733 research outputs found
Structural comparison of the cytochrome P450 enzymes CYP106A1 and CYP106A2 provides insight into their differences in steroid conversion
Understanding the structural basis of the selectivity of steroid hydroxylation
requires detailed structural and functional investigations on various steroid
hydroxylases with different selectivities, such as the bacterial cytochrome
P450 enzymes. Here, the crystal structure of the cytochrome P450
CYP106A1 from Priestia megaterium was solved. CYP106A1 exhibits a rare
additional structural motif of a cytochrome P450, a sixth β-sheet. The protein was found in different unusual conformations corresponding to both open
and closed forms even when crystallized without any known substrate. The
structural comparison of CYP106A1 with the previously investigated
CYP106A2, including docking studies for both isoforms with the substrate
cortisol, reveals a completely different orientation of the steroid molecule in
the active sites. This distinction convincingly explains the experimentally
observed differences in substrate conversion and product formation by the two
enzymes
Quadrupedal Robots with Stiff and Compliant Actuation
In the broader context of quadrupedal locomotion, this overview article introduces and compares two platforms that are similar in structure, size, and morphology, yet differ greatly in their concept of actuation. The first, ALoF, is a classically stiff actuated robot that is controlled kinematically, while the second, StarlETH, uses a soft actuation scheme based on Changedhighly compliant series elastic actuators. We show how this conceptual difference influences design and control of the robots, compare the hardware of the two systems, and show exemplary their advantages in different application
Spotlight on CYP4B1
The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of
xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities.
Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and
fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic
and endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by
the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly,
CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its
predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human
CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved
proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers
and potential roles in cancer development have been reported for the human enzyme. This review
will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism
of endogenous and exogenous compounds, structural properties, and cancer association, as well as
its potential application in suicide gene approaches for targeted cancer therapy
Identification and circumvention of bottlenecks in CYP21A2-mediated premedrol production using recombinant Escherichia coli
Synthetic glucocorticoids such as methylprednisolone are compounds of fundamental interest to the pharmaceutical industry as their modifications within the sterane scaffold lead to higher inflammatory potency and reduced side effects compared with their parent compound cortisol. In methylprednisolone production, the complex chemical hydroxylation of its precursor medrane in position C21 exhibits poor stereo‐ and regioselectivity making the process unprofitable and unsustainable. By contrast, the use of a recombinant E. coli system has recently shown high suitability and efficiency. In this study, we aim to overcome limitations in this biotechnological medrane conversion yielding the essential methylprednisolone‐precursor premedrol by optimizing the CYP21A2‐based whole‐cell system on a laboratory scale. We successfully improved the whole‐cell process in terms of premedrol production by (a) improving the electron supply to CYP21A2; here we use the N‐terminally truncated version of the bovine NADPH‐dependent cytochrome P450 reductase (bCPR−27) and coexpression of microsomal cytochrome b5; (b) enhancing substrate access to the heme by modification of the CYP21A2 substrate access channel; and (c) circumventing substrate inhibition which is presumed to be the main limiting factor of the presented system by developing an improved fed‐batch protocol. By overcoming the presented limitations in whole‐cell biotransformation, we were able to achieve a more than 100% improvement over the next best system under equal conditions resulting in 691 mg·L−1·d−1 premedrol
Real-Time qPCR-Based Detection of Circulating Tumor Cells from Blood Samples of Adjuvant Breast Cancer Patients: A Preliminary Study
Background: Circulating tumor cells (CTCs) are cells that detach from a primary tumor, circulate through the blood stream and lymphatic vessels, and are considered to be the main reason for remote metastasis. Due to their origin, tumor cells have different gene expression levels than the surrounding blood cells. Therefore, they might be detectable in blood samples from breast cancer patients by real-time quantitative polymerase chain reaction (RT-qPCR). Materials and Methods: Blood samples of healthy donors and adjuvant breast cancer patients were withdrawn and the cell fraction containing white blood cells and tumor cells was enriched by density gradient centrifugation. RNA was isolated and reverse transcribed to cDNA, which was then used in TaqMan real-time PCR against cytokeratin (CK)8, CK18 and CK19. 18S and GAPDH were used as controls. Results: All 3 CKs were, on average, found to be significantly higher expressed in adjuvant breast cancer samples compared to negative controls, probably due to the presence of CTCs. Unfortunately, gene expression levels could not be correlated to tumor characteristics. Conclusions: RT-qPCR could make up a new approach for the detection of CTCs from blood samples of breast cancer patients, but a correlation of the PCR data to gold standard methods in CTC detection would help to further improve the informative value of the qPCR results. (C) 2016 S. Karger GmbH, Freibur
Cellular automaton decoders of topological quantum memories in the fault tolerant setting
Active error decoding and correction of topological quantum codes—in particular the toric code—remains one of the most viable routes to large scale quantum information processing. In contrast, passive error correction relies on the natural physical dynamics of a system to protect encoded quantum information. However, the search is ongoing for a completely satisfactory passive scheme applicable to locally interacting two-dimensional systems. Here, we investigate dynamical decoders that provide passive error correction by embedding the decoding process into local dynamics. We propose a specific discrete time cellular-automaton decoder in the fault tolerant setting and provide numerical evidence showing that the logical qubit has a survival time extended by several orders of magnitude over that of a bare unencoded qubit. We stress that (asynchronous) dynamical decoding gives rise to a Markovian dissipative process. We hence equate cellular-automaton decoding to a fully dissipative topological quantum memory, which removes errors continuously. In this sense, uncontrolled and unwanted local noise can be corrected for by a controlled local dissipative process. We analyze the required resources, commenting on additional polylogarithmic factors beyond those incurred by an ideal constant resource dynamical decoder
The strong coupling constant at small momentum as an instanton detector
We present a study of at small p computed from the lattice.
It shows a dramatic law which can be understood within an
instanton liquid model. In this framework the prefactor gives a direct measure
of the instanton density in thermalised configurations. A preliminary result
for this density is 5.27(4) fm^{-4}.Comment: 12 pages, 4 figure
PANORAMIC - A Pure Parallel Wide Area Legacy Imaging Survey at 1-5 Micron
Where HST has characterized the UV universe to z=6-7 and beyond, JWST is designed to take the crucial next step and characterize the UV universe to z=12-15 (a factor of 2 in expansion rate), at only ~300 Myr after the Big Bang where we expect the first galaxies to form. Additionally, JWST for the first time allows studies of the restframe optical emission to z=10, a huge leap from the current z=3 (HST). To fully capitalize on JWST's unparalleled imaging AND spectroscopic capabilities, it is critical, however, to find the most precious intrinsically luminous candidate galaxies early in the mission. Large area imaging is thus needed from day one. Here, we propose to exploit the unique opportunity offered by pure parallel observing to efficiently obtain such a wide-area reference survey over 0.4 sq degrees in 6 NIRCam filters. By probing 7x larger area than any other currently planned (GTO/ERS) program our survey will probe a unique discovery space with unprecedented imaging at 1-5micron. These data overcome two major outstanding limitations in our current extragalactic census using yet-undiscovered populations: (1) the brightest and most distant sources that ended the cosmic Dark Ages at z>9 and (2) red sources at
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