Comportamiento mecánico de nuevas aleaciones de wolframio en función de la temperatura

La presente memoria de tesis tiene como objetivo principal la caracterización mecánica en función de la temperatura de nueve aleaciones de wolframio con contenidos diferentes en titanio, vanadio, itria y lantana. Las aleaciones estudiadas son las siguientes: W-0.5%Y2O3, W-2%Ti, W-2% Ti-0.5% Y2O3, W-4% Ti-0.5% Y2O3, W-2%V, W- 2%Vmix, W-4%V, W-1%La2O3 and W-4%V-1%La2O3. Todos ellos, además del wolframio puro se fabrican mediante compresión isostática en caliente (HIP) y son suministradas por la Universidad Carlos III de Madrid. La investigación se desarrolla a través de un estudio sistemático basado en ensayos físicos y mecánicos, así como el análisis post mortem de las muestras ensayadas. Para realizar dicha caracterización mecánica se aplican diferentes ensayos mecánicos, la mayoría de ellos realizados en el intervalo de temperatura de 25 a 1000 º C. Los ensayos de caracterización que se llevan a cabo son: • Densidad • Dureza Vicker • Módulo de elasticidad y su evolución con la temperatura • Límite elástico o resistencia a la flexión máxima, y su evolución con la temperatura • Resistencia a la fractura y su comportamiento con la temperatura. • Análisis microestructural • Análisis fractográfico • Análisis de la relación microestructura-comportamiento macroscópico. El estudio comienza con una introducción acerca de los sistemas en los que estos materiales son candidatos para su aplicación, para comprender las condiciones a las que los materiales serán expuestos. En este caso, el componente que determina las condiciones es el Divertor del reactor de energía de fusión por confinamiento magnético. Parece obvio que su uso en los componentes del reactor de fusión, más exactamente como materiales de cara al plasma (Plasma Facing Components o PFC), hace que estas aleaciones trabajen bajo condiciones de irradiación de neutrones. Además, el hecho de que sean materiales nuevos hace necesario un estudio previo de las características básicas que garantice los requisitos mínimos antes de realizar un estudio más complejo. Esto constituye la principal motivación de la presente investigación. La actual crisis energética ha llevado a aunar esfuerzos en el desarrollo de nuevos materiales, técnicas y dispositivos para la aplicación en la industria de la energía nuclear. El desarrollo de las técnicas de producción de aleaciones de wolframio, con un punto de fusión muy alto, requiere el uso de precursores de sinterizado para lograr densificaciones más altas y por lo tanto mejores propiedades mecánicas. Este es el propósito de la adición de titanio y vanadio en estas aleaciones. Sin embargo, uno de los principales problemas de la utilización de wolframio como material estructural es su alta temperatura de transición dúctil-frágil. Esta temperatura es característica de materiales metálicos con estructura cúbica centrada en el cuerpo y depende de varios factores metalúrgicos. El proceso de recristalización aumenta esta temperatura de transición. Los PFC tienen temperaturas muy altas de servicio, lo que facilita la recristalización del metal. Con el fin de retrasar este proceso, se dispersan partículas insolubles en el material permitiendo temperaturas de servicio más altas. Hasta ahora se ha utilizado óxidos de torio, lantano e itrio como partículas dispersas. Para entender cómo los contenidos en algunos elementos y partículas de óxido afectan a las propiedades de wolframio se estudian las aleaciones binarias de wolframio en comparación con el wolframio puro. A su vez estas aleaciones binarias se utilizan como material de referencia para entender el comportamiento de las aleaciones ternarias. Dada la estrecha relación entre las propiedades del material, la estructura y proceso de fabricación, el estudio se completa con un análisis fractográfico y micrográfico. El análisis fractográfico puede mostrar los mecanismos que están implicados en el proceso de fractura del material. Por otro lado, el estudio micrográfico ayudará a entender este comportamiento a través de la identificación de las posibles fases presentes. La medida del tamaño de grano es una parte de la caracterización microestructural. En esta investigación, la medida del tamaño de grano se llevó a cabo por ataque químico selectivo para revelar el límite de grano en las muestras preparadas. Posteriormente las micrografías fueron sometidas a tratamiento y análisis de imágenes. El documento termina con una discusión de los resultados y la compilación de las conclusiones más importantes que se alcanzan después del estudio. Actualmente, el desarrollo de nuevos materiales para aplicación en los componentes de cara al plasma continúa. El estudio de estos materiales ayudará a completar una base de datos de características que permita hacer una selección de ellos más fiable. The main goal of this dissertation is the mechanical characterization as a function of temperature of nine tungsten alloys containing different amounts of titanium, vanadium and yttrium and lanthanum oxide. The alloys under study were the following ones: W-0.5%Y2O3, W-2%Ti, W-2% Ti-0.5% Y2O3, W-4% Ti-0.5% Y2O3, W-2%V, W- 2%Vmix, W-4%V, W-1%La2O3 and W-4%V-1%La2O3. All of them, besides pure tungsten, were manufactured using a Hot Isostatic Pressing (HIP) process and they were supplied by the Universidad Carlos III de Madrid. The research was carried out through a systematic study based on physical and mechanical tests as well as the post mortem analysis of tested samples. Diverse mechanical tests were applied to perform this characterization; most of them were conducted at temperatures in the range 25-1000 ºC. The following characterization tests were performed: • Density • Vickers hardness • Elastic modulus • Yield strength or ultimate bending strength, and their evolution with temperature • Fracture toughness and its temperature behavior • Microstructural analysis • Fractographical analysis • Microstructure-macroscopic relationship analysis This study begins with an introduction regarding the systems where these materials could be applied, in order to establish and understand their service conditions. In this case, the component that defines the conditions is the Divertor of magnetic-confinement fusion reactors. It seems obvious that their use as fusion reactor components, more exactly as plasma facing components (PFCs), makes these alloys work under conditions of neutron irradiation. In addition to this, the fact that they are novel materials demands a preliminary study of the basic characteristics which will guarantee their minimum requirements prior to a more complex study. This constitutes the motivation of the present research. The current energy crisis has driven to join forces so as to develop new materials, techniques and devices for their application in the nuclear energy industry. The development of production techniques for tungsten-based alloys, with a very high melting point, requires the use of precursors for sintering to achieve higher densifications and, accordingly, better mechanical properties. This is the purpose of the addition of titanium and vanadium to these alloys. Nevertheless, one of the main problems of using tungsten as structural material is its high ductile-brittle transition temperature. This temperature is characteristic of metallic materials with body centered cubic structure and depends on several metallurgical factors. The recrystallization process increases their transition temperature. Since PFCs have a very high service temperature, this facilitates the metal recrystallization. In order to inhibit this process, insoluble particles are dispersed in the material allowing higher service temperatures. So far, oxides of thorium, lanthanum and yttrium have been used as dispersed particles. Tungsten binary alloys are studied in comparison with pure tungsten to understand how the contents of some elements and oxide particles affect tungsten properties. In turn, these binary alloys are used as reference materials to understand the behavior of ternary alloys. Given the close relationship between the material properties, structure and manufacturing process, this research is completed with a fractographical and micrographic analysis. The fractographical analysis is aimed to show the mechanisms that are involved in the process of the material fracture. Besides, the micrographic study will help to understand this behavior through the identification of present phases. The grain size measurement is a crucial part of the microstructural characterization. In this work, the measurement of grain size was carried out by chemical selective etching to reveal the boundary grain on prepared samples. Afterwards, micrographs were subjected to both treatment and image analysis. The dissertation ends with a discussion of results and the compilation of the most important conclusions reached through this work. The development of new materials for plasma facing components application is still under study. The analysis of these materials will help to complete a database of the features that will allow a more reliable materials selection.

Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation

Recent studies indicate that Caenorhabditis elegans CED-4 interacts with and promotes the activation of the death protease CED-3, and that this activation is inhibited by CED-9. Here we show that a mammalian homolog of CED-4, Apaf-1, can associate with several death proteases, including caspase-4, caspase-8, caspase-9, and nematode CED-3 in mammalian cells. The interaction with caspase-9 was mediated by the N-terminal CED-4-like domain of Apaf-1. Expression of Apaf-1 enhanced the killing activity of caspase-9 that required the CED-4-like domain of Apaf-1. Furthermore, Apaf-1 promoted the processing and activation of caspase-9 in vivo. Bcl-XL, an antiapoptotic member of the Bcl-2 family, was shown to physically interact with Apaf-1 and caspase-9 in mammalian cells. The association of Apaf-1 with Bcl-XL was mediated through both its CED-4-like domain and the C-terminal domain containing WD-40 repeats. Expression of Bcl-XL inhibited the association of Apaf-1 with caspase-9 in mammalian cells. Significantly, recombinant Bcl-XL purified from Escherichia coli or insect cells inhibited Apaf-1-dependent processing of caspase-9. Furthermore, Bcl-XL failed to inhibit caspase-9 processing mediated by a constitutively active Apaf-1 mutant, suggesting that Bcl-XL regulates caspase-9 through Apaf-1. These experiments demonstrate that Bcl-XL associates with caspase-9 and Apaf-1, and show that Bcl-XL inhibits the maturation of caspase-9 mediated by Apaf-1, a process that is evolutionarily conserved from nematodes to humans.

Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators

Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon–DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)-1(α,β)-N7Gua at 59–213 μmol/mol DNA–phosphate whereas the level of stable adducts was 0.1 μmol/mol DNA–phosphate. In female Sprague–Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 μmol 4-OHE2-1(α,β)-N7Gua/molDNA–phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87–440 μmol of 4-OHE1(E2)-1(α, β)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 μmol of adduct/mol DNA–phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

The neutral glycosphingolipid globotriaosylceramide promotes fusion mediated by a CD4-dependent CXCR4-utilizing HIV type 1 envelope glycoprotein

Previously, we showed that the addition of human erythrocyte glycosphingolipids (GSLs) to nonhuman CD4+ or GSL-depleted human CD4+ cells rendered those cells susceptible to HIV-1 envelope glycoprotein-mediated cell fusion. Individual components in the GSL mixture were isolated by fractionation on a silica-gel column and incorporated into the membranes of CD4+ cells. GSL-supplemented target cells were then examined for their ability to fuse with TF228 cells expressing HIV-1LAI envelope glycoprotein. We found that one GSL fraction, fraction 3, exhibited the highest recovery of fusion after incorporation into CD4+ nonhuman and GSL-depleted HeLa-CD4 cells and that fraction 3 contained a single GSL fraction. Fraction 3 was characterized by MS, NMR spectroscopy, enzymatic analysis, and immunostaining with an antiglobotriaosylceramide (Gb3) antibody and was found to be Gal(α1→4)Gal(β1→4)Glc-Cer (Gb3). The addition of fraction 3 or Gb3 to GSL-depleted HeLa-CD4 cells recovered fusion, but the addition of galactosylceramide, glucosylceramide, the monosialoganglioside, GM3, lactosylceramide, globoside, the disialoganglioside, GD3, or α-galactosidase A-digested fraction 3 had no effect. Our findings show that the neutral GSL, Gb3, is required for CD4/CXCR4-dependent HIV-1 fusion.

Hybrid Ty1/HIV-1 elements used to detect inhibitors and monitor the activity of HIV-1 reverse transcriptase

We previously demonstrated that hybrid retrotransposons composed of the yeast Ty1 element and the reverse transcriptase (RT) of HIV-1 are active in the yeast Saccharomyces cerevisiae. The RT activity of these hybrid Ty1/HIV-1 (his3AI/AIDS RT; HART) elements can be monitored by using a simple genetic assay. HART element reverse transcription depends on both the polymerase and RNase H domains of HIV-1 RT. Here we demonstrate that the HART assay is sensitive to inhibitors of HIV-1 RT. (−)-(S)-8-Chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione monohydrochloride (8 Cl-TIBO), a well characterized non-nucleoside RT inhibitor (NNRTI) of HIV-1 RT, blocks propagation of HART elements. HART elements that express NNRTI-resistant RT variants of HIV-1 are insensitive to 8 Cl-TIBO, demonstrating the specificity of inhibition in this assay. HART elements carrying NNRTI-resistant variants of HIV-1 RT can be used to identify compounds that are active against drug-resistant viruses.

Localization of α1,3-fucosyltransferase VI in Weibel–Palade bodies of human endothelial cells

Surface glycosylation of endothelial cells is relevant to various processes including coagulation, inflammation, metastasis, and lymphocyte homing. One of the essential sugars involved in these processes is fucose linked α1→3 to N-acetylglucosamine. A family of α1,3-fucosyltransferases (FucTs) called FucT-III, IV, V, VI, VII, and IX is able to catalyze such fucosylations. Reverse transcription–PCR analysis revealed that human umbilical vein endothelial cells express all of the FucTs except FucT-IX. The predominant activity, as inferred by acceptor specificity of enzyme activity in cell lysates, is compatible with the presence of FucT-VI. By using an antibody to recombinant soluble FucT-VI, the enzyme colocalized with β4-galactosyltransferase-1 to the Golgi apparatus. By using a polyclonal antiserum raised against a 17-aa peptide of the variable (stem) region of the FucT-VI, immunocytochemical staining of FucT-VI was restricted to Weibel–Palade bodies, as determined by colocalization with P-selectin and von Willebrand factor. SDS/PAGE immunoblotting and amino acid sequencing of internal peptides confirmed the identity of the antigen isolated by the peptide-specific antibody as FucT-VI. Storage of a fucosyltransferase in Weibel–Palade bodies suggests a function independent of Golgi-associated glycosylation.

Transforming Growth Factor-β Induces Nuclear Import of Smad3 in an Importin-β1 and Ran-dependent Manner

Smad proteins are cytoplasmic signaling effectors of transforming growth factor-β (TGF-β) family cytokines and regulate gene transcription in the nucleus. Receptor-activated Smads (R-Smads) become phosphorylated by the TGF-β type I receptor. Rapid and precise transport of R-Smads to the nucleus is of crucial importance for signal transduction. By focusing on the R-Smad Smad3 we demonstrate that 1) only activated Smad3 efficiently enters the nucleus of permeabilized cells in an energy- and cytosol-dependent manner. 2) Smad3, via its N-terminal domain, interacts specifically with importin-β1 and only after activation by receptor. In contrast, the unique insert of exon3 in the N-terminal domain of Smad2 prevents its association with importin-β1. 3) Nuclear import of Smad3 in vivo requires the action of the Ran GTPase, which mediates release of Smad3 from the complex with importin-β1. 4) Importin-β1, Ran, and p10/NTF2 are sufficient to mediate import of activated Smad3. The data describe a pathway whereby Smad3 phosphorylation by the TGF-β receptor leads to enhanced interaction with importin-β1 and Ran-dependent import and release into the nucleus. The import mechanism of Smad3 shows distinct features from that of the related Smad2 and the structural basis for this difference maps to the divergent sequences of their N-terminal domains.

Differential regulation of beta 1 and beta 2 integrin avidity by chemoattractants in eosinophils.

The CC chemokines regulated on activation normal T expressed and secreted (RANTES) and monocyte chemotactic protein 3 (MCP-3), and the anaphylatoxin C5a, induce activation, degranulation, chemotaxis, and transendothelial migration of eosinophils. Adhesion assays on purified ligands showed differential regulation of beta 1 and beta 2 integrin avidity in eosinophils. Adhesiveness of VLA-4 (alpha 4 beta 1, CD29/CD49d) for vascular cell adhesion molecule 1 or fibronectin was rapidly increased but subsequently reduced by RANTES, MCP-3, or C5a. The deactivation of VLA-4 lead to cell detachment, whereas phorbol 12-myristate 13-acetate induced sustained activation of VLA-4. In contrast, chemoattractants stimulated a prolonged increase in the adhesiveness of Mac-1 (alpha M beta 2, CD11b/CD18) for intercellular adhesion molecule 1. Inhibition by pertussis toxin confirmed signaling via G protein-coupled receptors. Chemoattractants induced transient, while phorbol 12-myristate 13-acetate induced sustained actin polymerization. Disruption of actin filaments by cytochalasins inhibited increases in avidity of VLA-4 but not of Mac-1. Chemoattractants did not upregulate a Mn2+-inducible beta 1 neoepitope defined by the mAb 9EG7, but induced prolonged expression of a Mac-1 activation epitope recognized by the mAb CBRM1/5. This mAb inhibited chemoattractant-stimulated adhesion of eosinophils to intercellular adhesion molecule 1. Thus, regulation of VLA-4 was dependent on the actin cytoskeleton, whereas conformational changes appeared to be crucial for activation of Mac-1. To our knowledge, this is the first demonstration that physiological agonists, such as chemoattractants, can differentially regulate the avidity of a beta 1 and a beta 2 integrin expressed on the same leukocyte.

Major histocompatibility complex class II DR alleles DRB1*1501 and those encoding HLA-DR13 are preferentially associated with a diminution in maternally transmitted human immunodeficiency virus 1 infection in different ethnic groups: determination by an automated sequence-based typing method.

Transmission of human immunodeficiency virus 1 (HIV-1) from an infected women to her offspring during gestation and delivery was found to be influenced by the infant's major histocompatibility complex class II DRB1 alleles. Forty-six HIV-infected infants and 63 seroreverting infants, born with passively acquired anti-HIV antibodies but not becoming detectably infected, were typed by an automated nucleotide-sequence-based technique that uses low-resolution PCR to select either the simpler Taq or the more demanding T7 sequencing chemistry. One or more DR13 alleles, including DRB1*1301, 1302, and 1303, were found in 31.7% of seroreverting infants and 15.2% of those becoming HIV-infected [OR (odds ratio) = 2.6 (95% confidence interval 1.0-6.8); P = 0.048]. This association was influenced by ethnicity, being seen more strongly among the 80 Black and Hispanic children [OR = 4.3 (1.2-16.4); P = 0.023], with the most pronounced effect among Black infants where 7 of 24 seroreverters inherited these alleles with none among 12 HIV-infected infants (Haldane OR = 12.3; P = 0.037). The previously recognized association of DR13 alleles with some situations of long-term nonprogression of HIV suggests that similar mechanisms may regulate both the occurrence of infection and disease progression after infection. Upon examining for residual associations, only only the DR2 allele DRB1*1501 was associated with seroreversion in Caucasoid infants (OR = 24; P = 0.004). Among Caucasoids the DRB1*03011 allele was positively associated with the occurrence of HIV infection (P = 0.03).

Assembly of regularly spaced nucleosome arrays by Drosophila chromatin assembly factor 1 and a 56-kDa histone-binding protein.

To ascertain the mechanism by which nucleosomes are assembled by factors derived from Drosophila embryos, two proteins termed Drosophila chromatin assembly factors (CAFs) 1 and 4 (dCAF-1 and dCAF-4) were fractionated and purified from a Drosophila embryo extract. The assembly of chromatin by dCAF-1, dCAF-4, purified histones, ATP, and DNA is a process that generates regularly spaced nucleosomal arrays with a repeat length that resembles that of bulk native Drosophila chromatin and is not obligatorily coupled to DNA replication. The assembly of chromatin by dCAF-1 and dCAF-4 is nearly complete within 10 min. The dCAF-1 activity copurified with the Drosophila version of chromatin assembly factor-1 (CAF-1), a factor that has been found to be required for the assembly of chromatin during large tumor (T) antigen-mediated, simian virus 40 (SV40) origin-dependent DNA replication. The dCAF-4 activity copurified with a 56-kDa core-histone-binding protein that was purified to > 90% homogeneity.

Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives).

Five structurally related thiophene and furane analogues of the oxathiin carboxanilide derivative NSC 615985 (UC84) (designated UC10, UC68, UC81, UC42, and UC16) were identified as potent inhibitors of HIV-1 replication in cell culture and HIV-1 reverse transcriptase activity. These compounds were markedly active against a series of mutant HIV-1 strains, containing the Leu-100-->Ile, Val-106-->Ala, Glu-138-->Lys, or Tyr-181-->Cys mutations in their reverse transcriptase. However, the thiocarboxanilide derivatives selected for mutations at amino acid positions 100 (Leu-->Ile), 101 (Lys-->Ile/Glu), 103 (Lys-->Thr/Asp) and 141 (Gly-->Glu) in the HIV-1 reverse transcriptase. The compounds completely suppressed HIV-1 replication and prevented the emergence of resistant virus strains when used at 1.3-6.6 microM--that is, 10- to 25-fold lower than the concentration required for nevirapine and bis(heteroaryl)piperazine (BHAP) U90152 to do so. If UC42 was combined with the [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)]-beta-D-pentofuranosyl (TSAO) derivative of N3-methylthymine (TSAO-m3T), virus breakthrough could be prevented for a much longer time, and at much lower concentrations, than if the compounds were used individually. Virus breakthrough could be suppressed for even longer, and at lower drug concentrations, if BHAP was added to the combination of UC42 with TSAO-m3T, which points to the feasibility of two- or three-drug combinations in preventing virus breakthrough and resistance development.

[Admittatur of Isaac Boyle], 1812 July 1

Published copy of the 1807 College Laws with the admittatur of undergraduate Isaac Boyle signed by President John Kirkland on July 1, 1812.

Die Balkan-Halbinsel in 4 Blättern: Türkei, Rumänien, Griechenland, Serbien, Montenegro, Bulgarien

entworfen von C. Vogel ; bearbeitet von B. Domann ; gestochen von Kern, Kühn u. Weiler.

Recent developments in the synthesis of novel xanthone-1,2,3-triazole dyads

The development of multi-target drugs for treating complex multifactorial diseases constitutes an active research ield. This kind of drugs has gained much importance as alternative strategy to combination therapy (“cocktail drugs”).1 A common way to design them brings together two different pharmacophores in one single molecule (so-called dyads). Following this idea and being aware that xanthones2 and 1,2,3-triazoles3 possess important pharmacological properties, we combined these two heterocycles in one molecule to create new dyads with improved therapeutic potential. In this work, new xanthone-1,2,3-triazole dyads were prepared from novel (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones by two different approaches to evaluate their eficiency and sustainability. Both methodologies involved Diels-Alder reactions to build the xanthone core, which were optimized using microwave irradiation as alternative heating method, and 1,3-dipolar cycloadditions to insert the 1,2,3-triazole moiety (Figure 1).4 All final and intermediate compounds were fully characterized by 1D and 2D NMR techniques.