Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP)-expressing Plasmodium bergheistrain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

Posicionament angular de dispositius en 3 plans ortogonals mitjançant processat de senyals de velocitat angular

El projecte el podem dividir en dos fragments: captura de les senyals de velocitat angular i temperatura de cada pla, i la implementació de l'algorisme que, a partir d'aquestes dades, permet calcular el moviment angular de cada eix. Per tal de desenvolupar aquest sistema emprem un microcontrolador de 32 bits: MCF5213 de Freescale. Per programar-lo, utilitzem l'entorn que ofereix el fabricant code warrior.

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for theiraffinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/orD3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structuralcharacteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexesbetween some of the most representative compounds of this series and the D2 and D3 receptors wereobtained with the aim of rationalizing the observed experimental results. Moreover, selected compoundsshowed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidalside effects as potential antipsychotics.

Oxidative folding of synthetic polypeptides S-protected as tert-butylthio derivatives.

A new method for oxidative folding of synthetic polypeptides assembled by stepwise solid phase synthesis is introduced. Folding is obtained in excellent yields by reacting S-tert-butylthiolated polypeptides with a 100-fold molar excess of cysteine at 37 degrees C in a slightly alkaline buffer containing chaotropic salts, and in the presence of air-oxygen. This novel protocol has been applied to the folding of S-tert-butylthiolated human thymus and activation-regulated chemokine (hu-TARC) derivatives as well as to larger segments of Plasmodium falciparum and Plasmodium berghei circumsporozoite proteins. Folded P. falciparum polypeptides have been used as substrates of endoproteinase Glu-C (Glu-C) and endoproteinase Asp-N (Asp-N) in an attempt to identify their disulfide connectivities. Particular practical advantages of the present method are (i) easy purification and storage of the S-protected peptide derivatives, (ii) elimination of the risk of cysteine alkylation during the acidolytic cleavage deprotection and resin cleavage steps, (iii) possibility to precisely evaluate the extent of folding and disulfide bond formation by mass spectrometry, and (iv) facile recovery of the final folded product.

Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.

Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).

The use of derivatives in the Spanish mutual fund industry

We study the use of derivatives in the Spanish mutual fund industry. The picture that emerges from our analysis is rather negative. In general, the use of derivatives does not improve the performance of the funds. In only one out of eight categories we find some (very weak and not robust) evidence of superior performance. In most of the cases users significantly underperform non users. Furthermore, users do not seem to exhibit superior timing or selectivity skills either, but rather the contrary. This bad performance is only partially explained by the larger fees funds using derivatives charge. Moreover,we do not find evidence of derivatives being used for hedging purposes. We do find evidence of derivatives being used for speculation. But users in only one category exhibit skills as speculators. Finally, we find evidence of derivatives being used to manage the funds cash inflows and outflows more efficiently.

On the robustness of least-squares Monte Carlo (LSM) for pricing American derivatives

This paper analyses the robustness of Least-Squares Monte Carlo, a techniquerecently proposed by Longstaff and Schwartz (2001) for pricing Americanoptions. This method is based on least-squares regressions in which theexplanatory variables are certain polynomial functions. We analyze theimpact of different basis functions on option prices. Numerical resultsfor American put options provide evidence that a) this approach is veryrobust to the choice of different alternative polynomials and b) few basisfunctions are required. However, these conclusions are not reached whenanalyzing more complex derivatives.

Credit derivatives in emerging markets

Credit Derivatives are securities that offer protection against credit or default risk ofbonds or loans. The credit derivatives emerging market has grown rapidly and creditderivatives are widely used. This paper describes the emerging credit derivativesmarket structure. The current market activity is analyzed through elementary pricingdynamics and the study of the term structure of default risk. Focusing on theperformance of credit derivatives in stress situation, including legal and market risks,we discuss the potential consequences of a debt restructuring in a large emergingmarket borrower. The contribution of credit derivatives to the risk sharing in emergingmarkets is also examined.

La substitution hormonale et ses dérivés dans la prévention et le traitement de l'ostéoporose [Hormone replacement therapy and its derivatives in the prevention and treatment of osteoporosis]

Hormone replacement therapy (HRT) is an established approach for the treatment and the prevention of osteoporosis. Many studies with bone mineral density as primary outcome have shown significant efficacy. Observational studies have indicated a significant reduction of hip fracture risk in cohorts of women who maintained HRT therapy. The Women's Health Initiative is the first prospective randomised controlled study which showed a positive effect of HRT in terms of reduction of vertebral and hip fractures risk. Unfortunately, this study has been interrupted after 5.2 years because of the unsupportable increase of risk of cardiovascular disease and breast cancer. Compliance with HRT, however, is typically poor because of the potential side effects and possible increased risk of breast or endometrial cancer. Nevertheless, there is now evidence that lower doses of estrogens in elderly women may prevent bone loss while minimizing the side effects seen with higher doses. Combination therapies using low doses estrogen should probably be reserved for patients who continue to fracture on single therapy. Selective estrogen receptor modulators (SERMs) are very interesting drugs. The goal of these agents is to maximize the beneficial effect of estrogen on bone and to minimize or antagonize the deleterious effects on the breast and endometrium. Raloxifene, approved for the prevention and the treatment of osteoporosis, has been shown to reduce the risks of vertebral fracture in large clinical trials. However, they don't reduce non vertebral fractures. Tibolone is a synthetic steroid that increased bone mineral density at lumbar spine and femoral neck. But no trial has been performed with fractures as end point.

Analysis of dyes in illicit pills (amphetamine and derivatives)

The determination of dyes present in illicit pills is shown to be useful and easy-to-get information in strategic and tactical drug intelligence. An analytical strategy including solid-phase extraction (SPE) thin-layer chromatography (TLC) and capillary zone electrophoresis equipped with a diode array detector (CZE-DAD) was developed to identify and quantify 14 hydrosoluble, acidic, synthetic food dyes allowed in the European Community. Indeed, these may be the most susceptible dyes to be found in illicit pills through their availability and easiness of use. The results show (1) that this analytical method is well adapted to small samples such as illicit pills, (2) that most dyes actually found belong to hydrosoluble, acidic, synthetic food dyes allowed in the European Community, and (3) that this evidence turns out to be important in drug intelligence and may be assessed into a Bayesian framework.

Off-axis vortices in trapped Bose-condensed gases: Angular momentum and frequency splitting

We consider noncentered vortices and their arrays in a cylindrically trapped Bose-Einstein condensate at zero temperature. We study the kinetic energy and the angular momentum per particle in the Thomas-Fermi regime and their dependence on the distance of the vortices from the center of the trap. Using a perturbative approach with respect to the velocity field of the vortices, we calculate, to first order, the frequency shift of the collective low-lying excitations due to the presence of an off-center vortex or a vortex array, and compare these results with predictions that would be obtained by the application of a simple sum-rule approach, previously found to be very successful for centered vortices. It turns out that the simple sum-rule approach fails for off-centered vortices.

Classification of urban multi-angular image sequences by aligning their manifolds

When dealing with multi-angular image sequences, problems of reflectance changes due either to illumination and acquisition geometry, or to interactions with the atmosphere, naturally arise. These phenomena interplay with the scene and lead to a modification of the measured radiance: for example, according to the angle of acquisition, tall objects may be seen from top or from the side and different light scatterings may affect the surfaces. This results in shifts in the acquired radiance, that make the problem of multi-angular classification harder and might lead to catastrophic results, since surfaces with the same reflectance return significantly different signals. In this paper, rather than performing atmospheric or bi-directional reflection distribution function (BRDF) correction, a non-linear manifold learning approach is used to align data structures. This method maximizes the similarity between the different acquisitions by deforming their manifold, thus enhancing the transferability of classification models among the images of the sequence.