Computational framework to support integration of biomolecular and clinical data within a translational approach

Background The use of the knowledge produced by sciences to promote human health is the main goal of translational medicine. To make it feasible we need computational methods to handle the large amount of information that arises from bench to bedside and to deal with its heterogeneity. A computational challenge that must be faced is to promote the integration of clinical, socio-demographic and biological data. In this effort, ontologies play an essential role as a powerful artifact for knowledge representation. Chado is a modular ontology-oriented database model that gained popularity due to its robustness and flexibility as a generic platform to store biological data; however it lacks supporting representation of clinical and socio-demographic information. Results We have implemented an extension of Chado – the Clinical Module - to allow the representation of this kind of information. Our approach consists of a framework for data integration through the use of a common reference ontology. The design of this framework has four levels: data level, to store the data; semantic level, to integrate and standardize the data by the use of ontologies; application level, to manage clinical databases, ontologies and data integration process; and web interface level, to allow interaction between the user and the system. The clinical module was built based on the Entity-Attribute-Value (EAV) model. We also proposed a methodology to migrate data from legacy clinical databases to the integrative framework. A Chado instance was initialized using a relational database management system. The Clinical Module was implemented and the framework was loaded using data from a factual clinical research database. Clinical and demographic data as well as biomaterial data were obtained from patients with tumors of head and neck. We implemented the IPTrans tool that is a complete environment for data migration, which comprises: the construction of a model to describe the legacy clinical data, based on an ontology; the Extraction, Transformation and Load (ETL) process to extract the data from the source clinical database and load it in the Clinical Module of Chado; the development of a web tool and a Bridge Layer to adapt the web tool to Chado, as well as other applications. Conclusions Open-source computational solutions currently available for translational science does not have a model to represent biomolecular information and also are not integrated with the existing bioinformatics tools. On the other hand, existing genomic data models do not represent clinical patient data. A framework was developed to support translational research by integrating biomolecular information coming from different “omics” technologies with patient’s clinical and socio-demographic data. This framework should present some features: flexibility, compression and robustness. The experiments accomplished from a use case demonstrated that the proposed system meets requirements of flexibility and robustness, leading to the desired integration. The Clinical Module can be accessed in http://dcm.ffclrp.usp.br/caib/pg=iptrans webcite.

Novel aryl beta-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: binding mode revised by docking and GRIND2-based 3D-QSAR procedures

Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid-Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl beta-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl beta-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease.

Corrole isomers: intrinsic gas-phase shapes via traveling wave ion mobility mass spectrometry and dissociation chemistries via tandem mass spectrometry

Corrole and four of its isomers with subtle structural changes promoted by exchange of nitrogen and carbon atoms in the corrole ring have been studied by traveling wave ion mobility mass spectrometry and collision induced dissociation experiments. Significant differences in shapes and charge distributions for their protonated molecules were found to lead to contrasting gas phase mobilities, most particularly for corrorin, the most "confused" isomer. Accordingly, corrorin was predicted by B3LYP/6-31g(d,p) and collisional cross section calculations to display the most compact tri-dimensional structure, whereas NCC4 and corrole were found to be the most planar isomers. Better resolution between the corrole isomers was achieved using the more polarizable and massive CO2 as the drift gas. Sequential losses of HF molecules were found to dominate the dissociation chemistry of the protonated molecules of these corrole isomers, but their unique structures caused contrasting labilities towards CID, whereas NCC4 showed a peculiar and structurally diagnostic loss of NH3, allowing its prompt differentiation from the other isomers.

VCD to determine absolute configuration of natural product molecules: secolignans from Peperomia blanda

The absolute configuration and solution-state conformers of three peperomin-type secolignans isolated from Peperomia blanda (Piperaceae) are unambiguously determined by using vibrational circular dichroism (VCD) spectroscopy associated with density functional theory (DFT) calculations. Advantages of VCD over the electronic form of CD for the analysis of diastereomers are also discussed. This work extends our growing knowledge about secondary metabolites within the Piperaceae family species while providing a definitive and straightforward method to assess the absolute stereochemistry of secolignans.

DNA damage profiles induced by sunlight at different latitudes

Despite growing knowledge on the biological effects of ultraviolet (UV) radiation on human health and ecosystems, it is still difficult to predict the negative impacts of the increasing incidence of solar UV radiation in a scenario of global warming and climate changes. Hence, the development and application of DNA-based biological sensors to monitor the solar UV radiation under different environmental conditions is of increasing importance. With a mind to rendering a molecular view-point of the genotoxic impact of sunlight, field experiments were undertaken with a DNA-dosimeter system in parallel with physical photometry of solar UVB/UVA radiation, at various latitudes in South America. Onapplying biochemical and immunological approaches based on specific DNA-repair enzymes and antibodies, for evaluating sunlight-induced DNA damage profiles, it became clear that the genotoxic potential of sunlight does indeed vary according to latitude. Notwithstanding, while induction of oxidized DNA bases is directly dependent on an increase in latitude, the generation of 6-4PPs is inversely so, whereby the latter can be regarded as a biomolecular marker of UVB incidence. This molecular DNA lesion-pattern largely reflects the relative incidence of UVA and UVB energy at any specific latitude. Hereby is demonstrated the applicability of this DNA-based biosensor for additional, continuous field experiments, as a means of registering variations in the genotoxic impact of solar UV radiation. Environ. Mol. Mutagen. 2012. (c) 2012 Wiley Periodicals, Inc.

The infrared fundamental intensities of some cyanopolyynes

Some cyanopolyynes, HCnN (n = 1, 3, ... , 17), are investigated by means of calculations at the MP2/cc-pVTZ and CCSD/cc-pVDZ levels. Although the MP2/cc-pVTZ results for geometries and molecular dipole moments are encouraging, the CCSD/cc-pVDZ level was superior for the study of infrared fundamental intensities. The main bands are also analyzed with a charge-charge flux-dipole flux (CCFDF) partition model based on quantities given by the Quantum Theory of Atoms in Molecules (QTAIM). The intensity of vibrations corresponding to the stretching of CH bonds (3471-3473 cm(-1)) increases in line with the number of carbon atoms (from 61 to 146 km mol(-1) between HCN and HC13N). This increase is due to the charge flux contribution while the other contributions remain roughly unaltered except for HCN. Moreover, the hydrogen atom loses an almost constant amount of electronic charge during the CH bond enlargement and a small fraction of this charge spreads to atoms farther and farther away from hydrogen as the molecule size increases. The band associated with the doubly degenerate CH bending vibrations (643-732 cm(-1)) presents approximately the same intensity in all the studied cyanopolyynes (from 67 to 76 km mol(-1)). The CCFDF/QTAIM contributions are also nearly the same for these bending modes in HC5N and larger systems. The intensity of the mode mostly identified as CN stretching (around 2378-2399 cm(-1) except for HCN) increases from HCN up to HC7N (from 0.3 to 83 km mol(-1)) and nearly stabilizes around 80-90 km mol(-1) for larger systems. The CCFDF/QTAIM contributions for this mode also change significantly up to HC7N and remain almost constant in larger systems. We also observed the appearing of a very relevant band between 2283 and 2342 cm(-1). This mode is mainly associated with the symmetric stretching of CC triple bonds near the molecule center and exhibits large charge fluxes while the other contributions are almost negligible in the largest cyanopolyynes. The two vibrational bands associated with the smallest frequencies are also studied and extrapolation equations are suggested to predict their positions in larger cyanopolyynes. (C) 2012 Elsevier B.V. All rights reserved.

Adsorption of caffeic acid on titanium dioxide: A spectroscopic study

Caffeic acid is an ortho-phenol found in vegetable tissues presenting important properties such as carcinogenesis inhibitor, anti-oxidant, anti-viral, anti-inflammatory and anti-rheumatic actions. It was observed that caffeic acid was not degraded in daylight during the adsorption on TiO2 at pH 4.8. The adsorption fit very well to a Brunauer-Emmett-Teller isotherm equation with a monolayer coverage of 68.15 mg(CA) g(TiO2)(-1) and saturation coverage of 195.4 mg(CA) g(TiO2)(-1). A strong adsorption of caffeic acid was verified on TiO2 for the dry solid obtained from the mixture. The Raman and IR spectroscopies revealed that the adsorption should occur through the interaction of the diphenol oxygens with contribution of CC double bond of the acrylic group, however, the carboxylic acid group did not have participation in the adsorption. (C) 2012 Elsevier B.V. All rights reserved.