• Title/Summary/Keyword: Open state block

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Neuronal injury in AIDS dementia: Potential treatment with NMDA open-channel blockers and nitric oxide-related species

  • Lipton, Stuart A.
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1996.04a
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    • pp.19-29
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    • 1996
  • The neurological manifestations of AIDS include dementia, encountered even in the absence of opportunistic superinfection or malignancy. The AIDS Dementia Complex appears to be associated with several neuropathological abnormalities, including astrogliosis and neuronal injury or loss. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the vitus\ulcorner In vitro experiments from several different laboratiories have lent support to the existence of HIV- and immune-related toxins. In one recently defined pathway to neuronal injury, HIV-infected macrophages/microglia as well as macrophages activated by HIV-1 envelope protein gp120 appear to secrete excitants/neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO - and O$_2$), glutamate, quinolinate, cysteine, cytokines (TNF-${\alpha}$, IL1-B, IL-6), and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for newonal suscepubility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves excessive activation of N-methyl-D-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca$\^$2+/ leading to neuronal damage, and thus offers hope for future pharmacological intervention. This chapter reviews two clinically-tolerated NMDA antagonists, memantine and nitroglycerin; (ⅰ) Memantine is an open-channel blocker of the NMDA-associated ion channel and a close congener of the anti-viral and anti-parkinsonian drug amantadine. Memantine blocks the effects of escalating levels of excitotoxins to a greater degree than lower (piysiological) levels of these excitatory amino acids, thus sparing to some extent normal neuronal function. (ⅱ) Niuoglycerin acts at a redox modulatory site of the NMDA receptor/complex to downregulate its activity. The neuroprotective action of nitroglycerin at this site is mediated by n chemical species related to nitric oxide, but in a higher oxidation state, resulting in transfer of an NO group to a critical cysteine on the NMDA receptor. Because of the clinical safety of these drugs, they have the potential for trials in humans. As the structural basis for redox modulation is further elucidated, it may become possible to design even better redox reactive reagents of chinical value. To this end, redox modulatory sites of NMDA receptors have begun to be characterized at a molecular level using site-directed mutagenesis of recombinant subunits (NMDAR1, NMDAR2A-D). Two types of redox modulation can be distinguished. The first type gives rise to a persistent change in the functional activity of the receptor, and we have identified two cysteine residues on the NMDARI subunit (#744 and #798) that are responsible for this action. A second site, presumably also a cysteine(s) because <1 mM N-ethylmaleimide can block its effect in native neurons, underlies the other, more transient redox action. It appears to be at this, as yet unidentified, site on the NMDA receptor that the NO group acts, at least in recombinant receptors.

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The Substates with Mutants That Negatively Charged Aspartate in Position 172 Was Replaced with Positive Charge in Murine Inward Rectifier Potassium Channel (Murine Kir2.1)

  • So, I.;Ashmole, I.;Stanfield, P.R.
    • The Korean Journal of Physiology and Pharmacology
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    • v.7 no.5
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    • pp.267-273
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    • 2003
  • We have investigated the effect on inducing substate(s) of positively charged residues replaced in position 172 of the second transmembrane domain in murine inward rectifier potassium channels, formed by stable or transient transfection of Kir2.1 gene in MEL or CHO cells. Single channel recordings were obtained from either cell-attached patches or inside-out patches excised into solution containing 10 mM EDTA to rule out the effect of $Mg^{2+}$ on the channel gating. The substate(s) could be recorded with all mutants D172H, D172K and D172R. The unitary current-voltage (I-V) relation was not linear with D172H at $pH_i$ 6.3, whereas the unitary I-V relation was linear at $pH_i$ 8.0. The relative occupancy at $S_{LC}$ was increased from 0.018 at $pH_i$ 8.0 to 0.45 at $pH_i$ 5.5. In H-N dimer, that was increased from 0.016 at $pH_i$ 8.0 to 0.23 at $pH_i$ 5.5. The larger the size of the side chain or $pK_a$ with mutants (D172H, D172K and D172R), the more frequent the transitions between the fully open state and substate within an opening. The conductance of the substate also depended upon the pKa or the size of the side chain. The relative occupancy at substate $S_{LC}$ with monomer D172K (0.50) was less than that in K-H dimer (0.83). However, the relative occupancy at substate with D172R (0.79) was similar to that with R-N dimer (0.82). In the contrary to ROMK1, positive charge as well as negative charge in position 172 can induce the substate rather than block the pore in murine Kir2.1. The single channel properties of the mutant, that is, unitary I-V relation, the voltage dependence of the mean open time and relative occupancy of the substates and the increased latency to the first opening, explain the intrinsic gating observed in whole cell recordings.

A Study of Yangshangsun(楊上善)'s theory of three-yum and three-yang(三陰三陽) - focus on attribute of three-yum and three-yang(三陰三陽), the bolt-leaf-hanges(關闔樞) theory, large of small of gi-blood(氣血多少) (양상선(楊上善)의 삼음삼양(三陰三陽) 학설(學說)에 대한 연구 - 음양속성(陰陽屬性), 관합추(關闔樞), 기혈다소(氣血多少)를 중심으로 -)

  • Lee, Yong Bum
    • Journal of Korean Medical classics
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    • v.10
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    • pp.450-493
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    • 1997
  • Three-yum and three-yang(三陰三陽) is the change state of yum-yang(陰陽) which is caused by six gi(六氣). They mean the flow of six gi(六氣) which exist throughout the viscera, the channel(經絡), and the skin. But it is not easy to understand the meaning because the contents of the attribute of three-yum and three-yang(三陰三陽), the bolt-leaf-hanges(關闔樞) theory and large or small of gi-blood(氣血多少) which is the main clue that explain it in ${\ll}$Somun(素問)${\gg}$ and ${\ll}$Yeongchu(靈樞)${\gg}$ don't coincide with each other. I, the writer, tried to understand the uncertain meaning and the contents which are written about three points above differently in each of the books that are ${\ll}$Somun(素問)${\gg}$ and ${\ll}$Yeongchu(靈樞)${\gg}$. So, from that the course that the book, ${\ll}$Huangjenegeong(黃帝內經)${\gg}$ is handed down is so relatively simple in a wood block-printed book, that the ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$ has less wong-words than the Somun(素問) and the Yeongchu(靈樞), and from that Yangshangsun(楊上善) wrote the note in the ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$ by royal order about 100 years former than Wangbing(王氷), as making projects of Yangshangsun(楊上善)'s note and the original of the ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$ which has relation to the yum-yang(陰陽) attribute of three-yum and three-yang(三陰三陽), the bolt-leaf-hanges(關闔樞) theory, and the large or small of gi-blood(氣血多少) and researching the Yangshangsun(楊上善)'s theory. The result is summarized like this. First, wherease the order of the change of three-yum and three-yang(三陰三陽) which is explained by Yangshangsun(楊上善) consider the change of yangi(陽氣) in body most important, the order of the change gaeggi(客氣)'s three-yum and three-yang(三陰三陽) considers chungi(天氣) most important, and the order of jugi(主氣)'s three-yum and three-yang(三陰三陽) considers jigi(地氣)'s change of ohaeng(五行) most important. If the order of change three-yum and three-yang(三陰三陽) in the ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$ is considered, each of taeyang(太陽) and soyum(少陰) are expressed as the base of yum-yang(陰陽) and yangmeong(陽明) and taeyum(太陰) are expressed as the palmy days of yum-yang(陰陽), soyang(少陽) and gyolyum(厥陰) are expressed as pacemaker(樞杻) which controls the change of yum-yang(陰陽). Thus, each has something in common that is fettered by the inside and outside. In the flow of channel(經絡), taeyang(太陽) and soyum(少陰) take charge of the behind of body, yangmeong(陽明) and taeyum(太陰) take charge of the front of body and soyang(少陽) and gyolyum(厥陰) take of the side of body. Second, in Yangshangsun(楊上善)'s bolt-leaf-hanges(關闔樞) theory, three-yum(三陰) is regarded as inside, three-yang(三陽) as outside, so when bolt, leaf and hanges fulfil their duties in inside and outside, the life(life force) is thought to be revealed normally. It is impossible to understand the bolt-leaf-hanges with the conception of the inside and outside which divide three-yum and three-yang(三陰三陽) into taeyang-soyum(太陽-少陰), yangmeong-taeyum(陽明-太陰), soyang-gyolyum(少陽-厥陰) according to yum-yang(陰陽) attribute, hence it need the special conception that is taeyang(太陽)-taeyum(太陰), yangmeong(陽明)-gyolyum(厥陰), soyang(少陽)-soyum(少陰) which center on their duties in inside and outside. In the denunciation of the word open(開) and bolt(關), because Yangshangsun(楊上善) said that the duities of taeyang(太陽) and taeyum(太陰) are shutter(閉禁), bolt(關) is coincided with that significance. Third, with explaining the large or small of gi-blood(氣血多少) of three-yum and three-yang(三陰三陽), Yangshangsun(楊上善) expressed the inside and outside either in the same way or differently. Because the inside and outside is interior of body and exterior of body, it is the explanation that is noticed by the fact that the property of large or small of gi-blood(氣血多少) is either able to be same or different. In this viewpoint, if we unite the contents about large or small of gi-blood(氣血多少) of ${\ll}$Somun(素問)${\gg}$, ${\ll}$Yeongchu(靈樞)${\gg}$, we will find that the descriptions of large or small of gi-blood(氣血多少) of three-yang(三陽) in ${\ll}$Somun(素問)${\gg}$ ${\ll}$Yeongchu(靈樞)${\gg}$ correspond with the ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$, but in three-yum(三陰), the contrary presentations exit. The reason is that large or small of gi-blood(氣血多少) of three-yum(三陰) isn't only expressed as che(體) in the point of che-yong(體用), but as a point of yong(用) that is a phenomenon. As researching the original of ${\ll}$Huangjenegeongtaeso(黃帝內經太素)${\gg}$ and Yangshangsun(楊上善)'s notes as a center about three problems that are yum-yang(陰陽) attribute, the bolt-leaf-hanges(關闔樞) and large or small of gi-blood(氣血多少) of three-yum and three-yang(三陰三陽), I, the writer, tried to explain the part which is written differently or has uncertain conception in the book ${\ll}$Somun(素問)${\gg}$ and the book ${\ll}$Yeongchu(靈樞)${\gg}$, but the concrete result of the work like this will be judged according to the question how many theories are correspondent with real presence at a sickbed. Hence, the work to veryfy the theories in the future will be left as assignment.

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The Variation of Natural Population of Pinus densiflora S. et Z. in Korea (III) -Genetic Variation of the Progeny Originated from Mt. Chu-wang, An-Myon Island and Mt. O-Dae Populations- (소나무 천연집단(天然集團)의 변이(變異)에 관(關)한 연구(硏究)(III) -주왕산(周王山), 안면도(安眠島), 오대산(五臺山) 소나무집단(集團)의 차대(次代)의 유전변이(遺傳變異)-)

  • Yim, Kyong Bin;Kwon, Ki Won
    • Journal of Korean Society of Forest Science
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    • v.32 no.1
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    • pp.36-63
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    • 1976
  • The purpose of this study is to elucidate the genetic variation of the natural forest of Pinus densiflora. Three natural populations of the species, which are considered to be superior quality phenotypically, were selected. The locations and conditions of the populations are shown in table 1 and 2. The morphological traits of tree and needle and some other characteristics were presented already in our first report of this series in which population and family differences according to observed characteristics were statistically analyzed. Twenty trees were sampled from each populations, i.e., 60 trees in total. During the autumn of 1974, matured cones were collected from each tree and open-pollinated seeds were extracted in laboratory. Immediately after cone collection, in closed condition, the morphological characteristics were measured. Seed and seed-wing dimensions were also studied. In the spring of 1975, the seeds were sown in the experimental tree nursery located in Suweon. And in the April of 1976, the 1-0 seedlings were transplanted according to the predetermined experimental design, randomized block design with three replications. Because of cone setting condition. the number of family from which progenies were raised by populations were not equal. The numbers of family were 20 in population 1. 18 in population 2 and 15 in population 3. Then, each randomized block contained seedlings of 53 families from 3 populations. The present paper is mainly concerned with the variation of some characteristics of cone, seed, needle, growth performance of seedlings, and chlorophyll and monoterpene compositions of needles. The results obtained are summerized as follows. 1. The meteorological data obtained by averaging the records of 30 year period, observed from the nearest station to each location of populations, are shown in Fig. 3, 4, and 5. The distributional pattern of monthly precipitation are quite similar among locations. However, the precipitation density on population 2, Seosan area, during growing season is lower as compared to the other two populations. Population 1. Cheong-song area, and population 3, Pyong-chang area, are located in inland, but population 2 in the western seacoast. The differences on the average monthly air temperatures and the average monthly lowest temperatures among populations can hardly be found. 2. Available information on the each mother trees (families) studied, such as age, stem height, diameter at breast height, clear-bole-length, crown conditions and others are shown in table 6,7, and 8. 3. The measurements of fresh cone weight, length and the widest diameter of cone are given in Tab]e 9. All these traits arc concerned with the highly significant population differences and family differences within population. And the population difference was also found in the cone-index, that is, length-diameter ratio. 4. Seed-wing length and seed-wing width showed the population differences, and the family differences were also found in both characteristics. Not discussed in this paper, however, seed-wing colours and their shapes indicate the specificity which is inherent to individual trees as shown in photo 3 on page 50. The colour and shape are fully the expression of genetic make up of mother tree. The little variations on these traits are resulted from this reason. The significant differences among populations and among families were found in those characteristics, such as 1000-seed weight, seed length, seed width, and seed thickness as shown in table 11. As to all these dimensions, the values arc always larger in population 1 which is younger in age than that of the other two. The population differences evaluated by cone, seed and seed-wing sizes could partly be attributed to the growth vigorousity. 5. The values of correlation between the characteristics of cone and seed are presented in table 12. As shown, the positive correlations between cone diameter and seed-wing width were calculated in all populations studied. The correlation between seed-wing length and seed length was significantly positive in population 1 and 3 but not in population 2, that is, the r-value is so small as 0.002. in the latter. The correlation between cone length and seed-wing length was highly significant in population 1, but not in population 2. 6. Differences among progenies in growth performances, such as 1-0 and 1-1 seedling height and root collar diameter were highly singificant among populations as well as families within population(Table 13.) 7. The heritability values in narrow sense of population characteristics were estimated on the basis of variance components. The values based on seedling height at each age stage of 1-1 and 1-0 ranged from 0.146 to 0.288 and the values of root collar diameter from 0.060 to 0.130. (Table 14). These heritability values varied according to characteristics and seedling ages. Here what must be stated is that, for calculation of heritability values, the variance values of population was divided by the variance value of environment (error) and family and population. The present authors want to add the heritability values based on family level in the coming report. It might be considered that if the tree age is increased in furture, the heritability value is supposed to be altered or lowered. Examining the heritability values studied previously by many authors, in pine group at age of 7 to 15, the values of height growth ranged from 0.2 to 0.4 in general. The values we obtained are further below than these. 8. The correlation between seedling growth and seed characteristics were examined and the values resulted are shown in table 16. Contrary to our hypothetical premise of positive correlation between 1-0 seedling height and seed weight, non-significance on it was found. However, 1-0 seedling height correlated positively with seed length. And significant correlations between 1-0 and 1-1 seedling height are calculated. 9. The numbers of stomata row calculated separately by abaxial and adaxial side showed highly significant differences among populations, but not in serration density. On serration density, the differences among families within population were highly significant. (Table 17) A fact must be noted is that the correlation between stomata row on abaxial side and adaxial side was highly significant in all populations. Non-significances of correlation coefficient between progenies and parents regarding to stomata row on abaxial side were shown in all populations studied.(Table 18). 10. The contents of chhlorophyll b of the needle were a little more than that of chlorophyll a irrespective of the populations examined. The differences of chlorophyll a, b and a plus b contents were highly significant but not among families within populations as shown in table 20. The contents of chlorophyll a and b are presented by individual trees of each populations in table 21. 11. The occurrence of monoterpene components was examined by gas liquid chromatography (Shimazu, GC-1C type) to evaluate the population difference. There are some papers reporting the chemical geography of pines basing upon monoterpene composition. The number of populations studied here is not enough to state this problem. The kinds of monoterpene observed in needle were ${\alpha}$-pinene, camphene, ${\beta}$-pinene, myrcene, limonene, ${\beta}$-phellandrene and terpinolene plus two unknowns. In analysis of monoterpene composition, the number of sample trees varied with population, I.e., 18 families for population 1, 15 for population 2 and 11 for population3. (Table 22, 23 and 24). The histograms(Fig. 6) of 7 components of monoterpene by population show noticeably higher percentages of ${\alpha}$-pinene irrespective of population and ${\beta}$-phellandrene in the next order. The minor Pinus densiflora monoterpene composition of camphene, myrcene, limonene and terpinolene made up less than 10 percent of the portion in general. The average coefficients of variation of ${\alpha}$-pinene and ${\beta}$-phellandrene were 11 percent. On the contrary to this, the average coefficients of variation of camphene, limonene and terpinolene varied from 20 to 30 percent. And the significant differences between populaiton were observed only in myrcene and ${\beta}$-phellandrene. (Table 25).

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