Discovering and quantifying nontrivial fixed points in multi-field models

We use the functional renormalization group and the $\epsilon$-expansion concertedly to explore multicritical universality classes for coupled $\bigoplus_i O(N_i)$ vector-field models in three Euclidean dimensions. Exploiting the complementary strengths of these two methods we show how to make progress in theories with large numbers of interactions, and a large number of possible symmetry-breaking patterns. For the three- and four-field models we find a new fixed point that arises from the mutual interaction between different field sectors, and we establish the absence of infrared-stable fixed point solutions for the regime of small $N_i$. Moreover, we explore these systems as toy models for theories that are both asymptotically safe and infrared complete. In particular, we show that these models exhibit complete renormalization group trajectories that begin and end at nontrivial fixed points.Comment: 10 pages, 6 figures; minor changes, as published in EPJ

Islands of Effective International Adjudication: Constructing an Intellectual Property Rule of Law in the Andean Community

The Andean Community - a forty-year-old regional integration pact of small developing countries in South America - is widely viewed as a failure. In this Article, we show that the Andean Community has in fact achieved remarkable success within one part of its legal system. The Andean Tribunal of Justice (ATJ) is the world\u27s third most active international court, with over 1400 rulings issued to date. Over 90% of those rulings concern intellectual property (IP). The ATJ has helped to establish IP as a rule of law island in the Andean Community where national judges, administrative officials, and private parties actively participate in regional litigation and conform their behavior to Andean IP rules. In the vast seas surrounding this island, by contrast, Andean rules remain riddled with exceptions, under-enforced, and often circumvented by domestic actors. We explain how the ATJ helped to construct the IP rule of law island and why litigation has not spilled over to other issue areas regulated by the Andean Community. Our analysis makes four broad contributions to international law and international relations scholarship. First, we adopt and apply a broad definition of an effective rule of law, using qualitative and quantitative analysis to explain how the Andean legal system contributes to changing national decision-making in favor of compliance with Andean rules. Our definition and our explanation of the ATJ\u27s contributions to constructing an effective rule of law provide a model that can be replicated elsewhere. Second, we explain how the Andean legal system has helped domestic IP administrative agencies in the region resist pressures for stronger IP protection from national executives, the United States, and American corporations. We emphasize the importance of these agencies rather than domestic judges as key constituencies that have facilitated the emergence of an effective rule of law for IP. As a result of the agencies\u27 actions, Andean IP rules remain more closely tailored to the economic and social needs of developing counties than do the IP rules of the Community\u27s regional neighbors. Third, the reality that the ATJ is effective, but only within a single issue area, makes the Andean experience of broader theoretical interest. We offer an explanation for why Andean legal integration has not extended beyond IP. But our answer suggests avenues for additional research. We note that Andean IP rules are more specific than other areas of Andean law and that most administrative agencies in the region lack the autonomy needed to serve as compliance partners for ATJ rulings. We also find that, outside of IP, the ATJ is unwilling to issue the sort of purposive interpretations that encourages private parties to invoke Andean rules in litigation. The result is both a lack of demand for and supply of ATJ rulings. Fourth, our study of the Andean legal system provides new evidence to assess three competing theories of effective international adjudication - theories that ascribe effectiveness to the design of international legal systems, to the ability of member states to sanction international judges, and to domestic legal and political factors. We also explore the possibility that rule of law islands may be emerging in other treaty-based systems subject to the jurisdiction of international tribunals

Non-apoptotic roles of caspase-8 and caspase-2

Caspases are proteolytic enzymes involved in committing apoptosis, but through the studies of knockout phenotypes in mice and Drosophila , it has been speculated that caspases might possess additional non-apoptotic functions.;We have found non-apoptotic functions for caspase-8 in both normal and tumor cell lines. Specifically, we found that caspase-8 promotes cell migration, adhesion, and Rac activation. Subsequently, we also found that caspase-8 interacts with the p85 subunit of PI3K. Accompanying stimulation of motility with epidermal growth factor the phosphorylation of caspase-8 on tyrosine-380 is induced and this phosphorylation allows for p85 interaction, cell migration, adhesion, and Rac activation. Caspase-8 also promoted EGF-induced Erk activation, stimulating cell migration.;Non-apoptotic functions also exist for caspase-2. We demonstrate that caspase-2 promotes cell-matrix adhesion, focal contact formation and FAK phosphorylation. Caspase 2 also mediates stress fiber dissolution in response to protein kinase-C activation. Insights into the mechanism whereby caspase 2 influences cytoskeletal processes with emphasis on Rho/ROCK/LIMK/cofilin and Rho/ROCK/MLC pathways are discussed.;These findings demonstrate a non-apoptotic function of a caspase involving signaling protein interactions rather than proteolysis. This is also the first report that caspase-2 and caspase-8 may mediate cytoskeletal functions independent of cell death

Multiple Roles of Brd4 in the Human Papillomavirus Life Cycle

ABSTRACT MULTIPLE ROLES OF BRD4 IN THE HUMAN PAPILLOMAVIRUS LIFE CYCLE Christine M. Helfer Jianxin You While human papillomavirus (HPV) vaccines protect against acquiring new infections, there is currently no antiviral treatment for eradicating persistent HPV infections. In this study, I demonstrated that the cellular chromatin binding protein, Brd4, in association with HPV E2 protein, is important for multiple HPV functions including replication, maintenance of viral genomes, and regulation of viral gene transcription. These studies suggest that the E2–Brd4 complex could be an effective target to disrupt the HPV life cycle. Using bimolecular fluorescence complementation, we demonstrate that E2 from high–risk HPV16 interacts with Brd4 on cellular chromosomes throughout mitosis while the BET bromodomain inhibitor, JQ1(+), dissociates Brd4–E2 complexes from mitotic chromosomes. These results suggest that Brd4 is important for tethering HPV16 E2 to mitotic chromosomes for stable viral genome maintenance and that abrogating Brd4\u27s chromatin association might disrupt stable HPV genome maintenance. I also found that JQ1(+) treatment of cells stably maintaining papillomavirus genomes reduces viral mRNA levels, demonstrating that HPV association with cellular chromatin through Brd4 is essential for HPV transcription and further supporting the importance of Brd4 for the HPV life cycle. My work also identified a novel role of Brd4 in HPV16 DNA replication. Immunofluorescence analyses show Brd4 is recruited to nuclear foci actively replicating HPV16 genomes. Replication assays further confirm that Brd4 is essential for HPV16 genome replication. Interestingly, JQ1(+) treatment stimulates viral genome replication. Since HPV genome amplification is normally limited to upper epithelial layers, we predict premature stimulation of viral DNA amplification induced by JQ1(+) in basal epithelial cells might activate host immune responses to clear HPV infection. Finally, this work identified a specific function of Brd4 in papillomavirus transcription activation. Using ChIP analysis and an E2–responsive luciferase assay, we show Brd4 actively recruits P–TEFb to papillomavirus genomes to support E2 transactivation function. Together, this study uncovers two novel functions of Brd4 in the HPV life cycle, improving our understanding of this complex virus–host relationship. Furthermore, we identify the E2–Brd4 complex as a promising antiviral target for eliminating HPV persistent infection

Multiple Roles of Brd4 in the Human Papillomavirus Life Cycle

ABSTRACT MULTIPLE ROLES OF BRD4 IN THE HUMAN PAPILLOMAVIRUS LIFE CYCLE Christine M. Helfer Jianxin You While human papillomavirus (HPV) vaccines protect against acquiring new infections, there is currently no antiviral treatment for eradicating persistent HPV infections. In this study, I demonstrated that the cellular chromatin binding protein, Brd4, in association with HPV E2 protein, is important for multiple HPV functions including replication, maintenance of viral genomes, and regulation of viral gene transcription. These studies suggest that the E2–Brd4 complex could be an effective target to disrupt the HPV life cycle. Using bimolecular fluorescence complementation, we demonstrate that E2 from high–risk HPV16 interacts with Brd4 on cellular chromosomes throughout mitosis while the BET bromodomain inhibitor, JQ1(+), dissociates Brd4–E2 complexes from mitotic chromosomes. These results suggest that Brd4 is important for tethering HPV16 E2 to mitotic chromosomes for stable viral genome maintenance and that abrogating Brd4\u27s chromatin association might disrupt stable HPV genome maintenance. I also found that JQ1(+) treatment of cells stably maintaining papillomavirus genomes reduces viral mRNA levels, demonstrating that HPV association with cellular chromatin through Brd4 is essential for HPV transcription and further supporting the importance of Brd4 for the HPV life cycle. My work also identified a novel role of Brd4 in HPV16 DNA replication. Immunofluorescence analyses show Brd4 is recruited to nuclear foci actively replicating HPV16 genomes. Replication assays further confirm that Brd4 is essential for HPV16 genome replication. Interestingly, JQ1(+) treatment stimulates viral genome replication. Since HPV genome amplification is normally limited to upper epithelial layers, we predict premature stimulation of viral DNA amplification induced by JQ1(+) in basal epithelial cells might activate host immune responses to clear HPV infection. Finally, this work identified a specific function of Brd4 in papillomavirus transcription activation. Using ChIP analysis and an E2–responsive luciferase assay, we show Brd4 actively recruits P–TEFb to papillomavirus genomes to support E2 transactivation function. Together, this study uncovers two novel functions of Brd4 in the HPV life cycle, improving our understanding of this complex virus–host relationship. Furthermore, we identify the E2–Brd4 complex as a promising antiviral target for eliminating HPV persistent infection

The electromagnetic field near a dielectric half-space

We compute the expectations of the squares of the electric and magnetic fields in the vacuum region outside a half-space filled with a uniform non-dispersive dielectric. This gives predictions for the Casimir-Polder force on an atom in the `retarded' regime near a dielectric. We also find a positive energy density due to the electromagnetic field. This would lead, in the case of two parallel dielectric half-spaces, to a positive, separation-independent contribution to the energy density, besides the negative, separation-dependent Casimir energy. Rough estimates suggest that for a very wide range of cases, perhaps including all realizable ones, the total energy density between the half-spaces is positive.Comment: Latex2e, IOP macros, 15 pages, 2 eps figure

`Operational' Energy Conditions

I show that a quantized Klein-Gordon field in Minkowski space obeys an `operational' weak energy condition: the energy of an isolated device constructed to measure or trap the energy in a region, plus the energy it measures or traps, cannot be negative. There are good reasons for thinking that similar results hold locally for linear quantum fields in curved space-times. A thought experiment to measure energy density is analyzed in some detail, and the operational positivity is clearly manifested. If operational energy conditions do hold for quantum fields, then the negative energy densities predicted by theory have a will-o'-the-wisp character: any local attempt to verify a total negative energy density will be self-defeating on account of quantum measurement difficulties. Similarly, attempts to drive exotic effects (wormholes, violations of the second law, etc.) by such densities may be defeated by quantum measurement problems. As an example, I show that certain attempts to violate the Cosmic Censorship principle by negative energy densities are defeated. These quantum measurement limitations are investigated in some detail, and are shown to indicate that space-time cannot be adequately modeled classically in negative energy density regimes.Comment: 18 pages, plain Tex, IOP macros. Expanded treatment of measurement problems for space-time, with implications for Cosmic Censorship as an example. Accepted by Classical and Quantum Gravit

Insertion reliability studies for the RBC-type control rods in ASTRID

International audienceThis paper reports on preliminary studies performed regarding the insertion reliability of theRBC-type Control Rods designed for the ASTRID Sodium-cooled Fast Reactor. At this stage, the primary aim of the analysis is to evaluate the mechanical behavior of RBC Control Rods under Emergency Shutdown conditions, for which reactor core structures are subjected to significant misalignments (including earthquakeimposed displacements). Using a Finite Element Model based on the Cast3M solver and developed specifically for these studies, computations are performed that allow assessing contact reactions (and the associated friction forces and contact pressures), deformations and stresses (mostly due to bending-induced deformations) which are considered for design. Based on these preliminary results, some optimization of the Control Rod design is proposed that ensures some stable behavior all along the rod drop, with substantial design margin

How effective are common medications: a perspective based on meta-analyses of major drugs

Study protocol. (PDF 161 kb

Force generation of curved actin gels characterized by combined AFM-epifluorescence measurements

Polymerization of actin into branched filaments is the driving force behind active migration of eukaryotic cells and motility of intracellular organelles. The site-directed assembly of a polarized branched array forms an expanding gel that generates the force that pushes the membrane. Here, we use atomic force microscopy to understand the relation between actin polymerization and the produced force. Functionalized spherical colloidal probes of varying size and curvature are attached to the atomic force microscopy cantilever and initiate the formation of a polarized actin gel in a solution mimicking the in vivo context. The gel growth is recorded by epifluorescence microscopy both against the cantilever and in the perpendicular (lateral) nonconstrained direction. In this configuration, the gel growth stops simultaneously in both directions at the stall force, which corresponds to a pressure of 0.15 nN/μm(2). The results show that the growth of the gel is limited laterally, in the absence of external force, by internal mechanical stresses resulting from a combination of the curved geometry and the molecular mechanism of site-directed assembly of a cohesive branched filament array