Institute Pasteur Fondazione Cenci Bolognetti

Rome, Italy

Institute Pasteur Fondazione Cenci Bolognetti

Rome, Italy
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Gimonneau G.,Montpellier University | Gimonneau G.,Institute Of Recherche En Science Of La Sante Irss | Pombi M.,University of Rome La Sapienza | Pombi M.,Institute Pasteur Fondazione Cenci Bolognetti | And 5 more authors.
Parasites and Vectors | Year: 2012

Background: Predation of aquatic immature stages has been identified as a major evolutionary force driving habitat segregation and niche partitioning in the malaria mosquito Anopheles gambiae sensu stricto in the humid savannahs of Burkina Faso, West Africa. Here, we explored behavioural responses to the presence of a predator in wild populations of the M and S molecular forms of An. gambiae that typically breed in permanent (e.g., rice field paddies) and temporary (e.g., road ruts) water collections. Methods. Larvae used in these experiments were obtained from eggs laid by wild female An. gambiae collected from two localities in south-western Burkina Faso during the 2008 rainy season. Single larvae were observed in an experimental arena, and behavioural traits were recorded and quantified a) in the absence of a predator and b) in the presence of a widespread mosquito predator, the backswimmer Anisops jaczewskii. Differences in the proportion of time allocated to each behaviour were assessed using Principal Component Analysis and Multivariate Analysis of Variance. Results: The behaviour of M and S form larvae was found to differ significantly; although both forms mainly foraged at the water surface, spending 60-90% of their time filtering water at the surface or along the wall of the container, M form larvae spent on average significantly more time browsing at the bottom of the container than S form larvae (4.5 vs. 1.3% of their overall time, respectively; P < 0.05). In the presence of a predator, larvae of both forms modified their behaviour, spending significantly more time resting along the container wall (P < 0.001). This change in behaviour was at least twice as great in the M form (from 38.6 to 66.6% of the time at the wall in the absence and presence of the predator, respectively) than in the S form (from 48.3 to 64.1%). Thrashing at the water surface exposed larvae to a significantly greater risk of predation by the notonectid (P < 0.01), whereas predation occurred significantly less often when larvae were at the container wall (P < 0.05) and might reflect predator vigilance. Conclusions: Behavioural differences between larvae of the M and S form of An. gambiae in response to an acute predation risk is likely to be a reflection of different trade-offs between foraging and predator vigilance that might be of adaptive value in contrasting aquatic ecosystems. Future studies should explore the relevance of these findings under the wide range of natural settings where both forms co-exist in Africa. © 2012 Gimonneau et al; licensee BioMed Central Ltd.

Milanetti E.,University of Rome La Sapienza | Raimondo D.,University of Rome La Sapienza | Tramontano A.,University of Rome La Sapienza | Tramontano A.,Institute Pasteur Fondazione Cenci Bolognetti | Tramontano A.,Italian Institute of Technology
Bioinformatics | Year: 2016

Motivation: Determination of drug absorption is an important component of the drug discovery and development process in that it plays a key role in the decision to promote drug candidates to clinical trials. We have developed a method that, on the basis of an analysis of the dynamic distribution of water molecules around a compound obtained by molecular dynamics simulations, can compute a parameter-free value that correlates very well with the compound permeability measured using the human colon adenocarcinoma (Caco-2) cell line assay. Results: The method has been tested on twenty-three neutral drugs for which a consistent set of experimental data is available. We show here that our method reproduces the experimental data better than other existing tools. Furthermore it provides a detailed view of the relationship between the hydration and the permeability properties of molecules. © The Author 2015. Published by Oxford University Press.

Carbajo D.,University of Rome La Sapienza | Tramontano A.,University of Rome La Sapienza | Tramontano A.,Institute Pasteur Fondazione Cenci Bolognetti | Tramontano A.,Italian Institute of Technology
BMC Bioinformatics | Year: 2012

Background: Increasingly, biologists and biochemists use computational tools to design experiments to probe the function of proteins and/or to engineer them for a variety of different purposes. The most effective strategies rely on the knowledge of the three-dimensional structure of the protein of interest. However it is often the case that an experimental structure is not available and that models of different quality are used instead. On the other hand, the relationship between the quality of a model and its appropriate use is not easy to derive in general, and so far it has been analyzed in detail only for specific application.Results: This paper describes a database and related software tools that allow testing of a given structure based method on models of a protein representing different levels of accuracy. The comparison of the results of a computational experiment on the experimental structure and on a set of its decoy models will allow developers and users to assess which is the specific threshold of accuracy required to perform the task effectively.Conclusions: The ModelDB server automatically builds decoy models of different accuracy for a given protein of known structure and provides a set of useful tools for their analysis. Pre-computed data for a non-redundant set of deposited protein structures are available for analysis and download in the ModelDB database.Implementation, availability and requirements: Project name: A resource for benchmarking the usefulness of protein structure models. Project home page: system(s): Platform independent. Programming language: Perl-BioPerl (program); mySQL, Perl DBI and DBD modules (database); php, JavaScript, Jmol scripting (web server). Other requirements: Java Runtime Environment v1.4 or later, Perl, BioPerl, CPAN modules, HHsearch, Modeller, LGA, NCBI Blast package, DSSP, Speedfill (Surfnet) and PSAIA. License: Free. Any restrictions to use by non-academics: No. © 2012 Carbajo and Tramontano; licensee BioMed Central Ltd.

Bonella S.,University of Rome La Sapienza | Raimondo D.,University of Rome La Sapienza | Milanetti E.,University of Rome La Sapienza | Tramontano A.,University of Rome La Sapienza | And 3 more authors.
Journal of Physical Chemistry B | Year: 2014

In spite of its relevant biological role, no general consensus exists on the quantitative characterization of amino acid's hydropathy. In particular, many hydrophobicity scales exist, often producing quite different rankings for the amino acids. To make progress toward a systematic classification, we analyze amino acids' hydropathy based on the orientation of water molecules at a given distance from them as computed from molecular dynamics simulations. In contrast with what is usually done, we argue that assigning a single number is not enough to characterize the properties of an amino acid, in particular when both hydrophobic and hydrophilic regions are present in a residue. Instead we show that appropriately defined conditional probability densities can be used to map the hydrophilic and hydrophobic groups on the amino acids with greater detail than possible with other available methods. Three indicators are then defined based on the features of these probabilities to quantify the specific hydrophobicity and hydrophilicity of each amino acid. The characterization that we propose can be used to understand some of the ambiguities in the ranking of amino acids in the current scales. The quantitative indicators can also be used in combination with standard bioinformatics tools to predict the location of transmembrane regions of proteins. The method is sensitive to the specific environment of the amino acids and can be applied to unnatural and modified amino acids, as well as to other small organic molecules. © 2014 American Chemical Society.

Claros C.,University of Rome La Sapienza | Tramontano A.,University of Rome La Sapienza | Tramontano A.,Institute Pasteur Fondazione Cenci Bolognetti | Tramontano A.,Italian Institute of Technology
PLoS ONE | Year: 2012

Comprehensive protein interaction maps can complement genetic and biochemical experiments and allow the formulation of new hypotheses to be tested in the system of interest. The computational analysis of the maps may help to focus on interesting cases and thereby to appropriately prioritize the validation experiments. We show here that, by automatically comparing and analyzing structurally similar regions of proteins of known structure interacting with a common partner, it is possible to identify mutually exclusive interactions present in the maps with a sensitivity of 70% and a specificity higher than 85% and that, in about three fourth of the correctly identified complexes, we also correctly recognize at least one residue (five on average) belonging to the interaction interface. Given the present and continuously increasing number of proteins of known structure, the requirement of the knowledge of the structure of the interacting proteins does not substantially impact on the coverage of our strategy that can be estimated to be around 25%. We also introduce here the Estrella server that embodies this strategy, is designed for users interested in validating specific hypotheses about the functional role of a protein-protein interaction and it also allows access to pre-computed data for seven organisms. © 2012 Sánchez Claros, Tramontano.

Sette M.,University of Rome Tor Vergata | D'Addabbo P.,University of Bari | Kelly G.,The Francis Crick Institute | Cicconi A.,University of Rome La Sapienza | And 9 more authors.
Biopolymers | Year: 2016

Regulatory regions in the genome can act through a variety of mechanisms that range from the occurrence of histone modifications to the presence of protein-binding loci for self-annealing sequences. The final result is often the induction of a conformational change of the DNA double helix, which alters the accessibility of a region to transcription factors and consequently gene expression. A ∼300 kb regulatory region on chromosome 14 at the 3' end (3'RR) of immunoglobulin (Ig) heavy-chain genes shows very peculiar features, conserved in mammals, including enhancers and transcription factor binding sites. In primates, the 3'RR is present in two copies, both having a central enhancer named hs1.2. We previously demonstrated the association between different hs1.2 alleles and Ig plasma levels in immunopathology. Here, we present the analysis of a putative G-quadruplex structure (tetraplex) consensus site embedded in a variable number tandem repeat (one to four copies) of hs1.2 that is a distinctive element among the enhancer alleles, and an investigation of its three-dimensional structure using bioinformatics and spectroscopic approaches. We suggest that both the role of the enhancer and the alternative effect of the hs1.2 alleles may be achieved through their peculiar three-dimensional-conformational rearrangement. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 768–778, 2016. © 2016 Wiley Periodicals, Inc.

Mannironi C.,National Research Council Italy | Mannironi C.,University of Rome La Sapienza | Camon J.,University of Rome La Sapienza | De Vito F.,University of Rome La Sapienza | And 10 more authors.
PLoS ONE | Year: 2013

The amygdala is a brain structure considered a key node for the regulation of neuroendocrine stress response. Stress-induced response in amygdala is accomplished through neurotransmitter activation and an alteration of gene expression. MicroRNAs (miRNAs) are important regulators of gene expression in the nervous system and are very well suited effectors of stress response for their ability to reversibly silence specific mRNAs. In order to study how acute stress affects miRNAs expression in amygdala we analyzed the miRNA profile after two hours of mouse restraint, by microarray analysis and reverse transcription real time PCR. We found that miR-135a and miR-124 were negatively regulated. Among in silico predicted targets we identified the mineralocorticoid receptor (MR) as a target of both miR-135a and miR-124. Luciferase experiments and endogenous protein expression analysis upon miRNA upregulation and inhibition allowed us to demonstrate that mir-135a and mir-124 are able to negatively affect the expression of the MR. The increased levels of the amygdala MR protein after two hours of restraint, that we analyzed by western blot, negatively correlate with miR-135a and miR-124 expression. These findings point to a role of miR-135a and miR-124 in acute stress as regulators of the MR, an important effector of early stress response. © 2013 Mannironi et al.

Pombi M.,University of Rome La Sapienza | Pombi M.,Institute Pasteur Fondazione Cenci Bolognetti | Guelbeogo W.M.,Center National Of Recherche Et Formation Sur Le Paludisme | Kreppel K.,University of Glasgow | And 9 more authors.
Parasites and Vectors | Year: 2014

Background: Monitoring densities of adult mosquito populations is a major challenge in efforts to evaluate the epidemiology of mosquito-borne diseases, and their response to vector control interventions. In the case of malaria, collection of outdoor-resting Anophelines is rarely incorporated into surveillance and control, partially due to the lack of standardized collection tools. Such an approach, however, is increasingly important to investigate possible changes in mosquito behaviour in response to the scale up of Insecticide Treated Nets and Indoor Residual Spraying. In this study we evaluated the Sticky Resting Box (SRB) - i.e. a sticky variant of previously investigated mosquito Resting Box, which allows passive collection of mosquitoes entering the box - and compared its performance against traditional methods for indoor and outdoor resting mosquito sampling. Methods. Daily collections were carried out in two neighbouring villages of Burkina Faso during rainy season 2011 and dry season 2012 by SRB located indoors and outdoors, and by Back-Pack aspiration inside houses (BP) and in ad hoc built outdoor pit-shelters (PIT). Results: Overall, almost 20,000 Culicidae specimens belonging to 16 species were collected and morphologically identified. Malaria vectors included Anopheles coluzzii (53%), An. arabiensis (12%), An. gambiae s.s. (2.0%) and An. funestus (4.5%). The diversity of species collected in the two villages was similar for SRB and PIT collections outdoors, and significantly higher for SRB than for BP indoors. The population dynamics of An. gambiae s.l. mosquitoes, as obtained by SRB-collections was significantly correlated with those obtained by the traditional methods. The predicted mean estimates of An. gambiae s.l. specimens/sampling-unit/night-of-collections was 6- and 5-times lower for SRB than for BP indoors and PIT outdoors, respectively. Conclusions: Overall, the daily performance of SRB in terms of number of malaria vectors/trap was lower than that of traditionally used approaches for in- and outdoor collections. However, unlike these methods, SRB could be set up to collect mosquitoes passively over at least a week. This makes SRB a promising tool for passively monitoring anopheline resting populations, with data presented here providing guidance for how to set up SRB-based collections to acquire information comparable to those obtained with other methods. © 2014 Pombi et al.; licensee BioMed Central Ltd.

Noto A.,University of Rome La Sapienza | Raffa S.,University of Rome La Sapienza | Raffa S.,Institute Pasteur Fondazione Cenci Bolognetti | De Vitis C.,University of Rome La Sapienza | And 13 more authors.
Cell Death and Disease | Year: 2013

In recent years, studies of cancer development and recurrence have been influenced by the cancer stem cells (CSCs)/cancerinitiating cells (CICs) hypothesis. According to this, cancer is sustained by highly positioned, chemoresistant cells with extensive capacity of self renewal, which are responsible for disease relapse after chemotherapy. Growth of cancer cells as three-dimensional non-adherent spheroids is regarded as a useful methodology to enrich for cells endowed with CSC-like features. We have recently reported that cell cultures derived from malignant pleural effusions (MPEs) of patients affected by adenocarcinoma of the lung are able to efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we were able to identify a set of genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. One of the most strongly upregulated gene was stearoyl-CoA desaturase (SCD1), the main enzyme responsible for the conversion of saturated into monounsaturated fatty acids. In the present study, we show both by RNA interference and through the use of a small molecule inhibitor that SCD1 is required for lung cancer spheroids propagation both in stable cell lines and in MPE-derived primary tumor cultures. Morphological examination and image analysis of the tumor spheroids formed in the presence of SCD1 inhibitors showed a different pattern of growth characterized by irregular cell aggregates. Electron microscopy revealed that the treated spheroids displayed several features of cellular damage and immunofluorescence analysis on optical serial sections showed apoptotic cells positive for the M30 marker, most of them positive also for the stemness marker ALDH1A1, thus suggesting that the SCD1 inhibitor is selectively killing cells with stem-like properties. Furthermore, SCD1-inhibited lung cancer cells were strongly impaired in their in vivo tumorigenicity and ALDH1A1 expression. These results suggest that SCD1 is a critical target in lung cancer tumor-initiating cells. © 2013 Macmillan Publishers Limited All rights reserved.

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