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Scheer, Nico ; Kapelyukh, Yury ; McEwan, Jillian ; Beuger, Vincent ; Stanley, Lesley A. ; Rode, Anja ; Wolf, C. Roland
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.
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.
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.
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.
Orzada, S. ; Maderwald, S. ; Poser, B. A. ; Johst, S. ; Kannengiesser, S. ; Ladd, M. E. ; Bitz, Andreas
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.
Kobus, Thiele ; Bitz, Andreas ; Uden, Mark J. van ; Lagemaat, Miram W. ; Rothgang, Eva ; Orzada, Stephan ; Heerschap, Arend ; Scheenen, Tom W. J.
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.
Prioritization is an essential task within requirements engineering to cope with complexity and to establish focus properly. The 3rd Workshop on Requirements Prioritization for customer oriented Software Development (RePriCo’12) focused on requirements prioritization and adjacent themes in the context of customer oriented development of bespoke and standard software. Five submissions have been accepted for the proceedings and for presentation. The report summarizes and points out key findings.
Stadler, Andreas M. ; Garvey, G. J. ; Bocahut, A. ; Sacquin-Mora, S. ; Digel, Ilya ; Schneider, G. J. ; Natali, F. ; Artmann, Gerhard ; Zaccai, G.
Thermodynamic stability, configurational motions and internal forces of haemoglobin (Hb) of three endotherms (platypus, Ornithorhynchus anatinus; domestic chicken, Gallus gallus domesticus and human, Homo sapiens) and an ectotherm (salt water crocodile, Crocodylus porosus) were investigated using circular dichroism, incoherent elastic neutron scattering and coarse-grained Brownian dynamics simulations. The experimental results from Hb solutions revealed a direct correlation between protein resilience, melting temperature and average body temperature of the different species on the 0.1 ns time scale. Molecular forces appeared to be adapted to permit conformational fluctuations with a root mean square displacement close to 1.2 Å at the corresponding average body temperature of the endotherms. Strong forces within crocodile Hb maintain the amplitudes of motion within a narrow limit over the entire temperature range in which the animal lives. In fully hydrated powder samples of human and chicken, Hb mean square displacements and effective force constants on the 1 ns time scale showed no differences over the whole temperature range from 10 to 300 K, in contrast to the solution case. A complementary result of the study, therefore, is that one hydration layer is not sufficient to activate all conformational fluctuations of Hb in the pico- to nanosecond time scale which might be relevant for biological function. Coarse-grained Brownian dynamics simulations permitted to explore residue-specific effects. They indicated that temperature sensing of human and chicken Hb occurs mainly at residues lining internal cavities in the β-subunits.
Loeb, Horst Wolfgang ; Schartner, Karl-Heinz ; Dachwald, Bernd ; Ohndorf, Andreas ; Seboldt, Wolfgang
There is common agreement within the scientific community that in order to understand our local galactic environment it will be necessary to send a spacecraft into the region beyond the solar wind termination shock. Considering distances of 200 AU for a new mission, one needs a spacecraft traveling at a speed of close to 10 AU/yr in order to keep the mission duration in the range of less than 25 yrs, a transfer time postulated by European Space Agency (ESA). Two propulsion options for the mission have been proposed and discussed so far: the solar sail propulsion and the ballistic/radioisotope-electric propulsion (REP). As a further alternative, we here investigate a combination of solar-electric propulsion (SEP) and REP. The SEP stage consists of six 22-cms diameter RIT-22 ion thrusters working with a high specific impulse of 7377 s corresponding to a positive grid voltage of 5 kV. Solar power of 53 kW at begin of mission (BOM) is provided by a lightweight solar array.
Disruption experiments targeted at the Bacillus licheniformis degSU operon and GFP-reporter analysis provided evidence for promoter activity immediately upstream of degU. pMutin mediated concomitant introduction of the degU32 allele – known to cause hypersecretion in Bacillus subtilis – resulted in a marked increase in protease activity. Application of 5-fluorouracil based counterselection through establishment of a phosphoribosyltransferase deficient Δupp strain eventually facilitated the marker-free introduction of degU32 leading to further protease enhancement achieving levels as for hypersecreting wild strains in which degU was overexpressed. Surprisingly, deletion of rapG – known to interfere with DegU DNA-binding in B. subtilis – did not enhance protease production neither in the wild type nor in the degU32 strain. The combination of degU32 and Δupp counterselection in the type strain is not only equally effective as in hypersecreting wild strains with respect to protease production but furthermore facilitates genetic strain improvement aiming at biological containment and effectiveness of biotechnological processes.
Abouzar, Maryam H. ; Poghossian, Arshak ; Cherstvy, Andrey G. ; Pedraza, Angela M. ; Ingebrandt, Sven ; Schöning, Michael Josef
Label-free electrical detection of consecutive deoxyribonucleic acid (DNA) hybridization/denaturation by means of an array of individually addressable field-effect-based nanoplate silicon-on-insulator (SOI) capacitors modified with gold nanoparticles (Au-NP) is investigated. The proposed device detects charge changes on Au-NP/DNA hybrids induced by the hybridization or denaturation event. DNA hybridization was performed in a high ionic-strength solution to provide a high hybridization efficiency. On the other hand, to reduce the screening of the DNA charge by counter ions and to achieve a high sensitivity, the sensor signal induced by the hybridization and denaturation events was measured in a low ionic-strength solution. High sensor signals of about 120, 90, and 80 mV were registered after the DNA hybridization, denaturation, and re-hybridization events, respectively. Fluorescence microscopy has been applied as reference method to verify the DNA immobilization, hybridization, and denaturation processes. An electrostatic charge-plane model for potential changes at the gate surface of a nanoplate field-effect sensor induced by the DNA hybridization has been developed taking into account both the Debye length and the distance of the DNA charge from the gate surface.
Real-time and reliable monitoring of the biogas process is crucial for a stable and efficient operation of biogas production in order to avoid digester breakdowns. The concentration of dissolved hydrogen (H₂) represents one of the key parameters for biogas process control. In this work, a one-chip integrated combined amperometric/field-effect sensor for monitoring the dissolved H₂ concentration has been developed for biogas applications. The combination of two different transducer principles might allow a more accurate and reliable measurement of dissolved H₂ as an early warning indicator of digester failures. The feasibility of the approach has been demonstrated by simultaneous amperometric/field-effect measurements of dissolved H₂ concentrations in electrolyte solutions. Both, the amperometric and the field-effect transducer show a linear response behaviour in the H₂ concentration range from 0.1 to 3% (v/v) with a slope of 198.4 ± 13.7 nA/% (v/v) and 14.9 ± 0.5 mV/% (v/v), respectively.
Field-effect capacitive electrolyte-insulator-semiconductor (EIS) sensors functionalised with citrate-capped gold nanoparticles (AuNP) have been used for the electrostatic detection of macromolecules by their intrinsic molecular charge. The EIS sensor detects the charge changes in the AuNP/macromolecule hybrids induced by the adsorption or binding events. A feasibility of the proposed detection scheme has been exemplary demonstrated by realising EIS sensors for the detection of poly-D-lysine molecules.
The construction of a statistical test is investigated which is based only on “reliability” and “precision” as quality criteria. The reliability of a statistical test is quantifiedin a straightforward way by the probability that the decision of the test is correct. However, the quantification of the precision of a statistical test is not at all evident. Thereforethe paper presents and discusses several approaches. Moreover the distinction of “nullhypothesis” and “alternative hypothesis” is not necessary any longer.