Cholinergic synaptic vesicles are metabolically and biophysically heterogeneous even in resting terminals.

The metabolic heterogeneity of synaptic vesicles in the cholinergic nerve terminals of the electromotor neurons ofTorpedp marmoratta has been studied in resting tissue by evaluating the molecular acetylcholine content (MAC) of synaptic vesicles after vesicles extraction from frozen and crushed tissue and high-resolution centrifugal density gradient separation in a zonal rotor. Although vesicular acetylcholine was distributed in the gradient as a single, more or less symmetrical peak, 3 subpopulations of synaptic vesicles could be identified: a small, relatively light subpopulation of low MAC on the ascending limb of the acetylcholine peak, designated V0, a main population of fully charged vesicles designated V1, and a small, denser subpopulation also of low MAC on the descending limb of the acetylcholine peak, designated V2. The mean proportions and MACs of the 3 pools were: V0, 13%, 58,00; V1, 53%, 246,000; V2, 34%, 79,000. When triated acetate was perfused through excised blocks of electric organ for 1–2 h before vesicle isolation, the specific radioactivity of thr acetylcholine in the V0 and V2 pools was 10–30 times higher than in the V1 pool. This suggest that both the V0 and V2 pools are not generated by the isolation procedure but are present in the intact endings and are functionally active. On the basis of their density and uptake of newly synthesized acetylcholine, the V0 and V2 pools were identified with the previously described VP0 pool of axonal vesicles and the VP2 pool of recycling vesicles in stimulated nerve terminals respectively. Since stimulation of electromotor nerve terminals is known to generate large proportions VP2 vesicles, variations in the proportion of V2 vesicles in unstimulated tissue are attributed to varying amounts of adventitous stimulation of the tissue during dissection and perfussion

Synthesis of thiolated, PEGylated and POZylated silica nanoparticles and evaluation of their retention on rat intestinal mucosa in vitro

In this study, we synthesised thiolated silica nanoparticles using 3-mercaptopropyltrimethoxysilane and functionalised them with either 5 kDa methoxy polyethylene glycol maleimide (PEG) or 5 kDa alkyne-terminated poly(2-ethyl-2-oxazoline) (POZ). The main objectives of this study are to investigate the effects of pH on the size and ξ-potential of these nanoparticles and evaluate their mucoadhesive properties ex vivo using rat intestinal mucosa. The sizes of thiolated, PEGylated and POZylated silica nanoparticles were 53 ± 1, 68 ± 1 and 59 ± 1 nm, respectively. The size of both thiolated and POZylated nanoparticles significantly increased at pH ≤ 2, whereas no size change was observed at pH 2.5–9 for both these two types of nanoparticles. On the other hand, the size of PEGylated nanoparticles did not change over the studied pH range (1.5–9). Moreover, thiolated nanoparticles were more mucoadhesive in the rat small intestine than both PEGylated and POZylated nanoparticles. After 12 cycles of washing (with a total of 20 mL of phosphate buffer solution pH 6.8), a significantly greater amount of thiolated nanoparticles remained on the intestinal mucosa than FITC-dextran (non-mucoadhesive polymer, p  0.1 for both). Thus, this study indicates that thiolated nanoparticles are mucoadhesive, whereas PEGylated and POZylated nanoparticles are non-mucoadhesive in the ex vivo rat intestinal mucosa model. Each of these nanoparticles has potential applications in mucosal drug delivery

A Quantitative analysis of the effect of tobacco smoke and phenylmethyloadiazole on rat airway epithelium

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Empleo de los índices topológicos y topográficos de Estrada en modelos QSAR de una familia de antibióticos g-lactámicos

Los índices topológicos y topográficos son dos tipos de descriptores ampliamente utilizados en estudios de relación cuantitativa estructura-actividad (QSAR por sus siglas en inglés). Por otra parte, en el trabajo de búsqueda de modelos estadísticos adecuados para la modelación molecular se utiliza ampliamente el análisis de regresión múltiple (ARM). El procedimiento consiste en asociar un conjunto de descriptores estructurales o químico-físicos de las moléculas, con la actividad en un modelo de análisis de regresión múltiple estable que permita describir la muestra y, en el mejor de los casos, orientar la obtención de nuevos derivados según la tendencia que indique cada variable en la ecuación. El método de regresión por pasos es frecuentemente la técnica de elección para la eliminación de variables no significativas. A partir de una muestra reportada de 36 antibióticos g-lactámicos sintetizados secuencialmente en una estrategia de diseño, se desarrolla un procedimiento iterativo de búsqueda de modelos predictivos de actividad utilizando ARM de forma similar al procedimiento aplicado por D.B. Boyd a esa familia, llamado proyección iterativa de hipersuperficies (PIH). Además de los descriptores empleados en el trabajo de referencia, se utilizaron índices topológicos y topográficos recientemente desarrollados por Estrada. Se comprueba que es posible emplear los nuevos índices topológicos y topográficos por su capacidad descriptora de la estructura química en estudios QSAR de antibióticos g-lactámicos. El empleo del ARM de forma iterativa análoga al PIH, brinda resultados semejantes a este

Some observations on classical QSAR

Classical QSAR began almost 30 years ago. This article briefly traces its development, use and impact in relation to drug design and medicinal chemistry. Particular aspects discussed include hydrophobicity, relative potency in a series, tissue selectivity, central nervous system penetration, pharmacokinetics, potency optimization, bioisosterism, mechanistic insights, synthesis termination, receptor mapping, and the design of marketed drugs and late-stage drug candidates. In addition, some recent QSAR studies and examples of the use of the Free-Wilson approach are reviewed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43354/1/11091_2005_Article_BF02174527.pd

Neuraminic acid, fucose and sulphate content of sputum in disease and during treatment

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