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Background: HIV-1 p17 binds heparin and heparan sulfate proteoglycans of the cell surface. Results: Heparin/p17interactionoccursthroughheparinsulfategroupsandalinearbasicmotifofp17Nterminus,alsoinvolved in p17/CXCR1 interaction. Conclusion: Targeting the basic motif inhibits p17-receptors interaction and consequent biological activities. Significance: Heparin-like molecules represent template for the development of new treatments of p17-dependent/AIDS- associated pathologies.

The paper presents a methodology for relative damage assessment for historical Landslide Events, i.e. periods during which damage caused by rainfall-triggered landslide affected wide areas. The approach requires a minimum amount of data and it is based on the assessment of direct, indirect and intangible damage indices at municipal and regional scale. An application to major events which occurred in Calabria (Italy) highlighted roads as the most vulnerable element, even representing the source of intangible damage for people forced to use alternative roads for their daily activities. Indirect costs seems mainly tied to both displacement of people even for short periods.

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations in reasonable time, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors.

Differences in genetic background within two or more populations are an important cause of disturbance in case control association studies. In fact, when mixing together populations of different ethnic groups, different allele frequencies between case and control samples could be due to the ancestry rather than a real association with the disease under study. This can easily lead to a large amount of false positive and negative results in association study analysis. Moreover, the growing need to put together several data sets coming from different studies in order to increase the statistical power of the analysis makes this problem particularly important in recent statistical genetics research. To overcome these problems, different correction strategies have been proposed, but currently there is no consensus about a common powerful strategy to adjust for population stratification. In this chapter, we discuss the state-of-the-art of strategies used for correcting the statistics for genome-wide association analysis by taking into account the ancestral structure of the population. After a short review of the most important methods and tools available, we will show the results obtained in two real data sets and discuss them in terms of advantages and disadvantages of each algorithm.

Calcium ions coordinate multiple cellular functions, among which the release of neurotransmitters, the gene expression, the regulation of inflammatory processes and the activation of apoptosis. The regulation of calcium metabolism involves several biochemical pathways, different sub-cellular compartments and it is strongly compromised during aging. In fact, alterations of the calcium signalling process are frequent in the neurodegenerative diseases and mainly result in the hyper-activation of the apoptotic process. To investigate molecular alterations occurring in neurodegenerative diseases, an integrative mathematical model designed to represent the calcium metabolism has been defined. The model, which is mathematically defined by ODEs system, reproduces the calcium ions functions during glutamate stimulation. In particular, a number of different situations, such as (i) the glutamatergic transmission using different impulse frequencies, (ii) the comparison between normal and excessive stimulation and (iii) the calcium homeostasis in young/aging neurons have been reproduced. In particular, the simulations of several features associated to neurodegenerative disease, especially at molecular level and with a particular focus on the apoptotic process, allow highlighting the differences occurring in calcium metabolism in normal and pathological states. Furthermore collecting the achieved simulation and sensitivity analysis results, we propose an in silico strategy for preventing the activation of the apoptotic pathway in the neurodegenerative diseases.

Molecular structure of the ligand binding domain of hAhR has been modelled by homology modelling techniques and used for docking simulations with dioxin and nine more xenobiotics and endogenous ligands. The study evidences that different sites may bind these ligands, whereas only one binding site has been previously indicated by past studies on the mouse homologous receptor. The differences in the sequence of mouse and human AhR ligand binding domain may explain this observation, being most of them in the additional sites observed. Preferences of the evaluated ligands for the different sites are reported and discussed in view of their functional role.

Aim of clustering of data is to analyze gene expression data. Recently, biclustering or simultaneous clustering of both genes and conditions have generated considerable interest over the past few decades, particularly related to the analysis of high-dimensional gene expression data in information retrieval, knowledge discovery, and data mining. In a gene expression data matrix, a bicluster is a submatrix of genes and conditions that exhibits a high correlation of expression activity across both rows and columns. Unfortunately, the problem of locating the most significant bicluster has been shown to be NP-complete. Therefore, given the inner “intractability” of the problem from a computational point of view, we have designed and implemented several GRASP-like heuristic algorithms to efficiently find good solutions in a reasonable running times.

Cancer cells differ from their normal counterparts more in terms of regulatory networks than of specific molecules. A recently recognized hallmark of cancer is the increased uptake of nutrients, particularly glucose, associated with a higher lactate pro- duction. A common step of tumorigenesis, which influences these metabolic alterations, is the constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Fol- lowing an integrative systems biology approach, we propose a model for the in silico investigation of the PI3K/Akt pathway effects on the central metabolism. This model represents a useful tool for the computational analysis of the metabolic differences be- tween normal and pathological conditions.

Endothelial protein C receptor (EPCR) is a CD1-like transmembrane glycoprotein with important regulatory roles in protein C (PC) pathway, enhancing PC's anticoagulant, anti-inflammatory, and antiapoptotic activities. Similarly to homologous CD1d, EPCR binds a phospholipid [phosphatidylethanolamine (PTY)] in a groove corresponding to the antigen-presenting site, although it is not clear if lipid exchange can occur in EPCR as in CD1d. The presence of PTY seems essential for PC gamma-carboxyglutamic acid (Gla) domain binding. However, the lipid-free form of the EPCR has not been characterized. We have investigated the structural role of PTY on EPCR, by multiple molecular dynamics (MD) simulations of ligand bound and unbound forms of the protein. Structural changes, subsequent to ligand removal, led to identification of two stable and folded ligand-free conformations. Compared with the bound form, unbound structures showed a narrowing of the A' pocket and a high flexibility of the helices around it, in agreement with CD1d simulation. Thus, a lipid exchange with a mechanism similar to CD1d is proposed. In addition, unbound conformations presented a reduced interaction surface for Gla domain, confirming the role of PTY in establishing the proper EPCR conformation for the interaction with its partner protein. Single MD simulations were also obtained for 29 mutant models with predicted structural stability and impaired binding ability. Ligand affinity calculations, based on linear interaction energy method, showed that substitution-induced conformational changes affecting helices around the A' pocket were associated to a reduced binding affinity. Mutants responsible for this effect may represent useful reagents for experimental tests.