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Background
Minor changes in protein structure induced by small organic and inorganic molecules can result in significant metabolic effects. The effects can be even more profound if the molecular players are chemically active and present in the cell in considerable amounts. The aim of our study was to investigate effects of a nitric oxide donor (spermine NONOate), ATP and sodium/potassium environment on the dynamics of thermal unfolding of human hemoglobin (Hb). The effect of these molecules was examined by means of circular dichroism spectrometry (CD) in the temperature range between 25°C and 70°C. The alpha-helical content of buffered hemoglobin samples (0.1 mg/ml) was estimated via ellipticity change measurements at a heating rate of 1°C/min.
Results
Major results were:
1) spermine NONOate persistently decreased the hemoglobin unfolding temperature T u irrespectively of the Na + /K + environment,
2) ATP instead increased the unfolding temperature by 3°C in both sodium-based and potassium-based buffers and
3) mutual effects of ATP and NO were strongly influenced by particular buffer ionic compositions. Moreover, the presence of potassium facilitated a partial unfolding of alpha-helical structures even at room temperature.
Conclusion
The obtained data might shed more light on molecular mechanisms and biophysics involved in the regulation of protein activity by small solutes in the cell.
The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.
Assessment of RF Safety of Transmit Coils at 7 Tesla by Experimental and Numerical Procedures (490.)
(2012)
Air- and water-stable phenyl complexes with nitridotechnetium(V) cores can be prepared by straightforward procedures. [TcNPh2(PPh3)2] is formed by the reaction of [TcNCl2(PPh3)2] with PhLi. The analogous N-heterocyclic carbene (NHC) compound [TcNPh2(HLPh)2], where HLPh is 1,3,4-triphenyl-1,2,4-triazol-5-ylidene, is available from (NBu4)[TcNCl4] and HLPh or its methoxo-protected form. The latter compound allows the comparison of different Tc–C bonds within one compound. Surprisingly, the Tc chemistry with such NHCs does not resemble that of corresponding Re complexes, where CH activation and orthometalation dominate.
N,N-Dialkylamino(thiocarbonyl)-N′-picolylbenzamidines react with (NEt4)2[M(CO)3X3] (M = Re, X = Br; M = Tc, X = Cl) under formation of neutral [M(CO)3L] complexes in high yields. The monoanionic NNS ligands bind in a facial coordination mode and can readily be modified at the (CS)NR1R2 moiety. The complexes [99Tc(CO)3(LPyMor)] and [Re(CO)3(L)] (L = LPyMor, LPyEt) were characterized by X-ray diffraction. Reactions of [99mTc(CO)3(H2O)3]+ with the N′-thiocarbamoylpicolylbenzamidines give the corresponding 99mTc complexes. The ester group in HLPyCOOEt allows linkage between biomolecules and the metal core.
Entwicklung eines Prototypen zur Prognose von Frühgeburten : ein biomedizintechnischer Ansatz
(2012)
Netzsektoren und deren adäquate Regulierung sind ein sehr relevantes und aktuelles Thema. Dies gilt sowohl für die ökonomische Theorie, die sich sehr intensiv damit auseinandersetzt und in den letzten Jahrzehnten zahlreiche neue Erkenntnisse gewonnen hat. Es gilt ebenso für die Politik, in der Regulierungsfragen kontrovers diskutiert werden und dies nicht nur unter ökonomischen Gesichtspunkten. Es gilt selbstverständlich für die regulierten Unternehmen selbst, deren Tätigkeit durch die staatlichen Regulierungsvorgaben markant beeinflusst wird. Nicht nur die konkreten Inhalte der Regulierungsregime sowie die verbleibenden Freiheitsgrade in der Ausgestaltung sind von Bedeutung, sondern ebenso die Umsetzung durch die Regulierungsbehörden. All dies gilt für den Strommarkt und seinen regulatorischen Hintergrund in besonderer Weise. Die Entflechtung der Stromübertragungsnetze von der Stromproduktion und damit die Vorgaben für die Organisation der Wertschöpfungsketten in den Elektrizitätsunternehmen sind seit dem Beginn des europäischen Liberalisierungsprozesses der Strommärkte ein wichtiges und kontrovers diskutiertes Regulierungselement. Den Fokus bildet das vertikale Unbundling, das letztlich die Diskriminierung von Wettbewerbern durch Anbieter mit aggregierten Wertschöpfungsketten verhindern soll, indem diese gezwungen werden, ihren "Netzteil" anders zu organisieren oder zu verkaufen. Den Mitgliedsstaaten blieben Freiräume in der Ausgestaltung, die in Deutschland erst vor kurzem konkretisiert wurden, und die für die regulierten Unternehmen die Nutzung eines Wahlrechts beinhalten. Der wirtschaftspolitischen folgt nun eine unternehmerische Abwägungsentscheidung.
As the potential of a next generation network (NGN) is recognised, telecommunication companies consider switching to it. Although the implementation of an NGN seems to be merely a modification of the network infrastructure, it may trigger or require changes in the whole company, because it builds upon the separation between service and transport, a flexible bundling of services to products and the streamlining of the IT infrastructure. We propose a holistic framework, structured into the layers ‘strategy’, ‘processes’ and ‘information systems’ and incorporate into each layer all concepts necessary for the implementation of an NGN, as well as the alignment of these concepts. As a first proof-of-concept for our framework we have performed a case study on the introduction of NGN in a large telecommunication company; we show that our framework captures all topics that are affected by an NGN implementation.
Die Veränderungen des Telekommunikationsmarktes haben in der Praxis zu einer Vielzahl von Transformationsprojekten geführt. Was gehört aber zu einem “Transformationsprojekt”, welche Prozesse und Systeme werden verändert? Zur Beantwortung dieser Frage haben wir 184 Berichte zu Projekten analysiert, die als "Transformationsprojekte" bezeichnet waren. Für die Analyse haben wir einen Kodierungsrahmen konzipiert und anhand dessen die Berichte mit einem hierarchischen Clustering-Verfahren in Themen gruppiert. Die Ergebnisse liefern Hinweise über die in der Praxis gesetzten Schwerpunkte und Prioritäten. Sie können
somit als Unterstützung für Unternehmen dienen, die ein Transformationsprojekt planen. Sie weisen zudem darauf hin, in welchen Bereichen eines Unternehmens Unterstützung durch wissenschaftlich erprobte Werkzeuge und Modelle nötig ist.
Wieder einmal hat eine Entscheidung des Europäischen Gerichtshofs (EuGH) das bisherige nationale Verständnis zu einer Frage des Rechts des Betriebsübergangs erheblich ins Wanken gebracht. Bisher entsprach es allgemeiner Auffassung, dass die Arbeitsverhältnisse von Zeit- bzw. Leiharbeitnehmern bei einem Betriebs(teil)übergang des die Leiharbeitnehmer entleihenden Betriebs nicht auf den Betriebserwerber übergehen. Der EuGH hat in der Rechtssache Albron Catering mit Urteil vom 21.10.2010 jedoch entschieden, dass auch Leiharbeitnehmer von einem Betriebs(teil)übergang erfasst sein können. Folglich kann der Erwerber eines Betriebs oder Betriebsteils gem. § 613a BGB zukünftig verpflichtet sein, auch die an den Betriebsveräußerer verliehenen Leiharbeitnehmer zu übernehmen. Die Entscheidung des EuGH hat somit zur Konsequenz, dass der Übergang von Leiharbeitsverhältnissen auf den Erwerber eines Betriebs jedenfalls nicht mehr pauschal ausgeschlossen werden kann. Dies gilt es bei künftigen Betriebs(teil)übertragungen zu berücksichtigen, um unliebsame Überraschungen zu vermeiden.
Determinants of earnings forecast error, earnings forecast revision and earnings forecast accuracy
(2012)
Earnings forecasts are ubiquitous in today’s financial markets. They are essential indicators of future firm performance and a starting point for firm valuation. Extremely inaccurate and overoptimistic forecasts during the most recent financial crisis have raised serious doubts regarding the reliability of such forecasts. This thesis therefore investigates new determinants of forecast errors and accuracy. In addition, new determinants of forecast revisions are examined. More specifically, the thesis answers the following questions: 1) How do analyst incentives lead to forecast errors? 2) How do changes in analyst incentives lead to forecast revisions?, and 3) What factors drive differences in forecast accuracy?
s the magnetic field strength and therefore the operational frequency in MRI are increased, the radiofrequency wavelength approaches the size of the human head/body, resulting in wave effects which cause signal decreases and dropouts. Especially, whole-body imaging at 7 T and higher is therefore challenging. Recently, an acquisition scheme called time-interleaved acquisition of modes has been proposed to tackle the inhomogeneity problems in high-field MRI. The basic premise is to excite two (or more) different Burn:x-wiley:07403194:media:MRM23081:tex2gif-stack-1 modes using static radiofrequency shimming in an interleaved acquisition, where the complementary radiofrequency patterns of the two modes can be exploited to improve overall signal homogeneity. In this work, the impact of time-interleaved acquisition of mode on image contrast as well as on time-averaged specific absorption rate is addressed in detail. Time-interleaved acquisition of mode is superior in Burn:x-wiley:07403194:media:MRM23081:tex2gif-stack-2 homogeneity compared with conventional radiofrequency shimming while being highly specific absorption rate efficient. Time-interleaved acquisition of modes can enable almost homogeneous high-field imaging throughout the entire field of view in PD, T2, and T2*-weighted imaging and, if a specified homogeneity criterion is met, in T1-weighted imaging as well.
31P MR spectroscopic imaging of the human prostate provides information about phosphorylated metabolites that could be used for prostate cancer characterization. The sensitivity of a magnetic field strength of 7 T might enable 3D 31P MR spectroscopic imaging with relevant spatial resolution in a clinically acceptable measurement time. To this end, a 31P endorectal coil was developed and combined with an eight-channel 1H body-array coil to relate metabolic information to anatomical location. An extensive safety validation was performed to evaluate the specific absorption rate, the radiofrequency field distribution, and the temperature distribution of both coils. This validation consisted of detailed Finite Integration Technique simulations, confirmed by MR thermometry and Burn:x-wiley:07403194:media:MRM24175:tex2gif-stack-1 measurements in a phantom and in vivo temperature measurements. The safety studies demonstrated that the presence of the 31P endorectal coil had no influence on the specific absorption rate levels and temperature distribution of the external eight-channel 1H array coil. To stay within a 10 g averaged local specific absorption rate of 10 W/kg, a maximum time-averaged input power of 33 W for the 1H array coil was allowed. For transmitting with the 31P endorectal coil, our safety limit of less than 1°C temperature increase in vivo during a 15-min MR spectroscopic imaging experiment was reached at a time-averaged input power of 1.9 W. With this power setting, a second in vivo measurement was performed on a healthy volunteer. Using adiabatic excitation, 3D 31P MR spectroscopic imaging produced spectra from the entire prostate in 18 min with a spatial resolution of 4 cm3. The spectral resolution enabled the separate detection of phosphocholine, phosphoethanolamine, inorganic phosphate, and other metabolites that could play an important role in the characterization of prostate cancer.
This contribution discusses the utilization of RF power in an MRI system with RF mode shimming which enables the superposition of circularly polarized modes of a transmit RF coil array driven by a Butler matrix. Since the required power for the individual modes can vary widely, mode-shimming can result in a significant underutilization of the total available RF power. A variable power combiner (VPC) is proposed to improve the power utilization: it can be realized as a reconfiguration of the MRI transmit system by the inclusion of one additional matrix network which receives the power from all transmit amplifiers at its input ports and provides any desired (combined) power distribution at its output ports by controlling the phase and amplitude of the amplifiers’ input signals. The power distribution at the output ports of the VPC is then fed into the “mode” ports of the coil array Butler matrix in order to superimpose the spatial modes at the highest achievable power utilization. The VPC configuration is compared to the standard configuration of the transmit chain of our MRI system with 8 transmit channels and 16 coils. In realistic scenarios, improved power utilization was achieved from 17% to 60% and from 14% to 55% for an elliptical phantom and a region of interest in the abdomen, respectively, and an increase of the power utilization of 1 dB for a region of interest in the upper leg. In general, it is found that the VPC allows significant improvement in power utilization when the shimming solution demands only a few modes to be energized, while the technique can yield loss in power utilization in cases with many modes required at high power level.