483 research outputs found

    The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

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    The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS

    Nonlinear Integer Programming

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    Research efforts of the past fifty years have led to a development of linear integer programming as a mature discipline of mathematical optimization. Such a level of maturity has not been reached when one considers nonlinear systems subject to integrality requirements for the variables. This chapter is dedicated to this topic. The primary goal is a study of a simple version of general nonlinear integer problems, where all constraints are still linear. Our focus is on the computational complexity of the problem, which varies significantly with the type of nonlinear objective function in combination with the underlying combinatorial structure. Numerous boundary cases of complexity emerge, which sometimes surprisingly lead even to polynomial time algorithms. We also cover recent successful approaches for more general classes of problems. Though no positive theoretical efficiency results are available, nor are they likely to ever be available, these seem to be the currently most successful and interesting approaches for solving practical problems. It is our belief that the study of algorithms motivated by theoretical considerations and those motivated by our desire to solve practical instances should and do inform one another. So it is with this viewpoint that we present the subject, and it is in this direction that we hope to spark further research.Comment: 57 pages. To appear in: M. J\"unger, T. Liebling, D. Naddef, G. Nemhauser, W. Pulleyblank, G. Reinelt, G. Rinaldi, and L. Wolsey (eds.), 50 Years of Integer Programming 1958--2008: The Early Years and State-of-the-Art Surveys, Springer-Verlag, 2009, ISBN 354068274

    Solar Neutrino Constraints on the BBN Production of Li

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    Using the recent WMAP determination of the baryon-to-photon ratio, 10^{10} \eta = 6.14 to within a few percent, big bang nucleosynthesis (BBN) calculations can make relatively accurate predictions of the abundances of the light element isotopes which can be tested against observational abundance determinations. At this value of \eta, the Li7 abundance is predicted to be significantly higher than that observed in low metallicity halo dwarf stars. Among the possible resolutions to this discrepancy are 1) Li7 depletion in the atmosphere of stars; 2) systematic errors originating from the choice of stellar parameters - most notably the surface temperature; and 3) systematic errors in the nuclear cross sections used in the nucleosynthesis calculations. Here, we explore the last possibility, and focus on possible systematic errors in the He3(\alpha,\gamma)Be7 reaction, which is the only important Li7 production channel in BBN. The absolute value of the cross section for this key reaction is known relatively poorly both experimentally and theoretically. The agreement between the standard solar model and solar neutrino data thus provides additional constraints on variations in the cross section (S_{34}). Using the standard solar model of Bahcall, and recent solar neutrino data, we can exclude systematic S_{34} variations of the magnitude needed to resolve the BBN Li7 problem at > 95% CL. Additional laboratory data on He3(\alpha,\gamma)Be7 will sharpen our understanding of both BBN and solar neutrinos, particularly if care is taken in determining the absolute cross section and its uncertainties. Nevertheless, it already seems that this ``nuclear fix'' to the Li7 BBN problem is unlikely; other possible solutions are briefly discussed.Comment: 21 pages, 3 ps figure
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