Fast kinetics of Taxol binding to microtubules:effects of solution variables and microtubule-associated proteins

14 p.-9 fig.-4 tab.The kinetics of Taxol association to and dissociation from stabilized microtubules has been measured by competition with the reference fluorescent derivative Flutax-1 (Diaz, J. F., Strobe, R., Engelborghs, Y., Souto, A. A., and Andreu, J. M. (2000) J. Biol. Chem. 275, 26265-26276). The association rate constant at 37 degrees C is k(+) = (3.6 +/- 0.1) x 10(6) m(-1) s(-1). The reaction profile is similar to that of the first step of Flutax-1 binding, which probably corresponds to the binding of the Taxol moiety. The rate constant of the initial binding of Flutax-1 is inversely proportional to the viscosity of the solution, which is compatible with a diffusion-controlled reaction. Microtubule-associated proteins bound to the microtubule outer surface slow down the binding of Flutax-1 and Flutax-2 10-fold. The binding site is fully accessible to Flutax-2 in native cytoskeletons of PtK2 cells; the observed kinetic rates of Flutax-2 microtubule staining and de-staining are similar to the reaction rates with microtubule associated proteins-containing microtubules. The kinetic data prove that taxoids bind directly from the bulk solution to an exposed microtubule site. Several hypotheses have been analyzed to potentially reconcile these data with the location of a Taxol-binding site at the model microtubule lumen, including dynamic opening of the microtubule wall and transport from an initial Taxol-binding site at the microtubule pores.This work was supported in part by MCyT Grants BIO2000-0748 (to J. M. A.) and BIO2001-1725 (to J. F. D.) and Programa de Grupos Estratégicos de la Comunidad de Madrid.Peer reviewe

Determinant factors of pull up performance in trainedathletes

Aim: to investigate the relationship among pull up and lat pull exercises and differentanthropometric dimensions in trained athletes. Methods: twenty-five males were evaluated for maximum number of pull ups, one-repetitionmaximum lat pull (1RM Lat Pull), lat pull repetitions at 80% 1RM (Lat Pull at 80% 1RM), latpull repetitions at a load equivalent to body mass (Lat Pull at BM-load), and differentanthropometric variables. Furthermore, the subjects were divided in higher (HPG, n = 12) andlower pull up performance (LPG, n = 13) to compare the differences in the variables analyzedbetween both levels. Results: pull ups were significantly correlated with Lat Pull at BM-load (r = .62, P < .01) butneither with 1RM Lat Pull (r = .09) nor with Lat Pull at 80% 1RM (r = -.15). Pull ups showed asignificant (P < .05) negative relationship with body mass (BM, r = -.55), lean body mass(LBM, r = -.51), and fat mass (FM, r = -.52), while BM and LBM were significantly correlatedwith 1RM Lat Pull (r = .55, P < .05). HPG showed significantly (P < .05) lower BM (0/3/97%),FM (1/3/97%) and LBM (1/4/95%) than LPG. Furthermore, HPG attained significantly (P < .05– .001) greater performance in Lat Pull at BM-load (100/0/0%) and 1RM Lat Pull•BM-1(96/3/2%) than LPG. Conclusion: these findings suggest that pull up and lat pull exercises have common elements.Moreover, the anthropometric dimensions seem to influence differently on both exercises,depending on the strength indicator evaluated

Modeling OpAmp-induced harmonic distortion for switched-capacitor ΣΔ modulator design

This communication reports a new modeling of opamp-induced harmonic distortion in SC ΣΔ modulators, which is aimed to optimum design of this kind of circuit for high-performance applications. We analyze incomplete transfer of charge in a SC integrator and use power expansion and nonlinear fitting to obtain analytical models to represent harmonic distortion as function of the opamp finite gain-bandwidth (GB), slew-rate (SR) and nonlinear DC gain. Calculated models apply for all modulator architectures where harmonic distortion is dominated by the first integrator in the chain. We show that results provided by the new analytical models fit well to that obtained by simulation in time domain and have accuracy levels much larger than that provided by previously reported modeling approaches

A Tool for automated design of sigma-delta modulators using statistical optimization

A tool is presented which starting from high level specifications of SC σδ modulators (resolution, bandwidth and oversampling ratio) calculates first optimum specifications for the building blocks (op-amps, comparator, etc.), and then, optimum sizes for their schematics. At both design levels (high-level synthesis and cell dimensioning), optimization is performed via using statistical techniques and innovative heuristics, which allow global design (independent on the initial conditions) and increased computer efficiency as compared to conventional statistical optimization techniques. The tool has been conceived to be flexible at the high-level part(via the use of an architecture independent, behaviourable modeling approach) and completely open at the cell-design part. Performance of the tool is demonstrated via the automatic design of a 16bit-dynamic range, 8Khz second-order SC σδ modulator in 1.2 μm CMOS technology, for which measurements on a fabricated prototype are reported

Agrupación robusta de Bancos en Argentina

The purpose of this paper is to classify and characterize 64 banks, active as of 2010 in Argentina, by means of robust techniques used on information gathered during the period 2001-2010. Based on the strategy criteria established in (Wang 2007) and (Werbin 2010), seven variables were selected. In agreement with bank theory, four “natural” clusters were obtained, named “Personal”, “Commercial”, “Typical” and “Other banks”. In order to understand this grouping, projection pursuit based robust principal component analysis was conducted on the whole set showing that essentially three variables can be attributed the formation of different clusters. In order to reveal each group inner structure, we used R package mclust to fit a finite Gaussian mixture to the data. This revealed approximately a similar component structure, granting a common principal components analysis as in (Boente and Rodrigues, 2002). This allowed us to identify three variables which suffice for grouping and characterizing each cluster. Boente’s influence measures were used to detect extreme cases in the common principal components analysis.El propósito de este documento es clasificar y caracterizar 64 bancos, activos en 2010 en la Argentina, mediante técnicas robustas utilizadas con información para el período 2001-2010. En base a los criterios de estrategia establecidos en (Wang 2007) y (Werbin 2010), se seleccionaron siete variables. De acuerdo con la teoría bancaria, se obtuvieron cuatro conglomerados "naturales", denominados "Personal", "Comercial", "Típico" y "Otros bancos". Para comprender este agrupamiento, se utilizó el todo el conjunto de banco y se realizó un análisis de los componentes principales basado en la proyección, que mostró que esencialmente tres variables pueden atribuirse a la formación de diferentes agrupaciones. A fin de revelar la estructura interna de cada grupo, utilizamos el paquete R mclust para ajustar una mezcla gaussiana finita a los datos. Esto reveló aproximadamente una estructura de componentes similar, lo que garantiza un análisis de componentes principales comunes como en (Boente y Rodrigues, 2002). Esto nos permitió identificar tres variables que son suficientes para agrupar y caracterizar cada cluster. Las medidas de influencia de Boente se utilizaron para detectar casos extremos en el análisis de componentes principales comunes

El mito de "Tren-Treng Kai-Kai" del Pueblo Mapuche

El artículo hace un análisis del relato mítico mapuche “Treng-Treng y Kai-Kai” del quela literatura histórica y etnológica ha dejado dos versiones que se citan en este trabajo, una que entrega el jesuita D. de Rosales y otra del folclorista E. Robles. El autor muestra asimismo su involucramiento en su experiencia pastoral, a través de la cual este relato le llegó a ser conocido por su estrecho contacto con las comunidades mapuche del Lago del Budi, entre los años 1989 y 1995. La motivación de este trabajo surgió principalmente cuando el autor encontró datos sobre el sacrificio humano en la zona, realizado poco después del terremoto y maremoto que el año 1960 afectó gravemente al litoral. Al verificar lo acaecido y confrontado con los significados del relato mítico, queda en evidencia que se está frente a un hecho y a una interpretación de profundo significado religioso. Este trabajo tiene como propósito original entender el sentido sacrificial propio de un hecho tan difícil de entender para una racionalidad científica, y dar cuenta de sus principales significados

El pueblo mapuche, un pueblo con historia

Análisis de hechos en la historia mapuche, relevantes para la comprensión de sus demandas

Apuntes sobre la actividad misionera junto al pueblo mapuche después del Vaticano II

Este trabajo pretende recoger algunos antecedentes y ofrecer algunos elementos para la reflexión de la actividad misionera junto al pueblo mapuche

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

13 p.-7 fig. Bohnacker, Thomas et al.BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom.We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K.Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120’s generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.This work was supported by the Swiss Commission for Technology and Innovation (CTI) by PFLS-LS grants 14032.1,15811.2 and 17241.1; the Stiftung für Krebsbekämpfung grant 341, Swiss National Science Foundation grants 310030_153211 and 316030_133860 (to M.P.W.), and 310030B_138659 and 31003A_166608 (to M.O.S.); in part by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 675392, and grants BIO2013-42984-R (Ministerio de Economia y Competitividad), S2010/BMD-2457 BIPEDD2 (Comunidad Autónoma de Madrid) to J.F.D.; and by the MRC to R.L.W. (U105184308Peer reviewe

Nueva lápida árabe de Trujillo

Fragment of a new Arab stone with Kufic inscription inside an arch and with merlons and flowers found at Trujillo (Cáceres).Fragmento de una nueva lápida árabe con inscripción cúfica enmarcada en un arco y con adornos de almenas y florones encontrada en Trujillo (Cáceres)