Funktionelle Konsequenzen von Mutationen im Melanocortin-4-Rezeptorgen bei adipösen Kindern und Jugendlichen

Der Melanocortin-4-Rezeptor spielt eine zentrale Rolle in der Gewichtsregulation, er vermittelt (indirekt) die anorexigenen Effekte des Leptin, indem er nach Aktivierung eine Einstellung der Nahrungsaufnahme und eine Erhöhung der Stoffwechselrate bedingt. Er ist der Familie der G-Protein-gekoppelten-Rezeptoren zuzuordnen und koppelt an ein Gs-Protein, welches die Adenylylcyclase aktivieren kann. Das Rezeptorprotein besteht aus 332 Aminosäuren und wird durch ein einziges Exon in der humanen Chromosomen-region 18q22 kodiert. Den endogenen Agonisten am Melanocortin-4-Rezeptor stellt das alpha-MSH dar, welches dem Vorläuferprotein Proopiomelanocortin (POMC) entstammt. Zahlreiche Mutationen im MC4R-Gen konnten bis zum heutigen Tage gefunden werden, die Hoffnung, hierin eine Hauptursache für die extreme kindliche Adipositas gefunden zu haben, hat sich leider nicht bestätigen können. Im Rahmen der vorliegenden Arbeit wurde eine sehr große Patientenpopulation (808 Kinder und Jugendlich mit einem durchschnittlichen BMI> 30 kg/m2), sowie deren Eltern auf Mutationen im Melanocortin-4-Rezeptor-Gen hin untersucht. Dabei ergab sich ein signifikant höherer Anteil von Trägern relevanter Mutationen als in der unter- bis normalgewichtigen Kontrollgruppe. Um die funktionelle Relevanz der 16 neu detektierten Mutationen untersuchen zu können, wurden diese zunächst in den Expressionsvektor pSG5 kloniert. Im Anschluss transfizierten wir COS7-Zellen mit den entsprechenden Proben und führten den cAMP-Akkumulations-Assay durch. Im Rahmen dieser Untersuchung zeigten die 16 Mutationen sehr unterschiedliche Verhaltensweisen. Ein Teil zeigte eine deutliche Reduktion der cAMP-Spiegel unter Stimulation mit alpha-MSH gegenüber denen des Wildtyp-Rezeptors. Ein anderer Teil zeigte Konzentrations-Wirkungskurven, die der des Wildtyps entsprachen. Zwei der von uns untersuchten Rezeptorvarianten (S127L und P230L) zeigten gar ohne Stimulation durch den entsprechenden Liganden Basalwerte, die weit über dem des Wildtyp-Allels lagen, so dass wir hier eine konstitutive Aktivität der Rezeptorproteine postulierten. Gerade die physiologische oder gar die gesteigerte Aktivität der veränderten Rezeptorproteine unter Agonisten-Stimulation lässt sich dabei nur schwer zur Erklärung des adipösen Phänotyps des betroffenen Probanden heranziehen. Der von uns ebenfalls im cAMP-Assay untersuchte, weit verbreitete Polymorphismus V103I zeigte in seiner Dosis-Wirkungskurve nur geringe Abweichungen von den Werten des Wildtyp-Rezeptors. Da sich ein Teil der Ausfälle in der Funktionalität bei Mutationen des MC4R-Gens durch einen gestörten Transport der veränderten Proteine in die Plasmamembran erklären lässt, untersuchten wir einige der Rezeptoren außerdem im Zelloberflächen-ELISA. Im ELISA ergab sich eine Reduktion der Oberflächen-expression der Mutationen G181D und S94R (welche bereits im cAMP-Assay einen totalen Funktionsausfall gezeigt hatten). Die von uns als konstitutiv aktiv deklarierten Rezeptorvarianten S127L und P230L zeigten jedoch wider Erwarten keinen behinderten Transport an die Zelloberfläche, im Gegenteil erschien die Zelloberflächen-Expression gegenüber der des Wildtyp-Rezeptors eher erhöht. Die restlichen im ELISA untersuchten Rezeptorvarianten zeigten eine ähnliche Expression an der Zelloberfläche wie der Wildtyp-MC4R. Auch der intrazelluläre Verbleib der veränderten Rezeptorproteine reicht hier also zur Klärung der Ursache der Fettsucht des betroffenen Patienten nicht aus. Die Frage, welche Bedeutung bestehenden Mutationen im Melanocortin-4-Rezeptor-Gen im Hinblick auf den adipösen Phänotyp des betroffenen Individuums zukommt, konnte von uns nur teilweise gelöst werden: Die Annahme eines autosomal dominanten Erbganges kann vor dem Hintergrund der Ergebnisse der funktionellen Untersuchungen (und vorheriger Beschreibungen schlanker, heterozygoter Träger funktionell relevanter Mutationen) eindeutig verneint werden. Aufgrund der Tatsache, dass in unserer Studienpopulation signifikant mehr Träger einer funktionell relevanten Mutation (15) auftraten (gegenüber keiner funktionell relevanten Mutation innerhalb der Kontrollgruppe) und alle funktionell relevanten Mutationen zudem von den Eltern auf ihre Kinder weitervererbt worden waren, konnten wir einen „major-gene-effect“ von funktionell relevanten MC4R-Varianten auf den Phänotyp des betroffenen Individuums postulieren. Da Melanocortin-4-Rezeptor-Mutationen jedoch nur für einen sehr geringen Prozentsatz der Adipositas-Fälle verantwortlich gemacht werden können, haben sie eine geringe epidemiologische, bei gleichzeitiger hoher individueller Relevanz

A Systematic Review

Music therapy (MT) and music-based interventions (MBIs) are increasingly used for the treatment of substance use disorders (SUD). Previous reviews on the efficacy of MT emphasized the dearth of research evidence for this topic, although various positive effects were identified. Therefore, we conducted a systematic search on published articles examining effects of music, MT and MBIs and found 34 quantitative and six qualitative studies. There was a clear increase in the number of randomized controlled trials (RCTs) during the past few years. We had planned for a meta-analysis, but due to the diversity of the quantitative studies, effect sizes were not computed. Beneficial effects of MT/ MBI on emotional and motivational outcomes, participation, locus of control, and perceived helpfulness were reported, but results were inconsistent across studies. Furthermore, many RCTs focused on effects of single sessions. No published longitudinal trials could be found. The analysis of the qualitative studies revealed four themes: emotional expression, group interaction, development of skills, and improvement of quality of life. Considering these issues for quantitative research, there is a need to examine social and health variables in future studies. In conclusion, due to the heterogeneity of the studies, the efficacy of MT/ MBI in SUD treatment still remains unclear

Toward Holistic Energy Management Strategies for Fuel Cell Hybrid Electric Vehicles in Heavy-Duty Applications

The increasing need to slow down climate change for environmental protection demands further advancements toward regenerative energy and sustainable mobility. While individual mobility applications are assumed to be satisfied with improving battery electric vehicles (BEVs), the growing sector of freight transport and heavy-duty applications requires alternative solutions to meet the requirements of long ranges and high payloads. Fuel cell hybrid electric vehicles (FCHEVs) emerge as a capable technology for high-energy applications. This technology comprises a fuel cell system (FCS) for energy supply combined with buffering energy storages, such as batteries or ultracapacitors. In this article, recent successful developments regarding FCHEVs in various heavy-duty applications are presented. Subsequently, an overview of the FCHEV drivetrain, its main components, and different topologies with an emphasis on heavy-duty trucks is given. In order to enable system layout optimization and energy management strategy (EMS) design, functionality and modeling approaches for the FCS, battery, ultracapacitor, and further relevant subsystems are briefly described. Afterward, common methodologies for EMS are structured, presenting a new taxonomy for dynamic optimization-based EMS from a control engineering perspective. Finally, the findings lead to a guideline toward holistic EMS, encouraging the co-optimization of system design, and EMS development for FCHEVs. For the EMS, we propose a layered model predictive control (MPC) approach, which takes velocity planning, the mitigation of degradation effects, and the auxiliaries into account simultaneously

New Enhanced Technical Capabilities of the ALD SMARTcoater

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Fourteen-Year Long-Term Results after Gastric Banding

Background. Gastric banding (GB) is a common bariatric procedure that is performed worldwide. Weight loss can be substantial after this procedure, but it is not sufficient in a significant portion of patients. Long-term rates for associated complications increase with every year of follow up, and only a few long-term studies have been published that examine these rates. We present our results after 14 years of postoperative follow up. Methods. Two hundred patients were operated upon form 01.02.1995 to 31.01.2009. Data collection was performed prospectively. In retrospective analysis, we analyzed weight loss, short- and long-term complications, amelioration of comorbidities and long-term outcome. Results. The mean postoperative follow up time was 94.4 months (range 2–144). The follow up rate was 83.5%. The incidence of postoperative complications for slippage was 2.5%, for pouch dilatation was 9.5%, for band migration was 5.5% and 12.0% for overall band removal. After 14 years, the reoperation rate was 30.5% with a reoperation rate of 2.2% for every year of follow up. Excess weight loss was 40.2% after 1 year, 46.3% after 2 years, 45.9% after 3 years, 41.9% after five years, 33.3% after 8 years, 30.8% after 10 years, 33.3% after 12 years and 15.6% after 14 years of follow up. Conclusion. The complication and reoperation rate after GB is high. Nevertheless, GB is still a therapeutic option in morbid obese patients, but the criteria for patient selection should be carefully evaluated

Efficient Intralogistics Planning Based on an Innovative Intralogistics Tool using the Example of a Flexible Battery Cell Factory

In the course of increasingly volatile markets, globalization as well as shorter product life cycles, factories and thus also the logistics system as a central component of a factory have to be designed in a more flexible way. Battery cell production faces a special challenge in this aspect. Due to the trend towards a sustainable and environmentally friendly energy supply and mobility, the demand is expected to increase significantly. New battery cell factories have to manage rising product volumes and simultaneously react versatile regarding new research findings. Thus, the market for battery cells, the product itself, and the corresponding manufacturing processes are constantly changing. New materials, manufacturing methods, variations of cell formats as well as the possibility of scalability and the associated changes in the requirements for the factory must be taken into account as early as possible in the planning stage. The logistics system as one of the core elements of a factory is always affected by changes in the product, manufacturing processes or input materials. If, for instance, other materials are used, the storage and transport of these goods with different dimensions, weight or even environmental requirements must still be guaranteed. In order to consider the required flexibility already in the planning process, simulation can provide a decisive benefit. It enables the planner to analyse the production and iteratively adapt logistics planning. Since there are many possibilities and combinations, especially in the design of warehouse and transport systems, a reduction of these should take place at an early stage. However, the preselection of suitable logistics systems that provide the necessary flexibility is currently often based on empirical knowledge and extensive market research. Therefore, this paper presents an efficient, holistic approach to logistics planning and an intralogistics tool in detail, which is based on established data. As a result, an optimal logistics system can be defined through an iterative optimization of the flexibility corridor, taking into account the factory goals

Model-Based Control of a Large-Scale Ball-on-Plate System With Experimental Validation

A ball-on-plate system is a widespread education oriented laboratory experiment for automation in mechatronics. The setup combines elements of mechanical, electrical and control engineering and is an adequate setup for learning the combination of theory and practice. This paper presents an example of a workshop result on automatic control in mechatronics. The aim of the workshop is to develop and compare model-based approaches for ball position control in a given large-scale ball-on-plate system. The result includes the derivation of a non-linear state space model of the system. The equations are linearized in the center of the horizontal plate as an operating point in order to apply cascade control, linear-quadratic optimal control and PI optimal state feedback control. The algorithms are implemented on a microcontroller and tested in the experimental setup. The results show a successful control development which achieves the control goal with good performance in terms of command response

A Novel Real Time PCR Method for the Detection and Quantification of Didymella pinodella in Symptomatic and Asymptomatic Plant Hosts

Didymella pinodella is the major pathogen of the pea root rot complex in Europe. This wide host range pathogen often asymptomatically colonizes its hosts, making the control strategies challenging. We developed a real-time PCR assay for the detection and quantification of D. pinodella based on the TEF-1 alpha gene sequence alignments. The assay was tested for specificity on a 54- isolate panel representing 35 fungal species and further validated in symptomatic and asymptomatic pea and wheat roots from greenhouse tests. The assay was highly consistent across separate qPCR reactions and had a quantification/detection limit of 3.1 pg of target DNA per reaction in plant tissue. Cross-reactions were observed with DNA extracts of five Didymella species. The risk of cross contamination, however, is low as the non-targets have not been associated with pea previously and they were amplified with at least 1000-fold lower sensitivity. Greenhouse inoculation tests revealed a high correlation between the pathogen DNA quantities in pea roots and pea root rot severity and biomass reduction. The assay also detected D. pinodella in asymptomatic wheat roots, which, despite the absence of visible root rot symptoms, caused wheat biomass reduction. This study provides new insights into the complex life style of D. pinodella and can assist in better understanding the pathogen survival and spread in the environament.info:eu-repo/semantics/publishedVersio

Adaption of the Level of Development to the Factory Layout Planning and Introduction of a Quality Assurance Process

Current developments and trends are causing an increasingly turbulent environment for manufacturing companies. In order to respond to these dynamic market conditions, products and thus also production systems have to be adapted more frequently and much faster. However, time and cost targets are often missed by classic factory planning approaches due to poor communication, inadequate tools, and lack of interfaces. Therefore, new ways have to be found in factory planning to overcome these problems. Building Information Modeling, which is already used in the construction industry, provides a promising method for the collaboration of stakeholders based on digital models. This would allow communication to be structured, new tools to be used, and interfaces to be stabilized to improve the target achievement in factory planning projects. However, which information should be provided in which level of detail in which phase of a factory planning project and how the quality of this information can be ensured has not yet been answered. A possible solution to these questions is addressed in this article. First, the concept of the so-called Level of Development, i.e. the geometric and non-geometric definition of the model contents, is transferred to factory layout planning. Then, based on two use cases, the process of quality assurance is defined