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The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.
This thesis introduces the Integrated Emitter Turn-Off (IETO) Thyristor as a new high-power device. Known state-of-the-art research activities like the Dual GCT, the ETO thyristor and the ICT were presented and critically reviewed. A comparison with commercialized solutions identifies the pros and cons of each type of device family. Based on this analysis, the IETO structure is proposed, covering most benefits of each device class. In particular the combination of a MOS-assisted turn-off with a thyristor-based device allows a voltage-controlled MOS switching and the low on-state voltage of the thyristors. The following synthesis of an IETO device stands on a three-dimensional field of optimization spanned by electric, mechanical and thermal aspects. From an electric point of view, the lowest possible parasitic inductance and resistance within the commutation path are optimization criteria. The mechanical construction has to withstand the required contact pressure of multiple kilo Newtons. Finally, thermal borders limit the maximum average current of the device. FEM simulations covering these three aspects are performed for several design proposals. An IETO prototype is constructed and measurements on various test benches attest thermal, mechanical and electric performance. A local decoupling of the external driver stage and the presspack housing is presented by a cable connection. This separation enables a thermal and mechanical independence, which is advantageous in terms of vibrations and thermal cycles including increased reliability. The electric pulse performance of the prototype device is a factor of 3.1 above today''s solutions. In single-pulse measurements, a current up to 1600 A was successfully turned off at 115°C with an active silicon area of 823 mm². One reason for this increased turn-off capability is the extremely low-inductive construction. Additional functionality of the IETO thyristor like over-current self-protection and defined short-circuit failure state are successfully verified.
Security Awareness ist derzeit ein viel diskutiertes Thema. Es reicht nicht, einfach nur ein paar technische Systeme (z.B. Firewalls) zu installieren, um ein angemessenes Schutzniveau zu erzielen. Neben einer guten Organisation von IT Security ist es auch notwendig, den Mitarbeiter einzubinden. Der vielzitierte "Faktor Mensch" ist derjenige, der die Technik korrekt anwenden muss und der durch falsches Verhalten technische und organisatorische Schutzmaßnahmen aushebeln kann. Deshalb reicht es nicht aus, wenn sich der Mitarbeiter der Gefahren bewusst ("aware") ist, er muss auch dementsprechend "sicher" handeln.
Der Temperaturanstieg der vergangenen Jahrzehnte war in Gebirgsregionen besonders ausgeprägt. Sollte sich dieser Temperaturtrend im 21. Jahrhundert fortsetzen, dann dürf-ten sich auch die Häufigkeit und Intensität von Niederschlä-gen und Trockenperioden verändern, was die Waldwirtschaft vor grosse Herausforderungen stellen wird. Trockenheit ist ein entscheidender Faktor für die Waldökosysteme der inner-alpinen Täler, wo seit Jahren trockenheitsbedingtes Baum-sterben festgestellt wird. Der vorliegende Beitrag hat zum Ziel, die Sensitivität der verschiedenen Waldökosysteme ge-genüber Klimawandel und alternative, teilweise extreme Bewirtschaftungsvarianten in der Region Visp zu testen. Me-thodische Ansätze wie Monitoring, Feldexperimente und dy-namische Modellierung wurden kombiniert, und es wurden verschiedene Ökosystemleistungen berücksichtigt, so Holz-produktion, Schutz vor Naturgefahren, Kohlenstoffspeiche-rung und Aspekte der Biodiversität. Die Resultate deuten da-rauf hin, dass auf den Trockenstandorten der Tieflagen die einheimischen Baumarten an ihre physiologischen Grenzen stossen und längerfristig über alternative Baumarten nach-gedacht werden sollte. In den mittleren Lagen dürften Tro-ckenheit und Schadinsekten wie die Borkenkäfer die zukünf-tige Waldentwicklung steuern. In den Hochlagen hingegen werden sich die Wälder ausdehnen und besser wachsen als heute. Alle untersuchten Ökosystemleistungen werden ge-bietsweise starken Veränderungen unterworfen sein. Die dis-kutierten Bewirtschaftungsvarianten scheinen dazu geeignet, die Wasserverfügbarkeit der Bestände, hauptsächlich in tief-eren Lagen, zu erhöhen und dadurch die Widerstandskraft der Bäume gegenüber Trockenperioden vorübergehend zu stärken. Es ist aber davon ausgehen, dass nur verhältnismäs-sig starke Eingriffe wesentliche Effekte erzielen können. Die Verknüpfung von Umweltmonitoring, Feldexperimenten und Modellierung unter Miteinbezug von Ökosystemleistungen ist vielversprechend, da sie eine differenzierte Abschätzung des zukünftigen Landschaftswandels und seiner Effekte auf die Waldleistungen ermöglicht.
Die Hochgradientenmagnetseparation (HGMS) ist eine Methode zur Aufreinigung von biopharmazeutischen Produkten. Mit dieser Methode lässt sich in nur einem Schritt eine Fest/Fest/Flüssig-Trennung erzielen, was zu einer erheblichen Zeit- und Kostenersparnis im Downstreaming führt. Dennoch steht ihr industrieller Einsatz noch aus, was u. a. am Mangel an Analysenmethoden liegt, um die HGMS quantifizierbar zu machen. Gerade in der Pharmaproduktion werden Prozesse gebraucht, die gemäß den einschlägigen Vorschriften (cGMP) validiert und deren verfahrenstechnische Anlagenteile qualifiziert werden können. Die Schwierigkeit ist die Messung der magnetischen Mikrosorbentien in der Suspension, in der auch Zellen oder Zelltrümmer vorliegen. Im Rahmen eines Forschungsprojektes im „Zentralen Innovationsprogramm Mittelstand“ des BMWi wurden verschiedene Analysenmethoden untersucht. Die Durchflusszytometrie ermöglicht eine Charakterisierung von Partikeln und eine simultane quantitative Messung. Durch die multiparametrige Messung kann zwischen Zellen, Zelltrümmern und Magnetpartikeln unterschieden werden. Die At-line-Einbindung des Durchflusszytometers ist durch den Einsatz einer externen Pumpe möglich. Über eine automatisierte Messwertanalyse kann der HGMS-Prozess mittels der Durchflusszytometrie gesteuert werden.
With its need for high SNR and short acquisition times, Cardiac MRI (CMR) is an intriguing target application for ultrahigh field MRI. Due to the sheer size of the upper torso, however, the known RF issues of 7T MRI are also most prominent in CMR. Recent years brought substantial progress but the full potential of the ultrahigh field for CMR is yet to be exploited. Parallel transmission (pTx) is a promising approach in this context and several groups have already reported B1 shimming for 7T CMR. In such a static pTx application amplitudes and phases of all Tx channels are adjusted individually but otherwise imaging techniques established in current clinical practice 1.5 T and 3 T are applied. More advanced forms of pTx as spatially selective excitation (SSE) using Transmit SENSE promise additional benefits like faster imaging with reduced fields of view or improved SAR control. SSE requires the full dynamic capabilities of pTx, however, and for the majority of today's implemented pTx hardware the internal synchronization of the Tx array does not easily permit external triggering as needed for CMR. Here we report a software solution to this problem and demonstrate the feasibility of CINE CMR at 7 T using a Tx array.
Einführung
(2012)
South Africa in recent years is the establishment of a number of research hubs involved in AI activities ranging from mobile robotics and computational intelligence, to knowledge representation and reasoning, and human language technologies. In this survey we take the reader through a quick tour of the research being conducted at these hubs, and touch on an initiative to maintain and extend the current level of interest in AI research in the country.
This paper presents the latest prototype of the integrated emitter turn-off thyristor concept, which potentially ranks among thyristor high-power devices like the gate turn-off thyristor and the integrated gate-commutated thyristor (IGCT). Due to modifications of the external driver stage and mechanical press-pack design optimization, this prototype allows for full device characterization. The turn-off capability was increased to 1600 A with an active silicon area of 823mm2 . This leads to a transient peak power of 672.1kW/cm² . Within this paper, measurements and concept assessment are presented and a comparison to state-of-the-art IGCT devices is provided.
In der Molkeverarbeitung dominieren Membranfiltrationsverfahren die Prozessführung. Hierbei werden üblicherweise Aufkonzentrierungen der Proteine und deren Trennung von dem Milchzucker Lactose durchgeführt. Der Prozess der adsorptiven Aufreinigung soll als kostengünstige Alternative zu den bisher gebräuchlichen Verfahren dienen. Weiterhin eröffnet sich durch das Verfahren die Möglichkeit, einzelne Proteinfraktionen während der Verarbeitung anzureichern. Als Proteinquellen wurden für die Untersuchungen Modellproteine, Lösungen aus Molkenproteinisolat, Dünnmolke und Molkekonzentrat verwendet. Die Eignung zur Proteinbindung wurden an Tonmaterialien, Silicaten und y-Aluminiumoxiden in Pulverform, in Form von Granulaten sowie Extrudaten als auch sphärischen Partikeln überprüft. Adsorbentien aus Bentonit/Silica und c-Aluminiumoxid können sowohl a-Lactalbumin (aLA) als auch b-Lactoglobulin (bLG) binden, wohingegen Materialien aus Siliciumoxid lediglich ein starkes Adsorptionsverhalten gegenüber bLG zeigen. Mischmaterialien aus Siliciumoxid und a-Aluminiumoxid zeigen dasselbe Verhalten wie Materialien aus Siliciumoxid, weisen jedoch eine geringere Kapazität auf. Die Materialen wurden hinsichtlich ihres Einsatzes in chromatographischen Verfahren und Batch-Prozessen untersucht und ein Prozessentwurf für einen zweistufigen Batch-Prozess im Rührkessel erarbeitet.
The assessment of the right ventricle (RV) is a challenge in today's cardiology, but of growing clinical impact regarding patient prognosis in different cardiac diseases. The detection and differentiation of small wall motion abnormalities may help to enhance the differentiation of cardiomyopathies including Arrhythmogenic Rightventricular Cardiomyopathy. Cardiovascular magnetic resonance (CMR) at 1.5T is the accepted gold standard for RV quantification. The higher spatial resolution achievable at ultrahigh field strength (UHF) offers the potential to gain new insights into the structure and function of the RV. To approach this goal accurate RV chamber quantification at 7T has to be proven. Consequently this study examines the feasibility of assessment of RV dimensions and function at 7T using improved spatial resolution enabled by the intrinsic sensitivity gain of UHF CMR. For this purpose, a dedicated 16 channel TX/RX RF coil array is used together with 2D CINE fast gradient echo (FGRE) imaging. For comparison RV chamber quantification is conducted at 1.5T using a SSFP based state of the art clinical protocol.
Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line
(2012)
The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(−/−)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(−/−) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2.
Cardiac MR (CMR) at ultrahigh (≥7.0 T) fields is regarded as one of the most challenging MRI applications. At 7.0 T image quality is not always exclusively defined by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Detrimental effects bear the potential to spoil the signal-to-noise (SNR) and contrast-to-noise (CNR) benefits of cardiac MR (CMR) at 7.0 T. B₁⁺-inhomogeneities and signal voids represent the main challenges. Various pioneering coil concepts have been proposed to tackle these issues, enabling cardiac MRI at 7.0 T. This includes a trend towards an ever larger number of transmit and receive channels. This approach affords multi-dimensional B₁⁺ modulations to improve B₁⁺ shimming performance and to enhance RF efficiency. Also, parallel imaging benefits from a high number of receive channels enabling two-dimensional acceleration. Realizing the limitations of existing coil designs tailored for UHF CMR and recognizing the opportunities of a many element TX/RX channel architecture this work proposes a modular, two dimensional 32-channel transmit and receive array using loop elements and examines its efficacy for enhanced B¹+ homogeneity and improved parallel imaging performance.
Purpose:
To investigate the feasibility of using magnetohydrodynamic (MHD) effects for synchronization of magnetic resonance imaging (MRI) with the cardiac cycle.
Materials and Methods:
The MHD effect was scrutinized using a pulsatile flow phantom at B0 = 7.0 T. MHD effects were examined in vivo in healthy volunteers (n = 10) for B0 ranging from 0.05–7.0 T. Noncontrast-enhanced MR angiography (MRA) of the carotids was performed using a gated steady-state free-precession (SSFP) imaging technique in conjunction with electrocardiogram (ECG) and MHD synchronization.
Results:
The MHD potential correlates with flow velocities derived from phase contrast MRI. MHD voltages depend on the orientation between B0 and the flow of a conductive fluid. An increase in the interelectrode spacing along the flow increases the MHD potential. In vivo measurement of the MHD effect provides peak voltages of 1.5 mV for surface areas close to the common carotid artery at B0 = 7.0 T. Synchronization of MRI with the cardiac cycle using MHD triggering is feasible. MHD triggered MRA of the carotids at 3.0 T showed an overall image quality and richness of anatomic detail, which is comparable to ECG-triggered MRAs.
Conclusion:
This feasibility study demonstrates the use of MHD effects for synchronization of MR acquisitions with the cardiac cycle. J. Magn. Reson. Imaging 2012;36:364–372. © 2012 Wiley Periodicals, Inc.
Climate change is challenging forestry management and practices. Among other things, tree species with the ability to cope with more extreme climate conditions have to be identified. However, while environmental factors may severely limit tree growth or even cause tree death, assessing a tree species' potential for surviving future aggravated environmental conditions is rather demanding. The aim of this study was to find a tree-ring-based method suitable for identifying very drought-tolerant species, particularly potential substitute species for Scots pine (Pinus sylvestris L.) in Valais. In this inner-Alpine valley, Scots pine used to be the dominating species for dry forests, but today it suffers from high drought-induced mortality. We investigate the growth response of two native tree species, Scots pine and European larch (Larix decidua Mill.), and two non-native species, black pine (Pinus nigra Arnold) and Douglas fir (Pseudotsuga menziesii Mirb. var. menziesii), to drought. This involved analysing how the radial increment of these species responded to increasing water shortage (abandonment of irrigation) and to increasingly frequent drought years. Black pine and Douglas fir are able to cope with drought better than Scots pine and larch, as they show relatively high radial growth even after irrigation has been stopped and a plastic growth response to drought years. European larch does not seem to be able to cope with these dry conditions as it lacks the ability to recover from drought years. The analysis of trees' short-term response to extreme climate events seems to be the most promising and suitable method for detecting how tolerant a tree species is towards drought. However, combining all the methods used in this study provides a complete picture of how water shortage could limit species.