WHO analgesic ladder gone astray: wider implications

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Anti-phase locking in a two-dimensional Josephson junction array

We consider theoretically phase locking in a simple two-dimensional Josephson junction array consisting of two loops coupled via a joint line transverse to the bias current. Ring inductances are supposed to be small, and special emphasis is taken on the influence of external flux. Is is shown, that in the stable oscillation regime both cells oscillate with a phase shift equal to $\pi$ (i.e. anti-phase). This result may explain the low radiation output obtained so far in two-dimensional Josephson junction arrays experimentally.Comment: 11 pages, REVTeX, 1 Postscript figure, Subm. to Appl. Phys. Let

Theory of phase-locking in generalized hybrid Josephson junction arrays

A recently proposed scheme for the analytical treatment of the dynamics of two-dimensional hybrid Josephson junction arrays is extended to a class of generalized hybrid arrays with ''horizontal'' shunts involving a capacitive as well as an inductive component. This class of arrays is of special interest, because the internal cell coupling has been shown numerically to favor in-phase synchronization for certain parameter values. As a result, we derive limits on the circuit design parameters for realizing this state. In addition, we obtain formulas for the flux-dependent frequency including flux-induced switching processes between the in-phase and anti-phase oscillation regime. The treatment covers unloaded arrays as well as arrays shunted via an external load.Comment: 24 pages, REVTeX, 5 Postscript figures, Subm. to Phys. Rev.

Intrinsic mechanism of phase locking in two-dimensional Josephson junction networks in presence of an external magnetic field

We present numerical simulations of the dynamics of two-dimensional Josephson junction arrays to study the mechanism of mutual phase locking. We show that in the presence of an external magnetic field two mechanisms are playing a role in phase locking: feedback through the external load and internal coupling between rows due to microwave currents induced by the field. We have found the parameter values (junction capacitance, cell loop inductance, impedance of the external load) for which the interplay of both these mechanisms leads to the in-phase solution. The case of unshunted arrays is discussed as well.Comment: 13 pages, incl. 6 ps figures, Subm. to Europhysics Letter

Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis

AbstractEbola virus (EBOV) is an enveloped negative-sense RNA virus that causes sporadic outbreaks with high case fatality rates. Ebola viral protein 30 (eVP30) plays a critical role in EBOV transcription initiation at the nucleoprotein (eNP) gene, with additional roles in the replication cycle such as viral assembly. However, the mechanistic basis for how eVP30 functions during the virus replication cycle is currently unclear. Here we define a key interaction between eVP30 and a peptide derived from eNP that is important to facilitate interactions leading to the recognition of the RNA template. We present crystal structures of the eVP30 C-terminus in complex with this eNP peptide. Functional analyses of the eVP30–eNP interface identify residues that are critical for viral RNA synthesis. Altogether, these results support a model where the eVP30–eNP interaction plays a critical role in transcription initiation and provides a novel target for the development of antiviral therapy.</jats:p

Regular and Irregular Boundary Conditions in the AdS/CFT Correspondence

We expand on Klebanov and Witten's recent proposal for formulating the AdS/CFT correspondence using irregular boundary conditions. The proposal is shown to be correct to any order in perturbation theory.Comment: 7 pages, typos correcte

VP24-Karyopherin alpha binding affinities differ between Ebolavirus species, nfluencing interferon inhibition and VP24 stability

Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. These data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. IMPORTANCE The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis

High-Grade Prostate Cancer: Favorable Results in the Modern Era Regardless of Initial Treatment

Purpose. We performed a retrospective study to determine the outcome of a modern cohort of patients with high-grade (Gleason score ≥ 8) prostate cancer treated with radical prostatectomy, radiation therapy, or hormone therapy. Methods. We identified 404 patients in the South Texas Veteran's Healthcare System Tumor Registry diagnosed with high grade prostate cancer between 1998 and 2008. Mean follow-up was 4.62 ± 2.61 years. End points were biochemical failure-free survival, overall survival, metastasis-free survival, and cancer-specific survival. Results. 5-year overall survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 88.9%, 76.3%, and 58.9%, respectively. 5-year metastasis-free survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 96.8%, 96.6%, and 88.4%, respectively, and 5-year cancer-specific survival was 97.2%, 100%, and 89.9%, respectively. Patients with a Gleason score of 10 and pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year biochemical failure-free and cancer-specific survival. Patients with a pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year overall survival. Discussion. Even for patients with high-grade disease, the outcome is not as dire in the modern era regardless of primary treatment modality chosen. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment