Singular Value Decomposition and Ligand Binding Analysis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Functions and vector fields on C(CPn)-singular manifolds

Let M2n+1 be a C(CPn) -singular manifold. We study functions and vector fields with isolated singularities on M2n+1. A C(CPn) -singular manifold is obtained from a smooth manifold M2n+1 with boundary in the form of a disjoint union of complex projective spaces CPn boolean OR CPn boolean OR ... boolean OR CPn with subsequent capture of a cone over each component of the boundary. Let M2n+1 be a compact C(CPn) -singular manifold with k singular points. The Euler characteristic of M2n+1 is equal to chi(M2n+1) = k(1 - n)/2. Let M2n+1 be a C(CPn)-singular manifold with singular points m(1), ..., m(k). Suppose that, on M2n+1, there exists an almost smooth vector field V (x) with finite number of zeros m(1), ..., m(k), x(1), ..., x(1). Then chi(M2n+1) = Sigma(l)(i=1) ind(x(i)) + Sigma(k)(i=1) ind(m(i)).

Geometrical hypercomplex coupling between electric and gravitational fields

The present work shows a coupling of electrical and gravitational fields through Cauchy-Riemann conditions for quaternions present in a previous paper [1]. It is also obtained an extended version of the Laplace-like equations for quaternions, now written in terms of both electric and gravitational fields.

Long-Term Occupational Exposure to Organic Solvents Affects Color Vision, Contrast Sensitivity and Visual Fields

The purpose of this study was to evaluate the visual outcome of chronic occupational exposure to a mixture of organic solvents by measuring color discrimination, achromatic contrast sensitivity and visual fields in a group of gas station workers. We tested 25 workers (20 males) and 25 controls with no history of chronic exposure to solvents (10 males). All participants had normal ophthalmologic exams. Subjects had worked in gas stations on an average of 9.6 +/- 6.2 years. Color vision was evaluated with the Lanthony D15d and Cambridge Colour Test (CCT). Visual field assessment consisted of white-on-white 24-2 automatic perimetry (Humphrey II-750i). Contrast sensitivity was measured for sinusoidal gratings of 0.2, 0.5, 1.0, 2.0, 5.0, 10.0 and 20.0 cycles per degree (cpd). Results from both groups were compared using the Mann-Whitney U test. The number of errors in the D15d was higher for workers relative to controls (p<0.01). Their CCT color discrimination thresholds were elevated compared to the control group along the protan, deutan and tritan confusion axes (p<0.01), and their ellipse area and ellipticity were higher (p<0.01). Genetic analysis of subjects with very elevated color discrimination thresholds excluded congenital causes for the visual losses. Automated perimetry thresholds showed elevation in the 9 degrees, 15 degrees and 21 degrees of eccentricity (p<0.01) and in MD and PSD indexes (p<0.01). Contrast sensitivity losses were found for all spatial frequencies measured (p<0.01) except for 0.5 cpd. Significant correlation was found between previous working years and deutan axis thresholds (rho = 0.59; p<0.05), indexes of the Lanthony D15d (rho = 0.52; p<0.05), perimetry results in the fovea (rho = -0.51; p<0.05) and at 3, 9 and 15 degrees of eccentricity (rho = -0.46; p<0.05). Extensive and diffuse visual changes were found, suggesting that specific occupational limits should be created.

Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Structure- and Ligand-Based Structure-Activity Relationships for a Series of Inhibitors of Aldolase

Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment-based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r(2) = 0.98 and q(2) = 0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pK(i) values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class.

Using national FADN database to describe Italian farms and arable fields. A comparison of sustainability level between organic versus conventional regimes.

The study defines a new farm classification and identifies the arable land management. These aspects and several indicators are taken into account to estimate the sustainability level of farms, for organic and conventional regimes. The data source is Italian Farm Account Data Network (RICA) for years 2007-2011, which samples structural and economical information. An environmental data has been added to the previous one to better describe the farm context. The new farm classification describes holding by general informations and farm structure. The general information are: adopted regime and farm location in terms of administrative region, slope and phyto-climatic zone. The farm structures describe the presence of main productive processes and land covers, which are recorded by FADN database. The farms, grouped by homogeneous farm structure or farm typology, are evaluated in terms of sustainability. The farm model MAD has been used to estimate a list of indicators. They describe especially environmental and economical areas of sustainability. Finally arable lands are taken into account to identify arable land managements and crop rotations. Each arable land has been classified by crop pattern. Then crop rotation management has been analysed by spatial and temporal approaches. The analysis reports a high variability inside regimes. The farm structure influences indicators level more than regimes, and it is not always possible to compare the two regimes. However some differences between organic and conventional agriculture have been found. Organic farm structures report different frequency and geographical location than conventional ones. Also different connections among arable lands and farm structures have been identified.

Climatological analysis of temperature and salinity fields in the Mediterranean sea

A climatological field is a mean gridded field that represents the monthly or seasonal trend of an ocean parameter. This instrument allows to understand the physical conditions and physical processes of the ocean water and their impact on the world climate. To construct a climatological field, it is necessary to perform a climatological analysis on an historical dataset. In this dissertation, we have constructed the temperature and salinity fields on the Mediterranean Sea using the SeaDataNet 2 dataset. The dataset contains about 140000 CTD, bottles, XBT and MBT profiles, covering the period from 1900 to 2013. The temperature and salinity climatological fields are produced by the DIVA software using a Variational Inverse Method and a Finite Element numerical technique to interpolate data on a regular grid. Our results are also compared with a previous version of climatological fields and the goodness of our climatologies is assessed, according to the goodness criteria suggested by Murphy (1993). Finally the temperature and salinity seasonal cycle for the Mediterranean Sea is described.

Radio relics and magnetic fields in galaxy clusters

Radio relics are diffuse synchrotron sources generally located in the peripheries of galaxy clusters in merging state. According to the current leading scenario, relics trace gigantic cosmological shock waves that cross the intra-cluster medium where particle acceleration occurs. The relic/shock connection is supported by several observational facts, including the spatial coincidence between relics and shocks found in the X-rays. Under the assumptions that particles are accelerated at the shock front and are subsequently deposited and then age downstream of the shock, Markevitch et al. (2005) proposed a method to constrain the magnetic field strength in radio relics. Measuring the thickness of radio relics at different frequencies allows to derive combined constraints on the velocity of the downstream flow and on the magnetic field, which in turns determines particle aging. We elaborate this idea to infer first constraints on magnetic fields in cluster outskirts. We consider three models of particle aging and develop a geometric model to take into account the contribution to the relic transverse size due to the projection of the shock-surface on the plane of the sky. We selected three well studied radio relics in the clusters A 521, CIZA J2242.8+5301 and 1RXS J0603.3+4214. These relics have been chosen primarily because they are almost seen edge-on and because the Mach number of the shock that is associated with these relics is measured by X-ray observations, thus allowing to break the degeneracy between magnetic field and downstream velocity in the method. For the first two clusters, our method is consistent with a pure radiative aging model allowing us to derive constraints on the relics magnetic field strength. In the case of 1RXS J0603.3+4214 we find that particle life-times are consistent with a pure radiative aging model under some conditions, however we also collect evidences for downstream particle re-acceleration in the relic W-region and for a magnetic field decaying downstream in its E-region. Our estimates of the magnetic field strength in the relics in A 521 and CIZA J2242.8+5301 provide unique information on the field properties in cluster outskirts. The constraints derived for these relics, together with the lower limits to the magnetic field that we derived from the lack of inverse Compton X-ray emission from the sources, have been combined with the constraints from Faraday rotation studies of the Coma cluster. Overall results suggest that the spatial profile of the magnetic field energy density is broader than that of the thermal gas, implying that the ε_th /ε_B ratio decreases with cluster radius. Alternatively, radio relics could trace dynamically active regions where the magnetic field strength is biased high with respect to the average value in the cluster volume.

The contribution of surface residues to membrane binding and ligand transfer by the -tocopherol transfer protein ( -TTP)

Previous work has shown that the -tocopherol transfer protein ( -TTP) can bind to vesicular or immobilized phospholipid membranes. Revealing the molecular mechanisms by which -TTP associates with membranes is thought to be critical to understanding its function and role in the secretion of tocopherol from hepatocytes into the circulation. Calculations presented in the Orientations of Proteins in Membranes database have provided a testable model for the spatial arrangement of -TTP and other CRAL-TRIO family proteins with respect to the lipid bilayer. These calculations predicted that a hydrophobic surface mediates the interaction of -TTP with lipid membranes. To test the validity of these predictions, we used site-directed mutagenesis and examined the substituted mutants with regard to intermembrane ligand transfer, association with lipid layers and biological activity in cultured hepatocytes. Substitution of residues in helices A8 (F165A and F169A) and A10 (I202A, V206A and M209A) decreased the rate of intermembrane ligand transfer as well as protein adsorption to phospholipid bilayers. The largest impairment was observed upon mutation of residues that are predicted to be fully immersed in the lipid bilayer in both apo (open) and holo (closed) conformations such as Phe165 and Phe169. Mutation F169A, and especially F169D, significantly impaired -TTP-assisted secretion of -tocopherol outside cultured hepatocytes. Mutation of selected basic residues (R192H, K211A, and K217A) had little effect on transfer rates, indicating no significant involvement of nonspecific electrostatic interactions with membranes.