HIV fusion inhibitor peptide T-1249 is able to insert or adsorb to lipidic bilayers. Putative correlation with improved efficiency

T-1249 is a HIV fusion inhibitor peptide under clinical trials. Its interaction with biological membrane models (large unilamellar vesicles) was studied using fluorescence spectroscopy. A gp41 peptide that includes one of the hydrophobic terminals of T-1249 was also studied. Both peptides partition extensively to liquid-crystalline POPC (1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine) (DeltaG = -7.0 kcal/mol and -8.7 kcal/mol, for T-1249 and terminal peptide, respectively) and are located at the interface of the membrane. T-1249 is essentially in a random coil conformation in this lipidic medium, although a small alpha-helix contribution is present. When other lipid compositions are used (DPPC, POPG + POPC, and POPC + cholesterol) (DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and POPG (1-palmitoyl-2-oleyl-sn-glycero-3-[phospho-rac-(1-glycerol)), partition decreases, the most severe effect being the presence of cholesterol. Partition experiments and fluorescence resonance energy transfer analysis show that T-1249 adsorbs to cholesterol-rich membranes. The improved clinical efficiency of T-1249 relative to enfuvirtide (T20) may be related to its bigger partition coefficient and ability to adsorb to rigid lipidic areas on the cell surface, where most receptors are inserted. Moreover, adsorption to the sterol-rich viral membrane helps to increase the local concentration of the inhibitor peptide at the fusion site.     

Contribution to the formulation of a structural model by the determination of kinetic data

The processes involved in the isothermal dehydration of hexaoxytelluric acid, Te(OH)₆, are studied and the kinetic equations and activation energies corresponding to these processes are determined. The results are in agreement with a previously proposed structural model.

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Zusammenfassung Die an der isothermen Dehydratisierung der Hexaoxytellursäure Te(OH)₆ beteiligten Vorgänge wurden untersucht und die diesen Vorgängen entsprechenden kinetischen Gleichungen und Aktivierungsenergien bestimmt. Die Ergebnisse sind mit einem früher vorgeschlagenen strukturellen Modell in Übereinstimmung.

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Résumé On a étudié les réactions qui interviennent lors de la déshydratation isotherme de l'acide hexaoxytellurique Te(OH)₆ et déterminé les équations cinétiques ainsi que les énergies d'activation correspondantes. Les résultats sont en accord avec un modèle structural proposé préalablement.

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Synthesis of chiral pyrrolo[1,2-c]thiazoles via intramolecular dipolar cycloaddition of münchnones: an interesting rearrangement to pyrrolo[1,2-c]thiazines

Intramolecular dipolar cycloaddition of bicyclic münchnones, 5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates, derived from cyclodehydration of 2-substituted-N-acylthiazolidine-4-carboxylic acids are reported. A range of new pyrrolo[1,2-c]thiazole derivatives (7, 14, 15, 20, 23, and 26) were obtained as single enantiomers from 2-phenylthiazolidines, 2-benzoylthiazolidines, and 2-methylthiazolidine-4-carboxylates. Pyrrolo[1,2-c][1,4]thiazine derivative 27 was also obtained from pyrrolo[1,2-c]thiazole derivative 26. The structures of methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-carboxylate (17a), methyl (2R,4R)-2-(p-methoxybenzoyl)-N-(prop-2-ynyloxyacetyl)thiazolidine- 4-carboxylate (18), and 3-oxo-4-phenyl-3,4,6,8-tetrahydro-1H-furo[3',4':2,3]pyrrolo[1,2-c][1,4]thiazine (27) were determined by X-ray crystallography. Chirooptical studies of the pyrrolo[1,2-c]thiazoles were done by confirming the absolute configuration at the chiral center C-3.     

A simple method for nicardipine hydrochloride quantification in plasma using solid-phase extraction and reversed-phase high-performance liquid chromatography

A simple and sensitive reversed-phase liquid chromatography method was developed and validated for the determination of nicardipine hydrochloride (NC) in rabbit plasma. Nicardipine hydrochloride and nimodipine, used as internal standard, were initially extracted from plasma by a rapid solid-phase extraction using C(18) cartridges. After extraction, nicardipine hydrochloride was separated by HPLC on a C(18) column and quantified by ultraviolet detection at 254 nm. A mixture of acetonitrile-0.02 M sodium phosphate buffer-methanol (45:40:15) with 0.2% of triethylamine of pH of 6.1 was used as mobile phase. The mean (+/-SD) extraction efficiency of NC was 77.56 +/- 5.4, 84.23 +/- 4.32 and 83.94 +/- 3.87% for drug concentrations of 5, 25 and 100 ng/mL, respectively. The method proved to be linear in the range of 5-100 ng/mL with a regression coefficient of 0.9993. The relative standard deviations of intra- and inter-day analysis for NC in plasma were 3.26-6.52% (n = 5) and 4.71-9.38% (n = 5), respectively. The differences of the mean value measured from the concentration prepared, expressed in percentages (bias percentage), were only - 5.2, 0.4 and 0.8% at NC 5, 25 and 50 ng/mL, which confirmed the accuracy of the method. The analytical technique was used to determine NC plasma concentration after drug oral administration to rabbits. The results inferred that NC is rapidly absorbed in rabbits and has a short half-life (t(1/2) = 1.34 h).     

A general route for the synthesis of pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine derivatives

Summary A facile synthesis of 8-substituted pyrimido[4,5:4,5]thieno[2,3-c]pyridazines (6a–i) has been accomplished. The sequence involves the ring closure of a heterocyclic aminonitrile precursor (3) after reaction with (dichloromethylene)-dimethylammonium chloride.

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Eine allgemeine Synthese von Pyrimido[4,5:4,5]thieno[2,3-c]pyridazin-Derivaten

Zusammenfassung Es wurde ein einfacher Syntheseweg für 8-substituierte Pyrimido[4,5:4,5]thieno-[2,3-c]pyridazine entwickelt. Die Reaktion verläuft über den Ringschluß eines heterocyclischen Aminonitrilvorläufers (3) nach Umsetzung mit Dichlormethylen-dimethylammoniumchlorid.

     

AnL p -theory for then-dimensional,stationary, compressible Navier-Stokes equations,and the incompressible limit for compressible fluids. The equilibrium solutions

In this paper we study the system (1.1), (1.3), which describes the stationary motion of a given amount of a compressible heat conducting, viscous fluid in a bounded domain ofR ⁿ, n2. Hereu(x) is the velocity field, (x) is the density of the fluid, (x) is the absolute temperature,f(x) andh(x) are the assigned external force field and heat sources per unit mass, andp(, ) is the pressure. In the physically significant case one hasg=0. We prove that for small data (f, g, h) there exists a unique solution (u, , ) of problem (1.1), (1.3)₁, in a neighborhood of (0,m, ₀); for arbitrarily large data the stationary solution does not exist in general (see Sect. 5). Moreover, we prove that (for barotropic flows) the stationary solution of the Navier-Stokes equations (1.8) is the incompressible limit of the stationary solutions of the compressible Navier-Stokes equations (1.7), as the Mach number becomes small. Finally, in Sect. 5 we will study the equilibrium solutions for system (4.1). For a more detailed explanation see the introduction.     

How relevant is the lack of reciprocity in pairwise comparisons? An experiment with AHP

We consider the 1-median problem with euclidean distances with uncertainty in the weights, expressed as possible changes within given bounds and a single budget constraint on the total cost of change. The upgrading (resp. downgrading) problem consists of minimizing (resp. maximizing) the optimal 1-median objective value over these weight changes. The upgrading problem is shown to belong to the family of continuous single facility location-allocation problems, whereas the downgrading problem reduces to a convex but highly non-differentiable optimization problem. Several structural properties of the optimal solution are proven for both problems, using novel planar partitions, the knapsack Voronoi diagrams, and lead to polynomial time solution algorithms.     

Digital pulse processing in Mössbauer spectroscopy

In this work we present some advances towards full digitization of the detection subsystem of a Mössbauer transmission spectrometer. We show how, using adequate instrumentation, preamplifier output of a proportional counter can be digitized with no deterioration in spectrum quality, avoiding the need of a shaping amplifier. A pipelined architecture is proposed for a digital processor, which constitutes a versatile platform for the development of pulse processing techniques. Requirements for minimization of the analog processing are considered and experimental results are presented.