48,115 research outputs found
Scanning Tunneling Microscopy and Spectroscopy investigations of Graphene on Ru(0001) and (CO+O) on Rh(111)
No full text[Letter from Arthur S. Rosichan to J. L. Zuber - August 11, 1944]
No full textLetter from Arthur S. Rosichan to J. L. Zuber: August 11, 1944. Subject of the letter is the author moving to Houston to work for the Jewish Community Council
Evidence for the decay B0→J/ψω and measurement of the relative branching fractions of meson decays to J/ψη and J/ψη′
No full textFirst evidence of the B 0 → J / ψ ω decay is found and the B s 0 → J / ψ η and B s 0 → J / ψ η ′ decays are studied using a dataset corresponding to an integrated luminosity of 1.0 fb -1 collected by the LHCb experiment in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV. The branching fractions of these decays are measured relative to that of the B 0 → J / ψ ρ 0 decay:frac(B (B 0 → J / ψ ω), B (B 0 → J / ψ ρ 0)) = 0.89 ± 0.19 (stat) - 0.13 + 0.07 (syst),frac(B (B s 0 → J / ψ η), B (B 0 → J / ψ ρ 0)) = 14.0 ± 1.2 (stat) - 1.5 + 1.1 (syst) - 1.0 + 1.1 (frac(f d, f s)),frac(B (B s 0 → J / ψ η ′), B (B 0 → J / ψ ρ 0)) = 12.7 ± 1.1 (stat) - 1.3 + 0.5 (syst) - 0.9 + 1.0 (frac(f d, f s)), where the last uncertainty is due to the knowledge of f d / f s, the ratio of b-quark hadronization factors that accounts for the different production rate of B 0 and B s 0 mesons. The ratio of the branching fractions of B s 0 → J / ψ η ′ and B s 0 → J / ψ η decays is measured to befrac(B (B s 0 → J / ψ η ′), B (B s 0 → J / ψ η)) = 0.90 ± 0.09 (stat) - 0.02 + 0.06 (syst)
PEPTIDOMIMETICS CONTAINING NEW BIFUNCTIONAL 2,5-DIKETOPIPERAZINE SCAFFOLDS: SYNTHESIS, CONFORMATIONAL ANALYSIS AND USE AS POTENT INTEGRIN LIGANDS
No full textA library of 11 bifunctional 2,5-diketopiperazine (DKP) scaffolds, derived from L- or D-Ser and either L- or D-Asp or D-Glu, was designed and synthesized. All the DKP scaffolds feature a carboxylic acid functionality and an amino group, either protected as Boc or masked as azide, which can be locked in a cis- or trans-relationship as a consequence of the absolute configurations of the two α-amino acids. Moreover, the DKP scaffolds differ from each other for the substitution at the intracyclic nitrogens (N-1, N-4), as they are either mono- or bis-benzylated. The DKP scaffolds, while being derived from α-amino acids, can be seen as constrained dipeptides formed by two β-amino acids or one β- and one γ-amino acid.
Two different synthetic strategies were devised to prepare the mono benzylated scaffolds, depending on the nitrogen substitution (N-1 or N-4). In particular, the synthesis of DKP scaffolds bearing a benzyl group at the serine-derived nitrogen N-4 was accomplished making use of a serine ligation strategy, via the isopeptide.[1] On the other hand, the synthesis of DKP scaffolds bearing a benzyl group at the aspartic acid-derived nitrogen N-1 occurred through the formation of a dipeptide intermediate. Bis N-benzyl substituted scaffolds were easily accessed benzylating mono-substituted advanced intermediates.
An efficient synthesis in solution of eight cyclic peptidomimetics containing a DKP scaffold and the Arg-Gly-Asp (RGD) motif[2] has been developed and optimized. The ligands were tested for their ability to inhibit biotinylated vitronectin binding to integrin αvβ3 and αvβ5 receptors. All the ligands, except for the one containing a cis-scaffold, displayed low nanomolar inhibitory activity for both αVβ3 and αVβ5 integrin receptors, with a slight selectivity in favour of the former receptor. In order to rationalize, on a molecular basis, the affinity of these cyclic RGD peptidomimetics for the αvβ3 receptor, conformational and docking studies were performed by NMR spectroscopy and computational methods.
Two cyclic peptidomimetics containing a DKP scaffold and the isoAsp-Gly-Arg (isoDGR) motif were prepared, combining a solid phase and a solution phase synthetic approach. Very promising results (low nanomolar inhibitory activity) were obtained for their ability to inhibit biotinylated vitronectin binding to the αvβ3 and αvβ5 integrin receptors.
Based on the good results recently obtained by the group of Prof. Oliver Reiser (Univ. Regensburg)[3] in the design of helices, alternating two α- and two β-amino acids, a linear pseudodecapeptide was prepared alternating a cis-DKP, which serves as a ββ-constrained dipeptide, and Ala-Ala as the αα-subunit. The folding properties of the αα,ββ-pseudodecapeptide were studied by NMR spectroscopy, CD spectroscopy and computational methods. The results obtained, though not exhaustive, are indicative of a turn-inducing ability of the cis-DKP.[4]
[1] M. Marchini, M. Mingozzi, R. Colombo, C. Gennari, M. Durini, U. Piarulli, Tetrahedron 2010, 66, 9528-9531.
[2] A. S. M. da Ressurreição, A. Vidu, M. Civera, L. Belvisi, D. Potenza, L. Manzoni, S. Ongeri, C. Gennari, U. Piarulli, Chem. Eur. J. 2009, 15, 12184-12188.
[3] L. Berlicki, L. Pilsl, E. Wéber, I. M. Mándity, C. Cabrele, T. A. Martinek, F. Fülöp, O. Reiser, Angew. Chem. Int. Ed., in press.
[4] a) A. S. M. Ressurreição, A. Bordessa, M. Civera, L. Belvisi, C. Gennari, U. Piarulli, J. Org. Chem. 2008, 73, 652-660; b) R. Delatouche, M. Durini, M. Civera, L. Belvisi, U. Piarulli, Tetrahedron Lett. 2010, 51, 4278-4280
Humanization of porcine pulmonary valvulated conduits after decellularization and repopulation with human endothelial cells
No full textIntroduction. In heart valve surgical replacement, the most suitable hemodynamic properties and mechanical performances depend on the preservation of cusp anatomical shape and stromal structure. In addition, post-operatory valve calcification can be avoided only after removing all native cells from bioprostheses. Previously, complete cell extraction was achieved from porcine valve leaflets with concurrent preservation of their extracellular matrix (ECM) (1). These acellular scaffolds allowed "in vitro" repopulation with homologous valve interstitial cells, which also re-differentiated into all four cell phenotypes existing in heart valves (2). Methods. Porcine pulmonary valvulated segments (PVCs) were decellularized using combined non -denaturating neutral detergents Triton X-100 and Cholate, followed by Benzonase® digestion. Acellular PVCs were (i) orthotopically implanted in recipient pigs for 1-2 months, or (ii) "in vitro" seeded with endothelial cells derived from human umbilical cord (HUVEC), and incubated for 1-2 weeks. Histological and TEM-SEM ultrastructural analysis was performed, also after histochemical reactions for glycosaminoglycan (GAG) localization and laminin immuno-localization. Results. The treated PVCs exhibited complete cell remotion, good ECM preservation and surface reactivity for laminin. (i) After 2-month implantation, "in vivo" cell colonization spontaneously occurred by two distinct cell populations: endothelial-like cells, adhering to PVC luminal areas, and mesenchimal-like cells, migrating through PVC interstitium. (ii) After cell seeding and 1-week incubation, monolayers of human endothelial cells completely covered PVC luminal surfaces. Cell adhesion to the retained basal "lamina" and cell junction formation were also observed. In addition, valve interstitium was enriched by newly secreted GAGs at the subendothelial aspects. After cell seeding and 2-week incubation, micropinocytotic activity by endothelium and increased GAG-reactivity were observed. Conclusions. The decellularized PVCs are propensive for both (i) "in vivo" homologous cell repopulation, and (ii) "in vitro" heterologous endothelization with HUVEC. In addition, PVC stroma acquired more and more hybrid character because human-endothelium-generated GAGs were added to the native ECM macromolecules retained within the treated porcine PVCs. Thus these engineered PVCs appear as promising autologous-like, glutaraldehyde-free, and anti-thrombogenic bioprostheses. 1. Spina M., Ortolani F., El Messlemani A., Gandaglia A., Bujan J., Garcia-Honduvilla N., Vesely I., Gerosa G., Casarotto D., Petrelli L., Marchini M.: Isolation of intact aortic valve scaffolds for heart valve bioprostheses: extracellular matrix structure, prevention from calcification and cell repopulation features. J. Biomed. Mater. Res., 67, 1338-1350, 2003. 2. Bertipaglia B., Ortolani F., Petrelli L., Gerosa G., Spina M.,, Pauletto P., Casarotto D., Marchini M., Sartore S.: Cell characterization of porcine aortic valve and decellularized leaflets repopulated with aortic valve interstitial cells. Ann. Thorac. Surg., 75, 1274-1282, 2003
Elastin and collagen interact with cell-derived acidic phospholipid membranes in the progression of mineralization in calcifying aortic valves
No full textINTRODUCTION Elastin fibers have been reported to be prone to mineralization in ageing and in a number of cardiovascular diseases including bioprosthetic valve calcification. Different mechanisms seem to exist which direct these mineralization processes such as in aorta atherosclerotic plaques, where calcification is preceded by accumulation of cholesterol esters and neutral lipids inside altered elastin fibers [1], or that in subdermally implanted aorta wall segments, where calcification occurs at the outer aspect of elastin fibers interacting with undefined amorphous material [2]. Recently, we found that fixation/reactions with glutaraldehyde and cationic copper-phthalocyanine Cuprolinic blue (GACB) at low salt-critical-electrolyte-concentration and pH were suitable for studying calcification in subdermally implanted aortic valves, because of tissue unmasking form mineral and simultaneous visualization at the ultrastructural level of unique, electrondense layers outlining calcifying cells and matrix-vesicle-like structures [3,4]. The observed reactivity and susceptibility to extraction with chloroform-methanol suggested these pericellular layers to be formed by acidic phospholipids which will cluster at cell surfaces replacing cell plasma membranes. Here, a modified glutaraldehyde-malachite-green method (GA-MG) was used to support the concept of lipid involvement in valve calcification and to assess how elastin fibers and collagen fibrils are involved in the mineralization progression from the cells into the extracellular matrix. MATERIAL AND METHODS Animal model inducing calcification: 6-week long implantation of porcine aortic valve leaflets in rat subcutis [5]. Processing of explanted samples: (A) immersion in 25mM sodium acetate buffer, containing 0.05% Cuprolinic blue + 0.05M MgCl2 + 2,5% glutaraldehyde, pH 4.8, at room temperature for 4 days (GACB); (B) immersion in 0.067 mol/L cacodylate buffer solution, containing 3% glutaraldehyde and 0.1% Malachite green, pH 4.8, at 4°C for 18h (GAMG). Post-fixation in 2% OsO4 in phosphate buffer, pH 7.2; dehydration in graded ethanols; embedding in Araldite/Epon. (A-C) thin section staining with uranyl acetate and lead citrate. RESULTS On thin sections, GAMG-subjected samples showed reactivity patterns superimposable to those observed for GACB-treated samples. Namely, decalcifying effect occurred with associated unmasking of cells and matrix vesicles, which appeared to be outlined by MG-reactive, electrondense borders (Fig.1). In addition, mineralization spreading from cells to adjacent extracellular matrix was characterized by outward growing of the MG-reactive material, which enveloped electron-lucent elastin fibers and collagen fibrils, and the additional presence of amorphous material embedding all these components (Fig.2). Despite demineralization, calcium precipitates were observed to be retained by most elastin fibers interacting with MG-reactive material , whereas no mineral deposits was found either on iuxta-cellular fibers still not involved in such a relationship, or those lying in uncalcified extracellular matrix. DISCUSSION GA-MG method reveals acidic phospholipid distribution because it allows lipid retention in the sample, with subsequent formation of electron-dense GA-MG-OsO4-lipid complexes during standard post-fixation with osmium tetroxyde [6]. The lower pH here used allowed to obtain tissue demineralization with preservation of proper reactivness. In the experimental conditions adopted, acidic phospholipids appeared to be accumulated at cell and matrix vesicle surfaces, i.e. where primary calcification occurs, and to be also involved in subsequent mineralization progression into the ECM. Here, elastic fibers and collagen fibrils seem to require prior surface interaction with cell-derived acidic phospholipids before undergoing mineralization, in agreement with the concept that their calcification need interaction with additional molecules [1,3] and/or cell degradation products [3,7]. The concept is supported that elastin fibers can undergo calcification according to different mechanisms which include intrinsic alterations as well as interaction with polyanionic molecules such as proteoglycans, as suggested for pseudoxanthoma elasticum [8], or acidic phospholipids, as suggested by the present data. ACKNOWLEDGEMENTS This work was supported by a special grant by Cassa di Risparmio di Padova e Rovigo Foundation. REFERENCES [1] Bobryshev YV, Lord RS. Atherosclerosis 42, 197-198 (1999). [2] Paule WJ, Bernick S, Strates B, Nimni ME. J. Biomed. Mater. Res. 26, 1169-1177 (1992). [3] Ortolani F, Petrelli L, Tubaro F, Spina M, Marchini M. Connect. Tiss. Res. 43, 44-55 (2002). [4] Ortolani F, Tubaro F, Petrelli L, Gandaglia A, Spina M, Marchini M. Histochem. J. 34, 41-50 (2002). [5] Schoen FJ, Tsao JW, Levy RJ. Am. J. Pathol. 123, 134-145(1986). [6] Bonucci E, Silvestrini G. Bone 15, 153-160 (1994). [7] Kim KM. Scan. Electron. Microsc. 9, 1137-1175 (1995). [8] Pasquali Ronchetti I, Baccarani-Contri M, Fornieri C., Mori G., Quaglino D. jr. Micron 24, 75-89 (1993)
Linda Talk : suporte distribuido a programação concorrente orientada a objetos
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro TecnologicoProblemas complexos são geralmente decompostos em subproblemas menores, que sejam tratáveis mais facilmente. O mesmo vale para sistemas de computação, os quais contam com uma gama rica de abordagens de decomposição (funcional, procedural, etc). Dentre estas, a decomposição orientada a objetos tem ganho cada vez mais espaço, dada sua riqueza e poder na modelagem e implementação de sistemas informáticos. A possibilidade de programar sistemas multiprocessadores e sistemas em redes de computadores, por outro lado, favoreceu as linhas de programação paralela/concorrente/distribuída. Contudo, se de um lado a orientação a objetos clássica promove uma modelagem natural de entidades no domínio do problema, por outro lado ela falha na tentativa de expressar atividades concorrentes/paralelas. Já sistemas que suportam a noção de processos paralelos, tais como Occam, Conic, Ada, etc, permitem preencher esta lacuna. Contudo, o poder de modelagem e abstração de entidades fica bastante limitado neste tipo de abordagem, levandogeralmente à produção de sistemas difíceis de adaptar, manter e recusar. Modelos com suporte à programação paralela orientada a objetos, tais como Emerald, ConcurrentSmalltalk, Act-1, ABCL/1, etc. surgem na tentativa de unificar objetos no sentido clássico de orientação a objetos com a noção de processos paralelos e comunicantes. Porém, tanto nesta abordagem quanto na programação orientada a objetos clássica e alguns modelos de programação concorrente/paralela/distribuída, a metófora de interação entre objetos/processo é a mesma: troca de mensagens. Troca de mensagens conforme presente em sistemas concorrentes orientados a objetos apresentam diversas fraquezas no que toca a implementação, manutenção e reusabilidade de sistemas distribuídos. Nossa proposta busca incorporar a uma linguagem orientada a objetos clássica - Smalltalk - um modelo que suporte a programação paralela/distribuída com um maior grau de flexibilidade. Este modelo é o de Espaço de Tuplas, de Linda. Através de um pequeno conjunto de primitivas, tem-se um modelo simples de criação e coordenação de processos ortogonal à linguagem em que se insere o modelo (Smalltalk, no caso). Através do uso extensivo do modelo, acreditamos ser possível a construção de sistemas realmente distribuídos e orientados a objetos com um maior grau de flexibilidade em sua implementação, reusabilidade e manutenção
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
No full textMultiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
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