P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Evaluate the potential role of p38 inhibitors for the treatment of osteoarthritis using an animal model of joint degeneration (iodoacetate-induced arthritis) and a pain model (Hargraeves assay).</p> <p>Methods</p> <p>P38 kinase activity was evaluated in a kinase assay by measuring the amount of phosphorylated substrate ATF2 using a phosphoATF2 (Thr⁷¹) specific primary antibody and an alkaline phosphate coupled secondary antibody and measuring the OD at 405 nm. TNFα and IL-1β secretion from LPS stimulated THP-1 monocytic cells and human peripheral blood mononuclear cells were measured by ELISA. Rats treated with vehicle or p38 inhibitor were injected intra-articularly in one knee with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The effect of p38 inhibitors on hyperalgesia was evaluated in rats given an intraplantar injection of carrageenan and 4 h later the paw withdrawal time to a radiant heat source was measured.</p> <p>Results</p> <p>SB-203580 and VX-745 are both potent inhibitors of p38 with IC₅₀s of 136 ± 64 nM and 35 ± 14 nM (mean ± S.D.), respectively. Similarly, SB-203580 and VX-745 potently inhibited TNF release from LPS stimulated human THP-1 cells with IC₅₀s of 72 ± 15 nM; and 29 ± 14 nM (mean ± S.D.) respectively. TNF release from LPS stimulated human peripheral blood mononuclear cells was inhibited with IC₅₀s 16 ± 6 nM and 14 ± 8 nM, (mean ± S.D.) for SB-203580 and VX-745 and IL-1 was inhibited with IC₅₀s of 20 ± 8 nM and 15 ± 4 nM (mean ± S.D.), respectively. SB-203580 and VX-745 administered orally at a dose of 50 mg/kg resulted in the significant (p < 0.05) inhibition of joint degeneration in the rat iodoacetate model of 45% and 31%, respectively. SB-203580 demonstrated a dose related inhibition of joint degeneration of 30, 25, 12 and 8% at 50, 25, 10 and 5 mg/kg p.o. b.i.d. in the rat iodoacetate model. Similarly, both p38 inhibitors significantly (p < 0.05) attenuated the pain response (paw withdrawal time) in the Hargraeves hyperalgesia assay when administered orally at 30, 10 and 3 mg/kg.</p> <p>Conclusion</p> <p>SB203580 and VX-745 demonstrated attenuation of both cartilage degeneration and pain in animal models and suggest that p38 inhibitors may be a useful approach for the treatment of osteoarthritis.</p

Learning Moore Machines from Input-Output Traces

The problem of learning automata from example traces (but no equivalence or membership queries) is fundamental in automata learning theory and practice. In this paper we study this problem for finite state machines with inputs and outputs, and in particular for Moore machines. We develop three algorithms for solving this problem: (1) the PTAP algorithm, which transforms a set of input-output traces into an incomplete Moore machine and then completes the machine with self-loops; (2) the PRPNI algorithm, which uses the well-known RPNI algorithm for automata learning to learn a product of automata encoding a Moore machine; and (3) the MooreMI algorithm, which directly learns a Moore machine using PTAP extended with state merging. We prove that MooreMI has the fundamental identification in the limit property. We also compare the algorithms experimentally in terms of the size of the learned machine and several notions of accuracy, introduced in this paper. Finally, we compare with OSTIA, an algorithm that learns a more general class of transducers, and find that OSTIA generally does not learn a Moore machine, even when fed with a characteristic sample

A Retrospective Look at the Monitoring and Checking (MaC) Framework

The Monitoring and Checking (MaC) project gave rise to a framework for runtime monitoring with respect to formally specified properties, which later came to be known as runtime verification. The project also built a pioneering runtime verification tool, Java-MaC, that was an instantiation of the approach to check properties of Java programs. In this retrospective, we discuss decisions made in the design of the framework and summarize lessons learned in the course of the project

Specification: The Biggest Bottleneck in Formal Methods and Autonomy

Advancement of AI-enhanced control in autonomous systems stands on the shoulders of formal methods, which make possible the rigorous safety analysis autonomous systems require. An aircraft cannot operate autonomously unless it has design-time reasoning to ensure correct operation of the autopilot and runtime reasoning to ensure system health management, or the ability to detect and respond to off-nominal situations. Formal methods are highly dependent on the specifications over which they reason; there is no escaping the “garbage in, garbage out” reality. Specification is difficult, unglamorous, and arguably the biggest bottleneck facing verification and validation of aerospace, and other, autonomous systems. This VSTTE invited talk and paper examines the outlook for the practice of formal specification, and highlights the on-going challenges of specification, from design-time to runtime system health management. We exemplify these challenges for specifications in Linear Temporal Logic (LTL) though the focus is not limited to that specification language. We pose challenge questions for specification that will shape both the future of formal methods, and our ability to more automatically verify and validate autonomous systems of greater variety and scale. We call for further research into LTL Genesis

Gewalt in der Schule

Vortrag auf der Tagung Bindung, Trauma und soziale Gewalt , 3.-5.12.2004 in Frankfurt am Main

Methodological developments in violence research

Über Jahrzehnte wurde Gewalt durch Interviews mit Betroffenen oder Tätern, durch teilnehmende Beobachtung oder Gewaltstatistiken untersucht, meist unter Verwendung entweder qualitativer oder quantitativer Analysemethoden. Seit der Jahrhundertwende stehen Forschenden eine Reihe neuer Ansätze zur Verfügung: Es gibt immer mehr Videoaufnahmen von gewaltsamen Ereignissen, Mixed Methods-Ansätze werden stetig weiterentwickelt und durch Computational Social Sciences finden Big Data-Ansätze Einzug in immer mehr Forschungsfelder. Diese drei Entwicklungen bieten großes Potenzial für die quantitative und qualitative Gewaltforschung. Der vorliegende Beitrag diskutiert Videodatenanalyse, Triangulation und Mixed Methods-Ansätze sowie Big Data und bespricht den gegenwärtigen und zukünftigen Einfluss der genannten Entwicklungen auf das Forschungsfeld. Das Augenmerk liegt besonders darauf, (1) wie neuere Videodaten genutzt werden können, um Gewalt zu untersuchen und wo ihre Vor- und Nachteile liegen, (2) wie Triangulation und Mixed Methods-Ansätze umfassendere Analysen und theoretische Verknüpfungen in der Gewaltforschung ermöglichen und (3) wo Anwendungen von Big Data und Computational Social Science in der Gewaltforschung liegen können.For decades violence research has relied on interviews with victims and perpetrators, on participant observation, and on survey methods, and most studies focused on either qualitative or quantitative analytic strategies. Since the turn of the millennium, researchers can draw on a range of new approaches: there are increasing amounts of video data of violent incidents, triangulation and mixed methods approaches become ever more sophisticated, and computational social sciences introduce big data analysis to more and more research fields. These three developments hold great potential for quantitative and qualitative violence research. This paper discusses video data analysis, mixed methods, and big data in the context of current and future violence research. Specific focus lies on (1) potentials and challenges of new video data for studying violence; (2) the role of triangulation and mixed methods in enabling more comprehensive violence research from multiple theoretical perspectives, and (3) what potential uses of big data and computational social science in violence research may look like

Fashionably Voluptuous: Repackaging the Fuller-Sized Figure

This article investigates the voluptuous female silhouette in fashion. Is it a superimposed image of a desired female form or a way of accentuating the ample assets of a larger-sized body? Body image has been identified as crucial to clothing provision and fashion consumption. Research has recognized that fuller-sized and obese people were considered unhappy, unconfident, unattractive, and identified a huge level of discrimination and negativity towards the overweight. Presenting and describing a body as voluptuous could be a more palatable way to repackage and reconceptualize the larger-sized. It is perhaps a more flattering description shrouding prejudices with regards to fashion, style, and garment selection. The investigation adopts a number of methodological approaches to identify the fashion choices available for voluptuous bodies and if these clothes involve levels of body modification. The research also suggests how the repackaged voluptuous body could continue to be represented in a future global marketplace