The Human Papillomavirus Type 11 E1∧E4 Protein Is Phosphorylated in Genital Epithelium

AbstractThe most abundant viral transcript in human papillomavirus (HPV) 11-infected xenograft tissue has been shown to encode the E1∧E4 protein. The function of E1∧E4 protein has not been determined. Several potential phosphorylation sequence motifs were identified in the HPV 11 E1∧E4 protein, including potential sites of phosphorylation by mitogen-activated protein kinase (MAPK), cAMP-dependent protein kinase (PKA), casein kinase II, and protein kinase C. To test phosphorylation of the HPV 11 E1∧E4 protein, a soluble maltose binding protein (MBP) fusion was produced in Escherichia coli. Only MAPK and PKA phosphorylated the E1∧E4 protein. Phosphoamino acid analysis showed that one or more threonine residues were phosphorylated by MAPK, and both serine and threonine residues were phosphorylated by PKA. MBP–E1∧E4 mutant proteins were designed to delineate the E1∧E4 phosphoacceptor residues. MAPK was shown to phosphorylate E1∧E4 on threonine 53 within a MAPK consensus phorphorylation sequence motif. PKA was shown to phosphorylate E1∧E4 at two residues: threonine 36 within a consensus motif and serine 44 within a variant of the PKA consensus phosphorylation sequence motif. HPV 11-infected human genital tissue grown as a xenograft in an athymic mouse was labeled with [32P]orthophosphate. Phosphoamino acid analysis of E1∧E4 protein immunoprecipitated from 32P-labeled tissue revealed that both serine and threonine residues were phosphorylated. Analysis by liquid chromatography–mass spectrophotometry was consistent with phosphorylation of residues within the PKA and MAPK phosphorylation sequence motifs. Expression of E1∧E4 protein containing phosphorylation substitution mutations showed that the PKA mutant did not differ from wild-type E1∧E4 protein in intracellular distribution. In contrast, the MAPK mutant did not localize exclusively to the cytoplasm nor did it colocalize with wild-type E1∧E4 protein. We conclude that HPV 11 E1∧E4 protein is phosphorylated in vitro and in vivo. Our data are consistent with phosphorylation of HPV 11 E1∧E4 protein by MAPK and PKA in infected tissue

Dynamical mechanism of atrial fibrillation: a topological approach

While spiral wave breakup has been implicated in the emergence of atrial fibrillation, its role in maintaining this complex type of cardiac arrhythmia is less clear. We used the Karma model of cardiac excitation to investigate the dynamical mechanisms that sustain atrial fibrillation once it has been established. The results of our numerical study show that spatiotemporally chaotic dynamics in this regime can be described as a dynamical equilibrium between topologically distinct types of transitions that increase or decrease the number of wavelets, in general agreement with the multiple wavelets hypothesis. Surprisingly, we found that the process of continuous excitation waves breaking up into discontinuous pieces plays no role whatsoever in maintaining spatiotemporal complexity. Instead this complexity is maintained as a dynamical balance between wave coalescence -- a unique, previously unidentified, topological process that increases the number of wavelets -- and wave collapse -- a different topological process that decreases their number.Comment: 15 pages, 14 figure

Finite to infinite steady state solutions, bifurcations of an integro-differential equation

We consider a bistable integral equation which governs the stationary solutions of a convolution model of solid--solid phase transitions on a circle. We study the bifurcations of the set of the stationary solutions as the diffusion coefficient is varied to examine the transition from an infinite number of steady states to three for the continuum limit of the semi--discretised system. We show how the symmetry of the problem is responsible for the generation and stabilisation of equilibria and comment on the puzzling connection between continuity and stability that exists in this problem

Domain Walls in Non-Equilibrium Systems and the Emergence of Persistent Patterns

Domain walls in equilibrium phase transitions propagate in a preferred direction so as to minimize the free energy of the system. As a result, initial spatio-temporal patterns ultimately decay toward uniform states. The absence of a variational principle far from equilibrium allows the coexistence of domain walls propagating in any direction. As a consequence, *persistent* patterns may emerge. We study this mechanism of pattern formation using a non-variational extension of Landau's model for second order phase transitions. PACS numbers: 05.70.Fh, 42.65.Pc, 47.20.Ky, 82.20MjComment: 12 pages LaTeX, 5 postscript figures To appear in Phys. Rev.

On well-posedness, stability, and bifurcation for the axisymmetric surface diffusion flow

In this article, we study the axisymmetric surface diffusion flow (ASD), a fourth-order geometric evolution law. In particular, we prove that ASD generates a real analytic semiflow in the space of (2 + \alpha)-little-H\"older regular surfaces of revolution embedded in R^3 and satisfying periodic boundary conditions. We also give conditions for global existence of solutions and prove that solutions are real analytic in time and space. Further, we investigate the geometric properties of solutions to ASD. Utilizing a connection to axisymmetric surfaces with constant mean curvature, we characterize the equilibria of ASD. Then, focusing on the family of cylinders, we establish results regarding stability, instability and bifurcation behavior, with the radius acting as a bifurcation parameter for the problem.Comment: 37 pages, 6 figures, To Appear in SIAM J. Math. Ana

The Speed of Fronts of the Reaction Diffusion Equation

We study the speed of propagation of fronts for the scalar reaction-diffusion equation $u_t = u_{xx} + f(u)$\, with $f(0) = f(1) = 0$. We give a new integral variational principle for the speed of the fronts joining the state $u=1$ to $u=0$. No assumptions are made on the reaction term $f(u)$ other than those needed to guarantee the existence of the front. Therefore our results apply to the classical case $f > 0$ in $(0,1)$, to the bistable case and to cases in which $f$ has more than one internal zero in $(0,1)$.Comment: 7 pages Revtex, 1 figure not include

Application of elastostatic Green function tensor technique to electrostriction in cubic, hexagonal and orthorhombic crystals

The elastostatic Green function tensor approach, which was recently used to treat electrostriction in numerical simulation of domain structure formation in cubic ferroelectrics, is reviewed and extended to the crystals of hexagonal and orthorhombic symmetry. The tensorial kernels appearing in the expressions for effective nonlocal interaction of electrostrictive origin are derived explicitly and their physical meaning is illustrated on simple examples. It is argued that the bilinear coupling between the polarization gradients and elastic strain should be systematically included in the Ginzburg-Landau free energy expansion of electrostrictive materials.Comment: 4 page

Insulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)–programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte–associated antigen 4 pathway. Anti–PD-1 and anti–PD-L1, but not anti–PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1–PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1–PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1–PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues

Traveling wave solutions in the Burridge-Knopoff model

The slider-block Burridge-Knopoff model with the Coulomb friction law is studied as an excitable medium. It is shown that in the continuum limit the system admits solutions in the form of the self-sustained shock waves traveling with constant speed which depends only on the amount of the accumulated stress in front of the wave. For a wide class of initial conditions the behavior of the system is determined by these shock waves and the dynamics of the system can be expressed in terms of their motion. The solutions in the form of the periodic wave trains and sources of counter-propagating waves are analyzed. It is argued that depending on the initial conditions the system will either tend to synchronize or exhibit chaotic spatiotemporal behavior.Comment: 12 pages (ReVTeX), 7 figures (Postscript) to be published in Phys. Rev.

PRISM protocol: A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established