Inter University Consortium for the Application of Super Computing for Universities and Research

Rome, Italy

Inter University Consortium for the Application of Super Computing for Universities and Research

Rome, Italy
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Sicca F.,Neurophysiology and Neurogenetics Unit | Imbrici P.,University of Perugia | D'Adamo M.C.,University of Perugia | Moro F.,Foundation Medicine | And 8 more authors.
Neurobiology of Disease | Year: 2011

The inwardly-rectifying potassium channel Kir4.1 is a major player in the astrocyte-mediated regulation of [K +] o in the brain, which is essential for normal neuronal activity and synaptic functioning. KCNJ10, encoding Kir4.1, has been recently linked to seizure susceptibility in humans and mice, and is a possible candidate gene for Autism Spectrum Disorders (ASD). In this study, we performed a mutational screening of KCNJ10 in 52 patients with epilepsy of "unknown cause" associated with impairment of either cognitive or communicative abilities, or both. Among them, 14 patients fitted the diagnostic criteria for ASD. We identified two heterozygous KCNJ10 mutations (p.R18Q and p.V84M) in three children (two unrelated families) with seizures, ASD, and intellectual disability. The mutations replaced amino acid residues that are highly conserved throughout evolution and were undetected in about 500 healthy chromosomes. The effects of mutations on channel activity were functionally assayed using a heterologous expression system. These studies indicated that the molecular mechanism contributing to the disorder relates to an increase in either surface-expression or conductance of the Kir4.1 channel. Unlike previous syndromic associations of genetic variants in KCNJ10, the pure neuropsychiatric phenotype in our patients suggests that the new mutations affect K + homeostasis mainly in the brain, by acting through gain-of-function defects. Dysfunction in astrocytic-dependent K + buffering may contribute to autism/epilepsy phenotype, by altering neuronal excitability and synaptic function, and may represent a new target for novel therapeutic approaches. © 2011 Elsevier Inc.


Di Marino D.,University of Rome Tor Vergata | Oteri F.,University of Rome Tor Vergata | Morozzo della Rocca B.,University of Rome Tor Vergata | Chillemi G.,Inter University Consortium for the Application of Super Computing for Universities and Research | Falconi M.,University of Rome Tor Vergata
Journal of Structural Biology | Year: 2010

Molecular dynamics simulations of the wild type bovine ADP/ATP mitochondrial carrier, and of the single Ala113Pro and double Ala113Pro/Val180Met mutants, embedded in a lipid bilayer, have been carried out for 30. ns to shed light on the structural-dynamical changes induced by the Val180Met mutation restoring the carrier function in the Ala113Pro pathologic mutant. Principal component analysis indicates that, for the three systems, the protein dynamics is mainly characterized by the motion of the matrix loops and of the odd-numbered helices having a conserved proline in their central region. Analysis of the motions shows a different behaviour of single pathological mutant with respect of the other two systems. The single mutation induces a regularization and rigidity of the H3 helix, lost upon the introduction of the second mutation. This is directly correlated to the salt bridge distribution involving residues Arg79, Asp134 and Arg234, hypothesized to interact with the substrate. In fact, in the wild type simulation two stable inter-helices salt bridges, crucial for substrate binding, are present almost over all the simulation time. In line with the impaired ADP transport, one salt interaction is lost in the single mutant trajectory but reappears in the double mutant simulation, where a salt bridge network matching the wild type is restored. Other important structural-dynamical properties, such as the trans-membrane helices mobility, analyzed via the principal component analysis, are similar for the wild type and double mutant while are different for the single mutant, providing a mechanistic explanation for their different functional properties. © 2010 Elsevier Inc.


Mancini G.,Inter University Consortium for the Application of Super Computing for Universities and Research | Mancini G.,Normal School of Pisa | D'Annessa I.,University of Rome Tor Vergata | Coletta A.,University of Rome Tor Vergata | And 4 more authors.
PLoS ONE | Year: 2012

Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect. © 2012 Mancini et al.


Bongiorni S.,University of Tuscia | Mancini G.,Inter University Consortium for the Application of Super Computing for Universities and Research | Chillemi G.,Inter University Consortium for the Application of Super Computing for Universities and Research | Pariset L.,University of Tuscia | Valentini A.,University of Tuscia
PLoS ONE | Year: 2012

Calving in cattle is affected by calf morphology and by dam characteristics. It is described by two different traits: maternal calving ease, which is the ability to generate dams with good physiological predisposition to calving, and direct calving ease, which is the ability to generate calves that are easily born. The aim of this study was to identify regions of cattle genome harboring genes possibly affecting direct calving ease in the Piedmontese cattle breed. A population of 323 bulls scored for direct calving ease (EBV) was analyzed by a medium-density SNP marker panel (54,001 SNPs) to perform a genome-wide scan. The strongest signal was detected on chromosome 6 between 37.8 and 38.7 Mb where 13 SNPs associated to direct calving ease were found. Three genes are located in this region: LAP3, encoding for a leucine aminopeptidase involved in the oxytocin hydrolysis; NCAPG, encoding for a non-SMC condensin I complex, which has been associated in cattle with fetal growth and carcass size; and LCORL, which has been associated to height in humans and cattle. To further confirm the results of the genome-wide scan we genotyped additional SNPs within these genes and analyzed their association with direct calving ease. The results of this additional analysis fully confirmed the findings of the GWAS and particularly indicated LAP3 as the most probable gene involved. Linkage Disequilibrium (LD) analysis showed high correlation between SNPs located within LAP3 and LCORL indicating a possible selection signature due either to increased fitness or breeders' selection for the trait. © 2012 Bongiorni et al.


Mancini G.,University of Tuscia | Mancini G.,Inter University Consortium for the Application of Super Computing for Universities and Research | Gargani M.,University of Tuscia | Chillemi G.,Inter University Consortium for the Application of Super Computing for Universities and Research | And 4 more authors.
Molecular Biology Reports | Year: 2014

In this study we used a medium density panel of SNP markers to perform population genetic analysis in five Italian cattle breeds. The BovineSNP50 BeadChip was used to genotype a total of 2,935 bulls of Piedmontese, Marchigiana, Italian Holstein, Italian Brown and Italian Pezzata Rossa breeds. To determine a genome-wide pattern of positive selection we mapped the F ST values against genome location. The highest FST peaks were obtained on BTA6 and BTA13 where some candidate genes are located. We identified selection signatures peculiar of each breed which suggest selection for genes involved in milk or meat traits. The genetic structure was investigated by using a multidimensional scaling of the genetic distance matrix and a Bayesian approach implemented in the STRUCTURE software. The genotyping data showed a clear partitioning of the cattle genetic diversity into distinct breeds if a number of clusters equal to the number of populations were given. Assuming a lower number of clusters beef breeds group together. Both methods showed all five breeds separated in well defined clusters and the Bayesian approach assigned individuals to the breed of origin. The work is of interest not only because it enriches the knowledge on the process of evolution but also because the results generated could have implications for selective breeding programs. © The Author(s) 2014.


Liberati A.,Inter University Consortium for the Application of Super Computing for Universities and Research | Okuno Y.,Tokyo Institute of Technology
Journal of Physics D: Applied Physics | Year: 2010

Two-dimensional large eddy simulations have been carried out in order to investigate the performance of two disc MHD generators with different disc walls cross-sectional profiles. The first disc MHD generator has been designed with a 'typically-used' straight disc walls profile; the second, on the other hand, presents a contoured disc walls profile. The numerical results, obtained for a set of realistic working conditions and very fine grid meshes, show that the generator with contoured walls achieves the highest generator performance, measured in terms of enthalpy extraction and isentropic efficiency, because of improvements in flow behaviour and plasma conditions. In particular, under optimum generator performance conditions, a high Mach number-low static pressure MHD flow is realized in the generator with contoured disc walls. Here, the Lorentz force is not able to significantly drag the supersonic MHD flow even if a high magnetic flux density (4-8 T) is applied. As a consequence, MHD generators with contoured disc walls could achieve the generator performance target for commercialization of MHD power generation. © 2010 IOP Publishing Ltd.


Minella D.,University of Rome Tor Vergata | Wannenes F.,National Research Council Italy | Biancolella M.,University of Rome Tor Vergata | Biancolella M.,University of Southern California | And 11 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2011

Hirsutism is the development of androgen-dependent terminal body hair in women in places in which terminal hair are normally not found. It is often associated with hyperandrogenemia and/or polycystic ovary syndrome (PCOS), but the existence of uncommom hirsutism forms that are not related to altered androgen plasma levels lead also to the definition of "idiopathic hirsutism". Although the pathophysiology of hirsutism has been linked to increasing 5-alpha reductase (SRD5A) activity and to an alteration of the androgen receptor (AR) transcriptional machinery, many aspects remain unclear. In particular, the relationships between androgens and local factors are poorly understood. In the present paper, we selected for a genital skin biopsy, 8 women affected with severe hirsutism (Ferriman-Gallway score >25) but with normal plasma androgen levels, with the exception of slightly higher serum 3α-diol-glucuronide levels, and 6 healthy controls and analyzed their androgen- and insulin-specific transcriptional profile using a specific custom low density microarray (AndroChip 2, GPL9164). We identified the over-expression of the Son of Sevenless-1 (SOS1) gene in all of the hirsute skin fibroblast primary cell cultures compared to control healthy women. Since SOS1 is a guanine nucleotide exchange factor that couples receptor tyrosine kinases to the RAS signaling pathway that controls cell proliferation and differentiation, we further analyzed SOS1 expression, protein level and RAS signaling activation pathway in an in vitro model (NHDF, normal human dermal fibroblast cell line). NHDF treated for 24 h with different concentrations of DHT and T showed an increase in SOS1 levels (both mRNA and protein) and also an activation of the RAS pathway. Our in vivo and in vitro data represent a novel preliminary observation that factors activating SOS1 could act as local proliferative modulators linked to the androgen pathway in the pilosebaceous unit. SOS1 over-expression may play a role in the regulation of the RAS/mitogen-activated protein kinase pathway in the skin, in the hair follicle proliferation and cell cycle, suggesting new perspectives in understanding the pathogenesis of idiopathic hirsutism. Copyright © by BIOLIFE s.a.s.


PubMed | Inter University Consortium for the Application of Super Computing for Universities and Research
Type: Journal Article | Journal: PloS one | Year: 2010

Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death.Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain) that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed.Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in both short-range interactions and long-range protein domain communications.


PubMed | Inter University Consortium for the Application of Super Computing for Universities and Research
Type: Journal Article | Journal: PloS one | Year: 2012

Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect.

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