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The practice of composing web services has received an increasing interest with the emerging application development architecture called Service Oriented Architecture (SOA). A web service composition can be done either manually or (semi-) automatically. Doing composition (semi-) automatically minimizes runtime problems that arise due to dynamic nature of runtime environments. However, the implementation of (semi-) automatic composition demands for the automation of a process model or a composition plan generation process. In addition, creating a composite service or applications from component services, that are developed and meant to work independently, causes unavoidable dependencies among the services involved. Consequently, in a composite service development, understanding, analyzing and tracking of such dependencies becomes important. This thesis views the process model generation sub-task of a service composition as a service dependency identifification and analysis problem. In this thesis, we propose a dependency based automatic process model generation methods. For this purpose, the following issues are explored. First, a top layer architecture with a composition engine is developed. The architecture gives a complete picture of dependency based automatic service composition. Second, the process model generation sub-task is formulated as a service dependency identification and analysis problem. Third, a two-stepped method for automatic process model generation, given a set of candidate web service descriptions, is proposed. The first step of the proposed approach deals with the identifification of potential direct and indirect dependencies between abstract services. The direct dependency extraction is done by assuming a semantic I/O matching of service parameters. The extraction of indirect dependency from direct dependency is done using a recursive algorithm derived from the transitive closure property. Alternatively the Warshall algorithm is used. The second step of the proposed approach deals with analysis of dependency information and generation of process model (PM) automatically. To execute this step, we propose two approaches: matrix based and graph based approaches. The matrix based approach utilizes both direct and indirect dependencies. This approach represents dependencies using matrix and takes advantages of a sorting algorithm. The matrix representation facilitates a simplistic mathematical dependency analysis for generating important indicators during automatic process model creation. The process model is generated using a sorting algorithm that uses the analysis result obtained from the dependency matrix as sorting criterion. The graph based approach uses only direct dependency among candidate services. As its name indicates, in this approach the extracted I/O dependencies are represented using a directed graph. A modifified topological sorting algorithm is used for generating a process model that shows the execution order of candidate services. Both of the proposed approaches (matrix and graph based approaches) recognize the existence of cyclic dependencies and provide ways of dealing with them. The resulting process model or composition plan from both approaches has a sequential, concurrent and loop control flows. Finally, the performance of the proposed approaches is studied theoretically as well as experimentally. For the experimental validation and evaluation purpose, the approaches are implemented in a prototype that facilitates the validation and evaluation of the approaches at a larger scale. An extensive experimental performance evaluation is done fifirst on each proposed approach. The two approaches are then compared and their pros and cons under difffferent scenarios are assessed.

Zellen sind in der Lage, gleichzeitig ganz unterschiedliche biochemische Prozesse zu bewältigen. Dies gelingt ihnen durch eine Einteilung ihres Inneren in Kompartiemente, sogennante Organellen, die die jeweils geeignete biochemische Umgebung für die unterschiedlichen Aufgaben schaffen. Bei membranumschlossenen Kompartimenten ist leicht vorstellbar, dass sie eine andere biochemische Zusammensetzung als ihre Umgebung haben können. Jedoch existieren auch Organelle ohne Membran die durch eine flüssig-flüssig Phasenseparation entstehen. Manche dieser Kompartiemente haben die Fähigkeit, RNA zu binden und Proteinkomplexe auszubilden, während andere auf die Veränderungen innerhalb der Zelle, wie z.B. die Veränderung des pH-Werts und der damit Verbunden Änderung ihres Protonierungszustands, reagieren können. Um diese Prozesse theoretisch analysieren zu können, entwickeln wir zunächst ein allgemeingültiges, thermodynamisches Gerüst, um Systeme zu untersuchen, die im chemischen Gleichgewicht flüssig-flüssig hasensepariert vorliegen können. Dies erlaubt, basierend auf den Erhaltungsgrößen, im chemischen Gleichgewicht thermodynamisch konjungierten Variablen zu identifizieren, welche aus den erhaltenen Komponenten und den zugehörigen chemischen Potentialen bestehen. Mithilfe des obig erwähnten Gerüsts können wir den Einfluss des pH-Wertes auf die flüssig-flüssig Phasenseparation in einem minimalen Modell untersuchen. Dies beschreibt die makromolekulare Phasenseparation, kontrolliert durch Protonierungs- und Deprotonierungreaktionen, welche wiederum vom pH-Wert abhängig sind. Unsere Untersuchung der pH-Abhängigkeit der Phasenseparation kommt zu folgenden Ergebnissen: Erstens liegt die größte Region von Phasenseparation im Phasendiagramm typischerweise im Bereich des isoelektrischen Punkts. Zweitens zeigt das Modell eine Fähigkeit der erneuten Mischung auf. Drittens ist die Topologie des Phasendiagrams von der dominantesten Interaktion bestimmt. Unser Modell stimmt mit experimentellen Beobachtungen zur Phasenseparation von intrinsisch ungeordneten, Proteinen, deren Struktur sich pH abhängig verändern, überein. Das Modell ist außerdem konsistent mit Beobachtungen von Phasenseparation von Proteinen im Zytosol von Hefezellen, die entsteht, wenn der intrazellulare pH-Wert in die Nähe des isoelektrischen Punkt dieser Proteine gebracht wird. Des Weiteren geht diese Arbeit auf den physikalischen Mechanismus ein, mit dem flüssigkeitsähnliche Organellen, sog. P granules, im Organismus Caenorhabditis elegans positioniert werden. Um dieses Phänomen zu analysieren, stellen wir zunächst experimentelle Beobachtungen vor, die zeigen, dass PGL-3, eine Hauptkomponente der P granules, flüssigkeitsähnliche Tropfen bildet, deren Zusammensetzung von RNA moduliert werden kann. Darüber hinaus zeigen wir Daten, die großen Unterschiede zwischen der RNA-Bindungsaffinität von Proteinen wie Mex-5, die für die Positionierung der P granules relevant sind, und solchen, die P granules bilden, wie PGL-3, zeigen. Dies deutet darauf hin, dass eine Konkurrenz zwischen den Bestandteilen der P Granula und MEX-5 um die zur Bindung zur Verfügung stehende RNA besteht, die die Kondensation und Auflösung von P Granula räumlich kontrollieren könnte. Auf diesen experimentellen Befunden aufbauend führen wir ein minimalles Modell ein, in dem wir die Phasenseparation von PGL-3 an Bindungsreaktionen der MEX-5 Proteine und RNA koppeln. Um die experimentellen Beobachtungen beschreiben zu können, muss die Neigung des PGL-3 Proteins zur Phasenseparation zunehmen, wenn es Komplexe mit RNA bildet. Dies unterstützt die Idee, dass MEX-5 diese Phasenseparation unterdrückt, indem es die Anzahl an möglichen RNA-Bindungspartner für PGL-3 herabsetzt und damit die weitere Entstehung derartiger Protein-RNA-Komplexe erschwert. Dieser einfache Mechanismus scheint die Hauptursache dafür zu sein, dass P granules auf der posterioren Seite des Caenorhabditis elegans Embryos zu finden sind. / One of the main features of cells is their incredible ability to control biochemical processes in space and time. They do so by organizing their interior in sub-compartments called organelles, each of them with a different biochemical environment that allows them to perform specific tasks in the cell. It is sometimes believed that these compartments need a membrane in order to have a stable biochemical environment and regulat their compositions. However, there are some organelles which lack a membrane and seem to form and organize via liquid-liquid phase separation. Some of the components that form these membraneless organelles have the ability to bind to RNA and form complexes, while some others react to changes in the intracellular environment such as pH variations, which in turn affects their protonation state. In order to study these processes from a theoretical perspective, we develop a generic thermodynamic framework to study systems exhibiting liquid-liquid phase separation at chemical equilibrium. This framework, based on the use of conservation laws in chemical reactions, allow us to identify thermodynamic conjugate variables at chemical equilibrium, which are given by a set of conserved quantities and the corresponding conjugate chemical potentials. Within the aforementioned framework, we introduce a minimal model to study the effect of pH on liquid-liquid phase separation. Our model explains macromolecular phase separation controlled by protonation and deprotonation reactions, which are tuned by the pH of the system. We study the phase behavior of the system as a function of pH. Our main findings are: Firstly, the broadest region of phase separation is typically found at the isoelectric point. Secondly, the system exhibits reentrant behavior. Thirdly, that the dominating interaction in the system determines the topology of the phase diagrams. Our model is in agreement with experimental observations of in vitro protein phase separation of pH-responsive intrinsically disordered proteins, as well as with observations of protein phase separation exhibited by many cytosolic proteins when the intracellular pH in yeast cells is brought close to the isoelectric point of such proteins. Moreover, this work analyses the physical mechanism behind the positioning of liquid-like organelles in the {\it{Caenorhabditis elegans}} organism known as P granules. In order to study this phenomenon, we first present firm experimental evidence showing that PGL-3 protein, a key component of P granules, forms liquid-like drops whose assembly can be modulated by RNA. We then present data showing that the RNA-binding affinity differs significantly between proteins relevant for the positioning of P granules, such as MEX-5 and the proteins forming the P granules, like the aforementioned PGL-3. This points to a possible mechanism of RNA-binding competition between P granule constituents and MEX-5 in order to spatially control the condensation and dissolution of P granules. Based on the experimental evidence, we propose a minimal model in which we couple phase separation of PGL-3 to a set of binding reactions involving the MEX-5 protein and RNA. We find that in order to explain the experimental data, the tendency for phase separation of the PGL-3 protein increases with the formation of complexes of PGL-3 bound to RNA. This therefore supports the idea that MEX-5 inhibits this protein phase separation by depleting the RNA available for PGL-3 to form such complexes. This simple mechanism is at the core of how P granules localize to the posterior side of the Caenorhabditis elegans embryo.

The practice of composing web services has received an increasing interest with the emerging application development architecture called Service Oriented Architecture (SOA). A web service composition can be done either manually or (semi-) automatically. Doing composition (semi-) automatically minimizes runtime problems that arise due to dynamic nature of runtime environments. However, the implementation of (semi-) automatic composition demands for the automation of a process model or a composition plan generation process. In addition, creating a composite service or applications from component services, that are developed and meant to work independently, causes unavoidable dependencies among the services involved. Consequently, in a composite service development, understanding, analyzing and tracking of such dependencies becomes important. This thesis views the process model generation sub-task of a service composition as a service dependency identifification and analysis problem. In this thesis, we propose a dependency based automatic process model generation methods. For this purpose, the following issues are explored. First, a top layer architecture with a composition engine is developed. The architecture gives a complete picture of dependency based automatic service composition. Second, the process model generation sub-task is formulated as a service dependency identification and analysis problem. Third, a two-stepped method for automatic process model generation, given a set of candidate web service descriptions, is proposed. The first step of the proposed approach deals with the identifification of potential direct and indirect dependencies between abstract services. The direct dependency extraction is done by assuming a semantic I/O matching of service parameters. The extraction of indirect dependency from direct dependency is done using a recursive algorithm derived from the transitive closure property. Alternatively the Warshall algorithm is used. The second step of the proposed approach deals with analysis of dependency information and generation of process model (PM) automatically. To execute this step, we propose two approaches: matrix based and graph based approaches. The matrix based approach utilizes both direct and indirect dependencies. This approach represents dependencies using matrix and takes advantages of a sorting algorithm. The matrix representation facilitates a simplistic mathematical dependency analysis for generating important indicators during automatic process model creation. The process model is generated using a sorting algorithm that uses the analysis result obtained from the dependency matrix as sorting criterion. The graph based approach uses only direct dependency among candidate services. As its name indicates, in this approach the extracted I/O dependencies are represented using a directed graph. A modifified topological sorting algorithm is used for generating a process model that shows the execution order of candidate services. Both of the proposed approaches (matrix and graph based approaches) recognize the existence of cyclic dependencies and provide ways of dealing with them. The resulting process model or composition plan from both approaches has a sequential, concurrent and loop control flows. Finally, the performance of the proposed approaches is studied theoretically as well as experimentally. For the experimental validation and evaluation purpose, the approaches are implemented in a prototype that facilitates the validation and evaluation of the approaches at a larger scale. An extensive experimental performance evaluation is done fifirst on each proposed approach. The two approaches are then compared and their pros and cons under difffferent scenarios are assessed.

Anhand einer prospektiven epidemiologischen Verlaufsstudie an einer repräsentativen Bevölkerungsstichprobe von ursprünglich 14- bis 17jährigen Jugendlichen (N=1395) werden die Häufigkeit und die Verlaufsmuster des Konsums, des Mißbrauchs und der Abhängigkeit von Cannabis untersucht. Die Jugendlichen wurden persönlich mit Hilfe eines Interviews befragt, wobei als diagnostisches Instrument das M-CIDI mit seinen DSM-IV Algorithmen verwendet wurde. Die Ergebnisse aus der Basiserhebung ergaben, daß 1995 etwa 20% aller 14- bis 17jährigen - in der Mehrzahl wiederholt - Cannabis probiert hatten und 6% der Population einen regelmäßigen Gebrauch aufweisen. Die Einjahres-Inzidenz (= Auftreten neuer Fälle) für den Cannabisgebrauch der nun 15- bis 19jährigen betrug zum Zeitpunkt der Nachuntersuchung 20,1% für die Männer und 16,3% für die Frauen. Für den regelmäßigen Gebrauch wurden Inzidenzraen von 12% (Männer) und 8,4% (Frauen) ermittelt. Die Stabilität des Konsumverhaltens zwischen der Basis- und der Nachuntersuchung war relativ hoch un stieg mit höherem Initialkonsum an. Angesichts der hohen Gebrauchsrate von 32,4% bei den 15- bis 19jährigen bei der Nachuntersuchung ergab sich im Vergleich zu anderen psychotropen Substanzen eine relativ niedrige Prävalenz für Mißbrauch und Abhängigkeit (4%). Das Vorliegen einer Diagnose bei der Erstuntersuchung weist allerdings eine relativ hohe Stabilität über die Nachuntersuchungskette auf. / The paper examines the prevalence, incidence and stability patterns of cannabis use and dependence in a prospective epidemiological study of a random community sample of adolescents, aged 14 to 17 years (N=1395) at time 1. Assesments are based on personal interviews by trained clinical psychologists using the computerized DSM-IV lifetime and 12-month change version of the M-CIDI. Results indicate that in 1995 every fifth person aged 14 to 17 years had used cannabis at least once and 6% reported regular use. The 12-month incidence rates (i.e. proportion of the sample reporting first cannabis use in the last year) among subjects, 15 to 19 years of age at time 2, was high, with 20,1% of males and 16,3% of females reporting first use. The incidence of regular use was 12,0% (males) and 8,4% (females). The stability of consumption patterns from time 1 to time 2 was high. Increasing with higher initial consumption. Given the reexamined samples overall high cannabis consumption rates of 32,4%, the prevalence of clinically manifest DSM-IV abuse and dependence was low in comparison to other psychologic drugs (4%). However there was remarkable diagnostic stability over time in this age group of those with an initial diagnosis at time 1 receiving a diagnosis again at time 2.

Die Arbeit gibt einen methodenkritischen Überblick über die in Deutschland vorliegenden Ergebnisse zur Prävalenz sowie Risikofaktoren von Substanzmißbrauch und -abhängigkeit (SMA). Es wird gezeigt, daß die vorliegenden epidemiologischen Studien unvollständig und methodisch unbefriedigend sind. Vor allem die fehlende Erfassung spezifischer diagnostischer Kriterien zur Ableitung klinisch relevanter Mißbrauchs- und Abhängigkeitsstörungen erschwert eine Interpretation der Ergebnisse der vorliegenden Repräsentativerhebungen. Diese geben zwar aussagekräftige populationsbezogene Informationen über die Häufigkeit und Verteilungsmuster von legalen und illegalen Substanzen, klinisch relevante Beurteilungsaspekte wie z.B. zu Schweregrad, Toleranz und Abstinenzproblemen sowie zu Einstieg und Verlauf der "Sucht"-Problematik fehlen jedoch vollständig. Dies trifft auch für Untersuchungen zu Risikofaktoren zu. Als ein durchgängiger Mangel wird ferner die Erfassungsmethodologie angesehen, die sich bislang fast ausschließlich auf Fragebögen oder Interviews stützt, über deren Reliabilität und Validität nur unzureichende psychometrische Daten vorliegen. / A critical review of prevalence and risk factor studies of substance abuse and dependence in Germany is presented. It is shown that currently available epidemiological data are incomplete due to the failure of instruments to allow for a detailed assessment of specific substance use disorders. The neglect of diagnostic criteria for clinically significant abuse and dependence disorders makes it especially difficult to draw conclusions about the results of representative surveys. Although the give clear population-related information about frequency and distribution patterns of legal and illegal substancees, relevant clinical data regarding aspects such as severity, tolerance, problems of abstinence, onset and course of abuse and dependence are completely lacking. This is also true of studies on risk factors. An additional problem is diagnostic assessment based almost exclusively on questionnaires and interviews whose reliability and validity have not been sufficiently established.

Prevalence findings for 1995 of illicit drug use as well as DSM-IV abuse and dependence are reported from a representative population sample of 3,021 respondents from Munich, Germany, aged 14–24 years. Results are based on personal interviews using the M-Composite International Diagnostic Interview (M-CIDI) with its DSM-IV diagnostic algorithms. Findings indicate that more than 30% of the adolescents and young adults are or have been using one or more illicit drugs at least once in their life. Men were slightly more likely to ever use drugs and used them more frequently than women. Cannabinoids were by far the most frequently used type of drug, followed by various stimulating drugs and hallucinogens. There is also considerable polysubstance use among 14- to 24-year-olds. Criteria for DSM-IV abuse without dependence were met by 4.1% of all men and 1.8% of all women, a dependence syndrome of any type of illicit drug was diagnosed in 2.5% of the men and 1.6% of the women. Cumulative age of onset incidence analyses suggest that substance use starts early, in about one-third before the age of 16 years and continues to rise for most drugs throughout adolescence and young adulthood. Overall these findings suggest that substance use and substance disorders are more prevalent than suggested in most previous German studies.

The objectives of the community-based Early Developmental Stages of Psychopathology (EDSP) Study are described along with a detailed account of the overall design, special design features, sample characteristics and instruments used. The EDSP employed a prospective-longitudinal design to study substance use and other mental disorders in a representative population sample of 3,021 subjects aged 14–24 years (birth cohorts 1970–1981) at ‘baseline’ – the outset of the study. Two follow-up investigations were conducted after the baseline investigation covering an overall period of 3–4 years. Special design features are the linkage with a family supplement (EDSP-FS) as well as neurobiological laboratory studies of high-risk subjects.

Objectives: To determine incidence and patterns of natural course of cannabis use and disorders as well as cohort effects in a community sample of adolescents and young adults. Method: Cumulative incidence and patterns of cannabis use and disorders were examined in a prospective longitudinal design (mean follow-up period=42 months) in a representative sample (N=2446) aged 14–24 years at the outset of the study. Patterns of cannabis use, abuse and dependence (DSM-IV) were assessed with the Composite International Diagnostic Interview (M-CIDI). Results: (1) Cumulative lifetime incidence for cannabis use (at second follow-up): 47%; 5.5% for cannabis abuse, 2.2% for dependence. (2) Men used and abused cannabis more often than women. (3) The majority of the older participants (18–24 years at baseline) had reduced their cannabis use at follow-up, while younger participants (14–17 years at baseline) more often had increased their use and developed abuse or dependence. (4) The younger birth cohort (1977–1981) tended to start earlier with substance (ab)use compared to the older birth cohort (1970–1977). (5) Cannabis use was associated with increasing rates of concomitant use of other licit and illicit drugs. Conclusions: Cannabis use is widespread in our sample, but the probability of developing cannabis abuse or dependence is relatively low (8%). The natural course of cannabis use is quite variable: about half of all cannabis users stopped their use spontaneously in their twenties, others report occasional or more frequent use of cannabis.

Objectives: To determine risk factors of incident onset of use, abuse and dependence of cannabis in a community sample of adolescents and young adults. Methods: Risk factors were examined in a prospective longitudinal design across 4 years in a representative sample (N=2446) aged 14-24 at the outset of the study (EDSP). Patterns of DSM-IV defined cannabis use, abuse and dependence were assessed with the Composite International Diagnostic Interview (M-CIDI). Potential risk factors were assessed at baseline. Incident cannabis use, abuse and dependence at second follow-up (on average 42 months after baseline) were the main outcome measures in this study. Associations were analyzed with logistic and negative binomial regressions. Results: Using 11 of a total of 56 variables examined, the predictive value of the final multiple logistic regression for incident cannabis use was moderately good (area under the ROC curve=0.78). Cannabis use frequency was predicted in the final model by 18 variables, cannabis abuse by two variables in the younger subsample and nine factors in the older group, and dependence by eight variables (dependence: ROC curve area=0.97). Incident cannabis use was predicted mainly by availability of drugs, peers’ drug use, a more ‘positive’ attitude towards future drug use, and regular previous use of licit drugs, while cannabis dependence was predicted primarily by parental death before age 15, deprived socio-economic status, and baseline use of other illicit drugs. Conclusion: Different factors predict the onset or severity of cannabis use and the progression to abuse and dependence. In addition to well-documented risk factors such as peer group pressure, drug availability, and low self-esteem, findings suggest that family history (e.g. parental mental disorders, early parental death), and prior experiences with legal drugs play a significant role in the initiation of cannabis consumption and the transition to cannabis use disorders in adolescents and young adults. Findings suggest that early intervention and prevention might be improved by better targeted treatment.