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991.
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993.
William Kemnitzer Nilantha Sirisoma Chris May Ben Tseng John Drewe Sui Xiong Cai 《Bioorganic & medicinal chemistry letters》2009,19(13):3536-3540
We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC50 values of 0.008 and 0.004 μM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization. 相似文献
994.
995.
Klilah Hershko Vijaya L. Simhadri Adam Blaisdell Ryan C. Hunt Jordan Newell Sandra C. Tseng Alon Y. Hershko Jae Won Choi Zuben E. Sauna Andrew Wu Richard J. Bram Anton A. Komar Chava Kimchi-Sarfaty 《The Journal of biological chemistry》2012,287(53):44361-44371
The protease ADAMTS13 (a
disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients. 相似文献
996.
As the speed of mass spectrometers, sophistication of sample fractionation, and complexity of experimental designs increase,
the volume of tandem mass spectra requiring reliable automated analysis continues to grow. Software tools that quickly, effectively,
and robustly determine the peptide associated with each spectrum with high confidence are sorely needed. Currently available
tools that postprocess the output of sequence-database search engines use three techniques to distinguish the correct peptide
identifications from the incorrect: statistical significance re-estimation, supervised machine learning scoring and prediction,
and combining or merging of search engine results. We present a unifying framework that encompasses each of these techniques
in a single model-free machine-learning framework that can be trained in an unsupervised manner. The predictor is trained
on the fly for each new set of search results without user intervention, making it robust for different instruments, search
engines, and search engine parameters. We demonstrate the performance of the technique using mixtures of known proteins and
by using shuffled databases to estimate false discovery rates, from data acquired on three different instruments with two
different ionization technologies. We show that this approach outperforms machine-learning techniques applied to a single
search engine’s output, and demonstrate that combining search engine results provides additional benefit. We show that the
performance of the commercial Mascot tool can be bested by the machine-learning combination of two open-source tools X!Tandem
and OMSSA, but that the use of all three search engines boosts performance further still. The Peptide identification Arbiter
by Machine Learning (PepArML) unsupervised, model-free, combining framework can be easily extended to support an arbitrary
number of additional searches, search engines, or specialized peptide–spectrum match metrics for each spectrum data set. PepArML
is open-source and is available from .
Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users. 相似文献
997.
998.
Lihoradova O Kalveram B Indran SV Lokugamage N Juelich TL Hill TE Tseng CT Gong B Fukushi S Morikawa S Freiberg AN Ikegami T 《Journal of virology》2012,86(14):7650-7661
Rift Valley fever virus (RVFV), belonging to the genus Phlebovirus, family Bunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-α) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-α nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans. 相似文献
999.
The gene for the DNA primase encoded by Salmonella typhimurium bacteriophage SP6 has been cloned and expressed in Escherichia coli and its 74-kDa protein product purified to homogeneity. The SP6 primase is a DNA-dependent RNA polymerase that synthesizes short oligoribonucleotides containing each of the four canonical ribonucleotides. GTP and CTP are both required for the initiation of oligoribonucleotide synthesis. In reactions containing only GTP and CTP, SP6 primase incorporates GTP at the 5'-end of oligoribonucleotides and CMP at the second position. On synthetic DNA templates, pppGpC dinucleotides are synthesized most rapidly in the presence of the sequence 5'-GCA-3'. This trinucleotide sequence, containing a cryptic dA at the 3'-end, differs from other known bacterial and phage primase recognition sites. SP6 primase shares some properties with the well-characterized E. colibacteriophage T7 primase. The T7 DNA polymerase can use oligoribonucleotides synthesized by SP6 primase as primers for DNA synthesis. However, oligoribonucleotide synthesis by SP6 primase is not stimulated by either the E. coli- or the T7-encoded ssDNA binding protein. An amino acid sequence alignment of the SP6 and T7 primases, which share only 22.4% amino acid identity, indicates amino acids likely critical for oligoribonucleotide synthesis as well as a putative Cys(3)His zinc finger motif that may be involved in DNA binding. 相似文献
1000.
This study investigated the neuromagnetic activities of self-paced finger lifting task and electrical median nerve stimulation in ten writer''s cramp patients and fourteen control subjects. The event-related de/synchronizations (ERD/ERS) of beta-band activity levels were evaluated and the somatosensory cortical activity levels were analyzed using equivalent-current dipole modeling. No significant difference between the patients and control subjects was found in the electrical stimulation-induced beta ERS and electrical evoked somatosensory cortical responses. Movement-related beta ERD did not differ between controls and patients. Notably, the amplitude of the beta ERS after termination of finger movement was significantly lower in the patients than in the control subjects. The reduced movement-related beta ERS might reflect an impairment of motor cortex deactivation. In conclusion, a motor dependent dysregulation of the sensorimotor network seems to be involved in the functional impairment of patients with writer''s cramp. 相似文献