A Monte Carlo study of the three-dimensional Coulomb frustrated Ising ferromagnet

We have investigated by Monte-Carlo simulation the phase diagram of a three-dimensional Ising model with nearest-neighbor ferromagnetic interactions and small, but long-range (Coulombic) antiferromagnetic interactions. We have developed an efficient cluster algorithm and used different lattice sizes and geometries, which allows us to obtain the main characteristics of the temperature-frustration phase diagram. Our finite-size scaling analysis confirms that the melting of the lamellar phases into the paramgnetic phase is driven first-order by the fluctuations. Transitions between ordered phases with different modulation patterns is observed in some regions of the diagram, in agreement with a recent mean-field analysis.Comment: 14 pages, 10 figures, submitted to Phys. Rev.

The structure of the ternary Eg5–ADP–ispinesib complex

The human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement. These complications may explain the lack of available structural information for this important agent and its analogues. The present structure represents the best interpretation of these data based on extensive data-reduction, structure-solution and refinement trials

The potential role of the extracellular matrix in the activity of trabectedin in UPS and L-sarcoma: evidences from a patient‐derived primary culture case series in tridimensional and zebrafish models

Background: Soft tissue sarcomas (STS) are a rare group of solid neoplasm including among others liposarcoma, leiomyosarcoma (L-sarcoma) and undifferentiated pleomorphic sarcoma (UPS) entities. The current first-line treatment is represented by anthracycline based- regimens, second-line may include trabectedin. Currently the activity of trabectedin and its mechanism of action is not completely elucidated. Methods: Taking the advantages of our 3D patient-derived primary culture translational model we performed genomic-, chemobiogram, proteomic- and in vivo analysis in a UPS culture (S1). Furthermore pharmacological profiling of a UPS and L-sarcoma patient-derived case series and in silico analysis were carried out. Results: Trabectedin exhibited an increased activity in 3D respect to 2D cultures suggesting an extracellular matrix (ECM) and timp1 involvement in its mechanism of action. Moreover 3D S1 xenotranspanted zebrafish model showed an increased sensitivity to trabectedin. Finally the results were further validated in a UPS and L-sarcoma case series. Conclusions: Taken together these results confirmed the activity of trabectedin in these STS histotypes. Moreover the data underline the ECM involvement in the cytotoxic effect mediated by trabectedin and could open the door for researches aimed to focus on the patient setting that could benefit from this agent

Geometry parametrization and aerodynamic characteristics of axisymmetric afterbodies

A key aspect of the preliminary design process for a new generation combat aircraft is the prediction of afterbody aerodynamic drag. Current prediction methods for preliminary design are constrained in terms of number of independent geometric degrees of freedom that can be studied due to the classic circular arc or conical afterbody geometry parametrization. In addition, the amount of data available for the construction of the reliable performance correlations is too sparse. This paper presents a methodology for the generation of aerodynamic performance maps for transonic axisymmetric afterbody and exhaust systems. It uses a novel parametric geometry definition along with a compressible flow solver to conduct an extensive design space exploration. The proposed geometry parametrization is based on the Class Shape Transformation method and it enables the assessment of the aerodynamic performance of a wider range of afterbodies at the expense of one additional geometric degree of freedom. Relative to the conventional approach, this enables the exploration of a wider design space and the construction of more complete aerodynamic performance maps. This research quantifies the impact of a number of geometric degrees of freedom on the aerodynamic performance of transonic afterbody and exhaust systems at different operating conditions

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Increased therapeutic potential of an experimental anti-mitotic inhibitor SB715992 by genistein in PC-3 human prostate cancer cell line

BACKGROUND: Kinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation. HsEg5, a KSP, is responsible for the formation of the bipolar spindle, which is critical for proper cell division during mitosis. The function of HsEg5 provides a novel target for the manipulation of the cell cycle and the induction of apoptosis. SB715992, an experimental KSP inhibitor, has been shown to perturb bipolar spindle formation, thus making it an excellent candidate for anti-cancer agent. Our major objective was a) to investigate the cell growth inhibitory effects of SB715992 on PC-3 human prostate cancer cell line, b) to investigate whether the growth inhibitory effects of SB715992 could be enhanced when combined with genistein, a naturally occurring isoflavone and, c) to determine gene expression profile to establish molecular mechanism of action of SB715992. METHODS: PC-3 cells were treated with varying concentration of SB715992, 30 μM of genistein, and SB715992 plus 30 μM of genistein. After treatments, PC-3 cells were assayed for cell proliferation, induction of apoptosis, and alteration in gene and protein expression using cell inhibition assay, apoptosis assay, microarray analysis, real-time RT-PCR, and Western Blot analysis. RESULTS: SB715992 inhibited cell proliferation and induced apoptosis in PC-3 cells. SB715992 was found to regulate the expression of genes related to the control of cell proliferation, cell cycle, cell signaling pathways, and apoptosis. In addition, our results showed that combination treatment with SB715992 and genistein caused significantly greater cell growth inhibition and induction of apoptosis compared to the effects of either agent alone. CONCLUSION: Our results clearly show that SB715992 is a potent anti-tumor agent whose therapeutic effects could be enhanced by genistein. Hence, we believe that SB715992 could be a novel agent for the treatment of prostate cancer with greater success when combined with a non-toxic natural agent like genistein

Search of Dark Matter Annihilation in the Galactic Centre using the ANTARES Neutrino Telescope

A search for high-energy neutrinos coming from the direction of the GalacticCentre is performed using the data recorded by the ANTARES neutrino telescopefrom 2007 to 2012. The event selection criteria are chosen to maximise thesensitivity to possible signals produced by the self-annihilation of weaklyinteracting massive particles accumulated around the centre of the Milky Waywith respect to the atmospheric background. After data unblinding, the numberof neutrinos observed in the line of sight of the Galactic Centre is found tobe compatible with background expectations. The 90% C.L. upper limits in termsof the neutrino+anti-neutrino flux, $\rm \Phi_{\nu_{\mu}+\bar{\nu}_\mu}$, andthe velocity averaged annihilation cross-section, $\rm$, arederived for the WIMP self-annihilation channels into \rmb\bar{b},W^{+}W^{-},\tau^{+}\tau^{-},\mu^{+}\mu^{-},\nu\bar{\nu}. The ANTARESlimits for $\rm$ are shown to be the most stringent for aneutrino telescope over the WIMP masses $\rm 25\,GeV < M_{WIMP} < 10\,TeV$

Polo-Like Kinase-1 Controls Aurora A Destruction by Activating APC/C-Cdh1

Polo-like kinase-1 (Plk1) is activated before mitosis by Aurora A and its cofactor Bora. In mitosis, Bora is degraded in a manner dependent on Plk1 kinase activity and the E3 ubiquitin ligase SCF-βTrCP. Here, we show that Plk1 is also required for the timely destruction of its activator Aurora A in late anaphase. It has been shown that Aurora A destruction is controlled by the auxiliary subunit Cdh1 of the Anaphase-Promoting Complex/Cyclosome (APC/C). Remarkably, we found that Plk1-depletion prevented the efficient dephosphorylation of Cdh1 during mitotic exit. Plk1 mediated its effect on Cdh1, at least in part, through direct phosphorylation of the human phosphatase Cdc14A, controlling the phosphorylation state of Cdh1. We conclude that Plk1 facilitates efficient Aurora A degradation through APC/C-Cdh1 activation after mitosis, with a potential role for hCdc14A

Supernova Neutrino Burst Detection with the Deep Underground Neutrino Experiment

The Deep Underground Neutrino Experiment (DUNE), a 40-kton underground liquid argon time projection chamber experiment, will be sensitive to the electron-neutrino flavor component of the burst of neutrinos expected from the next Galactic core-collapse supernova. Such an observation will bring unique insight into the astrophysics of core collapse as well as into the properties of neutrinos. The general capabilities of DUNE for neutrino detection in the relevant few- to few-tens-of-MeV neutrino energy range will be described. As an example, DUNE's ability to constrain the ν_e spectral parameters of the neutrino burst will be considered