Cyclin-dependent Kinase Inhibitor 3 (CDKN3) Mediates the Antiviral Effect of Alpha Interferon against HBV Replication through Inhibition of Pregenomic RNA Encapsidation

poster abstractHBV capsid (core) protein is a phosphoprotein that contains three major serine phosphoacceptor sites in its C-terminal domain. In our effort to investigate the potential site-specific and combinational roles of serine phosphorylation in HBV DNA replication, we found that the primary effect of core phosphorylation on HBV replication was on the pregenomic (pg) RNA encapsidation step. Further mechanistic studies revealed that the core phosphorylation state-dependent interaction between viral core and polymerase (pol) plays a critical role in HBV pgRNA encapsidation. It has been well documented that IFN-α prevents HBV pgRNA encapsidation in cell cultures, however, the underlying molecular mechanisms remain unclear. We report herein that IFN-α-elicited inhibition of HBV pgRNA encapsidation is associated with a loss of core/pol interaction without affecting the steady state level of either protein, indicating that IFN-α inhibits HBV pgRNA encapsidation through blocking core phosphorylation-dependent interaction with pol. Since cyclin-dependent kinase 2 (CDK2) was identified as a kinase for HBV core, we next analyzed the inductivity of CDK2 and its associated regulatory factors in IFN-α-treated cells. We found that a cellular CDK2 inhibitor, cyclin-dependent Kinase Inhibitor 3 (CDKN3), was significantly upregulated by IFN-α. We further demonstrated that overexpression of CDKN3 inhibited core/pol interaction and subsequent pgRNA encapsidation and DNA replication, which is reminiscent of IFN-α’s anti-HBV activity. What’s more, knockdown of CDKN3 in HBV replicating cells completely attenuated IFN-α-mediated inhibition of HBV core/pol interaction and pgRNA encapsidation. Taken together, CDKN3 is a host restriction factor for HBV replication through inhibition of viral nucleocapsid formation, and it plays a dominant role in IFN-α-elicited antiviral activity against HBV in cell cultures. The detailed profile of CDKN3-mediated alteration of HBV core phosphorylation in the context of IFN-α treatment is currently under investigation

Nonlinear management of the angular momentum of soliton clusters

We demonstrate an original approach to acquire nonlinear control over the angular momentum of a cluster of solitary waves. Our model, derived from a general description of nonlinear energy propagation in dispersive media, shows that the cluster angular momentum can be adjusted by acting on the global energy input into the system. The phenomenon is experimentally verified in liquid crystals by observing power-dependent rotation of a two-soliton cluster.Comment: 4 pages, 3 figure

Total cross-section and rapidity gap survival probability at the LHC through an eikonal with soft gluon resummation

New results are presented for total ${\rm pp}/ {\rm \bar p p}$ cross-sections, in the framework of our QCD based model (GGPS). This is an improved eikonal mini-jet model, where soft gluon radiation tames the fast energy rise normally present in mini-jet models. We discuss the variability in our predictions and provide a handy parametrization of our results for the LHC. We find that our model predictions span the range $\sigma_{tot}^{LHC}=100 ^{+10}_{-13} mb$. While this matches nicely with the range of most other models, it does not agree with recent ones which include a "hard" Pomeron, even though our model does include hard scattering. We compute the survival probability for Large Rapidity Gap (LRG) events at the LHC and at the Tevatron. These events are relevant, for example, for Higgs signal in the $WW$ fusion process. We also explore whether measurements of the total cross-sections at the LHC can help us sharpen the model parameters and hence estimates for these survival probabilities, further.Comment: 15 pages, 3 figures, LaTe

Conformal Symmetry and Universal Properties of Quantum Hall States

The low-lying excitations of a quantum Hall state on a disk geometry are edge excitations. Their dynamics is governed by a conformal field theory on the cylinder defined by the disk boundary and the time variable. We give a simple and detailed derivation of this conformal field theory for integer filling, starting from the microscopic dynamics of $(2+1)$-dimensional non-relativistic electrons in Landau levels. This construction can be generalized to describe Laughlin's fractional Hall states via chiral bosonization, thereby making contact with the effective Chern-Simons theory approach. The conformal field theory dictates the finite-size effects in the energy spectrum. An experimental or numerical verification of these universal effects would provide a further confirmation of Laughlin's theory of incompressible quantum fluids.Comment: 39 pages, 7 figures (not included, they are mailed on request), harvmac CERN-TH 6702/9

The signature of dark energy on the local Hubble flow

Using N-body simulations of flat, dark energy dominated cosmologies, we show that galaxies around simulated binary systems resembling the Local Group (LG) have low peculiar velocities, in good agreement with observational data. We have compared results for LG-like systems selected from large, high resolution simulations of three cosmologies: a LCDM model, a LWDM model with a 2 keV warm dark matter candidate and a quintessence model (QCDM) with an equation of state parameter w=-0.6. The Hubble flow is significant colder around LGs selected in a flat, Lambda dominated cosmology than around LGs in open or critical models, showing that a dark energy component manifests itself on the scales of nearby galaxies, cooling galaxy peculiar motions. Flows in the LWDM and QCDM models are marginally colder than in the LCDM one. The results of our simulations have been compared to existing data and a new data set of 28 nearby galaxies with robust distance measures (Cepheids and Surface Brightness Fluctuations). The measured line-of-sight velocity dispersion is sigma = 88 +- 20 km/sec x (R/7 Mpc). The best agreement with observations is found for LGs selected in the $\Lambda$CDM cosmology in environments with -0.1 <delta_rho/rho < 0.6 on scales of 7 Mpc, in agreement with existing observational estimates on the local matter density. These results provide new, independent evidence for the presence of dark energy on scales of few Mpc, corroborating the evidence gathered from observations of distant objects and the early Universe.Comment: 8 pages, 6 figures, minor changes to match the accepted version by MNRA

Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes

Purpose G lioblastoma (GB) is the most frequent brain tumor. Despite recent improvement in therapeutic strategies, the prognosis of GB remains poor. Growth hormone-releasing hormone (GHRH) may act as a growth factor; antagonists of GHRH have been successfully applied for experimental treatment of different types of tumors. The expression profile of GHRH receptor, its main splice variant SV1 and GHRH have not been investigated in human GB tissue samples. Methods We examined the expression of GHRH, fulllength pituitary-type GHRH receptor (pGHRHR), its functional splice variant SV1 and non-functional SV2 by RTPCR in 23 human GB specimens. Epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog gene (PTEN) expression levels were also evaluated by quantitative RT-PCR. Correlations between clinico-pathological parameters and gene expressions were analyzed. Results E xpression of GHRH was found to be positive in 61.9 % of samples. pGHRH receptor was not expressed in our sample set, while SV1 could be detected in 17.4 % and SV2 in 8.6 % of the GB tissues. In 65.2 and 78.3 % of samples, significant EGFR over-expression or PTEN under-representation could be detected, respectively. In 47.8 % of cases, EGFR up-regulation and PTEN down-regulation occurred together. Survival was significantly poorer in tumors lacking GHRH expression. This worse prognosis in GHRH negative group remained significant even if SV1 was also expressed. Conclusion Our study shows that GHRH and SV1 genes expressed in human GB samples and their expression patterns are associated with poorer prognosis

Actual and preferred place of death of home-dwelling patients in four European countries: making sense of quality indicators

Background: Dying at home and dying at the preferred place of death are advocated to be desirable outcomes of palliative care. More insight is needed in their usefulness as quality indicators. Our objective is to describe whether " the percentage of patients dying at home'' and "the percentage of patients who died in their place of preference'' are feasible and informative quality indicators. Methods and Findings: A mortality follow-back study was conducted, based on data recorded by representative GP networks regarding home-dwelling patients who died non-suddenly in Belgium (n = 1036), the Netherlands (n = 512), Italy (n = 1639) or Spain (n = 565). "The percentage of patients dying at home'' ranged between 35.3% (Belgium) and 50.6% (the Netherlands) in the four countries, while "the percentage of patients dying at their preferred place of death'' ranged between 67.8% (Italy) and 86.0% (Spain). Both indicators were strongly associated with palliative care provision by the GP (odds ratios of 1.55-13.23 and 2.30-6.63, respectively). The quality indicator concerning the preferred place of death offers a broader view than the indicator concerning home deaths, as it takes into account all preferences met in all locations. However, GPs did not know the preferences for place of death in 39.6% (the Netherlands) to 70.3% (Italy), whereas the actual place of death was known in almost all cases. Conclusion: GPs know their patients' actual place of death, making the percentage of home deaths a feasible indicator for collection by GPs. However, patients' preferred place of death was often unknown to the GP. We therefore recommend using information from relatives as long as information from GPs on the preferred place of death is lacking. Timely communication about the place where patients want to be cared for at the end of life remains a challenge for GPs

The short term debt vs. long term debt puzzle: a model for the optimal mix

This paper argues that the existing finance literature is inadequate with respect to its coverage of capital structure of small and medium sized enterprises (SMEs). In particular it is argued that the cost of equity (being both conceptually ill defined and empirically non quantifiable) is not applicable to the capital structure decisions for a large proportion of SMEs and the optimal capital structure depends only on the mix of short and long term debt. The paper then presents a model, developed by practitioners for optimising the debt mix and demonstrates its practical application using an Italian firm's debt structure as a case study