Study of pK Values and Effective Dielectric Constants of Ionizable Residues in Pentapeptides and in Staphylococcal Nuclease (SNase) Using a Mean-Field Approach

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: evidence for the testicular vasculature atrophy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Bourgin-Yang version of the Borsuk-Ulam theorem for Z(pk)-equivariant maps

Let G = Z(pk) be a cyclic group of prime power order and let V and W be orthogonal representations of G with V-G = W-G = W-G = {0}. Let S(V) be the sphere of V and suppose f: S(V) -> W is a G-equivariant mapping. We give an estimate for the dimension of the set f(-1){0} in terms of V and W. This extends the Bourgin-Yang version of the Borsuk-Ulam theorem to this class of groups. Using this estimate, we also estimate the size of the G-coincidences set of a continuous map from S(V) into a real vector space W'.

Measurement of CP asymmetries in $\lambda^0_b \to pk^-$ and $\lambda^0_b \to p \pi^-$ decays at LHCb

The LHCb experiment has been designed to perform precision measurements in the flavour physics sector at the Large Hadron Collider (LHC) located at CERN. After the recent observation of CP violation in the decay of the Bs0 meson to a charged pion-kaon pair at LHCb, it is interesting to see whether the same quark-level transition in Λ0b baryon decays gives rise to large CP-violating effects. Such decay processes involve both tree and penguin Feynman diagrams and could be sensitive probes for physics beyond the Standard Model. The measurement of the CP-violating observable defined as ∆ACP = ACP(Λ0b → pK−)−ACP(Λ0b →pπ−),where ACP(Λ0b →pK−) and ACP(Λ0b →pπ−) are the direct CP asymmetries in Λ0b → pK− and Λ0b → pπ− decays, is presented for the first time using LHCb data. The procedure followed to optimize the event selection, to calibrate particle identification, to parametrise the various components of the invariant mass spectra, and to compute corrections due to the production asymmetry of the initial state and the detection asymmetries of the final states, is discussed in detail. Using the full 2011 and 2012 data sets of pp collisions collected with the LHCb detector, corresponding to an integrated luminosity of about 3 fb−1, the value ∆ACP = (0.8 ± 2.1 ± 0.2)% is obtained. The first uncertainty is statistical and the second corresponds to one of the dominant systematic effects. As the result is compatible with zero, no evidence of CP violation is found. This is the most precise measurement of CP violation in the decays of baryons containing the b quark to date. Once the analysis will be completed with an exhaustive study of systematic uncertainties, the results will be published by the LHCb Collaboration.

Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 mug/mL and an IC(50) for R-ketoprofen of 1.6 mug/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.

Regulation of sodium/glucose cotransporter expression in LLC-PK$\sb1$ cells

Expression of the Na$\sp+$/glucose cotransporter (SGLT1), a differentiated function of the pig kidney epithelial cell line LLC-PK$\sb1$ derived from proximal tubule, was further investigated. The differentiation inducer hexamethylene bisacetamide (HMBA) and IBMX, an inhibitor of cAMP phosphodiesterase, each stimulated a significant increase in Na$\sp+$/glucose cotransport activity, levels of the 75 kD cotransporter subunit and steady-state levels of the SGLT1 message. The action of HMBA is associated with involvement of polyamines and protein kinase C, and is synergistic with cAMP. We provide evidence that cAMP-elevating agents increase Na$\sp+$/glucose cotransporter expression, at least in part, via a post-transcriptional mechanism. Two molecular species of SGLT1 mRNA (3.9 kb and 2.2 kb) are transcribed from the same gene in LLC-PK$\sb1$ cells and differ only in the length of the 3$\sp\prime$ untranslated region (3$\sp\prime$ UTR). cAMP elevation differentially stabilized the 3.9 kb SGLT1 transcript from degradation but not the 22 kb species. UV-cross-linking and label transfer experiments indicated that cyclic AMP elevation was associated with formation of a 48 kD protein complex with a specific domain within the 3$\sp\prime$ UTR of SGLT1 mRNA. The binding was competitively inhibited by poly (U) and other U-rich RNA species such as c-fos ARE, and modulated by a protein kinase A-mediated phosphorylation/dephosphorylation mechanism. The binding site was mapped to a 120-nucleotide 3$\sp\prime$ UTR sequence which contains a uridine-rich region (URE). Our study provides the first demonstration that renal SGLT1 is post-transcriptionally regulated by a phosphorylation/dephosphorylation mechanism, and provides a deeper insight into gene regulation of this physiologically important cotransporter. ^

Improved bioassay for the detection of porcine tumor necrosis factor using a homologous cell line: PK(15)

Close similarities of various physiological parameters makes the pig one of the preferred animal models for the study of human diseases, especially those involving the cardiovascular system. Unfortunately, the use of pig models to study diseases such as viral hemorrhagic fevers and endotoxic shock syndrome have been hampered by the lack of the necessary immunological tools to measure important immunoregulatory cytokines such as tumor necrosis factor (TNF). Here we describe a TNF-bioassay which is based on the porcine kidney cell line PK(15). Compared to the widely used murine fibroblastoid cell line L929, the PK(15) cell line displays a 100-1000-fold higher sensitivity for porcine TNF-alpha, a higher sensitivity for human TNF-alpha, and a slightly lower sensitivity for murine TNF-alpha. Using a PK(15) bioassay we can detect recombinant TNF-alpha as well as cytotoxic activity in the supernatants of lipopolysaccharide (LPS)-activated porcine monocytes at high dilutions. This suggests that the sensitivity of the test should permit the detection of TNF in biological specimens such as pig serum.

Rehabilitación del puente ferroviario de la línea Venta de Baños-Santander, en el pk. 507+435

El objeto del presente Proyecto es definir las reparaciones necesarias en el puente situado en el P.K. 507+435 de la línea Venta de Baños - Santander, subsanando aquellas singularidades detectadas en las estructuras que supongan mermas en la seguridad estructural, así como en la durabilidad y funcionalidad de todos los elementos que constituyen la estructura, de modo que la obra quede en las mejores condiciones posibles. Es importante destacar que esta estructura fue proyectada para unas condiciones de explotación muy diferentes a las actuales (cargas, intensidad de tráfico, etc.). Además, tras una larga vida útil, su estado actual (materiales, configuración estructural, incluso geometría) puede haber cambiado notablemente con relación al inicial. Todo esto hace imprescindible realizar una evaluación estructural del puente teniendo muy en cuenta su estado actual.

Corrección del deslizamiento de una ladera en la autovia A-4. PK. 340 en el término municipal de Marmolejo, Jaén mediante pantalla de pilotes y sistemas de drenaje

En este proyecto se describe el cálculo y diseño de una serie de medidas correctoras propuestas a raíz de un deslizamiento de ladera que tuvo lugar en noviembre de 2010 y afectó a parte de la calzada de la autovía A-4 en el P.K. 340 entre Córdoba y Jaén; principalmente en la ejecución de una pantalla de pilotes como elemento estructural de estabilización y contención del terreno, por medio del método de equilibrio límite y cálculo del módulo de reacción o coeficiente de balasto horizontal, a través del empleo de los programas Slope/W y RIDO respectivamente. ABSTRACT This project describes the calculation and design of a series of proposed corrective measures following a landslide of which took place in November 2010 and hit part of the road A-4 on the P.K. 340 between Cordoba and Jaen, mainly in the execution of a pile wall as a structural element of stabilization and containment of the terrain, through the limit equilibrium method and calculating the reaction module or horizontal ballast coefficient, through employment of the Slope/W and RIDO programs respectively.

Viaducto perteneciente a la Línea de Alta Velocidad Vitoria - Bilbao - San Sebastián. Tramo: Atxondo - Abadiño, a su paso por Atxondo pk. 0+0,47. Atxondo (Vizcaya).

El presente proyecto tiene como finalidad la construcción del viaducto que permita dar continuidad a la línea de alta velocidad denominada “Y Vasca” (Bilbao-Vitoria-San Sebastián). Más concretamente, se encuadra en el tramo Atxondo-Abadiño, estando ubicado el futuro viaducto a la altura del primer municipio. El objetivo principal del proyecto es realizar un estudio con el suficiente grado de detalle para que nos permita definir, diseñar y justificar la solución completa que mejor se adapte a nuestras necesidades, es decir, que se integre de una forma armónica en la línea de alta velocidad. Se pretende que este proyecto contenga todos los elementos necesarios que permitan la definición y la construcción del viaducto, cumpliendo en particular la adaptación al trazado de la Línea de Alta Velocidad (LAV) en la que se enmarca, y que se ajuste a la normativa vigente.

Viaducto para la mejora del trazado de la N-403 Toledo-Ávila, entre el pk. 111+050 y el pk. 111+450, término municipal de San Juan de la Nava (Ávila)

Las actuaciones que se definen en el presente Proyecto de Construcción consisten en una mejora de trazado de la actual N-403 Toledo-Ávila, mediante la construcción de un viaducto que une los puntos kilométricos 111+050 y 111+450 de dicha carretera, en el término municipal de San Juan de la Nava (Ávila). Esta mejora de trazado nace de la necesidad de aumentar la seguridad de un tramo con unas estadísticas de accidentalidad y mortalidad superiores a las del resto de la N- 403. Esos altos índices de accidentalidad no se pueden achacar al estado del pavimento ni a posibles desprendimientos de los taludes excavados, sino que se deben a la escasa visibilidad que se produce en ambos puntos kilométricos arriba señalados, en los cuales hay curvas cerradas con visibilidad reducida debido a que los taludes de las márgenes son prácticamente verticales, al estar éstos excavados en granito, que permite tales ángulos. A esto hay que sumar que la carretera existente es de tipo convencional, con una sola calzada y un carril por sentido, de manera que el riesgo de choque frontal en dichos puntos es elevado. Para resolver esta problemática, la Administración impone mejorar el actual trazado con otro recto que salva aquellos puntos kilométricos mediante un viaducto.

Acondicionamiento y mejora de la N-III, carretera convencional. Tramo desde pk. 35+000 hasta pk. 41+008, enlace con la A-3. Perales de Tajuña (Madrid)

En este Proyecto de Construcción se trata el acondicionamiento y mejora de un tramo de la N-III, entre el p.k. 35+000 y su enlace con la A-3, situado en la localidad madrileña de Perales de Tajuña. Esta carretera, que en otra época fue la principal vía de comunicación entre la capital de España y la costa levantina, ha visto reducida su importancia hasta convertirse en la práctica en una carretera de orden local. Se han estudiado, por tanto, distintas alternativas para adaptar las características de la vía a la demanda que actualmente presenta, prestando atención a todos los condicionantes que presenta, y se ha desarrollado la solución que se ha considerado más adecuada

Pasarela peatonal sobre el río Jarama, al norte de la autovía A-2, a la altura del pk 15+400, en el límite entre Madrid y San Fernando de Henares

El presente proyecto versa sobre la construcción de una pasarela peatonal sobre el río Jarama, al norte de la autovía A-2, a la altura del pk 15+400, en el límite entre Madrid y San Fernando de Henares

Analysis of variable (diversity) joining recombination in DNAdependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation

Previous studies have suggested that ionizing radiation causes irreparable DNA double-strand breaks in mice and cell lines harboring mutations in any of the three subunits of DNA-dependent protein kinase (DNA-PK) (the catalytic subunit, DNA-PKcs, or one of the DNA-binding subunits, Ku70 or Ku86). In actuality, these mutants vary in their ability to resolve double-strand breaks generated during variable (diversity) joining [V(D)J] recombination. Mutant cell lines and mice with targeted deletions in Ku70 or Ku86 are severely compromised in their ability to form coding and signal joints, the products of V(D)J recombination. It is noteworthy, however, that severe combined immunodeficient (SCID) mice, which bear a nonnull mutation in DNA-PKcs, are substantially less impaired in forming signal joints than coding joints. The current view holds that the defective protein encoded by the murine SCID allele retains enough residual function to support signal joint formation. An alternative hypothesis proposes that DNA-PKcs and Ku perform different roles in V(D)J recombination, with DNA-PKcs required only for coding joint formation. To resolve this issue, we examined V(D)J recombination in DNA-PKcs-deficient (SLIP) mice. We found that the effects of this mutation on coding and signal joint formation are identical to the effects of the SCID mutation. Signal joints are formed at levels 10-fold lower than in wild type, and one-half of these joints are aberrant. These data are incompatible with the notion that signal joint formation in SCID mice results from residual DNA-PKcs function, and suggest a third possibility: that DNA-PKcs normally plays an important but nonessential role in signal joint formation.