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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. Source

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. Source

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 9 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. Source

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. Source

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. Source

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