A Classification of BPEL Extensions

The Business Process Execution Language (BPEL) has emerged as de-facto standard for business processes implementation. This language is designed to be extensible for including additional valuable features in a standardized manner. There are a number of BPEL extensions available. They are, however, neither classified nor evaluated with respect to their compliance to the BPEL standard. This article fills this gap by providing a framework for classifying BPEL extensions, a classification of existing extensions, and a guideline for designing BPEL extensions

Distribution of Gold Nanoparticles in the Anterior Chamber of the Eye after Intracameral Injection for Glaucoma Therapy

In glaucoma therapy, nanoparticles (NPs) are a favorable tool for delivering drugs to the outflow tissues of the anterior chamber of the eye where disease development and progression take place. In this context, a prerequisite is an efficient enrichment of NPs in the trabecular meshwork with minimal accumulation in off-target tissues such as the cornea, lens, iris and ciliary body. We evaluated the optimal size for targeting the trabecular meshwork by using gold NPs of 5, 60, 80 and 120 nm with a bare surface (AuNPs) or coated with hyaluronic acid (HA-AuNPs). NPs were compared regarding their colloidal stability, distribution in the anterior chamber of the eye ex vivo and cellular uptake in vitro. HA-AuNPs demonstrated an exceptional colloidal stability. Even after application into porcine eyes ex vivo, the HA coating prevented an aggregation of NPs inside the trabecular meshwork. NPs with a diameter of 120 nm exhibited the highest volume-based accumulation in the trabecular meshwork. Off-target tissues in the anterior chamber demonstrated an exceptionally low gold content. Our findings are particularly important for NPs with encapsulated anti-glaucoma drugs because a higher particle volume would be accompanied by a higher drug payload

Chip-based human liver-intestine and liver-skin co-culture : A first step toward systemic repeated dose substance testing in vitro

Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called “human-on-a-chip” concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air–liquid interface for the skin model during their co-culture with the liver equivalents respectively at 1/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver–skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance – troglitazone – to the chip-based co-cultures.BMBF/0315569/GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipforma

A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents

Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances lack in most in vitro assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale. Preformed human intestine and skin models have been integrated into the four-organ-chip on standard cell culture inserts at a size 100000-fold smaller than their human counterpart organs. A 3D-based spheroid, equivalent to ten liver lobules, mimics liver function. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. A peristaltic on-chip micropump ensures pulsatile media flow interconnecting the four tissue culture compartments through microfluidic channels. A second microfluidic circuit ensures drainage of the fluid excreted through the kidney epithelial cell layer. This four-organ-chip system assures near to physiological fluid-to-tissue ratios. In-depth metabolic and gene analysis revealed the establishment of reproducible homeostasis among the co-cultures within two to four days, sustainable over at least 28 days independent of the individual human cell line or tissue donor background used for each organ equivalent. Lastly, 3D imaging two-photon microscopy visualised details of spatiotemporal segregation of the two microfluidic flows by proximal tubule epithelia. To our knowledge, this study is the first approach to establish a system for in vitro microfluidic ADME profiling and repeated dose systemic toxicity testing of drug candidates over 28 days.BMBF, 0315569, GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipforma

An event model for WS-BPEL 2.0

This report presents an engine-independent WS-BPEL 2.0 event model. It supports both passive monitoring and active control of process execution by external applications. Some of the assumptions in the presented event model are inspired by a particular implementation, e.g. fault handling and compensation; however they are kept as general as possible, so that they can be mapped on other engine-specific approaches to tackle faults and support compensation. In addition, the report draws on the experience of some of the authors in business process management and software development. The overall BPEL event model consists of a set of event models for the different types of BPEL entities that change their states: processes, process instances, general activities, scope activities, invoke activities, loops, links, variables, partner links, and correlation sets. The event model is used by the authors of the report in several projects, all utilizing process life cycle events in different scenarios

Correction of a Factor VIII genomic inversion with designer-recombinases

Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct the 140 kb inversion of the F8 gene frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we develop a coupled heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from patient-derived induced pluripotent stem cells (iPSCs) of a hemophilic donor, results in 12% correction of the inversion and restores Factor VIII mRNA expression. In this work, we present designer-recombinases as an efficient and specific means towards treatment of monogenic diseases caused by large gene inversions

Messmethodensammlung Feinstaub: Methodenvorschlag zur Feinstauberfassung an Feuerungsanlagen für feste biogene Brennstoffe

Bereits lange vor der Debatte über den Umbau der Energieversorgung, hin zu mehr erneuerbaren Energien, wurde Holz für die Erzeugung von Wärme verwendet. Gegenwärtig werden knapp drei Viertel aller aus Erneuerbaren Energien bereitgestellten Wärme durch feste biogene Brennstoffe gedeckt (Musiol et al., 2012). Der überwiegende Teil (knapp die Hälfte) kommt dabei aus kleinen Holzfeuerungsanlagen. Die Verbrennung von Holz und anderen festen Brennstoffen biogener Herkunft trägt damit zu einem sehr großen Teil dazu bei, dass die von den Menschen benötigte Energie aus nachwachsenden Rohstoffen erzeugt wird. Die von der Bundesregierung verfolgten Klimaschutzziele sind auch deshalb, ohne die Verbrennung von Holz in Kleinfeuerungsanlagen nicht erreichbar. Die aktuelle Forschung zeigt allerdings auch, dass die Verbrennung von Holz in Kleinfeuerungsanlagen nennenswerte Emissionen, vor allem auch Feinstaubemissionen, verursacht und so maßgeblich zur Luftbelastung beiträgt (Birmili et al., 2008; Hausmann, 2010; Struschka et al., 2008). Die in der Luft verteilten Feinstäube können sich dabei auf sehr unterschiedliche Weise negativ auswirken. Es können sich bestimmte Komponenten, auf Grund ihrer chemisch-physikalischen Eigenschaften in der Luft anreichern. Die Gefahr diesen Komponenten ausgesetzt zu sein, erhöht unter anderem das Risiko für Atemwegserkrankungen (Dockery et al., 1993). Daher ist eines der Ziele des Förderprogramms zur Optimierung der energetischen Biomassenutzung des BMU, den vermeintlichen Zielkonflikt zwischen Klimaschutz bzw. Treibhausgasminderung und der Luftreinhaltung durch Projekte zur Minderung von schädlichen Emissionen zu lösen. Dieses Spannungsfeld aus Luftreinhaltung und Ausbau der thermochemischen Biomassekonversion wurde bereits in der Vergangenheit erkannt und es wurden erste Ansätze zur Emissionsminderung aufgezeigt (Lenz et al., 2010). Im Förderprogramm werden nun gezielt innovative Ansätze zur Emissionsminderung entwickelt. Allen diesbezüglich bearbeiteten Projekten ist gemein, dass Emissionen gemessen werden müssen. Dies betrifft neben den gasförmigen Emissionen insbesondere eben auch die Feinstaubemissionen. Hierbei gibt es in der Praxis eine Reihe unterschiedlicher Randbedingungen, die einen Einfluss auf das Messergebnis haben und die Vergleichbarkeit der Ergebnisse einschränken können (Typenprüfungen, Labormessungen, Feldmessungen, Schornsteinfegermessungen usw.). Auch die verwendeten Messgeräte und die eingesetzten Messprozeduren unterscheiden sich teilweise deutlich voneinander. Dass das Messen von Staubpartikeln und insbesondere die Beurteilung der Wirkung, die diese Stäube auf den Menschen und die Umwelt ausüben keine leichte Aufgabe ist zeigen regelmäßig vorgestellte Studien (Mudgal & Turbé, 2009; Orthen et al., 2007; Rödelsperger et al., 2009; UBA, 2008; Wiedensohler et al., 2012). Mit der Novellierung der 1. BImSchV im Jahr 2010 wurden die Emissionsanforderungen, die an kleine Holzfeuerungsanlagen gestellt werden, verschärft. Die Untersuchung und Einführung neuer und vor allem präziser Messverfahren gewinnt seit dem kontinuierlich an Bedeutung. Vor allem für die Weiterentwicklung von Feuerungstechniken mit außerordentlich niedrigen Staubemissionen ist der Einsatz von hochauflösender Messtechnik erforderlich. Die etablierte zeitlich aufwendige gravimetrische Bestimmung von Staubkonzentrationen ist hierbei nicht immer ausreichend. Die zeitaufgelöste Bestimmung der Staubkonzentrationen z. B. durch Zählung von einzelnen Partikeln rückt in den Fokus des Interesses. Verschiedene Anbieter vertreiben Geräte, die auf den ersten Blick verlässliche Messwerte generieren, die aber im Vergleich der Geräte untereinander erhebliche Abweichungen offenbaren. Zudem zeigen die Erkenntnisse der letzten Jahre, dass sich gerade Aerosole aus einer unvollständigen Verbrennung fester Biomasse, abhängig von den Umgebungsbedingungen, erheblich verändern können. Neben diesen eher akademisch-wissenschaftlichen Herausforderungen weist der Alltag der Staubmessung im Labor, aber insbesondere auch im Feld zusätzliche – häufig nicht unerhebliche – Herausforderungen auf, die eine Vergleichbarkeit der Messwerte zwischen verschiedenen Projekten weiter erschweren. Insofern erscheint es als eine der wesentlichen Herausforderungen eines Begleitprogramms für Projekte zur Minderung von Staubemissionen diese Zielgröße so gut es möglich ist unter vergleichbaren, reproduzierbaren und allgemein anerkannten Methoden zu ermitteln – dies insbesondere auch in dem Kontext zunehmender europäischer Bemühungen, vereinheitlichte Messverfahren festzulegen

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file