Norbert Maggi

Comparative Analysis of Rac1 Binding Efficiency With Different Classes of Ligands: Morpholines, Flavonoids and Imidazoles

The focal adhesion pathway has a great impact on cellular growth and survival. Its disregulation is correlated with the loss of cellular mechanical properties. Such modifications are, in many cases, associated with pathologies such as cancer and cardiovascular diseases. Actin remodeling is a critical reaction cascade embedded in focal adhesion pathway, and Rac1 is one of the proteins involved in actin remodeling. In order to design highly selective pharmacophores against this target, it is necessary to maximize the binding affinity of chemical entities against Rac1. To this purpose we propose an integrative chemo-bioinformatics tool to screen ligand specificity for a target protein. Our integrative workflow includes chemo-informatics data mining (Chemical System), structural bioinformatics and combined exploratory data analysis. We have applied this integrative chemo-bioinformatics workflow to a comparative analysis of three different classes of ligands (morpholines, flavonoids and imidazoles) against the Rac1 protein. Our analysis emphasizes the presence of several ligands that preferentially dock Rac1 in the domain that seems to be responsible for Rac1-phospholipase C gamma 1 interaction. Recent studies have highlighted the Rac1 and PLC interactions in platelet adhesion. Our study has highlighted the role of Rac1-PLC gamma1 interaction in cytoskeleton remodeling associated with cardiovascular diseases. Rac1 PLC interaction is Calcium dependent. This suggest that some of the analysed ligands, could be used to control the Calcium dependent cytoskeleton remodeling since they dock Rac1 in the switch 2 domain. Our results, in a nanotechnology perspective, also endorse the use Rac1s switch 2 domain suitable for new highly specific biosensors.

In silicon evaluation of nanoparticle cell interaction via human TLR3

Nano materials are becoming widely used in nanomedicine for pharmaceutical applications. This paper addresses the analysis of the possible cytotoxic effects of nanostructured materials. Specifically, the behavior of some nanoparticles against Toll-like receptors (TLRs), a class of proteins that play a key role in the innate immune system, is considered by docking analysis. The results show that the nanoparticles that have been considered have the potential to affect the immune system via TLRs.

SNP analysis of Rac1 For personalized ligand interaction

This paper addresses mutational events that give rise to differing response to drugs focusing on Rac1, a protein that has been recognized as a target for drug design for cardiovascular disease due its regulatory role of angiogenesis. Rac1 has been considered with reference to Single Nucleotide Polymorphism (SNP), which has become of great value for personalized medicine. We have considered four variation of Rac1 registered in UNIPROTKB. Two of these variations are due to the environmental or population factors and two are mutation that we have selected because they are located near the binding sites of Rac1. Rac1 has been modelled by Rosetta software and by i-Tasser web server. We have chosen i-Tasser based modelling because the Rac1 structure obtained was more closely resembling crystallography data. In silico model have been used as receptors for docking with a set of 20 morpholines. The results that have been obtained on SNPs shows that a single ligand can react very differently with a mutated structure. Our analysis shows that all mutations that have been considered change Rac1 conformation and increase the accessible surface of Rac1. Our analysis highlights the effect of two sources of genetic variability: single base variation and alternative splicing.

Cancer precision medicine today: Towards omic information in healthcare systems

Introduction: This article focuses on the integration of omics data in electronic health records and on interoperability aspects relating to big data analysis for precision medicine. Methods: Omics data integration methods for electronic health record and for systems interoperability are considered, with special reference to the high number of specific software tools used to manage different aspects of patient treatment. This is an important barrier against the use of this integrated approach in daily clinical routine. Results: The correct use of all three levels of interoperability (technical, semantic, and process interoperability) plays a key role in order to achieve an easy access to a significant amount of data, all with correct contextualization, which is the only way to obtain a real value from data for precision medicine. Conclusions: The proposed architecture could improve the potentialities of data routinely collected in many health information systems to form a real patient center information environment.

Optimizing Texture Modified Foods for Oro-pharyngeal Dysphagia: A Difficult but Possible Target?

Dysphagia is a swallowing disorder characterized by the difficulty in transferring solid foods and/or liquids from the oral cavity to the stomach, imparing autonomous, and safe oral feeding. The main problems deriving from dysphagia are tracheo-bronchial aspiration, aspiration pneumonia, malnutrition and dehydration. In order to overcome dysphagia-induced problems, over the years water and food thickening has been used, focusing specifically on viscosity increase, but limited results have been obtained. Elastic components and their effects on the cohesiveness on the bolus should be taken into account in the first place. We provide an analysis of dysphagia and suggest possible corrections to the protocols which are being used at present, taking into account rheological properties of food and the effect of saliva on the bolus. We reckon that considering such aspects in the dysphagia management market and healthcare catering would result in significant clinical risk reduction.

Prediction of potential barcoding sites on ITS1 by wavelet transform

For sustainable development, biodiversity conservation and life-quality improvement must be simultaneously considered. Molecular techniques have greatly impacted biotechnology. These methods have, in particular, improved the capability to investigate the fine differences among organisms and, as a consequence, to better investigate the effects on environmental factors on them. We propose an approach to support the optimal selection of molecular probes for barcoding application in many biotechnological fields. The aim of our work is specificity maximization. To this purpose, we have integrated a filter system based on wavelet transforms with biological knowledge about the sequence proneness to mutation and post-translational modification. Specifically, we have tested the proposed method on ITS1 sequences that are a region of the rRNA locus. Our analysis has shown the presence of other local relative stable conformations in addition to known cleavage site. Their characteristics differ within the group of mammals selected for our analysis. These variations could be used to design new species-specific barcoding probes or other quick molecular screening tools.

Ribosomal DNA analysis by Wavelet Transform

Ribosomal DNA guides the transcription of rRna genes. The analysis of its sequence can clarify the high order regulatory structure leading to this transcription. A nucleotide sequence can be analysed by two main kinds of methods that is the supervised ones, based on the use of DNA databases to identify specific features, and the blind search of features that can be related to regulatory signals. One of the major limitation of both approaches is that they are based on known elements. Moreover, computational biophysics tools have been used to detect specific features. Digital signal processing has also been used to a great extent. However, all these methods fail to identify high order regulatory features. We have applied the Wavelet transform because of its capability to detect embedded structures in a signal. Wavelet bases analysis has been performed on human ribosomal DNA. The results show the presence of the potential regulatory landscape of each functionally specific domain. This suggests that these reg...

Self-assembled polyelectrolyte capsule for drug delivery: In vitro evaluation of their interaction with cell

Polyelectrolyte capsules based on layer by layer self-assembly show great promise for targeted delivery and smart release of drugs. A critical aspect for their clinical use is the evaluation of the interaction capsules-cell. The present paper is focused on the in vitro characterization of such interaction by optical magnetic twisting cytometry (OMCT).

Optimize ncRNA Targeting: A Signal Analysis Based Approach

Non-coding RNAs (ncRNAs) are ribonucleic acids capable to control different genetic and metabolic functions. Digital signal processing (DSP) has been widely applied for analyze DNA sequences. Herein we present a DSP application to filter out the most probable binding site of ncRNAs applied to a miRNA binding site recognition.

Drug design for cardiovascular disease: The effect of solvation energy on Rac1-ligand interactions

‘OMICS’ techniques have deeply changed the drug discovery process. The availability of many different potential druggable genes, generated by these new techniques, have exploited the complexity of new lead compounds screening. ‘Virtual screening’, based on the integration of different analytical tools on high performance hardware platforms, has speeded up the search for new chemical entities suitable for experimental validation. Docking is a key step in the screening process. The aim of this paper is the evaluation of binding differences due to solvation. We have compared two commonly used software, one of which takes into account solvation, on a set of small molecules (Morpholines, flavonoids and imidazoles) which are able to target the RAC1 protein — a cardiovascular target. We have evaluated the degree of agreement between the two different programs using a machine learning approach combined with statistical test. Our analysis, on a sample of small molecules, has pointed out that 35% of the molecules seem to be sensitive to solvation. This result, even though quite preliminary, stresses the need to combine different algorithms to obtain a more reliable filtered set of ligands.