1,200 research outputs found

    Slicing Strategies for the Generalised Type-2 Mamdani Fuzzy Inferencing System

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    The final publication is available at Springer via http://dx.doi.org/[insert DOI]".As a three-dimensional object, there are a number of ways of slicing a generalised type-2 fuzzy set. In the context of the Mamdani Fuzzy Inferencing System, this paper concerns three accepted slicing strategies, the vertical slice, the wavy slice, and the horizontal slice or alpha -plane. Two ways of de ning the generalised type-2 fuzzy set, vertical slices and wavy slices, are presented. Fuzzi cation and inferencing is presented in terms of vertical slices. After that, the application of all three slicing strategies to defuzzi cation is described, and their strengths and weaknesses assessed

    The de novo centriole assembly pathway in HeLa cells: cell cycle progression and centriole assembly/maturation

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    It has been reported that nontransformed mammalian cells become arrested during G1 in the absence of centrioles (Hinchcliffe, E., F. Miller, M. Cham, A. Khodjakov, and G. Sluder. 2001. Science. 291:1547–1550). Here, we show that removal of resident centrioles (by laser ablation or needle microsurgery) does not impede cell cycle progression in HeLa cells. HeLa cells born without centrosomes, later, assemble a variable number of centrioles de novo. Centriole assembly begins with the formation of small centrin aggregates that appear during the S phase. These, initially amorphous “precentrioles” become morphologically recognizable centrioles before mitosis. De novo–assembled centrioles mature (i.e., gain abilities to organize microtubules and replicate) in the next cell cycle. This maturation is not simply a time-dependent phenomenon, because de novo–formed centrioles do not mature if they are assembled in S phase–arrested cells. By selectively ablating only one centriole at a time, we find that the presence of a single centriole inhibits the assembly of additional centrioles, indicating that centrioles have an activity that suppresses the de novo pathway

    Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells

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    How centrosome removal or perturbations of centrosomal proteins leads to G1 arrest in untransformed mammalian cells has been a mystery. We use microsurgery and laser ablation to remove the centrosome from two types of normal human cells. First, we find that the cells assemble centrioles de novo after centrosome removal; thus, this phenomenon is not restricted to transformed cells. Second, normal cells can progress through G1 in its entirety without centrioles. Therefore, the centrosome is not a necessary, integral part of the mechanisms that drive the cell cycle through G1 into S phase. Third, we provide evidence that centrosome loss is, functionally, a stress that can act additively with other stresses to arrest cells in G1 in a p38-dependent fashion

    Uncertainty Measurement for the Interval Type-2 Fuzzy Set

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    In this paper, two measures of uncertainty for interval type-2 fuzzy sets are presented, evaluated, compared and contrasted. Wu and Mendel regard the length of the type-reduced set as a measure of the uncertainty in an interval set. Green eld and John argue that the volume under the surface of the type-2 fuzzy set is a measure of the uncertainty relating to the set. For an interval type-2 fuzzy set, the volume measure is equivalent to the area of the footprint of uncertainty of the set. Experiments show that though the two measures give di erent results, there is considerable commonality between them. The concept of invariance under vertical translation is introduced; the uncertainty measure of a fuzzy set has the property of invariance under vertical translation if the value it generates remains constant under any vertical translation of the fuzzy set. It is left unresolved whether invariance under vertical translation is an essential property of a type-2 uncertainty measure

    Linearization of Cohomology-free Vector Fields

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    We study the cohomological equation for a smooth vector field on a compact manifold. We show that if the vector field is cohomology free, then it can be embedded continuously in a linear flow on an Abelian group

    A continuous infusion of a minor histocompatibility antigen-immunodominant peptide induces a delay of male skin graft rejection.

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    We previously reported that an inhibition of antigen-specific Interferon-gamma release and cytotoxicity occurs after a continuous infusion of an HY immunodominant peptide although this treatment is not able to cause a significant delay of male skin grafts rejection. In vivo administration of high doses of an HY peptide, through mini-osmotic pumps, in naĂŻve female mice was used to study the effects on the male skin grafts rejection. A continuous infusion of 1mg of an HY peptide induces a significant delay of male skin graft rejection. In vitro HY-specific Interferon-gamma release was inhibited adding peptide-specific suppressor cells: the ability to inhibit Interferon-gamma release was evident when two HY peptides were present on the same dendritic cells indicating that the suppressor cells exert "linked-suppression". The phenotype of the suppressor cells is CD8(+)CD28(-) and these cells express more CD62 ligand and FOXP3 than controls. Suppressor cells were able to cause a significant delay of rejection of male skin grafts when injected in naive female mice. The inhibitory effects of these suppressor cells seem to be due to the impairment of antigen presentation; down-regulation of B7 molecules on dendritic cells occurred. Taken all together, our data demonstrate that a continuous infusion of an immunodominant HY peptide induces a T CD8 suppressor subset able to inhibit immune responses to male tissues and cells

    A Method for Structure–Activity Analysis of Quorum-Sensing Signaling Peptides from Naturally Transformable Streptococci

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    Many species of streptococci secrete and use a competence-stimulating peptide (CSP) to initiate quorum sensing for induction of genetic competence, bacteriocin production, and other activities. These signaling molecules are small, unmodified peptides that induce powerful strain-specific activity at nano-molar concentrations. This feature has provided an excellent opportunity to explore their structure–function relationships. However, CSP variants have also been identified in many species, and each specifically activates its cognate receptor. How such minor changes dramatically affect the specificity of these peptides remains unclear. Structure–activity analysis of these peptides may provide clues for understanding the specificity of signaling peptide–receptor interactions. Here, we use the Streptococcus mutans CSP as an example to describe methods of analyzing its structure–activity relationship. The methods described here may provide a platform for studying quorum-sensing signaling peptides of other naturally transformable streptococci

    epsilon-Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C9h Peptide to Induce Apoptosis in Cancer Cells

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    [EN] Apoptotic signaling pathways are altered in numerous pathologies such as cancer. In this scenario, caspase-9/PP2Ac alpha interaction constitutes a key target with pharmacological interest to re-establish apoptosis in tumor cells. Very recently, a short peptide (C9h) known to disrupt caspase-9/PP2Ac alpha interaction with subsequent apoptosis induction was described. Here, we prepared two sets of mesoporous silica nanoparticles loaded with safraninO (S2) or with C9h peptide (S4) and functionalized with epsilon-polylysine as capping unit. Aqueous suspensions of both nanoparticles showed negligible cargo release whereas in the presence of pronase, a marked delivery of safraninO or C9h was observed. Confocal microscopy studies carried out with HeLa cells indicated that both materials were internalized and were able to release their entrapped cargos. Besides, a marked decrease in HeLa cell viability (ca. 50%) was observed when treated with C9h-loaded S4 nanoparticles. Moreover, S4 provides peptide protection from degradation additionally allowing for a dose reduction to observe an apoptotic effect when compared with C9h alone or in combination with a cell-penetrating peptide (i.e., Mut3DPT-C9h). Flow cytometry studies, by means of Annexin V-FITC staining, showed the activation of apoptotic pathways in HeLa as a consequence of S4 internalization, release of C9h peptide and disruption of caspase-9/PP2Ac alpha interaction.The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1, SAF2012-31405, SAF2015-67077-R, AGL2015-70235-C2-2-R (MINECO/FEDER)), the Generalitat Valencia (Projects PROMETEOII/2014/047, PROMETEO/2012/061) and the CIBER-BBN for their support. C.T. is grateful to the Spanish Ministry of Science and Innovation for her Ph.D. fellowship.De La Torre-Paredes, C.; Domínguez-Berrocal, L.; Murguía, JR.; Marcos Martínez, MD.; Martínez-Máñez, R.; Bravo, J.; Sancenón Galarza, F. 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Emerging Frontiers in Drug Delivery. Journal of the American Chemical Society, 138(3), 704-717. doi:10.1021/jacs.5b09974Mai, W. X., & Meng, H. (2012). Mesoporous silica nanoparticles: A multifunctional nano therapeutic system. Integrative Biology, 5(1), 19-28. doi:10.1039/c2ib20137bDoadrio, A., Salinas, A., Sánchez-Montero, J., & Vallet-Regí, M. (2015). Drug release from ordered mesoporous silicas. Current Pharmaceutical Design, 21(42), 6213-6819. doi:10.2174/1381612822666151106121419Argyo, C., Weiss, V., Bräuchle, C., & Bein, T. (2013). Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Chemistry of Materials, 26(1), 435-451. doi:10.1021/cm402592tGagliardi, M. (2017). Recent Advances in Preclinical Studies and Potential Applications of Dendrimers as Drug Carriers in the Central Nervous System. Current Pharmaceutical Design, 23(21). doi:10.2174/1381612823666170313124811Zhang, R. X., Ahmed, T., Li, L. Y., Li, J., Abbasi, A. Z., & Wu, X. Y. (2017). Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks. Nanoscale, 9(4), 1334-1355. doi:10.1039/c6nr08486aGuo, X., Wang, L., Wei, X., & Zhou, S. (2016). Polymer-based drug delivery systems for cancer treatment. Journal of Polymer Science Part A: Polymer Chemistry, 54(22), 3525-3550. doi:10.1002/pola.28252Li, Z., Barnes, J. C., Bosoy, A., Stoddart, J. F., & Zink, J. I. (2012). Mesoporous silica nanoparticles in biomedical applications. Chemical Society Reviews, 41(7), 2590. doi:10.1039/c1cs15246gWang, Y., Zhao, Q., Han, N., Bai, L., Li, J., Liu, J., … Wang, S. (2015). Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomedicine: Nanotechnology, Biology and Medicine, 11(2), 313-327. doi:10.1016/j.nano.2014.09.014Sun, R., Wang, W., Wen, Y., & Zhang, X. (2015). Recent Advance on Mesoporous Silica Nanoparticles-Based Controlled Release System: Intelligent Switches Open up New Horizon. Nanomaterials, 5(4), 2019-2053. doi:10.3390/nano5042019Mura, S., Nicolas, J., & Couvreur, P. (2013). Stimuli-responsive nanocarriers for drug delivery. Nature Materials, 12(11), 991-1003. doi:10.1038/nmat3776Tarn, D., Ashley, C. E., Xue, M., Carnes, E. C., Zink, J. I., & Brinker, C. J. (2013). Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility. Accounts of Chemical Research, 46(3), 792-801. doi:10.1021/ar3000986Aznar, E., Oroval, M., Pascual, L., Murguía, J. R., Martínez-Máñez, R., & Sancenón, F. (2016). Gated Materials for On-Command Release of Guest Molecules. Chemical Reviews, 116(2), 561-718. doi:10.1021/acs.chemrev.5b00456Agostini, A., Mondragón, L., Bernardos, A., Martínez-Máñez, R., Marcos, M. D., Sancenón, F., … Murguía, J. R. (2012). Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 51(42), 10556-10560. doi:10.1002/anie.201204663Agostini, A., Mondragón, L., Bernardos, A., Martínez-Máñez, R., Marcos, M. D., Sancenón, F., … Murguía, J. R. (2012). Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles. Angewandte Chemie, 124(42), 10708-10712. doi:10.1002/ange.201204663Agostini, A., Mondragón, L., Coll, C., Aznar, E., Marcos, M. D., Martínez-Máñez, R., … Amorós, P. (2012). Dual Enzyme-Triggered Controlled Release on Capped Nanometric Silica Mesoporous Supports. ChemistryOpen, 1(1), 17-20. doi:10.1002/open.201200003Aznar, E., Villalonga, R., Giménez, C., Sancenón, F., Marcos, M. D., Martínez-Máñez, R., … Amorós, P. (2013). Glucose-triggered release using enzyme-gated mesoporous silica nanoparticles. Chemical Communications, 49(57), 6391. doi:10.1039/c3cc42210kGiménez, C., de la Torre, C., Gorbe, M., Aznar, E., Sancenón, F., Murguía, J. R., … Amorós, P. (2015). Gated Mesoporous Silica Nanoparticles for the Controlled Delivery of Drugs in Cancer Cells. Langmuir, 31(12), 3753-3762. doi:10.1021/acs.langmuir.5b00139De la Torre, C., Casanova, I., Acosta, G., Coll, C., Moreno, M. J., Albericio, F., … Martínez-Máñez, R. (2014). Gated Mesoporous Silica Nanoparticles Using a Double-Role Circular Peptide for the Controlled and Target-Preferential Release of Doxorubicin in CXCR4-Expresing Lymphoma Cells. Advanced Functional Materials, 25(5), 687-695. doi:10.1002/adfm.201403822De la Torre, C., Agostini, A., Mondragón, L., Orzáez, M., Sancenón, F., Martínez-Máñez, R., … Pérez-Payá, E. (2014). Temperature-controlled release by changes in the secondary structure of peptides anchored onto mesoporous silica supports. Chem. Commun., 50(24), 3184-3186. doi:10.1039/c3cc49421gAznar, E., Coll, C., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., Soto, J., … Ruiz, E. (2009). Borate-Driven Gatelike Scaffolding Using Mesoporous Materials Functionalised with Saccharides. Chemistry - A European Journal, 15(28), 6877-6888. doi:10.1002/chem.200900090Bringas, E., Köysüren, Ö., Quach, D. V., Mahmoudi, M., Aznar, E., Roehling, J. D., … Stroeve, P. (2012). Triggered release in lipid bilayer-capped mesoporous silica nanoparticles containing SPION using an alternating magnetic field. Chemical Communications, 48(45), 5647. doi:10.1039/c2cc31563gSancenón, F., Pascual, L., Oroval, M., Aznar, E., & Martínez-Máñez, R. (2015). Gated Silica Mesoporous Materials in Sensing Applications. ChemistryOpen, 4(4), 418-437. doi:10.1002/open.201500053Oroval, M., Climent, E., Coll, C., Eritja, R., Aviñó, A., Marcos, M. D., … Amorós, P. (2013). An aptamer-gated silica mesoporous material for thrombin detection. Chemical Communications, 49(48), 5480. doi:10.1039/c3cc42157kPascual, L., Baroja, I., Aznar, E., Sancenón, F., Marcos, M. D., Murguía, J. R., … Martínez-Máñez, R. (2015). Oligonucleotide-capped mesoporous silica nanoparticles as DNA-responsive dye delivery systems for genomic DNA detection. Chemical Communications, 51(8), 1414-1416. doi:10.1039/c4cc08306gGiménez, C., Climent, E., Aznar, E., Martínez-Máñez, R., Sancenón, F., Marcos, M. D., … Rurack, K. (2014). Über den chemischen Informationsaustausch zwischen gesteuerten Nanopartikeln. Angewandte Chemie, 126(46), 12838-12843. doi:10.1002/ange.201405580Llopis-Lorente, A., Díez, P., Sánchez, A., Marcos, M. D., Sancenón, F., Martínez-Ruiz, P., … Martínez-Máñez, R. (2017). Interactive models of communication at the nanoscale using nanoparticles that talk to one another. Nature Communications, 8(1). doi:10.1038/ncomms15511Lu, J., Liong, M., Li, Z., Zink, J. I., & Tamanoi, F. (2010). Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small, 6(16), 1794-1805. doi:10.1002/smll.201000538Baeza, A., Manzano, M., Colilla, M., & Vallet-Regí, M. (2016). Recent advances in mesoporous silica nanoparticles for antitumor therapy: our contribution. Biomaterials Science, 4(5), 803-813. doi:10.1039/c6bm00039hRosenholm, J. M., Sahlgren, C., & Lindén, M. (2010). Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles – opportunities & challenges. Nanoscale, 2(10), 1870. doi:10.1039/c0nr00156bPoh, S., Lin, J. B., & Panitch, A. (2015). Release of Anti-inflammatory Peptides from Thermosensitive Nanoparticles with Degradable Cross-Links Suppresses Pro-inflammatory Cytokine Production. Biomacromolecules, 16(4), 1191-1200. doi:10.1021/bm501849pPatel, A., Cholkar, K., & Mitra, A. K. (2014). Recent developments in protein and peptide parenteral delivery approaches. Therapeutic Delivery, 5(3), 337-365. doi:10.4155/tde.14.5Sung, B., Kim, C., & Kim, M.-H. (2015). Biodegradable colloidal microgels with tunable thermosensitive volume phase transitions for controllable drug delivery. Journal of Colloid and Interface Science, 450, 26-33. doi:10.1016/j.jcis.2015.02.068Witting, M., Molina, M., Obst, K., Plank, R., Eckl, K. M., Hennies, H. C., … Hedtrich, S. (2015). Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules. Nanomedicine: Nanotechnology, Biology and Medicine, 11(5), 1179-1187. doi:10.1016/j.nano.2015.02.017Yu, E., Galiana, I., Martínez-Máñez, R., Stroeve, P., Marcos, M. D., Aznar, E., … Amorós, P. (2015). Poly(N-isopropylacrylamide)-gated Fe3O4/SiO2 core shell nanoparticles with expanded mesoporous structures for the temperature triggered release of lysozyme. Colloids and Surfaces B: Biointerfaces, 135, 652-660. doi:10.1016/j.colsurfb.2015.06.048Braun, K., Pochert, A., Lindén, M., Davoudi, M., Schmidtchen, A., Nordström, R., & Malmsten, M. (2016). 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    Declining mortality following acute myocardial infarction in the Department of Veterans Affairs Health Care System

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    <p>Abstract</p> <p>Background</p> <p>Mortality from acute myocardial infarction (AMI) is declining worldwide. We sought to determine if mortality in the Veterans Health Administration (VHA) has also been declining.</p> <p>Methods</p> <p>We calculated 30-day mortality rates between 2004 and 2006 using data from the VHA External Peer Review Program (EPRP), which entails detailed abstraction of records of all patients with AMI. To compare trends within VHA with other systems of care, we estimated relative mortality rates between 2000 and 2005 for all males 65 years and older with a primary diagnosis of AMI using administrative data from the VHA Patient Treatment File and the Medicare Provider Analysis and Review (MedPAR) files.</p> <p>Results</p> <p>Using EPRP data on 11,609 patients, we observed a statistically significant decline in adjusted 30-day mortality following AMI in VHA from 16.3% in 2004 to 13.9% in 2006, a relative decrease of 15% and a decrease in the odds of dying of 10% per year (p = .011). Similar declines were found for in-hospital and 90-day mortality.</p> <p>Based on administrative data on 27,494 VHA patients age 65 years and older and 789,400 Medicare patients, 30-day mortality following AMI declined from 16.0% during 2000-2001 to 15.7% during 2004-June 2005 in VHA and from 16.7% to 15.5% in private sector hospitals. After adjusting for patient characteristics and hospital effects, the overall relative odds of death were similar for VHA and Medicare (odds ratio 1.02, 95% C.I. 0.96-1.08).</p> <p>Conclusion</p> <p>Mortality following AMI within VHA has declined significantly since 2003 at a rate that parallels that in Medicare-funded hospitals.</p

    Differential Subcellular Localization of the Splice Variants of the Zinc Transporter ZnT5 Is Dictated by the Different C-Terminal Regions

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    Zinc is emerging as an important intracellular signaling molecule, as well as fulfilling essential structural and catalytic functions through incorporation in a myriad of zinc metalloproteins so it is important to elucidate the molecular mechanisms of zinc homeostasis, including the subcellular localizations of zinc transporters.Two splice variants of the human SLC30A5 Zn transporter gene (ZnT5) have been reported in the literature. These variants differ at their N- and C-terminal regions, corresponding with the use of different 5' and 3' exons. We demonstrate that full length human ZnT5 variant B is a genuine transcript in human intestinal cells and confirm expression of both variant A and variant B in a range of untreated human tissues by splice variant-specific RT-PCR. Using N- or C-terminal GFP or FLAG fusions of both isoforms of ZnT5 we identify that the differential subcellular localization to the Golgi apparatus and ER respectively is a function of their alternative C-terminal sequences. These different C-terminal regions result from the incorporation into the mature transcript of either the whole of exon 14 (variant B) or only the 5' region of exon 14 plus exons 15-17 (variant A).We thus propose that exons 15 to 17 include a signal that results in trafficking of ZnT5 to the Golgi apparatus and that the 3' end of exon 14 includes a signal that leads to retention in the ER
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