996 resultados para 875.07[Sófocles]


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Handwritten letter from Timothy Merritt to Rev. Epaphras "Kibbe[sic]" regarding religious developments in Boston as well as the death of Merritt's son. Dated 10/07/1803

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Spank follows the journeys of two women as they reveal stories from private and public sources set apart by two centuries. It investigates notions of 'faction' and what is filtered out historically within a theme of female trauma and the body. [ABSTRACT BY THE AUTHOR]

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Photodynamic therapy of deep or nodular skin tumours is currently limited by the poor tissue penetration of the porphyrin precursor 5-aminolevulinic acid (ALA). In this study, silicon microneedle arrays were used, for the first time, to enhance skin penetration of ALA in vitro and in vivo. Puncturing excised murine skin with 6x7 arrays of microneedles 270 mum in height, with a diameter of 240 mum at the base and an interspacing of 750 mum led to a significant increase in transdermal delivery of ALA released from a bioadhesive patch containing 19 mg ALA cm(-2). Microneedle puncture enhanced ALA delivery to the upper regions of excised porcine skin but, at mean depths of 1.875 mm, ALA concentrations were similar to control values, possibly reflecting binding of ALA by tissue components. However, and importantly, in vivo experiments using nude mice showed that microneedle puncture could reduce application time and ALA dose required to induce high levels of the photosensitiser protoporphyrin IX in skin. This clearly has implications for clinical practice, as shorter application times would mean improved patient and clinician convenience and also that more patients could be treated in the same session. As ALA is expensive and degrades rapidly via a second order reaction, reducing the required dose is also a notable advantage.

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BACKGROUND: The free fatty acid receptors (FFAs), including FFA1 (orphan name: GPR40), FFA2 (GPR43) and FFA3 (GPR41) are G protein-coupled receptors (GPCRs) involved in energy and metabolic homeostasis. Understanding the structural basis of ligand binding at FFAs is an essential step toward designing potent and selective small molecule modulators.

RESULTS: We analyse earlier homology models of FFAs in light of the newly published FFA1 crystal structure co-crystallized with TAK-875, an ago-allosteric ligand, focusing on the architecture of the extracellular binding cavity and agonist-receptor interactions. The previous low-resolution homology models of FFAs were helpful in highlighting the location of the ligand binding site and the key residues for ligand anchoring. However, homology models were not accurate in establishing the nature of all ligand-receptor contacts and the precise ligand-binding mode. From analysis of structural models and mutagenesis, it appears that the position of helices 3, 4 and 5 is crucial in ligand docking. The FFA1-based homology models of FFA2 and FFA3 were constructed and used to compare the FFA subtypes. From docking studies we propose an alternative binding mode for orthosteric agonists at FFA1 and FFA2, involving the interhelical space between helices 4 and 5. This binding mode can explain mutagenesis results for residues at positions 4.56 and 5.42. The novel FFAs structural models highlight higher aromaticity of the FFA2 binding cavity and higher hydrophilicity of the FFA3 binding cavity. The role of the residues at the second extracellular loop used in mutagenesis is reanalysed. The third positively-charged residue in the binding cavity of FFAs, located in helix 2, is identified and predicted to coordinate allosteric modulators.

CONCLUSIONS: The novel structural models of FFAs provide information on specific modes of ligand binding at FFA subtypes and new suggestions for mutagenesis and ligand modification, guiding the development of novel orthosteric and allosteric chemical probes to validate the importance of FFAs in metabolic and inflammatory conditions. Using our FFA homology modelling experience, a strategy to model a GPCR, which is phylogenetically distant from GPCRs with the available crystal structures, is discussed.

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BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

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Estudia la estructura comunitaria del bentos, su variación espacio-temporal y su relación con las condiciones oceanográficas, realizando la determinación y seguimiento de los diferentes parámetros de la estructura comunitaria y su relación con la materia orgánica en el sedimiento.

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Presenta la composición, distribución, abundancia y frecuencia de las especies del ictioplancton; así mismo se hace un análisis cualitativo del zooplancton. Dentro del ictioplancton las larvas más frecuentes fueron Bremaceros bathymaster y Diogenichthys laternatus. Las que presentaron mayor abundancia fueron los huevos y larvas de Sardinops sagax sagax y Leuroglossus stilbius y las larvas de Engraulis ringens. La distribución de las larvass de merluza estuvo en la zona norte, frente a Puerto Pizarro y falso volador frente a Pimentel. Se determinó que los volúmenes del zooplancton total variaron entre 0,02 y 0,81 mL/m3. Dentro del zooplancton se registran por primera vez para el mar peruano los copépodos Augaptylus megalurus y Temeropia mayumbaensis.

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Estudia las muestras obtenidas en cuatro lances ubicados en el sublitoral peruano de fondo blando al norte de los 8°S frente a Puerto Pizarro, Paita, Sechura y Pimentel durante los meses de junio y julio de 1998. Los resultados obtenidos reflejan una relación directa entre las comunidades macrozoobentónicas y el recurso demersal. Se observa que las distribuciones de densidades, biomasas y diversidad son mayores en la subáreas al norte de los 6°S, teniendo como grupo más representativo a los anélidos Polychaeta.

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Se determinaron correlaciones entre diferentes parámetros de funcionamiento de la red de arrastre empleadas para las calas de comprobación. Abertura vertical con Abertura horizontal, profundidad con longitud de cable, abertura vertical y abertura horizontal versus velocidad de arrastre, analizándose un total de 72 lances de comprobación. Los datos de comportamiento de la red como la abertura horizontal y abertura vertical de la boca de la red, profundidad de la red y distancia entre la relinga inferior al fondo, etc. se obtuvo en forma directa por medio del sistema SCANMAR RX 400, los arrastres tuvieron una duración promedio de 13,58 minutos con una velocidad de arrastre promedio de 3,8 nudos. Se aplicó el modelo de regresión lineal para la correlación entre los valores de: (a) abertura vertical y abertura horizontal, (b) longitud del cable de arrastre principal con la profundidad de arrastre, (c) abertura horizontal-vertical y la velocidad de arrastre.