Geomorphologic nash model with variable width function

Nguyen, Thi Phuong Thuy 충남대학교 대학원 2015 국내석사

지형학적 확산의 개념은 유역 내 흐름경로 또는 흐름길이의 이질성에서 기인하며, 오랜 기간에 걸쳐 수문학적 응답함수에 지대한 영향을 미치는 중요한 인자중 하나임이 입증되었다. 특히 지형학적 확산은 배수 구조의 이질성을 고려하기 위하여 폭 함수를 기반으로 수많은 연구에서 적용된 바 있다. 이에 본 연구에서는 지형지수를 이용하여 유역의 포화도가 배수 구조에 미치는 영향에 관한 연구를 수행하고, Nash 모형을 기반으로 하는 순간단위도의 유도 과정에서 포화도를 고려하는 방법을 제시하고자 한다. 우선, 개별적인 포화도 조건에 다른 지형학적 매개변수의 통계학적 모멘트를 DEM을 기반으로 산정하고 포화도에 따른 배수구조의 변동성을 평가한다. 또한, 다양한 포화도에 따른 유효강우량을 개별적으로 산정하여 Nash 모형의 매개변수 추정에 이용하였다. 다수의 이벤트로부터 추출된 파라메터 n과 k의 평균 값을 활용하여 각 소유역의 IUH가 계산되었다. IUH의 확률적 모멘트와 수정된 폭함수 역시 서로를 비교하여 추정되었다. 이를 실제 호우사상 자료와의 비교를 통해 본 연구에서 제시된 방법론을 검증하였다. 상기의 과정을 비교적 다수의 수문자료를 보유한 보청천 수계 내 5개 소유역에 적용하였다. 보청천의 5개의 소유역에 적용한 결과, 함수율은 폭함수와 IUH의 첨두값에 민감하게 반응하였다. 본 연구에서 제시한 방법론 및 적용 결과는 강우-유출 현상의 본질적인 특징과 배수구조의 상관성에 대한 이해도를 높이는 데에 기여할 수 있을 것이라 판단된다. 추후 연구에서 지형학적 매개변수의 추정을 위하여 흐름방향과 유역의 격자크기를 고려하는 것이 필수적이라 할 수 있다. 추가적으로 호르톤 식 또는 필립식 등을 이용하여 수문학적 분석의 질을 향상시킬 수 있으리라 생각된다. Geomorphologic dispersion due to the heterogeneity characteristics of flow paths in a basin has been demonstrated as a major factor affecting to the hydrologic response function of a catchment. This effect has considered by many previous studies taking into account flow path length factors, especially in the application of width function. Based upon the analysis of topographic index, another important geomorphologic factor extracted from DEM data, this work presents a new factor named basin saturation to evaluate its effects to the formation of the well-known instantaneous unit hydrograph (IUH) from Nash model and drainage structure in a river basin through width function. First, the geomorphologic parameters such as PDF of water flow length to the outlet point and their statistical moments corresponding to different saturation conditions are computed from DEM data with the support of GIS software. Outcomes from this analysis are used to evaluate the effect of basin saturation on drainage structure through the shape of width function. Then, effective rainfall regarding to each basin saturation degree and each given rainfall runoff event are found based on the given rainfall-runoff data. In the combination of hydrologic and geomorphologic data, the Nash parameters n and k are calculated using new equations derived by Choi et al. (2011). From the average values of parameter n and k in many rainfall runoff events, IUH of each sub-basin is calculated using Nash model’s governing equation. The statistical moments of IUH and rescaled width function are also estimated to compare with each other. Finally, the verification process with observed and simulated direct runoff data is conducted using Fortran programming, Nash?Sutcliffe model Efficiency Coefficient, and Root Mean Square Error. The whole processes are applied to five sub-basins in Bocheong catchment (485.21 km2) in Korea. The results from this study show that basin saturation is sensitive to the peak values of IUH and width function in the five sub-basins of Bocheong catchment. Additionally, from the verification process, over 40% cases among given rainfall events in the five sub-basins presented the peak discharges corresponding to the lower 100% basin saturation. It can be concluded that basin saturation can be used as a suitable index to evaluate the peaks values of the IUH and the drainage structure of the basin. For further study, it is necessary to consider the effects of DEM resolution of the basin and flow direction method on the estimation of the geomorphologic parameters. In addition, the hydrologic analysis also could give better results if more advanced approaches are used for calculating abstraction such as Horton’s equation and Philip’s equation.

Studies on New Therapeutic Targets for the Treatment of Tamoxifen- Resistant Breast Cancer : 타목시펜 저항성 유방암에서 신규 치료 표적 연구

Nguyen Thi Thuy Phuong 조선대학교 대학원 2014 국내박사

유방암 치료에 있어서 중요한 난제중 하나는 항암제 저항성 생성이다. 따라서, 항암제 저항성 반전을 위한 새로운 치료표적을 찾는 것은 중요한 의미를 갖는다. 본 학위논문에서는 항암제저항성 유방암의 치료에 기여할 수 있는 신규 치료표적을 제시한다. 본 연구진은 에스트로겐 생합성의 핵심효소인 aromatase의 기저발현 및 활성이 대조유방암 (MCF-7) 세포에 비하여 타목시펜 저항성 유방암 (TAMR-MCF-7) 세포에서 현저하게 증가된 것을 발견하였다. 또한, 면역조직화학법을 통한 타목시펜 저항성이 있는 사람의 유방암 (TAMR-MCF-7) 세포조직에서 aromatase 면역반응성을 알아본 결과, 타목시펜에 반응성이 있는 사람 유방암 (MCF-7) 세포조직에 비해 높은 면역반응성을 보였다. TAMR-MCF-7 세포에서 phosphoinositide 3-kinase (PI3K)의 억제는 aromatase 유전자 전사활성 및 효소 활성을 억제하였고, PI3K/Akt-의존적 CREB의 활성화는 aromatase의 발현 증가에 관여함을 밝혔다. 테스토스테론은 에스트로겐 양성 및 음성유방암에서 세포성장을 억제한다고 알려져있다 (Chottanapund et al., 2013). 그러나 테스토스테론 처치시 MCF-7 세포에 비하여 높은 aromatase의 발현을 보이는 TAMR-MCF-7 세포에서는 세포성장 억제효과가 유의성있게 감소하였다. 또한, aromatase 억제제인 formestane이 TAMR-MCF-7 세포에서 4-hydroxytamoxifen 매개에 의한 세포사멸을 증가시켰다. 본 발견은 aromatase 효소와 PI3K/Akt-의존적 CREB 신호전달경로가 타목시펜 저항성 유방암의 치료에 있어서 유망한 타겟이라는 것을 제시한다. 본 연구진은 두번째로 유방암 진행에 있어서 시토크롬 P450 (CYP) epoxygenase을 통한 아라키돈산(AA)에서 epoxyeicosatrienoic acids (EETs)으로의 전환과정에 관심을 가졌다. 다른 CYP 효소와는 달리 CYP3A4 epoxygenase가 MCF-7 세포에 비하여 타목시펜 (TAM) 저항성 유방암 세포 (TAMR-MCF-7)에서 현저하게 증가하였다. 또한, EET 산물들 중 11,12-epoxyeicosatrienoic acid (11,12-EET) 농도가 MCF-7 세포에서의 비해 TAMR-MCF-7 세포에서 현저하게 증가하였다. 케토코나졸 (CYP3A4 억제제) 혹은 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 합성 EET 길항제) 처치는 TAMR-MCF-7 세포에서 세포증식을 감소시키고 4-hydroxy tamoxifen (4-OH-TAM)에 대한 세포독성을 증가 시켰다. 병아리 융모 막 (CAM) 분석시 대조 MCF-7 세포 이식군에 비하여 증가된 TAMR-MCF-7 세포에서의 암 증식 및 혈관신생이 케토코나졸과 14,15-EEZE 처리에 의해 유의성 있게 억제되었다. 또한, 세포이동능 평가에서도 TAMR-MCF-7 세포의 활발한 이동능은 상기 화합물 처치에 의하여 감소되었다. 이 결과들은 세포증식, 혈관형성 및 이동능을 포함하는 타목시펜 저항성 유방암의 특징들에서 CYP3A4 epoxygense 과발현과 CYP3A4-매개 11,12-EET 합성의 중요한 역할을 제시한다. 더 나아가 케토코나졸 또는 14,15- EEZE 처치는 본 연구진이 타목시펜 저항성 유방암세포의 혈관신생 및 상피-간질세포 형질전환 현상의 원인으로 제시했던 E2F1-의존성 Pin 1발현을 억제하였다. 반대로 MCF-7 세포에서 EET 처치는 Pin 1 발현을 증가시켰다. 본 연구에서는 aromatase 와 CYP3A4 매개성 EET 생성 과정이 유방암의 내분비 저항성을 해지시킬 수 있는 신규 치료 타겟이 될 수 있음을 제시한다. The frequent development of resistance has been being a serious problem in the treatment of breast cancer. Hence, finding new therapeutic targets for reversal of chemo-resistance is of great interest. In the present studies, we have revealed several potential therapeutic targets which could contribute to the treatment of tamoxifen-resistant breast cancer. Immunohistochemistry also showed that aromatase immunoreactivity in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive human breast cancer tissues. Inhibition of phosphoinositide 3-kinase (PI3K) suppressed the transactivation of aromatase gene and its enzyme activity, and PI3K/Akt-dependent CREB activation was required for the enhanced expression of aromatase in TAMR-MCF-7 cells. Testosterone displays an inhibitory activity on cell growth of several breast cancer cell lines, however in TAMR-MCF-7 cells where express higher level of aromatase than MCF-7 cells, the inhibitory effect of testosterone on cell growth was less than that in MCF-7 cells. In addition, formestane, an aromatase inhibitor significantly potentiated 4-hydroxytamoxifen-mediated apoptosis in TAMR-MCF-7 cells. The finding suggest that aromatase enzyme and the PI3K/Akt-dependent CREB signaling pathway are promising targets of the treatment of endocrine resistant breast cancer. We were also interested in cytochrome P450 (CYP) epoxygenases converting arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which closely correlate with breast cancer progression. CYP3A4 epoxygenase was dramatically up-regulated in TAMR-MCF-7 compared to control MCF-7 cells. Moreover, we also found that cellular 11,12-epoxyeicosatrienoic acid (11,12-EET) concentration in TAMR-MCF-7 cells was about 8 fold higher than MCF-7 cells. Either CYP3A4 inhibition by ketoconazole (a CYP3A inhibitor) or antaginism of EET activity by 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, a synthetic EET antagonist) decreased cell proliferation and increased the sensitivity of TAMR-MCF-7 cells to 4-hydroxytamoxifen (4-OH-TAM). Chick chorioallantoic membrane (CAM) assay demonstrated that the increased angiogenic intensity and tumor formation of TAMR-MCF-7 cells was significantly suppressed by ketoconazole or 14,15-EEZE treatment. Moreover, the greater migration of TAMR-MCF-7 cells was also attenuated by these chemicals. These data implicate a critical role of CYP3A4-mediated 11,12-EETs production during the development of TAM-resistant breast cancer. Interestingly, ketoconazole or 14,15-EEZE treatment diminished the overexpression of PB/E2F1-dependent Pin 1 which is crucial for endocrine resistance and higher angiogenesis and epithelial-mesenchymal transition in TAM-resistant breast cancer. We further found that exposure of MCF-7 cells to EETs enhanced Pin1 expression in MCF-7 cells. Pin 1 silencing also blocked cell proliferation, angiogenesis, and migration in TAMR-MCF-7 cells. The data suggest that the influences of CYP3A4-mediated EETs pathway may be partly mediated by Rb/E2F1-dependent Pin1 overexpression in TAMR-MCF-7 cells. Taken together, our studies have shown that aromatase overexpression and CYP3A4-mediated EET production are new potential therapeutic targets for the reversal of endocrine resistance in breast cancer.

Expression and purification of p300 CH1 and HIF-1α CTAD complex and screening of protein-protein interaction inhibitors

Nguyen Thi Phuong Thuy 동국대학교 2017 국내석사

The p300 CH1/HIF-1α CTAD interaction plays a key role in the transcription of hypoxia inducible genes and the inhibition of the protein-protein interaction can be a target for the development of cancer therapeutics since HIF-1 allows tumor growth in hypoxic environments by promoting angiogenesis and metabolic adaptations to hypoxia. Both proteins were expressed in E. coli and purified. By using NMR spectroscopy, the conformational status of p300 CH1/HIF-1α CTAD complex was confirmed. The p300 CH1 and HIF-1α CTAD were unstructured or partially structured without their binding partners; however, their complex had well-defined folded structures. The p300 CH1 and HIF-1α CTAD were co-purified and subjected to the measurement of 1H-15N HSQC spectrum. The fragment compounds were titrated to the complex and 1H-15N HSQC spectra were measured. Several compounds showed significant spectra change upon the fragment titration. Thus, based on the NMR measurement inhibitors of p300 CH1/HIF-1α CTAD interaction can be screened and the selected fragment compounds can be utilized to generate the lead molecules for cancer therapeutics.

Microfluidic technique for the fabrication of hollow fibers and its biomedical application for in vitro endothelial blood brain barrier research

NGUYEN THI PHUONG THUY 가천대학교 일반대학원 2019 국내석사

This study reports the advanced and effective approach employing a triple-flow polydimethylsiloxane (PDMS) microdevice to controllably generate the alginate-based hollow fibers which are applicable to become a friendly microcappililaries-like scaffold for supporting human umbilical vein endothelial cells (HUVECs) development. The use of PDMS-based cyclindrical device could not only eliminate the limitations of complicated assembly by using a commercially plastic or steel-based microcapillary system, but also enhance the biocompatibility of cell supportive scaffolds. The two PDMS replicas with semi-cylindrical microchannel were successfully assembled to eventually obtain the completed microchannel with circular cross section which permitted the coaxial flows formation for a mild and continuous hollow fiber fabrication without channel clogging. The mineral oil introduced into the central flow that served as an inert space inside the Ca-alginate wall to ensure the formation of hollow fibers obtained a consistent hollow structure. The hollow fibers owning the robust mechanical strength and high permeability with reasonable biocompatibility were used as scaffolds for the attachment and proliferation of HUVECs to mimic brain microcappilaries. The hollow fibers covered with a full layer of HUVECs were further integrated in a neurovascular construction to co-culture with astrocytes for mimicking blood brain barrier. The use of introduced neurovascular model for drug testing exhibited a great prospective in tissue engineering and drug delivery.

미국과 아시아 주식시장의 의존성 검증

응웬, 티 프엉 투이 부산대학교 2010 국내석사

This paper studies the relationship between the US stock market and six major Asian stock markets (KOSPI200, Nikkei225, STI, KLSE, Hangseng, and Shanghai) before the pre and after 2008, August 30th when the financial crisis was officially started. The data used in this study are daily closing stock market index time series obtained from KisValue which are then adjusted to account for the time zone differences. Each data time series consists of 1182 observations from January 2004 to September 2009. The descriptive static indicates that the Korea index suffers much loss, while the Hong Kong index suffers less loss. By analyzing the correlation between each stock market, the author finds out these markets have a slight relationship especially between the US and China stock markets. The unit root tests show that each price series is nonstationary in the levels but it is stationary after the first differencing. Both the pre and post financial crisis the time series of each market has unit root. In order to analyze the cointergration, the Engle-Granger analysis and Johansen test methods are used. By using a one-percent significance level, the Johansen test results suggest at least two cointegrating vectors for the entire time series, while the Engle-Granger analysis results suggest that there is no cointegrating vector at all. That means the long term equilibrium relationship between US and each Asian market does not exist. This leads to analysis VAR to estimate the influence between US and each Asian stock market. VAR analysis’s result indicates that in the pre period, US and Malaysia, Japan markets have a low forecast ability. But the remaining ones have a 1% level of significance. In the post period, except for Malaysia and China markets, the remaining markets also have a 1% level of significance. That means except for Malaysia and China markets, the remaining markets receive a past influence from US.