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Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors

  • Choi, Sun-Hye;Lee, Na-Eun;Cho, Hee-Jung;Lee, Ra Mi;Rhim, Hyewhon;Kim, Hyoung-Chun;Han, Mun;Lee, Eun-Hee;Park, Juyoung;Kim, Jeong Nam;Kim, Byung Joo;Nah, Seung-Yeol
    • Journal of Ginseng Research
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    • v.45 no.2
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    • pp.264-272
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    • 2021
  • Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

Visualization of the binding between gintonin, a Panax ginseng-derived LPA receptor ligand, and the LPA receptor subtypes and transactivation of the EGF receptor

  • Choi, Sun-Hye;Lee, Ra Mi;Cho, Han-Sung;Hwang, Sung Hee;Hwang, Hong-Ik;Rhim, Hyewhon;Kim, Hyoung-Chun;Kim, Do-Geun;Cho, Ik-Hyun;Nah, Seung-Yeol
    • Journal of Ginseng Research
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    • v.46 no.3
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    • pp.348-356
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    • 2022
  • Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin exerts its neuronal and non-neuronal in vitro and in vivo effects through LPA receptor subtypes. However, it is unknown whether gintonin can bind to the plasma membrane of cells and can transactivate the epidermal growth factor (EGF) receptor. In the present study, we examined whether gintonin-biotin conjugates directly bound to LPA receptors and transactivated the EGF receptor. Methods: We designed gintonin-biotin conjugates through gintonin biotinylation and examined whether gintonin-biotin conjugate binding sites co-localized with the LPA receptor subtype binding sites. We further examined whether gintonin-biotin transactivated the EGF receptor via LPA receptor regulation via phosphor-EGF and cell migration assays. Results: Gintonin-biotin conjugates elicit [Ca2+]i transient similar to that observed with unbiotinylated gintonin in cultured PC3 cells, suggesting that biotinylation does not affect physiological activity of gintonin. We proved that gintonin-biotin conjugate binding sites co-localized with the LPA1/6 receptor binding sites. Gintonin-biotin binding to the LPA1 receptor transactivates the epidermal growth factor (EGF) receptor through phosphorylation, while the LPA1/3 receptor antagonist, Ki16425, blocked phosphorylation of the EGF receptor. Additionally, an EGF receptor inhibitor AG1478 blocked gintonin-biotin conjugate-mediated cell migration. Conclusions: We observed the binding between ginseng-derived gintonin and the plasma membrane target proteins corresponding to the LPA1/6 receptor subtypes. Moreover, gintonin transactivated EGF receptors via LPA receptor regulation. Our results suggest that gintonin directly binds to the LPA receptor subtypes and transactivates the EGF receptor. It may explain the molecular basis of ginseng physiology/pharmacology in biological systems.

Recommended Method for Radioisotope Red-Cell Survival Studies (방사성(放射性) 동위원소(同位元素)를 이용(利用)한 적혈구수명측정법(赤血球壽命測定法)(ICSH 추천))

  • Berlin, N.I.;Dudley, R.A.;Garby, L.;Heimpel, H.;Lee, M.;Lewis, S.M.;McIntyre, P.;Mollison, P.L.;Najean, Y.;Pettit, J.
    • The Korean Journal of Nuclear Medicine
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    • v.14 no.2
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    • pp.1-9
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    • 1980
  • 혈액질환(血液疾患), 특히 용혈성빈혈(溶血性貧血)을 수반(隨伴)한 경우(境遇)에 적혈구(赤血球)의 생성(生成), 파괴과정(破壞過程)을 정확히 파악하는 것은 빈혈(貧血)의 발생기전(發生機轉) 및 병인(病因), 치료(治療), 예후(豫後) 결정(決定)에 매우 중요(重要)하다. 적혈수명측정법(赤血壽命測定法)은 최근(最近) 방사성(放射性)동위원소(同位元素)를 이용(利用)한 방법(方法)이 소개된 이래 널리 시행(施行)되어 왔다. 그러나 그 방법(方法) 및 결과(結果) 해석(解釋)에 표준화(標準化)가 되어 있지 않았던 중 1971년 ICSH (International Committee for Standardization in Hematology)에서 expert panel을 갖고 ICSH 추천 방법(方法)을 발표(發表)하였고, 본지(本誌)에서도 그 내용(內容)을 게재(揭載)한 바 있다. 1980년 ICSH는 전문기관 및 전문가의 협조(協調)를 얻어 다시 expert panal을 갖은 후 1971년에 추진한 적혈구수명측정법(赤血球壽命測定法)의 일부(一部)를 수정(修正)하여 ICSH의 표준방법(標準方法)으로 발표(發表)하였다. 개정(改正)된 표준방법(標準方法)과 1971년 ICSH추친 방법(方法)과의 차이(差異)는 다음과 같다. $^{51}Cr$표지방법중(標識方法中) 참고방법(參考方法)(Reference method)인 ACD법(法)에 수정(修正)을 가하여, ACD solution 구성성분(構成成分)이 차이(差異)가 있으며, 표지(標識)$^{51}Cr$의 양(量)을 체중당(體重當) $1.5{\mu}Ci$에서 $0.5{\mu}Ci$로 제한(制限)시켰다. 투여방법(投與方法)에 대한 언급 특히 투여하는 표지적혈구(標識赤血球)의 용적을 정확하게 측정 하기 위한 방법 4가지를 추가하였고, 검체준비(檢體準備) 과정중(過程中)의 pipet error를 방지(防止)하기위해 일정(一定)한 형태의 pipet을 사용(使用)하며, 1ml의 tuterculin syringe는 사용(使用)하지 않기로 하였다. 또한 결과분석시(結果分析時) 혈구용적(血球容積)의 항정성(恒定性)을 위해 Sodium pertectnetate($^{99m}Tc$)를 이용(利用)해 혈구용적(血球容積)을 반복(反復)해 측정(測定)하도록 하였으며 이때 사용(使用)하는 방사성동위원소(放射性同位元素)는 $^{32}P$ 대신 $^{99m}Tc$로 하였다. 결과해석시(結果解釋時) IgG 항체(抗體) 또는 IgM 항체(抗體)에 따른 차이점(差異點)에 대한 고려가 추가(追加)되었다. ICSH와 국제혈액학회(國際血液學會)에서 수정(修正)된 ICSH 표준방법(標準方法)에 의한 적혈수명측정법(赤血壽命測定法)을 널리 소개(紹介)하여 결과(結果)의 표준화(標準化)를 기하고자 연관잡지(聯관(關)雜誌)에 게재(揭載)할 것을 요청(要請)하였기에 전문(全文)을 본지(本誌)에 소개(紹介)하고자 한다.

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Development of a polystyrene phantom for quality assurance of a Gamma Knife®

  • Yona Choi;Kook Jin Chun;Jungbae Bahng;Sang Hyoun Choi;Gyu Seok Cho;Tae Hoon Kim;Hye Jeong Yang;Yeong Chan Seo;Hyun-Tai Chung
    • Nuclear Engineering and Technology
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    • v.55 no.8
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    • pp.2935-2940
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    • 2023
  • A polystyrene phantom was developed following the guidance of the International Atomic Energy Association (IAEA) for gamma knife (GK) quality assurance. Its performance was assessed by measuring the absorbed dose rate to water and dose distributions. The phantom was made of polystyrene, which has an electron density (1.0156) similar to that of water. The phantom included one outer phantom and four inner phantoms. Two inner phantoms held PTW T31010 and Exradin A16 ion chambers. One inner phantom held a film in the XY plane of the Leksell coordinate system, and another inner phantom held a film in the YZ or ZX planes. The absorbed dose rate to water and beam profiles of the machine-specific reference (msr) field, namely, the 16 mm collimator field of a GK PerfexionTM or IconTM, were measured at seven GK sites. The measured results were compared to those of an IAEA-recommended solid water (SW) phantom. The radius of the polystyrene phantom was determined to be 7.88 cm by converting the electron density of the plastic, considering a water depth of 8 g/cm2. The absorbed dose rates to water measured in both phantoms differed from the treatment planning program by less than 1.1%. Before msr correction, the PTW T31010 dose rates (PTW Freiberg GmbH, New York, NY, USA) in the polystyrene phantom were 0.70 (0.29)% higher on average than those in the SW phantom. The Exradin A16 (Standard Imaging, Middleton, WI, USA) dose rates were 0.76 (0.32)% higher in the polystyrene phantom. After msr correction factors were applied, there were no statistically significant differences in the A16 dose rates measured in the two phantoms; however, the T31010 dose rates were 0.72 (0.29)% higher in the polystyrene phantom. When the full widths at half maximum and penumbras of the msr field were compared, no significant differences between the two phantoms were observed, except for the penumbra in the Y-axis. However, the difference in the penumbra was smaller than variations among different sites. A polystyrene phantom developed for gamma knife dosimetry showed dosimetric performance comparable to that of a commercial SW phantom. In addition to its cost effectiveness, the polystyrene phantom removes air space around the detector. Additional simulations of the msr correction factors of the polystyrene phantom should be performed.

A Method for Estimating the Lung Clinical Target Volume DVH from IMRT with and without Respiratory Gating

  • J. H. Kung;P. Zygmanski;Park, N.;G. T. Y. Chen
    • Proceedings of the Korean Society of Medical Physics Conference
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    • 2002.09a
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    • pp.53-60
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    • 2002
  • Motion of lung tumors from respiration has been reported in the literature to be as large as of 1-2 cm. This motion requires an additional margin between the Clinical Target Volume (CTV) and the Planning Target Volume (PTV). While such a margin is necessary, it may not be sufficient to ensure proper delivery of Intensity Modulated Radiotherapy (IMRT) to the CTV during the simultaneous movement of the DMLC. Gated treatment has been proposed to improve normal tissues sparing as well as to ensure accurate dose coverage of the tumor volume. The following questions have not been addressed in the literature: a) what is the dose error to a target volume without gated IMRT treatment\ulcorner b) what is an acceptable gating window for such treatment. In this study, we address these questions by proposing a novel technique for calculating the 3D dose error that would result if a lung IMRT plan were delivered without gating. The method is also generalized for gated treatment with an arbitrary triggering window. IMRT plans for three patients with lung tumor were studied. The treatment plans were generated with HELIOS for delivery with 6 MV on a CL2100 Varian linear accelerator with a 26 pair MLC. A CTV to PTV margin of 1 cm was used. An IMRT planning system searches for an optimized fluence map ${\Phi}$ (x,y) for each port, which is then converted into a dynamic MLC file (DMLC). The DMLC file contains information about MLC subfield shapes and the fractional Monitor Units (MUs) to be delivered for each subfield. With a lung tumor, a CTV that executes a quasi periodic motion z(t) does not receive ${\Phi}$ (x,y), but rather an Effective Incident Fluence EIF(x,y). We numerically evaluate the EIF(x,y) from a given DMLC file by a coordinate transformation to the Target's Eye View (TEV). In the TEV coordinate system, the CTV itself is stationary, and the MLC is seen to execute a motion -z(t) that is superimposed on the DMLC motion. The resulting EIF(x,y)is inputted back into the dose calculation engine to estimate the 3D dose to a moving CTV. In this study, we model respiratory motion as a sinusoidal function with an amplitude of 10 mm in the superior-inferior direction, a period of 5 seconds, and an initial phase of zero.

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In-silico annotation of the chemical composition of Tibetan tea and its mechanism on antioxidant and lipid-lowering in mice

  • Ning Wang ;Linman Li ;Puyu Zhang;Muhammad Aamer Mehmood ;Chaohua Lan;Tian Gan ;Zaixin Li ;Zhi Zhang ;Kewei Xu ;Shan Mo ;Gang Xia ;Tao Wu ;Hui Zhu
    • Nutrition Research and Practice
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    • v.17 no.4
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    • pp.682-697
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    • 2023
  • BACKGROUND/OBJECTIVES: Tibetan tea is a kind of dark tea, due to the inherent complexity of natural products, the chemical composition and beneficial effects of Tibetan tea are not fully understood. The objective of this study was to unravel the composition of Tibetan tea using knowledge-guided multilayer network (KGMN) techniques and explore its potential antioxidant and hypolipidemic mechanisms in mice. MATERIALS/METHODS: The C57BL/6J mice were continuously gavaged with Tibetan tea extract (T group), green tea extract (G group) and ddH2O (H group) for 15 days. The activity of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) in mice was detected. Transcriptome sequencing technology was used to investigate the molecular mechanisms underlying the antioxidant and lipid-lowering effects of Tibetan tea in mice. Furthermore, the expression levels of liver antioxidant and lipid metabolism related genes in various groups were detected by the real-time quantitative polymerase chain reaction (qPCR) method. RESULTS: The results showed that a total of 42 flavonoids are provisionally annotated in Tibetan tea using KGMN strategies. Tibetan tea significantly reduced body weight gain and increased T-AOC and SOD activities in mice compared with the H group. Based on the results of transcriptome and qPCR, it was confirmed that Tibetan tea could play a key role in antioxidant and lipid lowering by regulating oxidative stress and lipid metabolism related pathways such as insulin resistance, P53 signaling pathway, insulin signaling pathway, fatty acid elongation and fatty acid metabolism. CONCLUSIONS: This study was the first to use computational tools to deeply explore the composition of Tibetan tea and revealed its potential antioxidant and hypolipidemic mechanisms, and it provides new insights into the composition and bioactivity of Tibetan tea.

A Study on the Vegetables Mentioned in the Bible (성서에 언급된 채소류에 관한 연구)

  • Woo, Ja-Won
    • Journal of the Korean Society of Food Culture
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    • v.22 no.1
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    • pp.1-9
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    • 2007
  • This paper is intended to study what kinds of the vegetables are mentioned in the Bible and how they were used in those days. While one hundred and twenty-eight different plants are mentioned in the Bible, there are today 2,384 plant species in modem Israel, most of which have been introduced in recent centuries. These plants obviously did not exist there in biblical times and were only recently introduced from Australia and South America, respectively. This article will study only the vegetables mentioned in the Bible and known to have existed in the old and new testament times. Since the first book devoted exclusively to biblical botany was that of Levinus Lemmens in 1566, the modem systematic study of biblical plants, began with F. Hasselquist, a student of Linnaeus, the founder of modem botany. In 1928, Immanuel Loew approached the subject differently, reviewing all known data pertaining to biblical plants. His work not only discussed biblical plants, but also plants in later Jewish literature, particularly the Talmud. The British scholar G. E. Post provided a broad field study of modem plants in Palestine, Syria, Lebanon, and Jordan. More recent major treatments of the subject include those of A. and H. Moldenke (1952), M. Zohary (1982), N. Hareuveni (1984), and Y. J. Choi(1996). Today, articles on specific biblical plants listed in the Bible can be found in any number of encyclopedias. This study attempts to provide a synthesis of the work of a number of scholars who studied the vegetables and plants mentioned in the Bible. As a preliminary study on the culture of food in the biblical period, this study has focused on the identity and features of the vegetables of the Bible. In only a limited number of instances, because of the paucity of the informations and the broad and generic descriptions of the plants, we can't be certain about the identification of the vegetables named in the Bible. In many instances the traditions established by the Greek, Aramaic, and English translations are helpful, although sometimes they are misleading. This paper subdivides the vegetables into broad areas, the general vegetables and the flavoring herbs. Vegetables formed very important part of the diet in the biblical times. Two main types were used: those whose nutritious seeds could be easily stored and those which were eaten freshly gathered from gardens. Pulse seeds provided a useful source of vegetable protein, while fresh green vegetables were vitamin rich. Pulses could be eaten boiled, or their dried seeds could be ground up into flour and then made into nutritious soups. Fresh vegetables were eaten either raw or lightly cooked, usually by boiling in water. The general vegetables in the Bible are herbs(garden rocket), cucumber(snake cucumber), watermelon, leeks, chicory, and onions. Also the flavoring herbs in the Bible are rue, dill, cummin, black cummin, frankincense, cinnamon, cassia, myrrh, black mustard, coriander, mint, saffron, ginger grass, syrian hyssop, aloes(eagle wood), manna which have the flavor, aroma, and medical values.

The Effect of the Death Education Program on the Death Anxiety and Attitudes toward Nursing Care of the Dying Patients of Nursing Student (죽음교육 프로그램이 간호 대학생의 죽음불안과 임종간호태도에 미치는 영향)

  • Cho, Hea-Jin;Kim, Eun-Sim
    • Journal of Hospice and Palliative Care
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    • v.8 no.2
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    • pp.163-172
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    • 2005
  • Purpose: This study is to identify the effect of a death education program to the nursing students on their anxiety of death and attitudes toward nursing care of the dying. Methods: The design of this study is nonequivalent control group pretest-posttest design. The subjects of experimental group 20 and control group 16 in senior grade of department of Nursing G university in J city. The experimental group had Death education Program, which was a three days per week program, for 2 weeks. And post-test was carried out in the same way as the pre-test. Data analysis was done using frequency, percentage, mean, standard deviation, Chi-square test, t-test, paired Sample t-test using with SPSS win 10.0. Results: the experimental group was decreased in degree of anxiety of death and was improved in degree of positive attitudes toward nursing care of the dying. Conclusion: The death Education Program can be an effective nursing education program for their Nursing students to decrease their death anxiety and to prepare care of the dying.

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Effect of Holding Time of Broiler at Slaughter House on Color, PSE, Appearance of Chicken Meat (육계의 계류 시간에 따른 닭고기의 육색, PSE 발생 및 외관 특성)

  • Chae, H.S.;Yoo, Y.M.;Jeong, S.G.;Ham, J.S.;Ahn, C.N.;Jang, A.R.;Yoo, H.S.
    • Korean Journal of Poultry Science
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    • v.35 no.2
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    • pp.177-182
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    • 2008
  • This studies were conducted to investigate the effect of holding time of broiler at slaughter house on chicken meat quality. Short holding time ($1{\sim}2hrs $) increased chicken meat quality compared to long holding time ($14{\sim}15 hrs$), which resulted in 14% higher grade $1^+$ chicken. In portioned meat, short holding time ($1{\sim}2 hrs$) resulted in 15% higher incidence of grade $1^+$ chicken breast. Also, long holding time occurred higher PSE incidence of chicken breast. pH value of the chicken meat with short holding time was similar to that with long holding time, and that with medium holding time showed the lowest. $L^*$ (lightness) value of the chicken meat was lower with medium holding time than with short holding time, but that in muscle and skin showed increasing tendency with long holding time. Holding time showed no effect on $a^*$ (redness) of the chicken meat, but longer holding time decreased $b^*$ (yellowness) value. This indicated that long holding time adversely affected chicken meat quality.

Linkage Map and Quantitative Trait Loci(QTL) on Pig Chromosome 6 (돼지 염색체 6번의 연관지도 및 양적형질 유전자좌위 탐색)

  • Lee, H.Y.;Choi, B.H.;Kim, T.H.;Park, E.W.;Yoon, D.H.;Lee, H.K.;Jeon, G.J.;Cheong, I.C.;Hong, K.C.
    • Journal of Animal Science and Technology
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    • v.45 no.6
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    • pp.939-948
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    • 2003
  • The objective of this study was to identify the quantitative traits loci(QTL) for economically important traits such as growth, carcass and meat quality on pig chromosome 6. A three generation resource population was constructed from cross between Korean native boars and Landrace sows. A total of 240 F$_2$ animals were produced using intercross between 10 boars and 31 sows of F$_1$ animals. Phenotypic data including body weight at 3 weeks, backfat thickness, muscle pH, shear force and crude protein level were collected from F$_2$ animals. Animals including grandparents(F$_0$), parents(F$_1$) and offspring(F$_2$) were genotyped for 29 microsatellite markers and PCR-RFLP marker on chromosome 6. The linkage analysis was performed using CRI-MAP software version 2.4(Green et al., 1990) with FIXED option to obtain the map distances. The total length of SSC6 linkage map estimated in this study was 169.3cM. The average distance between adjacent markers was 6.05cM. For mapping of QTL, we used F$_2$ QTL Analysis Servlet of QTL express, a web-based QTL mapping tool(http://qtl.cap.ed.ac.uk). Five QTLs were detected at 5% chromosome-wide level for body weight of 3 weeks of age, shear force, meat pH at 24 hours after slaughtering, backfat thickness and crude protein level on SSC6.