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151.
Ram Dixit Brian Barnett Jacob E. Lazarus Mariko Tokito Yale E. Goldman Erika L. F. Holzbaur 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(2):492-497
Microtubules are polarized polymers that exhibit dynamic instability, with alternating phases of elongation and shortening, particularly at the more dynamic plus-end. Microtubule plus-end tracking proteins (+TIPs) localize to and track with growing microtubule plus-ends in the cell. +TIPs regulate microtubule dynamics and mediate interactions with other cellular components. The molecular mechanisms responsible for the +TIP tracking activity are not well understood, however. We reconstituted the +TIP tracking of mammalian proteins EB1 and CLIP-170 in vitro at single-molecule resolution using time-lapse total internal reflection fluorescence microscopy. We found that EB1 is capable of dynamically tracking growing microtubule plus-ends. Our single-molecule studies demonstrate that EB1 exchanges rapidly at microtubule plus-ends with a dwell time of <1 s, indicating that single EB1 molecules go through multiple rounds of binding and dissociation during microtubule polymerization. CLIP-170 exhibits lattice diffusion and fails to selectively track microtubule ends in the absence of EB1; the addition of EB1 is both necessary and sufficient to mediate plus-end tracking by CLIP-170. Single-molecule analysis of the CLIP-170–EB1 complex also indicates a short dwell time at growing plus-ends, an observation inconsistent with the copolymerization of this complex with tubulin for plus-end-specific localization. GTP hydrolysis is required for +TIP tracking, because end-specificity is lost when tubulin is polymerized in the presence of guanosine 5′-[α,β-methylene]triphosphate (GMPCPP). Together, our data provide insight into the mechanisms driving plus-end tracking by mammalian +TIPs and suggest that EB1 specifically recognizes the distinct lattice structure at the growing microtubule end. 相似文献
152.
The purpose of this study was to investigate whether nipradilol, a beta-blocker having both vasodilating and alpha(1)-blocking activities, can protect retinal cells from the injury induced by ischemia and reperfusion. Rats were anesthetized and, after an intravitreal injection of nipradilol, the intraocular pressure was raised for 45 min to induce retinal ischemia and reperfusion. Before, and 3 and 7 days after the ischemia, electroretinograms were recorded. After the ischemia, the mean amplitude of the b-waves in rats receiving 5 microl of 1.0 x 10(-6) M nipradilol was significantly larger than of controls (injected with phosphate-buffered saline). Histologically, the reduction in the number of retinal ganglion cells (1.0 x 10(-6) M), and the thickness of the inner and outer plexiform layers and the inner nuclear layer (1.0 x 10(-6), 10(-7) and 10(-8) M) was suppressed by nipradilol. These results indicate that nipradilol protected the retina against retinal ischemia and reperfusion and should be considered for therapeutic use in cases of transient retinal ischemia. 相似文献
153.
Sano M Tazawa Y Nabeshima T Mita M 《Investigative ophthalmology & visual science》2002,43(5):1666-1672
PURPOSE: To report the properties of a newly detected positive wavelet on the descending limb of P1 of the first-order kernel of the human multifocal electroretinogram (mfERG). METHODS: Twenty eyes of 20 normal individuals, ages 21 to 29 years (mean, 25.6) and nine eyes of 6 patients with optic neuritis ages 5 to 38 years (mean, 17.3) were studied. mfERGs were recorded with a visual evoked response imaging system with the number of stimulus elements set at 37. The stimulus frequency was changed from 75 to 37, 18, 9.4, 4.7, and 2.3 Hz, and the contrast of the stimuli was lowered to 50%. RESULTS: In normal eyes, a positive wavelet appeared on the descending limb of P1 of the first-order kernel of the mfERG when the stimulus frequency was reduced from 75 to 18 Hz. The wavelet had a mean amplitude of 4.2 nV/deg(2) and a mean implicit time of 34 ms at 18 Hz. When the stimulus frequency was reduced further to 2.3 Hz, the amplitude of the wavelet increased significantly (P < 0.05) compared with that at 18 Hz. The amplitudes of the wavelet elicited from the nasal side of the retina were significantly larger (P < 0.05) than those from the temporal side and decreased significantly (P < 0.05) with increasing distance from the optic disc. The wavelet was not present in any of the patients with newly diagnosed optic neuritis, but reappeared with recovery from the disease. The recovery of the wavelet correlated significantly with the recovery of visual acuity and of central critical fusion frequency. CONCLUSIONS: The amplitude of the wavelet on the descending limb of P1 of the first-order kernel of the mfERG was dependent on the stimulus frequency and the retinal locus. The wavelet was not present in the mfERGs recorded in patients with optic neuritis, but returned with recovery from the disease. These findings suggest that the neural activity of the ganglion cells give rise to this wavelet. 相似文献
154.
PURPOSE: To determine the effects of aging on the first and second-order kernels of the multifocal electroretinogram (ERG). METHODS: Multifocal ERGs were recorded from 52 healthy subjects (52 eyes) (0 >or= refractive error >or= -3.0 diopter). The ages of the subjects ranged from 12-76 years with a mean (+/-SD) of 44.0 +/- 20.2 years. The Visual Evoked Response Imaging System was used. The effects of aging on the response densities and on the implicit times of the first positive wave (P1) of the first-order kernel, and of the second and third positive waves (P2 and P3) of the second-order kernel were analyzed for the different age groups. RESULTS: The response densities of the first-order kernel P1 and second-order kernel P2 waves decreased significantly, and the implicit times of the second-order kernel P2, and P3 were significantly prolonged (P <.05) in subjects over 50 years of age. CONCLUSION: The results suggest that the age of the subject should be considered when evaluating retinal function using multifocal ERGs in basic and clinical studies. 相似文献
155.
Kumagai K Ogino N Furukawa M Demizu S Atsumi K Kurihara H Iwaki M Ishigooka H Tachi N 《Nippon Ganka Gakkai zasshi》2002,106(9):595-601
PURPOSE: To examine the efficacy of surgical removal of subfoveal hard exudates during surgery in diabetic maculopathy. PATIENTS AND METHODS: This study was done on 60 patients (66 eyes) that all underwent surgical removal of subfoveal hard exudates under the same surgeon. Thirty-two men (37 eyes) and 28 women (29 eyes) were included in this study. The average age of the patients was 60 years (range, 30-77 years). The average follow-up period was 21 months (range, 12-48 months). All eyes were classified into 3 groups: 13 postoperative massive type eyes, 31 massive type eyes, and 22 scatter type eyes. We evaluated the visual results of these types. RESULTS: Preoperative and postoperative mean visual acuity was as follows: postoperative massive type 0.11, 0.22, massive type 0.12, 0.29, and scatter type 0.19, 0.33. Postoperatively visual acuity improved significantly in all types. There were no subfoveal hard exudates postoperatively in any eyes. CONCLUSION: Surgical removal of massive subfoveal hard exudates is effective, but its effects on vision are limited. Surgical removal of deposited subfoveal hard exudates may prevent massive subfoveal hard exudates postoperatively and improve visual prognosis. 相似文献
156.
Recombinant antibody Fab against the hypervariable region 1 of hepatitis C virus blocks the virus adsorption to susceptible cells in vitro 总被引:4,自引:0,他引:4
Antibodies against hypervariable region 1 (HVR1) of hepatitis C virus (HCV) are putatively considered to be neutralizing. We previously found that monoclonal antibodies (mAbs) (30F1 and 30F3) against the HVR1 of HCV neutralize HCV in vitro. To develop potentially therapeutic molecules against HCV, we cloned cDNAs of antibody Fab fragments from the mouse hybridoma cells secreting these two mAbs. Fab fragments produced in Escherichia coli were purified by a single step of nickel-chelate affinity chromatography via a hexa-histidine tag. The specificity of the Fabs was confirmed by competition ELISA, BIAcore analysis, and N-terminal amino acid sequencing. The binding constant for the interaction with HVR1 was 1.39 nM for Fab 30F1 and 3.96 nM for Fab 30F3. The HCV capture assay and inhibition of HCV adsorption test demonstrated that both Fabs had neutralizing activity. The data may be useful for designing immunological therapy of HCV. 相似文献
157.
Sunakawa K Nonoyama M Fujii R Iwai N Sakata H Shirai M Sato T Kajino M Toyonaga Y Sano T Naito A Minagawa K Niida Y Oda T Yokozawa M Asanuma H Shimura K Fujimura M Kitajima H Fujinami K Numazaki K Fujikawa T Kobayashi Y Sato Y Nishimura T Iwata S Tsuchihashi N Oishi T Matsumoto S Motohiro T Osawa M Sunahara M Shirakawa S Nishida H Takahashi N Nakano R Sai N Iyoda K Yoshimitsu K Ogawa K Okazaki T Tsukimoto I Motoyama O Takada Y Kawasaki M Sunaoshi W Nakamura S Ueda Y Kamata M Kato T Chiba M 《The Japanese journal of antibiotics》2002,55(5):656-677
Pharmacokinetics, clinical efficacy and safety of teicoplanin (TEIC) were evaluated in pediatric and neonate patients with MRSA sepsis in the dosages approved in overseas. The administrated dose for pediatrics patients was 10 mg/kg once at hour 0, 12 and 24, followed by every 24 hours intervals. In neonates patients, first dose was 16 mg/kg, then 8 mg/kg every 24 hours intervals. 1. Pharmacokinetic results. All 17 patients (9 neonates and 8 pediatrics) who received TEIC were evaluated for pharmacokinetics. Trough concentrations were analyzed in 16 patients (9 neonates and 7 pediatrics) excluding one patient for lack of measurement of drug concentration at day 7. No patient with a concentration exceeding 60 micrograms/mL in peak or trough concentrations were reported. Mean concentrations in trough at day 3, 4 and 7 in neonates were 15.2, 14.7 and 17.8 micrograms/mL, and in pediatrics were 12.5, 12.2 and 13.1 micrograms/mL, respectively. These results were similar to those reported in foreign pediatrics and neonates patients. 2. Efficacy and safety results. Since no patient was excluded, all patients were evaluated for efficacy and safety. Microbiological efficacy as well as clinical cure were secondarily evaluated in 2 patients for whom MRSA was isolated from blood. Clinical efficacy rate was 76.5% (13/17) and number of cases in judgments of excellent, good, fairly improved and no change were 12, 1, 3 and 1 cases respectively. The patients for whom MRSA was isolated from blood were judged as MRSA eradicated case and cured without any additional anti-MRSA drugs. Adverse events were reported in 2 neonates and 3 pediatric patients. Possibly related adverse events to study drug (adverse drug reactions) were: 1 case of respiratory disorder, thrombocythemia, gamma-GTP increased, GOT increased and GPT increased in 3 pediatrics. These results suggest that an application of overseas dose regimen of TEIC for neonate and pediatrics is appropriate in Japan. 相似文献
158.
Cisplatin (cis-DDP) is subject to nucleophilic displacement of chloride in water, forming aquated species, subsequently liberating hydrogen ion(s) with increasing pH. This study intends to theoretically analyze the hydrolysis and polyprotic dissociation behavior of cis-DDP in various aqueous media. A mathematical model was expressed by nonlinear simultaneous equations in terms of the total drug concentration, pH and pCl based on the hydrolysis and acid dissociation constants already published. Some of the interesting simulation results include that (1) in water, cis-DDP behaves in a very complicated manner, highly depending on the total drug concentration, pH and pCl, (2) in normal saline, about 3% of the total concentration is a positively charged chloro-aqua that may be very reactive, (3) in assumed blood (pH 7.4, [Cl(-)]=0.11 mol/l, mu=0.15), the drug is stabilized at the level of 85% and the remnants are the chloro-hydroxo (11%) and the chloro-aqua (4%), (4) in assumed intracellular conditions (pH 7.1, [Cl(-)]=0.01 mol/l, mu=0.15), the drug is converted to a large extent to various species including the parent species (44%), the chloro-hydroxo (30%), hydroxo-aqua (2%), chloro-aqua (24%) diaqua (less than 1%) and dihydroxo (null). The results of this analysis may provide a useful preliminary knowledge of existing species in a system concerned and a rationale for re-evaluating the reactions between cis-DDP and various nucleophilic substances already reported while there are somewhat conflicting interpretations of some cis-DDP reactions. 相似文献
159.
Kamano Y Yamashita A Nogawa T Morita H Takeya K Itokawa H Segawa T Yukita A Saito K Katsuyama M Pettit GR 《Journal of medicinal chemistry》2002,45(25):5440-5447
QSAR analysis has been used to identify the essential structural requirements for increasing the inhibitory activities of selected bufadienolides from the Chinese drug Ch'an Su (and other sources) against the primary liver carcinoma cell line PLC/PRF/5 (PLC) and the derived colchicine-resistant line (COL). The variable substituent domain of the proposed pharmacophore of the bufadienolides was investigated using a Comparative Molecular Field Analysis (CoMFA) approach. A model with considerable predictive ability was obtained. In addition, the CoMFA results agreed well with the pharmacophore bufadienolide model for the parent PLC line proposed earlier. 相似文献
160.
Furukawa H Hamada T Hayashi MK Haga T Muto Y Hirota H Yokoyama S Nagasawa K Ishiguro M 《Molecular pharmacology》2002,62(4):778-787
Many biogenic amines evoke a variety of physiological responses by acting on G protein-coupled receptors. We have determined the conformation of two acetylcholine analogs, (S)-methacholine and (2S,4R,5S)-muscarine, bound to the M(2) muscarinic acetylcholine receptor (M(2) mAChR) by NMR spectroscopy. The analysis of the transferred nuclear Overhauser effect indicated that the receptor selectively recognized the conformers of (S)-methacholine and (2S,4R,5S)-muscarine with the gauche O-C2-C1-N dihedral angle at +60 degrees. This is distinct from the predominant conformations of these ligands in solution with O-C2-C1-N dihedral angle (+80 to approximately 85 degrees ) in the absence of the M(2) mAChR, as assessed by analyses of the coupling constants and nuclear Overhauser effect spectroscopy. We have also built a molecular model of the M(2) mAChR-(S)-methacholine complex, based on the X-ray crystallographic structure of rhodopsin. This model indicated that the conformation with the gauche O-C2-C1-N dihedral angle at +55.5 degrees, which is similar to the one determined by NMR measurement, is energetically favored in the binding of (S)-methacholine to the receptor. We suggest that this conformation represents the binding of the agonist to the M(2) mAChR in the absence of G protein. 相似文献