Ambiguity, multiple streams, and EU policy

The multiple streams framework draws insight from interactions between agency and institutions to explore the impact of context, time, and meaning on policy change and to assess the institutional and issue complexities permeating the European Union (EU) policy process. The authors specify the assumptions and structure of the framework and review studies that have adapted it to reflect more fully EU decision-making processes. The nature of policy entrepreneurship and policy windows are assessed to identify areas of improvement. Finally, the authors sketch out a research agenda that refines the logic of political manipulation which permeates the lens and the institutional complexity which frames the EU policy process

\u3csup\u3e1\u3c/sup\u3eH, \u3csup\u3e15\u3c/sup\u3eN, \u3csup\u3e13\u3c/sup\u3eC, and \u3csup\u3e13\u3c/sup\u3eCO Assignments of Human Interleukin-4 Using Three-Dimensional Double- and Triple-Resonance Heteronuclear Magnetic Resonance Spectroscopy

The assignment of the 1H, 15N, 13CO, and 13C resonances of recombinant human interleukin-4 (IL-4), a protein of 133 residues and molecular mass of 15.4 kDa, is presented based on a series of 11 three-dimensional (3D) double- and triple resonance heteronuclear NMR experiments. These studies employ uniformly labeled 15N- and 15N/13C-labeled IL-4 with an isotope incorporation of \u3e95% for the protein expressed in yeast. Five independent sequential connectivity pathways via one-, two-, and three-bond heteronuclear J couplings are exploited to obtain unambiguous sequential assignments. Specifically, CO(i)-N(i+l),NH(i+l) correlations are observed in the HNCO experiment, the CαH(i),Cα(i)-N(i+l) correlations in the HCA(CO)N experiment, the Cα(i)-N(i+l),NH(i+ 1) correlations in the HNCA and HN(C0)CA experiments, the CαH(i)-N(i+ l),NH(i+l) correlations in the H(CA)NH and HN(CO)HB experiments, and the Cβ(i)-N(i+ l),NH(i+ 1) correlations in the HN(CO)HB experiments. The backbone intraresidue CαH(i)-15N(i)-NH(i) correlations are provided by the 15N-edited Hartmann-Hahn (HOHAHA) and H(CA)NH experiments, the CβH(i)-15N(i)-NH(i) correlations by the 15N-edited HOHAHA and HNHB experiments, the l3Cα(i)-l5N(i)-NH(i) correlations by the HNCA experiment, and the CαH(1)-13Cα(i)-13CO(i) correlations by the HCACO experiment. Aliphatic side-chain spin systems are assigned by 3D 1H-13C-13C-1H correlated (HCCH-COSY) and total correlated (HCCH-TOCSY) spectroscopy. Because of the high resolution afforded by these experiments, as well as the availability of multiple sequential connectivity pathways, ambiguities associated with the limited chemical shift dispersion associated with helical proteins are readily resolved. Further, in the majority of cases (88%), four or more sequential correlations are observed between successive residues. Consequently, the interpretation of these experiments readily lends itself to semiautomated analysis which significantly simplifies and speeds up the assignment process. The assignments presented in this paper provide the essential basis for studies aimed at determining the high-resolution three-dimensional structure of IL-4 in solution

Inhomogeneous Neutrino Degeneracy and Big Bang Nucleosynthesis

We examine Big Bang nucleosynthesis (BBN) in the case of inhomogenous neutrino degeneracy, in the limit where the fluctuations are sufficiently small on large length scales that the present-day element abundances are homogeneous. We consider two representive cases: degeneracy of the electron neutrino alone, and equal chemical potentials for all three neutrinos. We use a linear programming method to constrain an arbitrary distribution of the chemical potentials. For the current set of (highly-restrictive) limits on the primordial element abundances, homogeneous neutrino degeneracy barely changes the allowed range of the baryon-to-photon ratio. Inhomogeneous degeneracy allows for little change in the lower bound on the baryon-to-photon ratio, but the upper bound in this case can be as large as 1.1 \times 10^{-8} (only electron neutrino degeneracy) or 1.0 \times 10^{-9} (equal degeneracies for all three neutrinos). For the case of inhomogeneous neutrino degeneracy, we show that there is no BBN upper bound on the neutrino energy density, which is bounded in this case only by limits from structure formation and the cosmic microwave background.Comment: 6 pages, no figure

Big Bang Nucleosynthesis with Gaussian Inhomogeneous Neutrino Degeneracy

We consider the effect of inhomogeneous neutrino degeneracy on Big Bang nucleosynthesis for the case where the distribution of neutrino chemical potentials is given by a Gaussian. The chemical potential fluctuations are taken to be isocurvature, so that only inhomogeneities in the electron chemical potential are relevant. Then the final element abundances are a function only of the baryon-photon ratio $\eta$, the effective number of additional neutrinos $\Delta N_\nu$, the mean electron neutrino degeneracy parameter $\bar \xi$, and the rms fluctuation of the degeneracy parameter, $\sigma_\xi$. We find that for fixed $\eta$, $\Delta N_\nu$, and $\bar \xi$, the abundances of helium-4, deuterium, and lithium-7 are, in general, increasing functions of $\sigma_\xi$. Hence, the effect of adding a Gaussian distribution for the electron neutrino degeneracy parameter is to decrease the allowed range for $\eta$. We show that this result can be generalized to a wide variety of distributions for $\xi$.Comment: 9 pages, 3 figures, added discussion of neutrino oscillations, altered presentation of figure

GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

BackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.Peer reviewe

Gentle Perturbations of the Free Bose Gas I

It is demonstrated that the thermal structure of the noncritical free Bose Gas is completely described by certain periodic generalized Gaussian stochastic process or equivalently by certain periodic generalized Gaussian random field. Elementary properties of this Gaussian stochastic thermal structure have been established. Gentle perturbations of several types of the free thermal stochastic structure are studied. In particular new models of non-Gaussian thermal structures have been constructed and a new functional integral representation of the corresponding euclidean-time Green functions have been obtained rigorously.Comment: 51 pages, LaTeX fil

Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety

Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach

Thermal Relic Abundances of Particles with Velocity-Dependent Interactions

We reexamine the evolution of thermal relic particle abundances for the case where the interaction rate depends on the particle velocities. For the case of Sommerfeld enhancement, we show that the standard analytic approximation, modified in a straightforward way, provides an estimate of the relic particle abundance that is accurate to within 10% (in comparison to less than 1% error for the non-Sommerfeld-enhanced case). We examine the effect of kinetic decoupling on relic particle abundances when the interaction rate depends on the velocity. For the case of pure p-wave annihilation, the effect of kinetic decoupling is an increase in the relic abundance, but the effect is negligible when the kinetic decoupling temperature is much less than the chemical decoupling temperature. For the case of Sommerfeld-enhanced s-wave annihilations, after kinetic decoupling occurs, annihilations continue to change the particle abundance down to arbitrarily low temperatures, until either matter domination begins or the Sommerfeld effect cuts off. We derive analytic approximations to give the final relic particle abundances for both of these cases.Comment: 6 pages, 5 figures. Discussion and clarification added. To appear in Phys. Lett. B

Relational Contracts and Organizational Capabilities

A large literature identifies unique organizational capabilities as a potent source of competitive advantage, yet our knowledge of why capabilities fail to diffuse more rapidly—particularly in situations in which competitors apparently have strong incentives to adopt them and a well-developed understanding of how they work—remains incomplete. In this paper we suggest that competitively significant capabilities often rest on managerial practices that in turn rely on relational contracts (i.e., informal agreements sustained by the shadow of the future). We argue that one of the reasons these practices may be difficult to copy is that effective relational contracts must solve the twin problems of credibility and clarity and that although credibility might, in principle, be instantly acquired, clarity may take time to develop and may interact with credibility in complex ways so that relational contracts may often be difficult to build