P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp), a plasma membrane ATP-binding cassette (ABC) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD) which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR). In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR, such as hydrophobic steroids, at a region close to the ATP site. Interestingly, flavonoids also bind to NBDs with high affinity. Their binding site partly overlaps both the ATP-binding site and the steroid-interacting region. Therefore flavonoids constitute a new promising class of bifunctional modulators of Pgp.

L'adquisició del catalá en una nena monolingüe dels 2 anys i 3 mesos als 3 anys i dos mesos. 'La adquisición del catalán en una niña monolingüe desde los 2 años y 3 meses hasta los 3 años y 2 meses'.

Establecer un orden en las flexiones catalanas que posibilite la comparación con otros estudios. La muestra la compone un solo individuo, niña de 2 años y 3 meses (al empezar la investigación, tres años y tres meses al terminarla), de ámbito socio-cultural medio, lengua materna catalana (residente en Badalona). La investigación lineal (12 meses) se articula alrededor de la bibliografía consultada y de las grabaciones (18 sesiones de 30-45 minutos) y análisis mediante el MLU de Brown, del lenguaje del sujeto de la muestra. Grabaciones magnetofónicas (18 grabaciones de 30, 45 minutos cada una). Bibliografía. MLU de Brown adaptado al catalán por Vilá (pero con las normas de cálculo de Brown). La adquisición de las flexiones es el resultado de un nivel determinado de complejidad cognitiva y lingüística, pero no se discierne en qué medida intervienen ambos factores. Para conocer cómo influyen los aspectos semánticos, sintácticos, pragmáticos y fonológicos en la adquisición del lenguaje son necesarios estudios transversales en niños bilingües.

Identification and Analyses of Candidate Genes for Rpp4-Mediated Resistance to Asian Soybean Rust in Soybean

Asian soybean rust is a formidable threat to soybean (Glycine max) production in many areas of the world, including the United States. Only five sources of resistance have been identified (Resistance to Phakopsora pachyrhizi1 [Rpp1], Rpp2, Rpp3, Rpp4, and Rpp5). Rpp4 was previously identified in the resistant genotype PI459025B and mapped within 2 centimorgans of Satt288 on soybean chromosome 18 (linkage group G). Using simple sequence repeat markers, we developed a bacterial artificial chromosome contig for the Rpp4 locus in the susceptible cv Williams82 (Wm82). Sequencing within this region identified three Rpp4 candidate disease resistance genes (Rpp4C1-Rpp4C3 [Wm82]) with greatest similarity to the lettuce (Lactuca sativa) RGC2 family of coiled coil-nucleotide binding site-leucine rich repeat disease resistance genes. Constructs containing regions of the Wm82 Rpp4 candidate genes were used for virus-induced gene silencing experiments to silence resistance in PI459025B, confirming that orthologous genes confer resistance. Using primers developed from conserved sequences in the Wm82 Rpp4 candidate genes, we identified five Rpp4 candidate genes (Rpp4C1-Rpp4C5 [PI459025B]) from the resistant genotype. Additional markers developed from the Wm82 Rpp4 bacterial artificial chromosome contig further defined the region containing Rpp4 and eliminated Rpp4C1 (PI459025B) and Rpp4C3 (PI459025B) as candidate genes. Sequencing of reverse transcription-polymerase chain reaction products revealed that Rpp4C4 (PI459025B) was highly expressed in the resistant genotype, while expression of the other candidate genes was nearly undetectable. These data support Rpp4C4 (PI459025B) as the single candidate gene for Rpp4-mediated resistance to Asian soybean rust.

Tolkning av rekvisitet ”Annat socialt nedbrytande beteende” i § 3 LVU

Syfte med uppsatsen är att ge en bättre förståelse av vad som menas med begreppet ”annat socialt nedbrytande beteende” i § 3 LVU och visa eventuella skillnader i hur lagstiftningen, domstolar och socialtjänsten använder detta begrepp. Vi har undersökt hur begreppsdefinitionen har utvecklats genom lagstiftningsprocessen och hur den återspeglas i förarbeten, juridisk litteratur, prejudikat och praxis. Uppsatsen är skriven utifrån en juridisk metod. Vi genomförde åtta semistrukturerade intervjuer med socialsekreterare i Hälsingland och en länsrättsdomare för att ta reda på hur dessa använder begreppet. Vi har gjort en sammanställning av olika problembeteenden som ungdomar kan uppvisa och diskuterat om dessa är socialt nedbrytande beteende i lagens mening. I lagstiftningen är definitionen av rekvisitet diffus och generell, detta innebär problem för socialsekreterare att använda rekvisitet. Socialsekreterarna är inte vana och tillräckligt utbildade att använda begreppet vilket kan leda till en mindre rättssäker prövning för den enskilde.

Interferon-α antagonizes IL-3-mediated immunoregulatory functions of human basophils

Human basophils are major inflammatory cells in maintaining chronic allergic asthma. It has been published that interferon-α (IFN-α) improves clinical symptoms of asthma patients. In contrast, IL-3 exacerbates airway inflammation by inducing IL-4, IL-8 and IL-13 secretion from human basophils thus regulating their immunoregulatory functions. Furthermore, IL-3 exceptionally promotes survival of basophils. Here, we assessed cellular response of human basophils treated with IFN-α alone or in combination with IL-3. Our data show that IFN-α enhances apoptosis in purified human blood basophils compared to spontaneous apoptosis of controls or IFN-γ treated cells. Furthermore, we demonstrate that both IFN-α and FasL enhance apoptosis in human basophils with similar efficiency in a rather additive than synergistic way. IFN-α inhibits IL-3-induced survival to a minor degree. Particularly however, it suppresses IL-3-induced de-novo production of IL-8 and IL-13 up to 80%. In contrast, the production of IL-4 is not affected. Analyses of signaling pathways reveal that IFN-α promotes prolonged phosphorylation of STAT1/STAT2. By using a pan-JAK inhibitor the phosphorylation of STAT1/STAT2 is inhibited and most importantly the pro-apoptotic effect of IFN-α is abolished. Although the phosphorylation of p38-MAPK in IFN-α-treated cells is comparable to non-treated cells, inhibition of p-p38 activity abrogates IFN-α-enhanced apoptosis as well. We conclude that IFN-α-enhanced apoptosis is tightly regulated by the cooperation of JAK/STAT and p38-MAPK pathways. Our study identifies IFN-α as a novel inhibitor of IL-3-induced IL-8 and IL-13 production of human basophils. Taken together our study may explain the improved clinical symptoms of asthma patients treated with IFN-α.

Na 1 Nachlass Max Horkheimer, 6 - Korrespondenzen u.a. mit Célestin Bouglé (p. I 3, 188-402)

66 Briefe zwischen Célestin Bouglé, C. Bouglé, Jeanne Bouglé und Max Horkheimer, 1933-1940; 2 Briefe von Henri Bergson an Célestin Bouglé, 1933, 1935; 1 Brief von Bouvier & Beale an Max Horkheimer, 19.08.1936; 8 Briefe zwischen C. M. Bowra und Max Horkheimer, 1936-1937; 13 Briefe zwischen Ralph Raoul Boyer und Max Horkheimer, 1943-1946; 1 Brief von Max Horkheimer an Justice Louis Brandeis, 18.06.1940; 1 Brief von Karl Brandt von der Notgemeinschaft Deutscher Wissenschaftler im Ausland New York an Max Horkheimer, 27.11.1935; 4 Briefe zwischen Alfred Braunthal und Max Horkheimer, 03.08.1938, 1936-1938; 1 Brief von Trude Briess an Max Horkheimer, 07.06.1938; 4 Briefe zwsichen Lilly Brill und Max Horkheimer, 1947-1948; 1 Brief von Max Horkheimer an Chandis H. Brauchler, 03.09.1949; 1 Brief von Max Horkheimer an Lilian Broadwin, 07.03.1939; 4 Briefe zwischen Lola Bronstein und Max Horkheimer, 1940; 1 Brief von Ferdinand Bruckner an Max Horkheimer, 02.02.1938; 6 Briefe zwischen Paul Bruell udn Max Horkheimer, 1939; 1 Brief von H. Brungs an Max Horkheimer, 20.07.1949; 2 Briefe zwischen Fritz Brupbacher und Max Horkheimer, 31.03.1940, 17.04.1940; 4 Briefe zwischen Gerhard Bry und Max Horkheimer, 1937-1940, 26.01.1940; 1 Brief von Max Horkheimer an Richard Büchner, 29.06.1937; 2 Briefe zwischen Erika Buhlmann und Max Horkheimer, 1949; 13 Briefe zwischen Else Buki und Max Horkheimer, 1940-1941; 1 Brief von Max Horkheimer an Hans Buki, 14.07.1943; 1 Brief von Max Horkheimer an Friedrich Burschell, 29.08.1938; 7 Briefe und 5 Entwürfe zwischen dem Präsident der Columbia University Nicholas Murray Butler und Max Horkheimer, 1938-1941; 1 Brief von Max Horkheimer an Pierce Butler, 03.05.1938;

Fragm. lat. I 3 - Glossarium latinum

Trägerband: Ms. Praed. 123; Vorbesitzer: Konrad Textoris; Dominikanerkloster Frankfurt am Main

Lohengrin (I. 3.)

Signatur des Originals: S 36/F07559

Tannhäuser (I. 3.)

Signatur des Originals: S 36/F07571

Preparing Exercise I-3: Optimization of cross-section tables using sensitivity coefficients in COBAYA3

Preparing Exercise I-3: Optimization of cross-section tables using sensitivity coefficients in COBAYA3

High-affinity RNA-binding domains of alfalfa mosaic virus coat protein are not required for coat protein-mediated resistance.

A virus-based vector was used for the transient expression of the alfalfa mosaic virus coat protein (CP) gene in protoplasts and plants. The accumulation of wild-type CP conferred strong protection against subsequent alfalfa mosaic virus infection, enabling the efficacy of CP mutants to be determined without developing transgenic plants. Expression of the CP mRNA alone without CP accumulation conferred weaker protection against infection. The activity of the N-terminal mutant CPs in protection did not correlate with their activities in genome activation. The activity of a C-terminal mutant suggested that encapsidation did not have a role in protection. Our results indicate that interaction of the CP with alfalfa mosaic virus RNA is not important in protection, thereby leaving open the possibility that interactions with host factors lead to protection.