2,848 research outputs found
Exploring the feasibility of on-site earthquake early warning using close-in records of the 2007 Noto Hanto earthquake
No full textSynthesis of Simplified YM-254890 Analogs
Full text linkG Protein Coupled Receptors (GPCR’s) are responsible for a multitude of physiological, cellular, and disease processes. GPCR’s signal through non-receptor based heterotrimeric G proteins and since G proteins effectively mediate GPCR signal transduction they are attractive therapeutic targets. However, little is known about the signaling pathways associated with individual G proteins. For this reason, there is intense interest in the development of chemical probes that can help identify the downstream biochemistry of individual G proteins.
One small molecule natural product that shows promise along these lines is YM-254890 (YM). YM has been shown to specifically and potently inhibit the α subunit of the G protein Gq. Further studies of the natural product have been hampered because YM has yet to be synthesized due to its complex cyclic depsipeptide structure. By studying the X-ray crystal structure of YM bound to Gqα, the contact points between the molecule and the protein have been elucidated, and from this we targeted a simplified analog substructure. This analog structure preserves the protein contact points of YM while reducing the complexity of 22 member ring structure of YM. The heart of the project undertaken centers on the development of a convergent synthetic route to the analog’s core ring structure that is general enough to enable the synthesis of a variety of derivatives in the future.
To this effect we have synthesized two different YM analogs. The first, WU-07047, was completed with an overall yield of 6.4% and a longest linear reaction sequence of 10 steps. Initial biological testing of WU-07047 has shown that the simplified molecule is biologically active, albeit at a less potent level than YM. We currently have multiple collaborators testing the effectiveness of WU-07047 in different in-vivo studies. Before undertaking further biological studies in our labs, we wanted to increase the potency of the molecule.
To this end we reintroduced an intramolecular hydrogen bond in the molecule that had been lost in simplified WU-0747 molecule. The 2nd molecule synthesized, WU-09060, was completed using the same convergent synthetic approach developed for WU-07047 and yielded the target molecule with an overall yield of 1.8% and a longest linear reaction sequence of 10 steps. Initial biological testing has shown that the reintroduction of the intramolecular hydrogen bond has had little effect on the potency of the molecule and therefore is not worth the extra synthetic effort. During the synthesis of the WU-09060 molecule we were also able to probe the effects of the top bridging structure of the molecule on ease of overall molecule synthesis, which has larger implications on the synthesis of this class of molecule
Toward the Selective Inhibition of G Proteins: Total Synthesis of a Simplified YM-254890 Analog
No full textA simplified analog
(WU-07047) of the selective Gαq/11 inhibitor
YM-254890 has been synthesized, and an initial probe of its activity
conducted. In the analog, the two peptide-based linkers in the cyclic
YM-254890 have been replaced with hydrocarbon chains. This enables
a convergent approach to the synthesis of the analog. Biochemical
assays showed that while the simplified analog is not as potent as
YM-254890, it does still inhibit Gq
Tissue distribution of arsenic species in rabbits after single and multiple parenteral administration of arsenic trioxide: tissue accumulation and the reversibility after washout are tissue-selective.
No full text
SAPS 3 at dialysis commencement is predictive of hospital mortality in patients supported by extracorporeal membrane oxygenation and acute dialysis
No full textThe construction of binary Huffman equivalent codes with a greater number of synchronising codewords
No full text[[abstract]]An inherent problem with a Variable-Length Code (VLC) is that even a single bit error can cause a loss of synchronisation, and thus lead to error propagation. Codeword synchronisation has been extensively studied as a means to overcome this drawback and efficiently stop error propagation. In this paper, we first present the sufficient and necessary conditions for the existence of binary Huffman equivalent codes with the shortest, or at most two shortest, synchronising codeword(s) of length m + 1, where m (>1) is the shortest codeword length. Next, based on the results, we propose a unified approach for constructing each of these binary Huffman equivalent codes with the shortest, or at most two shortest, synchronising codeword(s) of length m + 1, if such a code exists for a given length vector.[[note]]SC
Measuring ERP success: the ultimate users' view
No full text[[abstract]]Purpose - Enterprise resource planning (ERP) is now considered to be the price of entry for running a business. However, ERP systems are complex and expensive, and the decision to install an ERP system necessitates a choice of mechanisms for determining whether ERP is needed and, once implemented, whether it is successful. User satisfaction is one evaluation mechanism for determining system success. This study develops a reliable and valid instrument for measuring ERP ultimate-user satisfaction. Design/methodology/approach - Initial ERP system characteristics and the implementation context were investigated. Some previously validated instruments were selected for examination using rigorous interview techniques. A modified version was developed and pre-tested. The instrument was then used to administer a test to 264 Taiwanese users that interact directly with an ERP system. Findings - The results suggest a ten-item instrument to measure three components of ultimate-user satisfaction in an ERP environment: ERP project team and service, ERP product, and user knowledge and involvement. Originality/value - This study has conducted a rigorous scale development procedure to establish a reliable and valid instrument for measuring ERP ultimate-user satisfaction.[[note]]SSC
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