLC

  7. Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Alice Krezymon

    Full Text Available At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

  8. Scenario-based modeling for multiple allocation hub location problem under disruption risk: multiple cuts Benders decomposition approach

    Science.gov (United States)

    Yahyaei, Mohsen; Bashiri, Mahdi

    2017-03-01

    The hub location problem arises in a variety of domains such as transportation and telecommunication systems. In many real-world situations, hub facilities are subject to disruption. This paper deals with the multiple allocation hub location problem in the presence of facilities failure. To model the problem, a two-stage stochastic formulation is developed. In the proposed model, the number of scenarios grows exponentially with the number of facilities. To alleviate this issue, two approaches are applied simultaneously. The first approach is to apply sample average approximation to approximate the two stochastic problem via sampling. Then, by applying the multiple cuts Benders decomposition approach, computational performance is enhanced. Numerical studies show the effective performance of the SAA in terms of optimality gap for small problem instances with numerous scenarios. Moreover, performance of multi-cut Benders decomposition is assessed through comparison with the classic version and the computational results reveal the superiority of the multi-cut approach regarding the computational time and number of iterations.

  9. Adverse effects in risk assessment: Modeling polychlorinated biphenyls and thyroid hormone disruption outcomes in animals and humans☆

    Science.gov (United States)

    Parham, Fred; Wise, Amber; Axelrad, Daniel A.; Guyton, Kathryn Z.; Portier, Christopher; Zeise, Lauren; Zoeller, R. Thomas; Woodruff, Tracey J.

    2016-01-01

    There is a growing need for quantitative approaches to extrapolate relationships between chemical exposures and early biological perturbations from animals to humans given increasing use of biological assays to evaluate toxicity pathways. We have developed such an approach using polychlorinated biphenyls (PCBs) and thyroid hormone (TH) disruption as a case study. We reviewed and identified experimental animal literature from which we developed a low-dose, linear model of PCB body burdens and decrements in free thyroxine (FT4) and total thyroxine (TT4), accounting for 33 PCB congeners; extrapolated the dose–response from animals to humans; and compared the animal dose–response to the dose–response of PCB body burdens and TH changes from eleven human epidemiological studies. We estimated a range of potencies for PCB congeners (over 4 orders of magnitude), with the strongest for PCB 126. Our approach to developing toxic equivalency models produced relative potencies similar to the toxicity equivalency factors (TEFs) from the World Health Organization (WHO). We generally found that the dose–response extrapolated from the animal studies tends to under-predict the dose–response estimated from human epidemiological studies. A quantitative approach to evaluating the relationship between chemical exposures and TH perturbations, based on animal data can be used to assess human health consequences of thyroid toxicity and inform decision-making. PMID:22575326

  10. Plasmalemmal Vesicle Associated Protein-1 (PV-1 is a marker of blood-brain barrier disruption in rodent models

    Directory of Open Access Journals (Sweden)

    Ali Zarina S

    2008-02-01

    Full Text Available Abstract Background Plasmalemmal vesicle associated protein-1 (PV-1 is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. Results We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. Conclusion Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

  11. Anion exchange membranes for fuel cells and flow batteries : transport and stability of model systems

    OpenAIRE

    Marino, Michael G

    2015-01-01

    Polymeric anion exchange materials in membrane form can be key components in emerging energy storage and conversions systems such as the alkaline fuel cell and the RedOx flow battery. For these applications the membrane properties need to include good ionic conductivity and sufficient chemical stability, two aspects, that are not sufficiently understood in terms of materials science. Materials fulfilling both criteria are currently not available. The transport of ions and water in a model...

  12. How Membrane-Active Peptides Get into Lipid Membranes.

    Science.gov (United States)

    Sani, Marc-Antoine; Separovic, Frances

    2016-06-21

    mechanism by which these membrane-active peptides lyse membranes. The last class of membrane-active peptides discussed are the CPPs, which translocate across the lipid bilayer without inducing severe disruption and have potential as drug vehicles. CPPs are typically highly charged and can show antimicrobial activity by targeting an intracellular target rather than via a direct membrane lytic mechanism. A critical aspect in the structure-function relationship of membrane-active peptides is their specific activity relative to the lipid membrane composition of the cell target. Cell membranes have a wide diversity of lipids, and those of eukaryotic and prokaryotic species differ greatly in composition and structure. The activity of AMPs from Australian tree frogs, toxins, and CPPs has been investigated within various lipid systems to assess whether a relationship between peptide and membrane composition could be identified. NMR spectroscopy techniques are being used to gain atomistic details of how these membrane-active peptides interact with model membranes and cells, and in particular, competitive assays demonstrate the difference between affinity and activity for a specific lipid environment. Overall, the interactions between these relatively small sized peptides and various lipid bilayers give insight into how these peptides function at the membrane interface.

  13. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    Science.gov (United States)

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  14. Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy.

    Science.gov (United States)

    Martin, Tamara P; Hortigon-Vinagre, Maria P; Findlay, Jane E; Elliott, Christina; Currie, Susan; Baillie, George S

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20-phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20-PDE4D interaction leads to attenuation of pathological cardiac remodelling.

  15. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    Directory of Open Access Journals (Sweden)

    Tamara P. Martin

    2014-01-01

    Full Text Available Phosphorylated heat shock protein 20 (HSP20 is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling.

  16. 树形供应链中断风险应急模型研究%Fortification Models Hedging Disruption Risks Based on Arborescent Supply Chain

    Institute of Scientific and Technical Information of China (English)

    张松

    2011-01-01

    Based on the arborescent supply chain, the fortification model hedging disruption risks is built with the tactic of strategic emergency inventory and real options.Furthermore, the optimal strategies are derived from the solution of the model.The model concerns not only the cost of protection and emergency supply, but also the expected cost of lost revenues from disruption.Finally, some numerical simulation is given, and the result shows that the model can significantly reduce the disruption risk cost and disruption time of the arborescent supply chain.%基于战略应急库存与实物期权组合策略,设计了树形供应链中断风险应急模型,并通过求解模型得到系统最优策略.应急模型既考虑了风险防范与应急供应所引发的成本,同时考虑了供应链系统中断导致的损失收益.最后进行了仿真分析,结果表明应急模型能够显著降低树形供应链系统的中断风险成本与系统中断时间.

  17. Rubber particle proteins, HbREF and HbSRPP, show different interactions with model membranes.

    Science.gov (United States)

    Berthelot, Karine; Lecomte, Sophie; Estevez, Yannick; Zhendre, Vanessa; Henry, Sarah; Thévenot, Julie; Dufourc, Erick J; Alves, Isabel D; Peruch, Frédéric

    2014-01-01

    The biomembrane surrounding rubber particles from the hevea latex is well known for its content of numerous allergen proteins. HbREF (Hevb1) and HbSRPP (Hevb3) are major components, linked on rubber particles, and they have been shown to be involved in rubber synthesis or quality (mass regulation), but their exact function is still to be determined. In this study we highlighted the different modes of interactions of both recombinant proteins with various membrane models (lipid monolayers, liposomes or supported bilayers, and multilamellar vesicles) to mimic the latex particle membrane. We combined various biophysical methods (polarization-modulation-infrared reflection-adsorption spectroscopy (PM-IRRAS)/ellipsometry, attenuated-total reflectance Fourier-transform infrared (ATR-FTIR), solid-state nuclear magnetic resonance (NMR), plasmon waveguide resonance (PWR), fluorescence spectroscopy) to elucidate their interactions. Small rubber particle protein (SRPP) shows less affinity than rubber elongation factor (REF) for the membranes but displays a kind of "covering" effect on the lipid headgroups without disturbing the membrane integrity. Its structure is conserved in the presence of lipids. Contrarily, REF demonstrates higher membrane affinity with changes in its aggregation properties, the amyloid nature of REF, which we previously reported, is not favored in the presence of lipids. REF binds and inserts into membranes. The membrane integrity is highly perturbed, and we suspect that REF is even able to remove lipids from the membrane leading to the formation of mixed micelles. These two homologous proteins show affinity to all membrane models tested but neatly differ in their interacting features. This could imply differential roles on the surface of rubber particles.

  18. Rapid actions of xenoestrogens disrupt normal estrogenic signaling.

    Science.gov (United States)

    Watson, Cheryl S; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A

    2014-03-01

    Some chemicals used in consumer products or manufacturing (e.g. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (e.g. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities.

  19. A Hidden Markov Model method, capable of predicting and discriminating β-barrel outer membrane proteins

    Directory of Open Access Journals (Sweden)

    Hamodrakas Stavros J

    2004-03-01

    Full Text Available Abstract Background Integral membrane proteins constitute about 20–30% of all proteins in the fully sequenced genomes. They come in two structural classes, the α-helical and the β-barrel membrane proteins, demonstrating different physicochemical characteristics, structure and localization. While transmembrane segment prediction for the α-helical integral membrane proteins appears to be an easy task nowadays, the same is much more difficult for the β-barrel membrane proteins. We developed a method, based on a Hidden Markov Model, capable of predicting the transmembrane β-strands of the outer membrane proteins of gram-negative bacteria, and discriminating those from water-soluble proteins in large datasets. The model is trained in a discriminative manner, aiming at maximizing the probability of correct predictions rather than the likelihood of the sequences. Results The training has been performed on a non-redundant database of 14 outer membrane proteins with structures known at atomic resolution; it has been tested with a jacknife procedure, yielding a per residue accuracy of 84.2% and a correlation coefficient of 0.72, whereas for the self-consistency test the per residue accuracy was 88.1% and the correlation coefficient 0.824. The total number of correctly predicted topologies is 10 out of 14 in the self-consistency test, and 9 out of 14 in the jacknife. Furthermore, the model is capable of discriminating outer membrane from water-soluble proteins in large-scale applications, with a success rate of 88.8% and 89.2% for the correct classification of outer membrane and water-soluble proteins respectively, the highest rates obtained in the literature. That test has been performed independently on a set of known outer membrane proteins with low sequence identity with each other and also with the proteins of the training set. Conclusion Based on the above, we developed a strategy, that enabled us to screen the entire proteome of E. coli for

  20. Plasma cysteine/cystine redox couple disruption in animal models of temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Li-Ping Liang

    2016-10-01

    Full Text Available Currently the field of epilepsy lacks peripheral blood-based biomarkers that could predict the onset or progression of chronic seizures following an epileptogenic injury. Thiol/disulfide ratios have been shown to provide a sensitive means of assessing the systemic redox potential in tissue and plasma. In this study, we utilized a rapid, simple and reliable method for simultaneous determination of several thiol-containing amino acids in plasma using HPLC with electrochemical detection in kainic acid (KA and pilocarpine rat models of epilepsy. In contrast to GSH and GSSG levels, the levels of cysteine (Cys were decreased by 42% and 62% and cystine (Cyss were increased by 46% and 23% in the plasma of KA- and pilocarpine-injected rats, respectively after 48 h. In chronically epileptic rats, plasma cysteine was decreased by 40.4% and 37.7%, and plasma GSSG increased by 33.8% and 35.0% following KA and pilocarpine, respectively. Treatment of rats with a catalytic antioxidant, 60 min after KA or pilocarpine significant attenuated the decrease of plasma Cys/Cyss ratios at the 48 h time point in both models. These observations suggest that the decreased cysteine and ratio of Cys/Cyss in plasma could potentially serve as redox biomarkers in temporal lobe epilepsy.

  1. Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology.

    LENUS (Irish Health Repository)

    2011-01-01

    Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.

  2. Experiments and Modeling of Boric Acid Permeation through Double-Skinned Forward Osmosis Membranes.

    Science.gov (United States)

    Luo, Lin; Zhou, Zhengzhong; Chung, Tai-Shung; Weber, Martin; Staudt, Claudia; Maletzko, Christian

    2016-07-19

    Boron removal is one of the great challenges in modern wastewater treatment, owing to the unique small size and fast diffusion rate of neutral boric acid molecules. As forward osmosis (FO) membranes with a single selective layer are insufficient to reject boron, double-skinned FO membranes with boron rejection up to 83.9% were specially designed for boron permeation studies. The superior boron rejection properties of double-skinned FO membranes were demonstrated by theoretical calculations, and verified by experiments. The double-skinned FO membrane was fabricated using a sulfonated polyphenylenesulfone (sPPSU) polymer as the hydrophilic substrate and polyamide as the selective layer material via interfacial polymerization on top and bottom surfaces. A strong agreement between experimental data and modeling results validates the membrane design and confirms the success of model prediction. The effects of key parameters on boron rejection, such as boron permeability of both selective layers and structure parameter, were also investigated in-depth with the mathematical modeling. This study may provide insights not only for boron removal from wastewater, but also open up the design of next generation FO membranes to eliminate low-rejection molecules in wider applications.

  3. Electrophorus electricus as a model system for the study of membrane excitability.

    Science.gov (United States)

    Gotter, A L; Kaetzel, M A; Dedman, J R

    1998-01-01

    The stunning sensations produced by electric fish, particularly the electric eel, Electrophorus electricus, have fascinated scientists for centuries. Within the last 50 years, however, electric cells of Electrophorus have provided a unique model system that is both specialized and appropriate for the study of excitable cell membrane electrophysiology and biochemistry. Electric tissue generates whole animal electrical discharges by means of membrane potentials that are remarkably similar to those of mammalian neurons, myocytes and secretory cells. Electrocytes express ion channels, ATPases and signal transduction proteins common to these other excitable cells. Action potentials of electrocytes represent the specialized end function of electric tissue whereas other excitable cells use membrane potential changes to trigger sophisticated cellular processes, such as myofilament cross-bridging for contraction, or exocytosis for secretion. Because electric tissue lacks these functions and the proteins associated with them, it provides a highly specialized membrane model system. This review examines the basic mechanisms involved in the generation of the electrical discharge of the electric eel and the membrane proteins involved. The valuable contributions that electric tissue continues to make toward the understanding of excitable cell physiology and biochemistry are summarized, particularly those studies using electrocytes as a model system for the study of the regulation of membrane excitability by second messengers and signal transduction pathways.

  4. Phospholipid diffusion coefficients of cushioned model membranes determined via z-scan fluorescence correlation spectroscopy.

    Science.gov (United States)

    Sterling, Sarah M; Allgeyer, Edward S; Fick, Jörg; Prudovsky, Igor; Mason, Michael D; Neivandt, David J

    2013-06-25

    Model cellular membranes enable the study of biological processes in a controlled environment and reduce the traditional challenges associated with live or fixed cell studies. However, model membrane systems based on the air/water or oil/solution interface do not allow for incorporation of transmembrane proteins or for the study of protein transport mechanisms. Conversely, a phospholipid bilayer deposited via the Langmuir-Blodgett/Langmuir-Schaefer method on a hydrogel layer is potentially an effective mimic of the cross section of a biological membrane and facilitates both protein incorporation and transport studies. Prior to application, however, such membranes must be fully characterized, particularly with respect to the phospholipid bilayer phase transition temperature. Here we present a detailed characterization of the phase transition temperature of the inner and outer leaflets of a chitosan supported model membrane system. Specifically, the lateral diffusion coefficient of each individual leaflet has been determined as a function of temperature. Measurements were performed utilizing z-scan fluorescence correlation spectroscopy (FCS), a technique that yields calibration-free diffusion information. Analysis via the method of Wawrezinieck and co-workers revealed that phospholipid diffusion changes from raftlike to free diffusion as the temperature is increased-an insight into the dynamic behavior of hydrogel supported membranes not previously reported.

  5. FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression.

    Science.gov (United States)

    Heuer, Timothy S; Ventura, Richard; Mordec, Kasia; Lai, Julie; Fridlib, Marina; Buckley, Douglas; Kemble, George

    2017-02-01

    Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers. Copyright © 2016 3-V Biosciences. Published by Elsevier B.V. All rights reserved.

  6. FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression

    Directory of Open Access Journals (Sweden)

    Timothy S. Heuer

    2017-02-01

    Full Text Available Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.

  7. Coastal flooding impact evaluation using an INtegrated DisRuption Assessment (INDRA) model for Varna region, Western Black Sea

    Science.gov (United States)

    Andreeva, Nataliya; Eftimova, Petya; Valchev, Nikolay; Prodanov, Bogdan

    2017-04-01

    The study presents evaluation and comparative analysis of storm induced flooding impacts on different coastal receptors at a scale of Varna region using INtegrated DisRuption Assessment (INDRA) model. The model was developed within the FP7 RISC-KIT project, as a part of Coastal Risk Assessment Framework (CRAF) consisting of two phases. CRAF Phase 1 is a screening process that evaluates coastal risk at a regional scale by means of coastal indices approach, which helps to identify potentially vulnerable coastal sectors: hot spots (HS). CRAF Phase 2 has the objective to assess and rank identified hotspots by detailed risk analysis done by jointly performing a hazard assessment and an impact evaluation on different categories (population, businesses, ecosystems, transport and utilities) using INDRA model at a regional level. Basically, the model assess the shock of events by estimating the impact on directly exposed to flooding hazard receptors of different vulnerability, as well as the potential ripple effects during an event in order to assess the "indirect" impacts, which occur outside the hazard area and/or continue after the event for all considered categories. The potential impacts are expressed in terms of uniform "Impact Indicators", which independently score the indirect impacts of these categories assessing disruption and recovery of the receptors. The ultimate hotspot ranking is obtained through the use of a Multi Criteria analysis (MCA) incorporated in the model, considering preferences of stakeholders. The case study area - Varna regional coast - is located on the western Black Sea, Bulgaria. The coastline, with a length of about 70 km, stretches from cape Ekrene to cape St. Atanas and includes Varna Bay. After application of CRAF Phase 1 three hotspots were selected for further analysis: Kabakum beach (HS1), Varna Central beach plus Port wall (HS2) and Artificial Island (HS3). For first two hotspots beaches and associated infrastructure are the assets

  8. Chronic Subordination Stress Induces Hyperphagia and Disrupts Eating Behavior in Mice Modeling Binge-Eating-Like Disorder

    Science.gov (United States)

    Razzoli, Maria; Sanghez, Valentina; Bartolomucci, Alessandro

    2015-01-01

    Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge-eating disorder (BED) is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress-induced hyperphagia associated with the development of obesity. Here, we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress (CSS) associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol we tested the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or to the acute application of a social defeat. Notably, the obese phenotype but not the fasting hyperglycemia of subordinate mice was abrogated by preventing hyperphagia in a pair-feeding paradigm. Conclusion: Overall, these results support the validity of our CSS to model BED allowing for the determination of the underlying molecular mechanisms and the generation of testable predictions for innovative therapies, based on the understanding of the regulation and the control of food intake. PMID:25621284

  9. Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder

    Directory of Open Access Journals (Sweden)

    Maria eRazzoli

    2015-01-01

    Full Text Available Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge eating disorder (BED is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress induced hyperphagia associated with the development of obesity. Here we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol was test the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or t