Empowering precision medicine through high performance computing clusters

The role of High Performance Computing (HPC) in Medicine is greatly increase in these last years, moving from basic research to the clinics. With the advent of Next Generation Sequencing (NGS) technologies, diverse areas of human health have been investigated through different omics techniques. The extensive use of these NGS platforms to high throughput profile human health issues in a cost-efficient manner, is generating huge amount of sequencing data pushing " (https://www.facebook.com/pages/Oatext/1439466783004774) # $ % (https://www.youtube.com/user/users/oatext) ○ ○ ○ Article Article Info Author Info Figures & Data bioinformatic research in the big-data field. Speed, accuracy and reproducibility of massively sequencing analysis have allowed to transfer molecular biology knowledge into precision medicine. Furthermore, Molecular Dynamics (MD) earned a great importance in aiding genome research. Sequencing studies of cancer have allowed to detect and characterize mutated genes that drive tumorigenesis. As a complementary approach, from a biophysical perspective, MD simulations, executed on HPC architectures, have permitted to investigate the role played by pathological mutations on the molecular mechanism of activation

Smyd2 conformational changes in response to p53 binding: role of the C-terminal domain.

Smyd2 lysine methyltransferase regulates monomethylation of histone and nonhistone lysine residues using S-adenosylmethionine cofactor as the methyl donor. The nonhistone interactors include several tumorigenic targets, including p53. Understanding this interaction would allow the structural principles that underpin Smyd2-mediated p53 methylation to be elucidated. Here, we performed μ-second molecular dynamics (MD) simulations on binary Smyd2-cofactor and ternary Smyd2-cofactor-p53 peptide complexes. We considered both unmethylated and monomethylated p53 peptides (at Lys370 and Lys372). The results indicate that (a) the degree of conformational freedom of the C-terminal domain of Smyd2 is restricted by the presence of the p53 peptide substrate, (b) the Smyd2 C-terminal domain shows distinct dynamic properties when interacting with unmethylated and methylated p53 peptides, and (c) Lys372 methylation confines the p53 peptide conformation, with detectable influence on Lys370 accessibility to the cofactor. These MD results are therefore of relevance for studying the biology of p53 in cancer progression

Sexual enhancement products for sale online : raising awareness of the psychoactive effects of Yohimbine, Maca, Horny Goat Weed and Ginkgo Biloba

Copyright © 2014 Ornella Corazza et al.This is an open access article distributed under theCreativeCommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedIntroduction. The use of unlicensed food and herbal supplements to enhance sexual functions is drastically increasing. This phenomenon, combined with the availability of these products over the Internet, represents a challenge from a clinical and a public health perspective. Methods. A comprehensive multilingual assessment of websites, drug fora, and other online resources was carried out between February and July 2013 with exploratory qualitative searches including 203 websites. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN). Once the active constitutes of the products were identified, a comprehensive literature search was carried out using PsycInfo and PubMed. Results. The most common sexual enhancement products available on the Internet were identified. Their active ingredients included yohimbine, maca, horny goat weed and Ginkgo biloba. These four substances were reported with the occurrence of adverse events and the induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours. Conclusions. Uncontrolled availability of sexual enhancement products that contain potentially harmful substances is a major public healthconcern.Thepossible impact on population health, particularly among subjects with psychiatric disorders, usually at risk for sexual dysfunction, may be significant. This new trend needs to be extensively studied and monitoredPeer reviewedFinal Published versio

Massive NGS data analysis reveals hundreds of potential novel gene fusions in human cell lines

Background: Gene fusions derive from chromosomal rearrangements and the resulting chimeric transcripts are often endowed with oncogenic potential. Furthermore, they serve as diagnostic tools for the clinical classification of cancer subgroups with different prognosis and, in some cases, they can provide specific drug targets. So far, many efforts have been carried out to study gene fusion events occurring in tumor samples. In recent years, the availability of a comprehensive Next Generation Sequencing dataset for all the existing human tumor cell lines has provided the opportunity to further investigate these data in order to identify novel and still uncharacterized gene fusion events. Results: In our work, we have extensively reanalyzed 935 paired-end RNA-seq experiments downloaded from "The Cancer Cell Line Encyclopedia" repository, aiming at addressing novel putative cell-line specific gene fusion events in human malignancies. The bioinformatics analysis has been performed by the execution of four different gene fusion detection algorithms. The results have been further prioritized by running a bayesian classifier which makes an in silico validation. The collection of fusion events supported by all of the predictive softwares results in a robust set of ∼ 1,700 in-silico predicted novel candidates suitable for downstream analyses. Given the huge amount of data and information produced, computational results have been systematized in a database named LiGeA. The database can be browsed through a dynamical and interactive web portal, further integrated with validated data from other well known repositories. Taking advantage of the intuitive query forms, the users can easily access, navigate, filter and select the putative gene fusions for further validations and studies. They can also find suitable experimental models for a given fusion of interest. Conclusions: We believe that the LiGeA resource can represent not only the first compendium of both known and putative novel gene fusion events in the catalog of all of the human malignant cell lines, but it can also become a handy starting point for wet-lab biologists who wish to investigate novel cancer biomarkers and specific drug targets

The different cleavage DNA sequence specificity explains the camptothecin resistance of the human topoisomerase I Glu418Lys mutant

Yeast cells expressing the Glu418Lys human topoisomerase I mutant display a camptothecin resistance that slowly decreases as a function of time. Molecular characterization of the single steps of the catalytic cycle of the purified mutant indicates that it has a relaxation activity identical to the wild-type protein but a different DNA sequence specificity for the cleavage sites when compared to the wild-type enzyme, as assayed on several substrates. In particular the mutant has a low specificity for CPT sensitive cleavable sites. In fact, the mutant has, at variance of the wild-type enzyme, a reduced preference for cleavage sites having a thymine base in position −1 of the scissile strand. This preference, together with the strict requirement for a thymine base in position −1 for an efficient camptothecin binding, explains the temporary camptothecin resistance of the yeast cell expressing the mutant and points out the importance of the DNA sequence in the binding of the camptothecin drug

Molecular dynamics recipes for genome research

Molecular dynamics (MD) simulation allows one to predict the time evolution of a system of interacting particles. It is widely used in physics, chemistry and biology to address specific questions about the structural properties and dynamical mechanisms of model systems. MD earned a great success in genome research, as it proved to be beneficial in sorting pathogenic from neutral genomic mutations. Considering their computational requirements, simulations are commonly performed on HPC computing devices, which are generally expensive and hard to administer. However, variables like the software tool used for modeling and simulation or the size of the molecule under investigation might make one hardware type or configuration more advantageous than another or even make the commodity hardware definitely suitable for MD studies. This work aims to shed lights on this aspect

The open state of human topoisomerase I as probed by molecular dynamics simulation

The open state of human topoisomerase I has been probed by molecular dynamics simulation, starting from the coordinates of the closed structure of the protein complexed with DNA, after elimination of the 22-bp DNA duplex oligonucleotide. A repulsion force between the two lips of the protein has been introduced for a short time to induce destabilization of the local minimum, after which an unperturbed simulation has been carried out for 10 ns. The simulation shows that the protein undergoes a large conformational change due to rearrangements in the orientation of the protein domains, which however move as a coherent unit, fully maintaining their secondary and tertiary structures. Despite movements between the domains as large as 80–90 Å, the catalytic pentad remains preassembled, the largest deviation of the active site backbone atoms from the starting crystallographic structure being only 1.7 Å. Electrostatic calculation of the open protein structure shows that the protein displays a vast positive region with the active site residues located nearly at its center, in a conformation perfectly suited to interact with the negatively charged supercoiled DNA substrate

Microarray gene expression profiling of neural tissues in bovine spastic paresis

Abstract: Background: Bovine Spastic Paresis (BSP) is a neuromuscular disorder which affects both male and female cattle. BSP is characterized by spastic contraction and overextension of the gastrocnemious muscle of one or both limbs and is associated with a scarce increase in body weight. This disease seems to be caused by an autosomal and recessive gene, with incomplete penetration, although no genes clearly involved with its onset have been so far identified. We employed cDNA microarrays to identify metabolic pathways affected by BSP in Romagnola cattle breed. Investigation of those pathways at the genome level can help to understand this disease. Results: Microarray analysis of control and affected individuals resulted in 268 differentially expressed genes. These genes were subjected to KEGG pathway functional clustering analysis, revealing that they are predominantly involved in Cell Communication, Signalling Molecules and Interaction and Signal Transduction, Diseases and Nervous System classes. Significantly enriched KEGG pathway's classes for the differentially expressed genes were calculated; interestingly, all those significantly under-expressed in the affected samples are included in Neurodegenerative Diseases. To identify genome locations possibly harbouring gene(s) involved in the disease, the chromosome distribution of the differentially expressed genes was also investigated. Conclusions: The cDNA microarray we used in this study contains a brain library and, even if carrying an incomplete transcriptome representation, it has proven to be a valuable tool allowing us to add useful and new information to a poorly studied disease. By using this tool, we examined nearly 15000 transcripts and analysed gene pathways affected by the disease. Particularly, our data suggest also a defective glycinergic synaptic transmission in the development of the disease and an alteration of calcium signalling proteins. We provide data to acquire knowledge of a genetic disease for which literature still presents poor results and that could be further and specifically analysed in the next future. Moreover this study, performed in livestock, may also harbour molecular information useful for understanding human diseases

Role of Flexibility in Protein-DNA-Drug Recognition: The Case of Asp677Gly-Val703Ile Topoisomerase Mutant Hypersensitive to Camptothecin

Topoisomerases I are ubiquitous enzymes that control DNA topology within the cell. They are the unique target of the antitumor drug camptothecin that selectively recognizes the DNA-topoisomerase covalent complex and reversibly stabilizes it. The biochemical and structural-dynamical properties of the Asp677Gly-Val703Ile double mutant with enhanced CPT sensitivity have been investigated. The mutant displays a lower religation rate of the DNA substrate when compared to the wild-type protein. Analyses of the structural dynamical properties by molecular dynamics simulation show that the mutant has reduced flexibility and an active site partially destructured at the level of the Lys532 residue. These results demonstrate long-range communication mechanism where reduction of the linker flexibility alters the active site geometry with the consequent lowering of the religation rate and increase in drug sensitivity