C e n t r u m v o o r W i s k u n d e e n I n f o r m a t i c a Software ENgineeringWhen and how to develop domain-specific languages

The Asf+Sdf Meta-environment is an interactive development environment for the automatic generation of interactive systems for constructing language definitions and generating tools for them. Over the years, this system has been used in a variety of academic and commercial projects ranging from formal program manipulation to conversion of COBOL systems. Since the existing implementation of the Meta-environment started exhibiting more and more characteristics of a legacy system, we decided to build a completely new, component-based, version. We demonstrate this new system and stress its open architecture.

SDF is a formalism for the definition of syntax which is comparable to BNF in some respects, but h_ as a wider scope in that it also covers the definition of lexical and abstract syntax. Its design and implementation are tailored towards the language designer who wants to develop new languages as well as implement existing ones in a highly interactive manner. It emphasizes comP,actness of syntax definitions by offering (a) a standard interface between lexical and context-free syntax; (b) a standard correspondence between context-free and abstract syntax; (c) pow~rful disambiguation and list constructs; and (d) an efficient incremental implementation which accepts arbitrary context-free syntax definitions. SDF can be combined with a variety of progr:amming and specification languages. In this way these obtain fully general user-definable syntax.

An axiomatic algebraic calculus of modules is given that is based on the operators combination/ union, export, renaming, and taking the visible signature. Four different models of module algebra are discussed and compared.

Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.

Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease's multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.

Preface This book collects the efforts developed by a series of researchers, presented at AMAST Workshops on Real-Time Systems. The authors whose papers were selected for this book are major players in this area, and they were given the opportunity to refine the text of their papers as a result of the lively discussions that took place during the workshops. The refining of the papers continued all through the editing process as well. The papers were carefully selected and revised by the editors and grouped into six parts debating subjects on the modeling and analysis, verification, synthesis, tools, and applications of real-time systems. The editors considered that these divisions made the book more coherent, and therefore, more readable. It is almost futile to say that there is a large amount of research and literature on the subject of real-time systems. The subject is of great importance and it is resuscitating large interest in the research community. Great efforts have been made towards a clear understanding of the nature, features and particularities of real-time systems. As a result, a series of approaches of the field problems have been attempted. The variety of the latter spans over a vast spectrum of theoretical frameworks, from finite state machines to mathematical models expressed in various versions of the lambda calculus and so are also the practical methodologies that have resulted by applying the above. As real-time systems are, as the name shows, systems, a systemic approach is needed, which unfortunately is very difficult to set. The difficulty stems from the combination of processes, some modeled by a set of differential/difference equations, and others by logic statements and their computer control algorithms, which usually involve first-order and/or temporal logic statements. The above facts have led to an arabesque of WorldScientific/ws-b8-5x6-0 amastBook viii Preface mathematical symbols and "theories" generated for the purpose of finding an appropriate model for the above combination of processes. It is needless to say that the field has attracted the attention of mathematicians, computer engineers, and computer and control theory scientists. It is also needless to say that the application of theoretical findings has had a large echo in the designers' and implementers' of real-time systems communities activating in the domains of telecommunications, power generation, metallurgy , aviation, and many other industries. Confronted with the difficulty of the field, the practitioners' community is in permanent expectation of new approaches and results, which should show them the light: a unified theory and practice capturing the essence of designing correct and at least sound real-time applications. As in other fields, designers and implementers of real-time applications expect to map in a coherent way the theoretical conquests to the reality of their projects. Thus, any book in this field should be in great demand. Related to the above, a fact must be mentioned: "the book" is not yet out. Here...

The nucleotide-based second messenger bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes. Myxococcus xanthus undergoes major lifestyle changes in response to nutrient availability, with the formation of spreading colonies in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. Here, we investigated the function of c-di-GMP in M. xanthus and show that this bacterium synthesizes c-di-GMP during growth. Manipulation of the c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase correlated with defects in type IV pilus (T4P)-dependent motility, whereas gliding motility was unaffected. An increased level of c-di-GMP correlated with reduced transcription of the pilA gene (which encodes the major pilin of T4P), reduced the assembly of T4P, and altered cell agglutination, whereas a decreased c-di-GMP level correlated with altered cell agglutination. The systematic inactivation of the 24 genes in M. xanthus encoding proteins containing GGDEF, EAL, or HD-GYP domains, which are associated with c-di-GMP synthesis, degradation, or binding, identified three genes encoding proteins important for T4P-dependent motility, whereas all mutants had normal gliding motility. Purified DmxA had diguanylate cyclase activity, whereas the hybrid histidine protein kinases TmoK and SgmT, each of which contains a GGDEF domain, did not have diguanylate cyclase activity. These results demonstrate that c-di-GMP is important for T4P-dependent motility in M. xanthus.IMPORTANCE We provide the first direct evidence that M. xanthus synthesizes c-di-GMP and demonstrate that c-di-GMP is important for T4P-dependent motility, whereas we did not obtain evidence that c-di-GMP regulates gliding motility. The data presented uncovered a novel mechanism for regulation of T4P-dependent motility, in which increased levels of c-di-GMP inhibit transcription of the pilA gene (which encodes the major pilin of T4P), ultimately resulting in the reduced assembly of T4P. Moreover, we identified an enzymatically active diguanylate cyclase that is important for T4P-dependent motility.