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161.
Kosuke Anan Moriyasu Masui Shinichiro Hara Miho Ohara Masaharu Kume Shoichi Yamamoto Shunji Shinohara Hiroki Tsuji Shinji Shimada Shigenori Yagi Nobuyoshi Hasebe Hiroyuki Kai 《Bioorganic & medicinal chemistry letters》2017,27(17):4194-4198
NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases. 相似文献
162.
Shigenori Hiraoka Shinichiro Maeshima Hideto Okazaki Hirokazu Hori Shinichiro Tanaka Sayaka Okamoto Reisuke Funahashi Kei Yagihashi Ikuko Fuse Naoki Asano Shigeru Sonoda 《BMC neurology》2017,17(1):211
Background
Thalamic hemorrhages cause motor paralysis, sensory impairment, and cognitive dysfunctions, all of which may significantly affect walking independence. We examined the factors related to independent walking in patients with thalamic hemorrhage who were admitted to a rehabilitation hospital.Methods
We evaluated 128 patients with thalamic hemorrhage (75 men and 53 women; age range, 40–93 years) who were admitted to our rehabilitation hospital. The mean duration from symptom onset to rehabilitation hospital admission was 27.2 ± 10.3 days, and the mean rehabilitation hospital stay was 71.0 ± 31.4 days. Patients’ neurological and cognitive functions were examined with the National Institutes of Health Stroke Scale (NIHSS) and Mini-Mental State Examination (MMSE), respectively. The relationship between patients’ scores on these scales and their walking ability at discharge from the rehabilitation hospital was analyzed. Additionally, a decision-tree analysis was used to create a model for predicting independent walking upon referral to the rehabilitation hospital.Results
Among the patients, 65 could walk independently and 63 could not. The two patient groups were significantly different in terms of age, duration from symptom onset to rehabilitation hospital admission, hematoma type, hematoma volume, neurological symptoms, and cognitive function. The decision-tree analysis revealed that the patient’s age, NIHSS score, MMSE score, hematoma volume, and presence of ventricular bleeding were factors that could predict independent walking.Conclusions
In patients with thalamic hemorrhage, the neurological symptoms, cognitive function, and neuroimaging factors at onset are useful for predicting independent walking.163.
164.
Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4): an archaeal DinB-like DNA polymerase with lesion-bypass properties akin to eukaryotic polη
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Franois Boudsocq Shigenori Iwai Fumio Hanaoka Roger Woodgate 《Nucleic acids research》2001,29(22):4607-4616
Phylogenetic analysis of Y-family DNA polymerases suggests that it can be subdivided into several discrete branches consisting of UmuC/DinB/Rev1/Rad30/Rad30A and Rad30B. The most diverse is the DinB family that is found in all three kingdoms of life. Searches of the complete genome of the crenarchaeon Sulfolobus solfataricus P2 reveal that it possesses a DinB homolog that has been termed DNA polymerase IV (Dpo4). We have overproduced and purified native Dpo4 protein and report here its enzymatic characterization. Dpo4 is thermostable, but can also synthesize DNA at 37°C. Under these conditions, the enzyme exhibits misinsertion fidelities in the range of 8 × 10–3 to 3 × 10–4. Dpo4 is distributive but at high enzyme to template ratios can synthesize long stretches of DNA and can substitute for Taq polymerase in PCR. On damaged DNA templates, Dpo4 can facilitate translesion replication of an abasic site, a cis-syn thymine–thymine dimer, as well as acetyl aminofluorene adducted- and cisplatinated-guanine residues. Thus, although phylogenetically related to DinB polymerases, our studies suggest that the archaeal Dpo4 enzyme exhibits lesion-bypass properties that are, in fact, more akin to those of eukaryotic polη. 相似文献
165.
Katarzyna H Masowska Florencia Villafaez Luisa Laureti Shigenori Iwai Vincent Pags 《Nucleic acids research》2022,50(4):2074
The DNA damage response (DDR) preserves the genetic integrity of the cell by sensing and repairing damages after a genotoxic stress. Translesion Synthesis (TLS), an error-prone DNA damage tolerance pathway, is controlled by PCNA ubiquitination. In this work, we raise the question whether TLS is controlled locally or globally. Using a recently developed method that allows to follow the bypass of a single lesion inserted into the yeast genome, we show that (i) TLS is controlled locally at each individual lesion by PCNA ubiquitination, (ii) a single lesion is enough to induce PCNA ubiquitination and (iii) PCNA ubiquitination is imperative for TLS to occur. More importantly, we show that the activation of the DDR that follows a genotoxic stress does not increase TLS at individual lesions. We conclude that unlike the SOS response in bacteria, the eukaryotic DDR does not promote TLS and mutagenesis. 相似文献
166.
Morimoto R Uehara S Yatsushiro S Juge N Hua Z Senoh S Echigo N Hayashi M Mizoguchi T Ninomiya T Udagawa N Omote H Yamamoto A Edwards RH Moriyama Y 《The EMBO journal》2006,25(18):4175-4186
Osteoclasts are involved in the catabolism of the bone matrix and eliminate the resulting degradation products through transcytosis, but the molecular mechanism and regulation of transcytosis remain poorly understood. Upon differentiation, osteoclasts express vesicular glutamate transporter 1 (VGLUT1), which is essential for vesicular storage and subsequent exocytosis of glutamate in neurons. VGLUT1 is localized in transcytotic vesicles and accumulates L-glutamate. Osteoclasts secrete L-glutamate and the bone degradation products upon stimulation with KCl or ATP in a Ca2+-dependent manner. KCl- and ATP-dependent secretion of L-glutamate was absent in osteoclasts prepared from VGLUT1-/- knockout mice. Osteoclasts express mGluR8, a class III metabotropic glutamate receptor. Its stimulation by a specific agonist inhibits secretion of L-glutamate and bone degradation products, whereas its suppression by a specific antagonist stimulates bone resorption. Finally, it was found that VGLUT1-/- mice develop osteoporosis. Thus, in bone-resorbing osteoclasts, L-glutamate and bone degradation products are secreted through transcytosis and the released L-glutamate is involved in autoregulation of transcytosis. Glutamate signaling may play an important role in the bone homeostasis. 相似文献
167.
Sulaiman S Yamato S Kanaya E Kim JJ Koga Y Takano K Kanaya S 《Applied and environmental microbiology》2012,78(5):1556-1562
The gene encoding a cutinase homolog, LC-cutinase, was cloned from a fosmid library of a leaf-branch compost metagenome by functional screening using tributyrin agar plates. LC-cutinase shows the highest amino acid sequence identity of 59.7% to Thermomonospora curvata lipase. It also shows the 57.4% identity to Thermobifida fusca cutinase. When LC-cutinase without a putative signal peptide was secreted to the periplasm of Escherichia coli cells with the assistance of the pelB leader sequence, more than 50% of the recombinant protein, termed LC-cutinase*, was excreted into the extracellular medium. It was purified and characterized. LC-cutinase* hydrolyzed various fatty acid monoesters with acyl chain lengths of 2 to 18, with a preference for short-chain substrates (C(4) substrate at most) most optimally at pH 8.5 and 50°C, but could not hydrolyze olive oil. It lost activity with half-lives of 40 min at 70°C and 7 min at 80°C. LC-cutinase* had an ability to degrade poly(ε-caprolactone) and polyethylene terephthalate (PET). The specific PET-degrading activity of LC-cutinase* was determined to be 12 mg/h/mg of enzyme (2.7 mg/h/μkat of pNP-butyrate-degrading activity) at pH 8.0 and 50°C. This activity is higher than those of the bacterial and fungal cutinases reported thus far, suggesting that LC-cutinase* not only serves as a good model for understanding the molecular mechanism of PET-degrading enzyme but also is potentially applicable for surface modification and degradation of PET. 相似文献
168.
Mika Okumura Kohki Ishikawa Shigenori Kanaya Mitsuhiro Itaya Kosuke Morikawa 《Proteins》1993,15(1):108-111
Ribonuclease H from an extreme thermophile, Thermus thermophilus HB8, has been crystallized from solutions at low ionic strength. The crystals belong to the hexagonal space group P6 122 (or P6 522), with unit cell parameters a = b = 44.7 Å, c = 314.7 Å. They contain one 18,000 Mr molecule per asymmetric unit and diffract to 2.8 Å resolution. © 1993 Wiley-Liss, Inc. 相似文献
169.
Arakawa Taku; Jongsareejit Boonsri; Tatsumi Yusaku; Tanaka Keiko; Ikeda Katsunori; Komatsubara Hideyuki; Inoue Hiroaki; Kawakami Bunsei; Oka Masanori; Emi Shigenori; Yomo Tetsuya; Shima Yasufumi; Negoro Seiji; Urabe Itaru 《DNA research》1996,3(2):87-92
N-Terminally truncated DNA polymerase from Thermus thermophilus(Tth polymerase) lacking 5'-3' exonuclease activity was usedfor DNA sequencing and polymerase chain reaction (PCR). In contrastto the high background of the sequencing ladder observed withthe wild-type Tth polymerase, Tth polymerase gave readable sequencingpatterns which extend up to more than 500 bases from the primersite on cycle sequencing and automated sequencing. The Tth polymerasewas used for the standard and mutagenic PCR, and net amplificationof the DNA and the mutations accumulated during PCR were analyzed.Under mutagenic PCR, the mutation rates were 7.0 x 104(Tth) and 8.3 x 104 (Tth) per nucleotide per cycle ofamplification, which were 49 times higher than the ratesunder standard PCR. 相似文献
170.
Gene Cloning and Characterization of Recombinant RNase HII from a Hyperthermophilic Archaeon 总被引:1,自引:0,他引:1
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Mitsuru Haruki Keiko Hayashi Takayuki Kochi Ayumu Muroya Yuichi Koga Masaaki Morikawa Tadayuki Imanaka Shigenori Kanaya 《Journal of bacteriology》1998,180(23):6207-6214
We have cloned the gene encoding RNase HII (RNase HIIPk) from the hyperthermophilic archaeon Pyrococcus kodakaraensis KOD1 by screening of a library for clones that suppressed the temperature-sensitive growth phenotype of an rnh mutant strain of Escherichia coli. This gene was expressed in an rnh mutant strain of E. coli, the recombinant enzyme was purified, and its biochemical properties were compared with those of E. coli RNases HI and HII. RNase HIIPk is composed of 228 amino acid residues (molecular weight, 25,799) and acts as a monomer. Its amino acid sequence showed little similarity to those of enzymes that are members of the RNase HI family of proteins but showed 40, 31, and 25% identities to those of Methanococcus jannaschii, Saccharomyces cerevisiae, and E. coli RNase HII proteins, respectively. The enzymatic activity was determined at 30°C and pH 8.0 by use of an M13 DNA-RNA hybrid as a substrate. Under these conditions, the most preferred metal ions were Co2+ for RNase HIIPk, Mn2+ for E. coli RNase HII, and Mg2+ for E. coli RNase HI. The specific activity of RNase HIIPk determined in the presence of the most preferred metal ion was 6.8-fold higher than that of E. coli RNase HII and 4.5-fold lower than that of E. coli RNase HI. Like E. coli RNase HI, RNase HIIPk and E. coli RNase HII cleave the RNA strand of an RNA-DNA hybrid endonucleolytically at the P-O3′ bond. In addition, these enzymes cleave oligomeric substrates in a similar manner. These results suggest that RNase HIIPk and E. coli RNases HI and HII are structurally and functionally related to one another. 相似文献