A molecular signature of myalgia in myotonic dystrophy 2

Background: Chronic muscle pain affects close to 20% of the population and is a major health burden. The underlying mechanisms of muscle pain are difficult to investigate as pain presents in patients with very diverse histories. Treatment options are therefore limited and not tailored to underlying mechanisms. To gain insight into the pathophysiology of myalgia we investigated a homogeneous group of patients suffering from myotonic dystrophy type 2 (DM2), a monogenic disorder presenting with myalgia in at least 50% of affected patients. Methods: After IRB approval we performed an observational cross-sectional cohort study and recruited 42 patients with genetically confirmed DM2 plus 20 healthy age and gender matched control subjects. All participants were subjected to an extensive sensory-testing protocol. In addition, RNA sequencing was performed from 12 muscle biopsy specimens obtained from DM2 patients. Findings: Clinical sensory testing as well as RNA sequencing clearly separated DM2 myalgic from non-myalgia patients and also from healthy controls. In particular pressure pain thresholds were significantly lowered for all muscles tested in myalgic DM2 patients but were not significantly different between non-myalgic patients and healthy controls. The expression of fourteen muscle expressed genes in myalgic patients was significantly up or down-regulated in myalgic compared to non-myalgic DM2 patients. Interpretation: Our data support the idea that molecular changes in the muscles of DM2 patients are associated with muscle pain. Further studies should address whether muscle-specific molecular pathways play a significant role in myalgia in order to facilitate the development of mechanism-based therapeutic strategies to treat musculoskeletal pain

Kühlmittelvermischung in Druckwasserreaktoren Teil 1: Möglichkeiten geschlossener analytischer Lösungen und Simulation der Vermischung mit CFX-4

Ziel des Vorhabens war die analytische und numerische Simulation der Kühlmittelvermischung im Ringraum und unteren Plenum von Druckwasserreaktoren. Generell ist die Kühlmittelvermischung relevant für zwei große Störfallgruppen - Borsäureverdünnungsstörfälle und Kaltwassertransienten. Zur Untersuchung der Vermischungsphänomene aus diesen Störfallszenarien wurde die Rossendorfer Versuchsanlage ROCOM konzipiert, die ein 1:5 skaliertes Plexiglasmodell des DWR Konvoi darstellt, in dem auch Geschwindigkeitsmessungen mit Hilfe von LDA-Technik möglich sind. Konstruktion, Errichtung und meßtechnische Ausstattung von ROCOM erfolgten in einem 2. Teil des Vorhabens. Im Vorfeld der Errichtung des ROCOM-Versuchsstandes wurden mit Hilfe des dreidimensionalen Strömungsberechnungsprogrammes CFX-4 Skalierungseffekte untersucht. Die Vergleichsrechnungen belegten, daß eine 1:5 Skalierung ausreichend ist. Nach dem Aufbau des Versuchsstandes und der Inbetriebnahme im 2. Teil des Vorhabens wurden die Vorausberechnungen anhand von experimentellen Ergebnissen bestätigt. Es wurde weiterhin ein Verfahren zur vereinfachten analytischen 2D-Beschreibung des Strömungsfeldes im Ringraum von Druckwasserreaktoren aufgestellt. Es beruht auf der Potentialtheorie, wobei Quellen an den Kühlmitteleintrittspositionen und Wirbel unter Beachtung der Randbedingungen der typischen Ringspaltgeometrie von DWR überlagert wurden. Der Schwerpunkt des Projektes lag jedoch in der numerischen Simulation der Kühlmittelvermischung unterschiedlicher Reaktoranlagen mit CFX-4 und der Validierung des Rechenprogramms anhand von Vermischungsexperimenten. Dabei wurden sowohl stationäre Schleifendurchsätze bei Nominalbetrieb und Teilschleifenbetrieb bzw. transiente Strömungsbedingungen der Reaktortypen DWR Konvoi und WWER-440 untersucht. Die Ergebnisse der CFX-4 Rechnungen im Vergleich mit den Leitfähigkeits- bzw. LDA-Messungen sind im Abschlußbericht dokumentiert. Grundlage für diesen Abschlußbericht ist eine Promotionsarbeit von T. Höhne zum gleichnamigen Thema im Rahmen des Kompetenzerhaltungsprogrammes Kerntechnik

Statins aggravate the risk of insulin resistance in human muscle

Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main site for insulin-stimulated glucose uptake and therefore, a primary target for insulin resistance in the human body. We analyzed localization and expression of proteins related to GLUT4 mediated glucose uptake via AMPKα or AKT in human skeletal muscle tissue from patients with statin-intake >6 months and in primary human myotubes after 96 h statin treatment. The ratio for AMPKα activity significantly increased in human skeletal muscle cells treated with statins for long- and short-term. Furthermore, the insulin-stimulated counterpart, AKT, significantly decreased in activity and protein level, while GSK3ß and mTOR protein expression reduced in statin-treated primary human myotubes, only. However, GLUT4 was normally distributed whereas CAV3 was internalized from plasma membrane around the nucleus in statin-treated primary human myotubes. Statin-treatment activates AMPKα-dependent glucose uptake and remains active after long-term statin treatment. Permanent blocking of its insulin-dependent counterpart AKT activation may lead to metabolic inflexibility and insulin resistance in the long run and may be a direct consequence of statin-treatment

Rasosomes originate from the Golgi to dispense Ras signals

Ras proteins undergo an incompletely understood trafficking process in the cell. Rasosomes are protein nanoparticles of 80–100 nm diameter that carry lipidated Ras isoforms (H-Ras and N-Ras) as well as their effectors through the cytoplasm and near the plasma membrane (PM). In this study, we identified the subcellular origin of rasosomes and how they spread Ras proteins through the cell. We found no dependency of rasosome formation on galectins, or on the GDP-/GTP-bound state of Ras. We found that significantly more rasosomes are associated with forms of Ras that are localized to the Golgi, namely N-Ras or the singly palmitoylated H-Ras mutant (C181S). To explore the possibility that rasosome originate from the Golgi, we used photoactivatable (PA)-GFP-H-Ras mutants and showed that rasosomes bud from the Golgi in a two-step mechanism. Newly released rasosomes first move in an energy-dependent directed fashion and then convert to randomly diffusing rasosomes. Dual fluorescence time-lapse imaging revealed the appearance of dually labeled rasosomes, indicating a dynamic exchange of cytoplasmic and PM-associated Ras with rasosome-associated Ras. Finally, higher levels of rasosomes correlate with higher levels of ERK phosphorylation, a key marker of Ras downstream signaling. We suggest that H-Ras and N-Ras proteins exchange with rasosomes that can function as carriers of palmitoylated Ras and its signals

Thermoelectric Response of an Interacting Two-Dimensional Electron Gas in Quantizing Magnetic Field

We present a discussion of the linear thermoelectric response of an interacting electron gas in a quantizing magnetic field. Boundary currents can carry a significant fraction of the net current passing through the system. We derive general expressions for the bulk and boundary components of the number and energy currents. We show that the local current density may be described in terms of ``transport'' and ``internal magnetization'' contributions. The latter carry no net current and are not observable in standard transport experiments. We show that although Onsager relations cannot be applied to the local current, they are valid for the transport currents and hence for the currents observed in standard transport experiments. We relate three of the four thermoelectric response coefficients of a disorder-free interacting two-dimensional electron gas to equilibrium thermodynamic quantities. In particular, we show that the diffusion thermopower is proportional to the entropy per particle, and we compare this result with recent experimental observations.Comment: 18 pages, 2 postscript figures included. Revtex with epsf.tex and multicol.sty. In the revised version, the comparison with experimental observations at $\nu=1/2, 3/2$ is extended to include the possibility of corrections due to weak impurity scattering. The conclusions that we reach regarding the applicability of the composite fermion model at these filling fractions are not affecte

Versuchsanlage ROCOM zur Untersuchung der Kühlmittelvermischung in Druckwasserreaktoren - Ergebnisse quasistationärer Vermischungsexperimente

The test facility ROCOM (Rossendorf Coolant Mixing Model) has been built for the investigation of coolant mixing processes in the reactor pressure vessel of pressurised water reactors (PWR). ROCOM is a 1:5 model of the German PWR KONVOI and has been designed for a wide range of different mixing scenarios. ROCOM disposes of four loops with fully controllable coolant pumps. The test facility is operated with demineralised water. For the investigation of mixing, tracer solution (water labelled with salt) is injected into the facility. The transient distribution of the electrical conductivity is is measured at different positions of the flow path by means of wire-mesh sensor technique with high resolution in space and time. The measured conductivity is transformed into a dimensionless mixing scalar. The mixing at quasi-stationary conditions (constant loop mass flow rates) has been investigated in the presented experiments. That concerned nominal operation conditions, the operation with a reduced number of loops and the investigation of cold-water transients with running pumps and conditions of developed natural circulation. In special experimental series, the reproducibility of the results at identicla boundary conditions within the confidence intervalls has been shown. Further, the influence of various factors on the mixing has been investigated. This included the pressure losses at the core bottom plate, the global coolant flow level and the influence of the loop flow rate on the perturbed sector at the core inlet. An analysis of the measurement error of the used measurement technique completes the report

Roadmap Umwelttechnologien 2020 - State-of-the-Art-Report (Kurzfassung)

Globale Umweltprobleme wie der Klimawandel, die Verknappung des Süßwasserdargebots, der Verlust an Biodiversität oder der rasant steigende Verbrauch nicht erneuerbarer Rohstoffe werden den Handlungsdruck im Umweltbereich in den nächsten Jahrzehnten deutlich erhöhen. Obwohl viele der heutigen Umweltprobleme direkt oder indirekt durch Technik verursacht sind, beinhalten moderne Umwelttechnologien gleichzeitig das Potential zu ihrer Bewältigung. Vor diesem Hintergrund untersucht das BMBF-Projekt „Roadmap Umwelttechnologien 2020“ welche Beiträge Forschung und Technik für künftige Umweltinnovationen leisten können. Ziel des Projekts ist es, strategische Handlungsoptionen für die Forschungsförderung und die Unterstützung des Wissenstransfers in die Praxis aufzuzeigen. Als erstes Ergebnis des Projekts wurden in einem umfassenden State-of-the-Art-Report, Umweltprobleme und zugehörige technische Lösungsansätze entlang von sieben Umwelthandlungsfeldern dargestellt. Diese sind: Klimaschutz, Luftreinhaltung, Wasserschutz, Bodenschutz, Schonung endlicher Ressourcen, Abfallwirtschaft, Erhalt von Natur und Biodiversität. Der Report gibt einen umfassenden Überblick über reife Technologien und ihr Marktumfeld, neue Technologien und ihre Potentiale sowie mögliche Hemmnisse, die der Weiterentwicklung und Marktdurchdringung im Weg stehen. In der hier vorgelegten Kurzfassung des State-of-the-Art-Reports sind wesentliche Ergebnisse aus den sieben Handlungsfeldern zusammengefasst. Jedem Handlungsfeld ist ein so genannter „Kompass“ zugeordnet, der das Beziehungsgeflecht von Problemen, Lösungsansätzen und Technologien grafisch darstellt

Innate recognition of water bodies in echolocating bats

In the course of their lives, most animals must find different specific habitat and microhabitat types for survival and reproduction. Yet, in vertebrates, little is known about the sensory cues that mediate habitat recognition. In free flying bats the echolocation of insect-sized point targets is well understood, whereas how they recognize and classify spatially extended echo targets is currently unknown. In this study, we show how echolocating bats recognize ponds or other water bodies that are crucial for foraging, drinking and orientation. With wild bats of 15 different species (seven genera from three phylogenetically distant, large bat families), we found that bats perceived any extended, echo-acoustically smooth surface to be water, even in the presence of conflicting information from other sensory modalities. In addition, naive juvenile bats that had never before encountered a water body showed spontaneous drinking responses from smooth plates. This provides the first evidence for innate recognition of a habitat cue in a mammal

What a Plant Sounds Like: The Statistics of Vegetation Echoes as Received by Echolocating Bats

A critical step on the way to understanding a sensory system is the analysis of the input it receives. In this work we examine the statistics of natural complex echoes, focusing on vegetation echoes. Vegetation echoes constitute a major part of the sensory world of more than 800 species of echolocating bats and play an important role in several of their daily tasks. Our statistical analysis is based on a large collection of plant echoes acquired by a biomimetic sonar system. We explore the relation between the physical world (the structure of the plant) and the characteristics of its echo. Finally, we complete the story by analyzing the effect of the sensory processing of both the echolocation and the auditory systems on the echoes and interpret them in the light of information maximization. The echoes of all different plant species we examined share a surprisingly robust pattern that was also reproduced by a simple Poisson model of the spatial reflector arrangement. The fine differences observed between the echoes of different plant species can be explained by the spatial characteristics of the plants. The bat's emitted signal enhances the most informative spatial frequency range where the species-specific information is large. The auditory system filtering affects the echoes in a similar way, thus enhancing the most informative spatial frequency range even more. These findings suggest how the bat's sensory system could have evolved to deal with complex natural echoes