Refine
Year of publication
- 2014 (167) (remove)
Institute
- Fachbereich Medizintechnik und Technomathematik (58)
- INB - Institut für Nano- und Biotechnologien (34)
- Fachbereich Chemie und Biotechnologie (25)
- Fachbereich Elektrotechnik und Informationstechnik (24)
- IfB - Institut für Bioengineering (24)
- Fachbereich Energietechnik (22)
- Fachbereich Luft- und Raumfahrttechnik (13)
- Fachbereich Wirtschaftswissenschaften (6)
- Fachbereich Bauingenieurwesen (4)
- Solar-Institut Jülich (4)
Language
- English (167) (remove)
Document Type
- Article (93)
- Conference Proceeding (51)
- Part of a Book (14)
- Book (3)
- Conference: Meeting Abstract (1)
- Conference Poster (1)
- Doctoral Thesis (1)
- Master's Thesis (1)
- Patent (1)
- Report (1)
Keywords
In co-operation with the German Aerospace Center, the Solar-Institut Jülich has been analyzing the different technologies that are available for methanol production from CO2 using solar energy. The aim of the project is to extract CO2 from industrial exhaust gases or directly from the atmosphere to recycle it by use of solar energy. Part of the study was the modeling and simulating of a methane reformer for the production of synthesis gas, which can be operated by solar or hybrid heat sources. The reformer has been simplified in such a way that the model is accurate and enables fast calculations. The developed pseudo-homogeneous one- dimensional model can be regarded as a kind of counter-current heat exchanger and is able to incorporate a steam reforming reaction as well as a dry reforming reaction.
Successful bone sawing requires a high level of skill and experience, which could be gained by the use of Virtual Reality-based simulators. A key aspect of these medical simulators is realistic force feedback. The aim of this paper is to model the bone sawing process in order to develop a valid training simulator for the bilateral sagittal split osteotomy, the most often applied corrective surgery in case of a malposition of the mandible. Bone samples from a human cadaveric mandible were tested using a designed experimental system. Image processing and statistical analysis were used for the selection of four models for the bone sawing process. The results revealed a polynomial dependency between the material removal rate and the applied force. Differences between the three segments of the osteotomy line and between the cortical and cancellous bone were highlighted.
This paper describes the modeling of a high-temperature storage system for an existing solar tower power plant with open volumetric receiver technology, which uses air as heat transfer medium (HTF). The storage system model has been developed in the simulation environment Matlab/Simulink®. The storage type under investigation is a packed bed thermal energy storage system which has the characteristics of a regenerator. Thermal energy can be stored and discharged as required via the HTF air. The air mass flow distribution is controlled by valves, and the mass flow by two blowers. The thermal storage operation strategy has a direct and significant impact on the energetic and economic efficiency of the solar tower power plants.
Developing a new production host from a blueprint: Bacillus pumilus as an industrial enzyme producer
(2014)
Therefore Fermat is right
(2014)
It was Fernat's idea to investigate how many numbers would fulfill the equation according to the Pythagorean Theorem if the exponent were increased to random, e.g. to a3 + b3 = c3. His question became therefore: are there two whole numbers the cubes of which add up to the volume of the cube of a third whole number? He posed this same question, of course, for all kinds of higher exponents, so that the equation could be generalized: is there an integral solution for the equation an + bn = cn, if the exponent n is higher than 2? Although in 1993, the English mathematician Andrew Wiles was able to produce an arithmetical proof for Fermat's famous theorem, I will show that there is a simple logical explanation which is also pragmatic and plausible and what is the result of a fundamental alternative idea how our world seems to be constructed.
In any books about genetics it can still today be read that our genetic code is called “degenerate” because it is still believed that 43 = 64 triplets encode the 20 essential amino acids. Indeed we have to assume the inverse law, what means that 34 = 81 exact code positions are really effective for our genetic code and encode the amino acids, compiled to proteins. This very important discovery leads to two completely new results that are limits-overlooking: 1) 34 (=81) genetic code positions mean exactly the same number as there are stable and naturally existing chemical elements in our universe. This famous argument should now lead to some alternative, as well as new fundamental conclusions about our existence. 2) A genetic code positioning system shows that nature is much smarter than expected: mutations are made less dangerous than believed, because they won't be that easily able any more to cause severe damages in the protein-synthesis. This should also lead to some alternative views upon evolution of life.
Objectives
The aim of this study was to identify characteristics of phosphorus (³¹P) spectra of the human prostate and to investigate changes of individual phospholipid metabolites in prostate cancer through in vivo ³¹P magnetic resonance spectroscopic imaging (MRSI) at 7 T.
Materials and Methods
In this institutional review board–approved study, 15 patients with biopsy-proven prostate cancer underwent T₂-weighted magnetic resonance imaging and 3-dimensional ³¹P MRSI at 7 T. Voxels were selected at the tumor location, in normal-appearing peripheral zone tissue, normal-appearing transition zone tissue, and in the base of the prostate close to the seminal vesicles. Phosphorus metabolite ratios were determined and compared between tissue types.
Results
Signals of phosphoethanolamine (PE) and phosphocholine (PC) were present and well resolved in most ³¹P spectra in the prostate. Glycerophosphocholine signals were observable in 43% of the voxels in malignant tissue, but in only 10% of the voxels in normal-appearing tissue away from the seminal vesicles. In many spectra, independent of tissue type, 2 peaks resonated in the chemical shift range of inorganic phosphate, possibly representing 2 separate pH compartments. The PC/PE ratio in the seminal vesicles was highly elevated compared with the prostate in 5 patients. A considerable overlap of ³¹P metabolite ratios was found between prostate cancer and normal-appearing prostate tissue, preventing direct discrimination of these tissues. The only 2 patients with high Gleason scores tumors (≥4+5) presented with high PC and glycerophosphocholine levels in their cancer lesions.
Conclusions
Phosphorus MRSI at 7 T shows distinct features of phospholipid metabolites in the prostate gland and its surrounding structures. In this exploratory study, no differences in ³¹P metabolite ratios were observed between prostate cancer and normal-appearing prostate tissue possibly because of the partial volume effects of small tumor foci in large MRSI voxels.
Network theory provides novel concepts that promise an improved characterization of interacting dynamical systems. Within this framework, evolving networks can be considered as being composed of nodes, representing systems, and of time-varying edges, representing interactions between these systems. This approach is highly attractive to further our understanding of the physiological and pathophysiological dynamics in human brain networks. Indeed, there is growing evidence that the epileptic process can be regarded as a large-scale network phenomenon. We here review methodologies for inferring networks from empirical time series and for a characterization of these evolving networks. We summarize recent findings derived from studies that investigate human epileptic brain networks evolving on timescales ranging from few seconds to weeks. We point to possible pitfalls and open issues, and discuss future perspectives.
It is well known that the degradation environment can strongly influence the biodegradability and kinetics of biodegradation processes of polymers. Therefore, besides the monitoring of the degradation process, it is also necessary to control the medium in which the degradation takes place. In this work, a micromachined multi-parameter sensor chip for the control of the polymer-degradation medium has been developed. The chip combines a capacitive field-effect pH sensor, a four-electrode electrolyte-conductivity sensor and a thin-film Pt-temperature sensor. The results of characterization of individual sensors are presented. In addition, the multi-parameter sensor chip together with an impedimetric polymer-degradation sensor was simultaneously characterized in degradation solutions with different pH and electrolyte conductivity. The obtained results demonstrate the feasibility of the multi-parameter sensor chip for the control of the polymer-degradation medium.
The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
Purpose
To demonstrate that high quality T₂-weighted (T2w) turbo spin-echo (TSE) imaging of the complete prostate can be achieved routinely and within safety limits at 7 T, using an external transceive body array coil only.
Methods
Nine healthy volunteers and 12 prostate cancer patients were scanned on a 7 T whole-body system. Preparation consisted of B₀ and radiofrequency shimming and localized flip angle calibration. T₁ and T₂ relaxation times were measured and used to define the T2w-TSE protocol. T2w imaging was performed using a TSE sequence (pulse repetition time/echo time 3000–3640/71 ms) with prolonged excitation and refocusing pulses to reduce specific absorption rate.
Results
High quality T2w TSE imaging was performed in less than 2 min in all subjects. Tumors of patients with gold-standard tumor localization (MR-guided biopsy or prostatectomy) were well visualized on 7 T imaging (n = 3). The number of consecutive slices achievable within a 10-g averaged specific absorption rate limit of 10 W/kg was ≥28 in all subjects, sufficient for full prostate coverage with 3-mm slices in at least one direction.
Conclusion
High quality T2w TSE prostate imaging can be performed routinely and within specific absorption rate limits at 7 T with an external transceive body array.
A technology reference study for a solar polar mission is presented. The study uses novel analytical methods to quantify the mission design space including the required sail performance to achieve a given solar polar observation angle within a given timeframe and thus to derive mass allocations for the remaining spacecraft sub-systems, that is excluding the solar sail sub-system. A parametric, bottom-up, system mass budget analysis is then used to establish the required sail technology to deliver a range of science payloads, and to establish where such payloads can be delivered to within a given timeframe. It is found that a solar polar mission requires a solar sail of side-length 100–125 m to deliver a ‘sufficient value’ minimum science payload, and that a 2.5 μm sail film substrate is typically required, however the design is much less sensitive to the boom specific mass.
One of the priority trends of carbon nanotechnology is creation of nanocomposite systems. Such carbon nanostructured composites were produced using - raw materials based on the products of agricultural waste, such as grape stones, apricot stones, rice husk. These products have a - wide spectrum of application and can be obtained in large quantities. The Institute of Combustion Problems has carried out the work on synthesis of the nanostructured carbon sorbents for multiple applications including the field of biomedicine. The article presents the data on the synthesis and physico-chemical properties of carbonaceous sorbents using physicochemical methods of investigation: separation and purification of biomolecules; isolation of phytohormone - fusicoccin; adsorbent INGO-1 in the form of an adsorption column for blood detoxification, oral (entero) sorbent - INGO-2; the study of efferent and probiotic properties and sorption activity in regard to the lipopolysaccharide (LPS), new biocomposites - based on carbonized rice husk (CRH) and cellular microorganisms; the use of CRH in wound treatment. A new material for blood detoxication (INGO-1) has been obtained. Adsorption of p-cresyl sulfate and indoxyl sulfate has shown that active carbon adsorbent can remove clinically significant level of p-cresyl sulfate and indoxyl sulfate from human plasma. Enterosorbent INGO-2 possesses high adsorption activity in relation to Gram-negative bacteria and their endotoxins. INGO-2 slows down the growth of conditionally pathogenic microorganisms, without having a negative effect on bifido and lactobacteria. The use of enterosorbent INGO-2 for sorption therapy may provide a solution to a complex problem - detoxication of the digestive tract and normalization of the intestinal micro ecology. The immobilized probiotic called "Riso-lact" was registered at the Ministry of Health of the Republic of Kazakhstan as a biologically active food additive. The developed technology is patented and provides production of the medicine in the form of freeze-dried biomass immobilized in vials.
A technology reference study for a displaced Lagrange point space weather mission is presented. The mission builds on previous concepts, but adopts a strong micro-spacecraft philosophy to deliver a low mass platform and payload which can be accommodated on the DLR/ESA Gossamer-3 technology demonstration mission. A direct escape from Geostationary Transfer Orbit is assumed with the sail deployed after the escape burn. The use of a miniaturized, low mass platform and payload then allows the Gossamer-3 solar sail to potentially double the warning time of space weather events. The mission profile and mass budgets will be presented to achieve these ambitious goals.
The chemical imaging sensor, which is based on the principle of the light-addressable potentiometric sensor (LAPS), is a powerful tool to visualize the spatial distribution of chemical species on the sensor surface. The spatial resolution of this sensor depends on the diffusion of photocarriers excited by a modulated light. In this study, a novel hybrid fiber-optic illumination was developed to enhance the spatial resolution. It consists of a modulated light probe to generate a photocurrent signal and a ring of constant light, which suppresses the lateral diffusion of minority carriers excited by the modulated light. It is demonstrated that the spatial resolution was improved from 92 μm to 68 μm.
In this study, a high-speed chemical imaging system was developed for visualization of the interior of a microfluidic channel. A microfluidic channel was constructed on the sensor surface of the light-addressable potentiometric sensor (LAPS), on which the ion concentrations could be measured in parallel at up to 64 points illuminated by optical fibers. The temporal change of pH distribution inside the microfluidic channel was recorded at a maximum rate of 100 frames per second (fps). The high frame rate allowed visualization of moving interfaces and plugs in the channel even at a flow velocity of 111 mm/s, which suggests the feasibility of plug-based microfluidic devices for flow-injection analysis (FIA).
An enzyme system organized in a flow device was used to mimic a reversible Controlled NOT (CNOT) gate with two input and two output signals. Reversible conversion of NAD⁺ and NADH cofactors was used to perform a XOR logic operation, while biocatalytic hydrolysis of p-nitrophenyl phosphate resulted in an Identity operation working in parallel. The first biomolecular realization of a CNOT gate is promising for integration into complex biomolecular networks and future biosensor/biomedical applications.
A microcavity-based deoxyribonucleic acid (DNA) optical biosensor is demonstrated for the first time using synthetic sapphire for the optical cavity. Transmitted and elastic scattering intensity at 1510 nm are analyzed from a sapphire microsphere (radius 500 μm, refractive index 1.77) on an optical fiber half coupler. The 0.43 nm angular mode spacing of the resonances correlates well with the optical size of the sapphire sphere. Probe DNA consisting of a 36-mer fragment was covalently immobilized on a sapphire microsphere and hybridized with a 29-mer target DNA. Whispering gallery modes (WGMs) were monitored before the sapphire was functionalized with DNA and after it was functionalized with single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). The shift in WGMs from the surface modification with DNA was measured and correlated well with the estimated thickness of the add-on DNA layer. It is shown that ssDNA is more uniformly oriented on the sapphire surface than dsDNA. In addition, it is shown that functionalization of the sapphire spherical surface with DNA does not affect the quality factor (Q≈104) of the sapphire microspheres. The use of sapphire is especially interesting because this material is chemically resilient, biocompatible, and widely used for medical implants.
Validation of a novel method for detecting and stabilizing malfunctioning areas in fuel cell stacks
(2014)
In this paper a setup for detecting malfunctioning areas of MEAs in fuel cell stacks is described. Malfunctioning areas generate electric cross currents inside bipolar plates. To exploit this we suggest bipolar plates consisting not of two but of three layers. The third one is a highly conducting layer and segmented such that the cross currents move along the segments to the surface of the stack where they can be measured by an inductive sensor. With this information a realistic model can be used to detect the malfunctioning area. Furthermore the third layer will prevent any current inhomogeneity of a malfunctioning cell to spread to neighbouring cells in the stack. In this work the results of measurements in a realistic cell setup will be compared with the results obtained in simulation studies with the same configuration. The basis for the comparison is the reliable characterisation of the electrical properties of the cell components and the implication of these results into the simulation model. The experimental studies will also show the limits in the maximum number of segments, which can be used for a reliable detection of cross currents.
The problem of fair and privacy-preserving ordered set reconciliation arises in a variety of applications like auctions, e-voting, and appointment reconciliation. While several multi-party protocols have been proposed that solve this problem in the semi-honest model, there are no multi-party protocols that are secure in the malicious model so far. In this paper, we close this gap. Our newly proposed protocols are shown to be secure in the malicious model based on a variety of novel non-interactive zero-knowledge-proofs. We describe the implementation of our protocols and evaluate their performance in comparison to protocols solving the problem in the semi-honest case.
A new trend in automation is to deploy so-called cyber-physical systems (CPS) which combine computation with physical processes. The novel RoboCup Logistics League Sponsored by Festo (LLSF) aims at such CPS logistic scenarios in an automation setting. A team of robots has to produce products from a number of semi-finished products which they have to machine during the game. Different production plans are possible and the robots need to recycle scrap byproducts. This way, the LLSF is a very interesting league offering a number of challenging research questions for planning, coordination, or communication in an application-driven scenario. In this paper, we outline the objectives of the LLSF and present steps for developing the league further towards a benchmark for logistics scenarios for CPS. As a major milestone we present the new automated referee system which helps in governing the game play as well as keeping track of the scored points in a very complex factory scenario.
In this work, the catalyst manganese(IV) oxide (MnO2), of calorimetric gas sensors (to monitor the sterilization agent vaporized hydrogen peroxide) has been investigated in more detail. Chemical analyses by means of X-ray-induced photoelectron spectroscopy have been performed to unravel the surface chemistry prior and after exposure to hydrogen peroxide vapor at elevated temperature, as applied in the sterilization processes of beverage cartons. The surface characterization reveals a change in oxidation states of the metal oxide catalyst after exposure to hydrogen peroxide. Additionally, a cleaning effect of the catalyst, which itself is attached to the sensor surface by means of a polymer interlayer, could be observed.
High gradient magnetic separation (HGMS) has been established since the early 1970s. A more recent application of these systems is the use in bioprocesses. To integrate the HGMS in a fermentation process, it is necessary to optimize the separation matrix with regard to the magnetic separation characteristics and permeability of the non-magnetizable components of the fermentation broth. As part of the work presented here, a combined fluidic and magnetic force finite element model simulation was created using the software COMSOL Multiphysics and compared with separation experiments. Finally, as optimal lattice orientation of the separation matrix, a transversal rhombohedral arrangement was defined. The high suitability of the new filter matrix has been verified by separation experiments.
This paper develops a new finite element method (FEM)-based upper bound algorithm for limit and shakedown analysis of hardening structures by a direct plasticity method. The hardening model is a simple two-surface model of plasticity with a fixed bounding surface. The initial yield surface can translate inside the bounding surface, and it is bounded by one of the two equivalent conditions: (1) it always stays inside the bounding surface or (2) its centre cannot move outside the back-stress surface. The algorithm gives an effective tool to analyze the problems with a very high number of degree of freedom. Our numerical results are very close to the analytical solutions and numerical solutions in literature.
This paper describes two courses on
simulation methods for graduate students:
“Simulation Methods” and “Simulation and
Optimization in Virtual Engineering” The
courses were planned to teach young engineers
how to work with simulation software as well as
to understand the necessary mathematical background.
As simulation software COMSOL is
used. The main philosophy was to combine
theory and praxis in a way that motivates the
students. In addition “soft skills” should be
improved. This was achieved by project work as
final examination. As underlying didactical principle
the ideas of Bloom’s revised taxonomy
were followed. The paper basically focusses on
educational aspects, e.g. how to structure the
course, plan the exercises, organize the project
work and include practical COMSOL examples.
Among the variety of transducer concepts proposed for label-free detection of biomolecules, the semiconductor field-effect device (FED) is one of the most attractive platforms. As medical techniques continue to progress towards diagnostic and therapies based on biomarkers, the ability of FEDs for a label-free, fast and real-time detection of multiple pathogenic and physiologically relevant molecules with high specificity and sensitivity offers very promising prospects for their application in point-of-care and personalized medicine for an early diagnosis and treatment of diseases. The presented paper reviews recent advances and current trends in research and development of different FEDs for label-free, direct electrical detection of charged biomolecules by their intrinsic molecular charge. The authors are mainly focusing on the detection of the DNA hybridization event, antibody-antigen affinity reaction as well as clinically relevant biomolecules such as cardiac and cancer biomarkers.
An array of electrically isolated nanoplate field-effect silicon-on-insulator (SOI) capacitors as a new transducer structure for multiparameter (bio-)chemical sensing is presented. The proposed approach allows addressable biasing and electrical readout of multiple nanoplate field-effect capacitive (bio-)chemical sensors on the same SOI chip, as well as differential-mode measurements. The realized sensor chip has been applied for pH and penicillin concentration measurements, electrical monitoring of polyelectrolyte multilayer formation, and the label-free electrical detection of consecutive deoxyribonucleic acid (DNA) hybridization and denaturation events.
In this work the transient simulations of four hybrid solar tower power plant concepts with open-volumetric receiver technology for a location in Barstow-Daggett, USA, are presented. The open-volumetric receiver uses ambient air as heat transfer fluid and the hybridization is realized with a gas turbine. The Rankine cycle is heated by solar-heated air and/or by the gas turbine's flue gases. The plant can be operated in solar-only, hybrid parallel or combined cycle-only mode as well as in any intermediate load levels where the solar portion can vary between 0 to 100%.
The simulated plant is based on the configuration of a solar-hybrid power tower project, which is in planning for a site in Northern Algeria. The meteorological data for Barstow-Daggett was taken from the software meteonorm. The solar power tower simulation tool has been developed in the simulation environment MATLAB/Simulink and is validated.
This study describes a label-free impedimetric sensor based on short ssDNA recognition elements for the detection of hybridization events. We concentrate on the elucidation of the influence of target length and recognition sequence position on the sensorial performance. The impedimetric measurements are performed in the presence of the redox system ferri-/ferrocyanide and show an increase in charge transfer resistance upon hybridization of ssDNA to the sensor surface. Investigations on the impedimetric signal stability demonstrate a clear influence of the buffers used during the sensor preparation and the choice of the passivating mercaptoalcanol compound. A stable sensor system has been developed, enabling a reproducible detection of 25mer target DNA in the low nanomolar range. After hybridization, a sensor regeneration can be reached with deionized water by adjustment of effective convection conditions, ensuring a sensor reusability. By investigations of longer targets with overhangs exposed to the solution, we can demonstrate applicability of the impedimetric detection for longer ssDNA. However, a decreasing charge transfer resistance change (ΔRct) is found by extending the overhang. As a strategy to increase the impedance change for longer target strands, the position of the recognition sequence can be designed in a way that a small overhang is exposed to the electrode surface. This is found to result in an increase in the relative Rct change. These results suggest that DNA and consequently negative charge near the electrode possess a larger impact on the impedimetric signal than DNA further away.
The 2nd edition of the lightning risk management
standard (IEC 62305-2) considers structures, which may
endanger environment. In these cases, the loss is not limited to
the structure itself, which is valid for usual structures. In the past
(Edition 1) this danger was simply taken into account by a special
hazard factor, multiplying the existing risk for the structure with
a number. Now, in the edition 2, we add to the risk for the
structure itself a “second risk” due to the losses outside the
structure. The losses outside can be treated independently from
what occurs inside. This is a major advantage to analyze the risk
for sensitive structures, like chemical plants, nuclear plants, or
structures containing explosives, etc. In this paper, the existing
procedure given by the European version EN 62305-2 Ed.2 is
further developed and applied to a few structures.
Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography–tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans.
Multimodal bioimage sensor
(2014)
To visualize the biochemical distribution two-dimensionally, we invented a solid-state-type ion image sensor that indicates the chemical activity of solutions and cells. The device, which consists of a CCD array covered with a functionalized membrane to detect charge accumulation, is highly sensitive to changes in the concentration and two-dimensional distribution of ions and biomaterials.
In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.