本文選題：生態(tài)流行病學(xué) + 基因組流行病學(xué)　； 參考：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2015年博士論文

【摘要】：研究目的 近十年,由于測(cè)序技術(shù)的迅速發(fā)展,使得我們能夠在短時(shí)間內(nèi)低成本完成大量基因組的測(cè)序,也為細(xì)菌的群體遺傳學(xué)研究和表型性狀與遺傳基礎(chǔ)的關(guān)聯(lián)分析研究提供了前所未有的機(jī)遇。與此同時(shí),如何合理處理和分析海量基因組數(shù)據(jù),給生物統(tǒng)計(jì)學(xué)帶來了新的機(jī)遇和挑戰(zhàn),也極大的促進(jìn)了該學(xué)科的發(fā)展。本研究以鼠疫菌為研究對(duì)象,將生態(tài)流行病學(xué)涉及的氣候與鼠疫疫情的研究與基因組流行病學(xué)涉及的鼠疫菌全基因組范圍的遺傳變異綜合在一起,探討鼠疫菌在局部地區(qū)氣候影響下的進(jìn)化規(guī)律。這樣的跨學(xué)科研究,開啟了鼠疫菌研究的新領(lǐng)域,為其它人畜共患病原菌研究提供參考。研究對(duì)象 鼠疫菌在人類歷史上曾有三次大流行,造成上億人死亡。目前雖然沒有在人類中大規(guī)模流行,但仍存在于鼠疫自然疫源地中,并可通過蚤等媒介在嚙齒類動(dòng)物間傳播流行。烏蘇地區(qū)位于新疆維吾爾自治區(qū),屬于北天山灰旱獺、長尾黃鼠鼠疫疫源地,是重點(diǎn)的疫情監(jiān)測(cè)地,在該地區(qū)自然環(huán)境中動(dòng)物間鼠疫常年流行。本研究從該地區(qū)保存的120株歷史菌株中篩選了102株菌進(jìn)行測(cè)序,并最終確定93株菌用于本研究分析。同時(shí),為了分析在50年的歷史中環(huán)境因素和宿主媒介動(dòng)態(tài)變化,本研究還收集和使了用該地區(qū)的鼠疫監(jiān)測(cè)信息和氣候環(huán)境數(shù)據(jù)。研究內(nèi)容與結(jié)果-局部地區(qū)鼠疫菌進(jìn)化對(duì)采樣得到的烏蘇地區(qū)93株鼠疫菌鑒定出166個(gè)可靠SNP位點(diǎn)。通過這些位點(diǎn),可以對(duì)這些菌株構(gòu)建系統(tǒng)發(fā)育樹,分析其進(jìn)化關(guān)系。系統(tǒng)發(fā)育分析表明,烏蘇地區(qū)的鼠疫菌可以分為2個(gè)大群,分別位于古爾圖地區(qū)的兩片區(qū)域(記為A和B)(共78株)和巴音溝地區(qū)(共14株),另外還有1株距離兩個(gè)群關(guān)系都比較遠(yuǎn),可能是由于兩個(gè)地區(qū)地理隔離導(dǎo)致不同種群的形成。另外,本研究還將93株菌與全球鼠疫菌系統(tǒng)發(fā)育樹做比較,發(fā)現(xiàn)這93株菌均可定位在0.ANT1分支中�？紤]到古爾圖和巴音溝地區(qū)距離較遠(yuǎn),海拔相差上千米,生態(tài)環(huán)境差別較大,本研究將焦點(diǎn)聚集在古爾圖地區(qū)分離的78株鼠疫菌以及該地區(qū)的鼠疫生境中。古爾圖地區(qū)鼠疫分離株中共鑒定出54個(gè)SNP。通過多種不同建樹方法,均得到一致系統(tǒng)發(fā)育關(guān)系。78株菌可以分為3個(gè)主要群,并可進(jìn)一步細(xì)分為Group 1.1,1.2,2.1,2.2和3。通過觀察各群在時(shí)間上的動(dòng)態(tài)變化,我們發(fā)現(xiàn)在A地區(qū)Group 1明顯被Group 2所逐漸替代,發(fā)生時(shí)間約在1987年到1989年之間,1990年后Group1在A地區(qū)僅觀測(cè)到1例。通過BEAST2推測(cè)各種群分化時(shí)間,Group 1和Group 2兩群在1929年(95%置信區(qū)間為1900到1954年)產(chǎn)生分化。種群的替代可能是由于某種外部因素影響,導(dǎo)致另一個(gè)種群Group 2取得優(yōu)勢(shì)地位。通過有效種群大小和有效種群復(fù)制率分析,可以發(fā)現(xiàn)在1983年到1989年中,有效復(fù)制率明顯降低,而有效種群大小也在1987年后明顯下降,這些事實(shí)都表明在這個(gè)時(shí)期內(nèi)可能有異常的外部環(huán)境變化,形成選擇壓力,從而改變了鼠疫菌的種群構(gòu)成。基于鼠疫菌的SNP、Indel和附加基因組變異分析結(jié)果,本研究分析了基因組中受自然選擇的區(qū)域,最終發(fā)現(xiàn)12個(gè)變異熱區(qū),并對(duì)其進(jìn)行了詳細(xì)注釋。其中受選擇最顯著的熱區(qū)位于rpo Z編碼基因,基因總長只有276bp,發(fā)生了8個(gè)變異,其變異發(fā)生率(8/276≈2.90×10-2)遠(yuǎn)高于78株菌的全基因組變異發(fā)生率(128/4653728≈2.73×10-5)。rpo Z基因與鼠疫菌的生長速率以及在蚤體內(nèi)生物膜形成有關(guān),因而這些變異可能會(huì)影響鼠疫菌在跳蚤和老鼠中間的傳播,但由于生長速率降低這些變異均未在種群中固定下來。-局部地區(qū)鼠疫疫情與氣候環(huán)境變化關(guān)聯(lián)為了充分挖掘疫情監(jiān)測(cè)數(shù)據(jù),本研究對(duì)各指標(biāo)首先進(jìn)行了兩兩之間的相關(guān)分析。對(duì)蚤指數(shù)、鼠密度和血清陽性率進(jìn)行Pearson相關(guān)分析,結(jié)果顯示三者之間相關(guān)性不高,甚至相關(guān)系數(shù)都沒有超過0.5。理論上三者之間應(yīng)該是有著直接的影響作用,因此相關(guān)度不高可能是由于其它因素如氣候和環(huán)境導(dǎo)致。三個(gè)指標(biāo)的自相關(guān)和兩兩之間的互相關(guān)也不存在規(guī)律性,說明這三個(gè)指標(biāo)間在一定時(shí)延下也無顯著的相關(guān)性。參考與古爾圖地區(qū)相臨的哈薩克斯坦地區(qū)鼠疫疫情規(guī)律所做的監(jiān)測(cè)數(shù)據(jù)隨時(shí)間變化圖表示,該地區(qū)不存在與哈薩克斯坦地區(qū)相同的疫情規(guī)律,仍需要進(jìn)一步深入研究其成因。對(duì)氣候環(huán)境數(shù)據(jù)的探索性分析中,首先分析了降水、溫度和NDVI數(shù)據(jù)的季節(jié)性,通過譜分析確定了有且僅有以1年為單位的周期分量。通過對(duì)時(shí)間序列季節(jié)項(xiàng)分解過濾周期分量后,得到了不包含周期波動(dòng)的三項(xiàng)氣候環(huán)境數(shù)據(jù)。這三個(gè)時(shí)間序列(季節(jié)分量調(diào)整后三項(xiàng)氣候環(huán)境數(shù)據(jù))本身前后數(shù)據(jù)之間仍存在一定的相關(guān)性,為了能有效鑒定在50年間何時(shí)出現(xiàn)異常氣候情況,則需要將該規(guī)律部分進(jìn)一步分解。通過使用時(shí)間序列中ARIMA模型方法,對(duì)這三項(xiàng)數(shù)據(jù)進(jìn)一步分解后,得到了接近高斯白噪聲,前后之間相關(guān)性也不存在。這里剩余的殘差項(xiàng)就是氣候環(huán)境數(shù)據(jù)在排除規(guī)律性因素后剩余的隨機(jī)分量,此數(shù)據(jù)中的異常數(shù)據(jù)即為氣候環(huán)境異常點(diǎn)。通過廣義極端學(xué)生化偏差(ESD)方法,最終鑒定出8個(gè)溫度異常值,9個(gè)降水異常值以及1個(gè)NDVI異常值。異常點(diǎn)的分布并不均勻,在1986年到1990年間,多次出現(xiàn)降水異常以及溫度異常。為研究監(jiān)測(cè)指標(biāo)之間以及與氣候環(huán)境指標(biāo)之間的相互關(guān)系,希望通過建立定量化的回歸方程來研究這些指標(biāo)之間的規(guī)律。由于涉及變量數(shù)目過多,因而采用遺傳算法解決變量篩選問題,以AICc為標(biāo)準(zhǔn)選擇最優(yōu)模型。通過該方法得到的方程揭示了監(jiān)測(cè)指標(biāo)與當(dāng)年和前一年的監(jiān)測(cè)指標(biāo)以及氣候環(huán)境指標(biāo)中影響最大的分量。所建立的三個(gè)方程中,都包含有鼠密度指標(biāo),說明鼠密度在鼠疫菌流行的生態(tài)系統(tǒng)中發(fā)揮著重要的作用。將氣候環(huán)境異常與基因組變異相聯(lián)系,發(fā)現(xiàn)1986年到1990年間,是氣候異常頻發(fā)的時(shí)段,正好對(duì)應(yīng)了檢測(cè)到的鼠疫菌變異最多的一段時(shí)間,可能是導(dǎo)致鼠疫菌種群克隆群轉(zhuǎn)換的原因。結(jié)論與意義 本研究通過對(duì)局部地區(qū)——古爾圖地區(qū)鼠疫菌的基因組進(jìn)化、動(dòng)物鼠疫疫情與氣候變化的相關(guān)和回歸分析,給出了鼠疫菌所處生態(tài)系統(tǒng)在歷史中的動(dòng)態(tài)變化過程,為后續(xù)深入探索鼠疫菌在鼠疫自然疫源地的流行規(guī)律做出鋪墊。rpo Z基因很可能與鼠疫菌環(huán)境適應(yīng)性密切相關(guān),可能會(huì)導(dǎo)致鼠疫菌的流行強(qiáng)度增加。結(jié)合氣候與環(huán)境數(shù)據(jù),發(fā)現(xiàn)連續(xù)的氣候異常同鼠疫菌克隆群轉(zhuǎn)換時(shí)間恰好一致,可能是由于極端天氣導(dǎo)致鼠疫菌種群下降,從而引起鼠疫菌種群克隆群變化。這提示我們應(yīng)當(dāng)注意連續(xù)極端天氣下鼠疫菌發(fā)生的變異,預(yù)防具有高傳染性鼠疫菌種群出現(xiàn)。通過回歸分析,發(fā)現(xiàn)宿主密度在整個(gè)鼠疫菌流行的生態(tài)系統(tǒng)中,可能是最重要的一項(xiàng)因素。本研究所得到的線性方程,可用于對(duì)古爾圖地區(qū)鼠疫疫情的流行進(jìn)行預(yù)測(cè)。
[Abstract]:For the last ten years, the rapid development of sequencing technology has made it possible for us to complete a large number of genome sequencing in a short period of time. It also provides unprecedented opportunities for bacterial population genetics research and association analysis of phenotypic traits and genetic bases. At the same time, how to deal with and analyze mass bases reasonably The data of the group have brought new opportunities and challenges to biometrics, which also greatly promoted the development of the subject. This study takes the Yersinia pestis as the object of study, and combines the study of the epidemic of ecologic epidemiology with the epidemic of plague and the genetic variation of the scope of the whole group of Yersinia pestis involved in the genome epidemiology. The evolution of Phytophthora under the influence of local climate. This interdisciplinary study opens a new field for the study of Yersinia pestis and provides reference for the study of other zoonosis. The research object of Yersinia pestis has three pandemics in human history, causing hundreds of millions of deaths. It exists in the natural foci of plague and can spread among rodents through fleas and other vectors. The Wusu area is located in the Xinjiang Uygur Autonomous Region, belongs to the Northern Tianshan gray marmot, the plague foci of the long tail yellow squirrel plague, the key epidemic monitoring site, and the perennial epidemic of the plague among the animals in the natural environment of the region. This study is preserved from this area. Of the 120 strains of historical strains, 102 strains were sequenced and 93 strains were determined for this study. In order to analyze the dynamic changes of environmental factors and host media in the history of 50 years, this study also collected and made the monitoring information of plague and climate and environment data in the area. Phytophthora evolution has identified 166 reliable SNP loci for 93 strains of Yersinia pestis in Wusu area. Through these loci, we can construct phylogenetic trees and analyze their evolutionary relationships. Phylogenetic analysis shows that the Yersinia pestis can be divided into 2 large groups in the two regions of the guertu region (A and B). A total of 78 strains and 14 strains of Ba Yin gully (a total of 1 strains) are far from two groups, which may be caused by geographical isolation in two regions. In addition, the study also compares 93 strains with the global Yersinia phylogenetic tree, and found that these 93 strains can be located in the 0.ANT1 branch. The area of the bayergou area is far distance, the altitude difference is thousands of meters, and the ecological environment is different. This study focuses on 78 strains of Yersinia pestis isolated in guertu area and the plague habitat in this area. The isolated strains of plague in guertu area have identified 54 SNP. through a variety of different methods of tree building, all of which are consistent with the phylogenetic relationship of.78 strain. Bacteria can be divided into 3 main groups and can be further subdivided into Group 1.1,1.2,2.1,2.2 and 3. by observing the dynamic changes in time. We found that Group 1 in A area was gradually replaced by Group 2. The occurrence time was between 1987 and 1989. After 1990, only 1 cases were observed in A region. All kinds of groups were conjectured through BEAST2. Differentiation time, Group 1 and Group 2 two groups were differentiated in 1929 (95% confidence interval from 1900 to 1954). The substitution of the population may be due to some external factors, resulting in the dominant position of another population Group 2. The effective population size and the effective population replication rate can be found to be effectively replicated from 1983 to 1989. The rate of the population decreased significantly, and the effective population size decreased significantly after 1987. These facts indicate that there may be abnormal external environment changes during this period, forming selection pressure, thus changing the population composition of Yersinia pestis. Based on the analysis of SNP, Indel and additional gene group variation of Yersinia pestis, this study analyzed the genome in the genome. In the area of natural selection, 12 variation heat regions were found and the most significant heat areas were selected as the RPO Z coding gene, and the total gene length was only 276bp, and 8 variations occurred. The mutation rate (8/276 2.90 * 10-2) was far higher than that of 78 strains (128/4653728 2.73 * 10-5).Rpo. The Z gene is related to the growth rate of Yersinia pestis and the formation of biofilm in the flea body, so these variations may affect the spread of Yersinia pestis between fleas and mice, but these variations are not fixed in the population due to the decrease of the growth rate. - the epidemic of plague in local areas is associated with the climate change in order to fully excavate the epidemic situation. Monitoring data, this study first carried out 22 correlation analysis of each index. The Pearson correlation analysis was carried out on the flea index, rat density and the positive rate of serum. The results showed that the correlation between the three was not high, even the correlation coefficient did not exceed the theory of the 0.5., which should be directly affected by the three, so the correlation was not high. It may be due to other factors such as climate and environment. The autocorrelation of the three indicators and the intercorrelation between the 22 are also not regular, indicating that there is no significant correlation between the three indicators under a certain delay. The map indicates that the region does not have the same epidemic situation as the Kazakhstan area and still needs to further study its causes. In the exploratory analysis of climate and environmental data, the seasonal characteristics of precipitation, temperature and NDVI data are analyzed, and the periodic components with only 1 years as units are determined by spectral analysis. After the sequence seasonal term is decomposed and filtered, the three climatic environment data, which does not contain periodic fluctuations, are obtained. The three time series (three climatic environment data after the seasonal component adjustment) still have a certain correlation between the data and the data itself. In order to effectively identify when the abnormal climate occurs in the period of 50, it needs to be taken. The rule part is further decomposed. By using the ARIMA model method in the time series, after the further decomposition of the three data, we get close to Gauss white noise, and there is no correlation between before and after. The remaining residual term is the residual random component after the climatic environment data are excluded from the regular factors and the abnormal data in this data By means of generalized extreme student deviation (ESD) method, 8 temperature anomaly values, 9 anomalous values of precipitation and 1 NDVI anomalies are identified. The distribution of abnormal points is not uniform. From 1986 to 1990, there are many abnormal precipitation and temperature anomalies. The relationship between indexes is expected to be studied by establishing a quantitative regression equation. As the number of variables is too large, the genetic algorithm is used to solve the problem of variable selection, and the optimal model is selected as the standard of AICc. The formula obtained through this method reveals the monitoring index and the year and the previous year. The three equations which have the greatest impact on the monitoring indicators and climate and environmental indicators all contain mouse density indicators, indicating that the rat density plays an important role in the ecological system of Yersinia pestis. It is found that between 1986 and 1990, the climate and environmental anomalies are associated with genomic variation, and it is a period of abnormal climate. It is exactly corresponding to the time of the most mutation of the detected Yersinia pestis, which may be the cause of the transformation of the clone group of the Yersinia pestis population. The dynamic change process of the ecosystem in the history, in order to further explore the epidemic law of Yersinia pestis in the plague natural foci, the.Rpo Z gene may be closely related to the environmental adaptability of the Yersinia pestis, which may lead to the increase of the epidemic intensity of the Yersinia pestis. The conversion time of bacteria clones is exactly the same. It may be caused by the decline of Yersinia pestis population due to extreme weather, which leads to the change of the population clones of Yersinia pestis. This suggests that we should pay attention to the variation of Yersinia pestis in the continuous extreme weather and prevent the emergence of highly contagious plague strains. The epidemic of Yersinia may be the most important factor in the epidemic. The linear equation obtained in this study can be used to predict the epidemic of plague in the guertu region.

【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R516.8

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 唐玉珍,尹家祥,羅大文,唐永朝,曾建芬,江明;兩種鼠疫菌培養(yǎng)基現(xiàn)場(chǎng)應(yīng)用效果評(píng)價(jià)[J];地方病通報(bào);2001年04期

2 席亞芳;開發(fā)西部嚴(yán)防旱獺鼠疫發(fā)生[J];青海醫(yī)藥雜志;2001年06期

3 ;鼠疫可能與基因轉(zhuǎn)移有關(guān)[J];口岸衛(wèi)生控制;2002年03期

4 戴瑞霞,李敏,趙海紅,金泳,席亞芳,金星,李存香,辛有全,楊曉艷,馮建萍;中國鼠疫菌耐鏈霉素菌株的監(jiān)測(cè)[J];中華流行病學(xué)雜志;2003年11期

5 戴瑞霞,李敏,趙海紅,金泳,席亞芳,金星,李存香,辛有全,楊曉艷,馮建萍;我國鼠疫菌耐鏈霉素菌株的監(jiān)測(cè)[J];中國地方病學(xué)雜志;2003年06期

6 石麗媛,王鵬,郭英,于國林,董興齊;云南省家、野兩型鼠疫菌營養(yǎng)需求的比較試驗(yàn)[J];地方病通報(bào);2004年02期

7 陸洪潮,杜暉,楊華,胡靜英,凱金祥,吳國剛,何成友,王仕香,王世華,張永榮;貴州省首次鼠疫暴發(fā)流行的調(diào)查結(jié)果[J];中國地方病防治雜志;2004年04期

8 王光惠;云南省德宏州鼠疫概況[J];醫(yī)學(xué)動(dòng)物防制;2004年12期

9 何劍峰,羅會(huì)明,梁文佳;鼠疫的基本知識(shí)與預(yù)防控制[J];華南預(yù)防醫(yī)學(xué);2005年03期

10 王春風(fēng) ,黃江泉;中國鼠疫形成的三大地域特征[J];湖南安全與防災(zāi);2005年10期

相關(guān)會(huì)議論文 前9條

1 張濤;李麗;趙建華;;鼠疫研究概述[A];中華醫(yī)學(xué)會(huì)全國新發(fā)和再發(fā)傳染病2012年學(xué)術(shù)研討會(huì)論文匯編[C];2012年

2 王信惠;阿不力米提;史建勇;布仁明德;甫拉提;安文嚴(yán);李東會(huì);木合亞提;蔣衛(wèi);廖力夫;雷剛;;灰倉鼠在新疆溫泉縣阿拉套山鼠疫自然疫源地調(diào)查中的檢菌應(yīng)用[A];中國實(shí)驗(yàn)動(dòng)物學(xué)會(huì)第六屆學(xué)術(shù)年會(huì)論文集[C];2004年

3 薛強(qiáng);王靜;鄒明強(qiáng);李錦豐;王楠;周朋;邱月明;陳彥長;;應(yīng)用微流控芯片快速檢測(cè)血清中鼠疫抗體[A];第三屆全國微全分析系統(tǒng)學(xué)術(shù)會(huì)議論文集[C];2005年

4 戴二黑;;鼠疫耶爾森菌基因組重排譜分型的研究[A];第五次全國中青年檢驗(yàn)醫(yī)學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2006年

5 魏東;王國治;;鼠疫F1蛋白原核分泌性表達(dá)及鑒定[A];2012年中國藥學(xué)大會(huì)暨第十二屆中國藥師周論文集[C];2012年

6 常婭莉;吳智遠(yuǎn);祁芝珍;焦磊;韓少波;戴瑞霞;胡麗娜;卜培英;王秉翔;;鼠疫基因工程疫苗有穩(wěn)定的免疫學(xué)應(yīng)答和保護(hù)[A];2012年中國藥學(xué)大會(huì)暨第十二屆中國藥師周論文集[C];2012年

7 陳貴春;海榮;張志凱;董黎;姚光海;龔曉俊;劉昭兵;黃紅武;;貴州省鼠疫耶爾森菌生物學(xué)特征研究[A];貴州省科學(xué)技術(shù)優(yōu)秀學(xué)術(shù)論文集（2004年度）[C];2004年

8 宋亞軍;;鼠疫耶爾森氏菌比較與進(jìn)化基因組學(xué)研究[A];2006中國微生物學(xué)會(huì)第九次全國會(huì)員代表大會(huì)暨學(xué)術(shù)年會(huì)論文摘要集[C];2006年

9 董興齊;張洪英;彭和碧;Chu C.May;;鼠疫菌—新質(zhì)粒的限制性酶切圖譜[A];西部大開發(fā) 科教先行與可持續(xù)發(fā)展——中國科協(xié)2000年學(xué)術(shù)年會(huì)文集[C];2000年

相關(guān)重要報(bào)紙文章 前10條

1 前屆衛(wèi)生部鼠疫專家咨詢委員會(huì)委員 樊振亞教授;鼠疫：可防 可控 可治[N];保健時(shí)報(bào);2005年

2 李偉;中蒙聯(lián)手開展鼠疫等病原監(jiān)測(cè)研究[N];中國國門時(shí)報(bào);2007年

3 馬曉華;鼠疫之戰(zhàn)[N];第一財(cái)經(jīng)日?qǐng)?bào);2009年

4 崔尚金;聚焦老而不朽的人畜共患�。菏笠遊N];中國畜牧獸醫(yī)報(bào);2005年

5 賀雄 北京市疾控中心副主任 夏連續(xù) 劉汀;鼠疫來臨科學(xué)防控不恐慌[N];中國中醫(yī)藥報(bào);2009年

6 本報(bào)記者 金振婭;嚴(yán)防鼠疫[N];光明日?qǐng)?bào);2010年

7 楊順義;鼠疫與旅行[N];中國國門時(shí)報(bào)(中國出入境檢驗(yàn)疫報(bào));2002年

8 自治區(qū)地方病防治研究所供稿;提高防護(hù)意識(shí) 消除鼠疫危害[N];西藏日?qǐng)?bào);2003年

9 崔尚金;聚焦老而不朽的人畜共患�。菏笠遊N];中國畜牧獸醫(yī)報(bào);2005年

10 記者 樂紹延;731部隊(duì)研制細(xì)菌武器新證據(jù)被發(fā)現(xiàn)[N];人民日?qǐng)?bào);2005年

相關(guān)博士學(xué)位論文 前10條

1 郭辰儀;鼠疫自然疫源地局部生態(tài)與鼠疫菌基因組變異的關(guān)聯(lián)分析[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2015年

2 李艷君;鼠疫耶爾森氏菌基因組多態(tài)性研究及快速鑒定溯源系統(tǒng)的建立[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2009年

3 周蕾;鼠疫耶爾森氏菌密度感應(yīng)系統(tǒng)研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2007年

4 楊慧盈;一、鼠疫菌毒力相關(guān)蛋白與人蛋白相互作用的初步研究 二、鼠疫菌Ⅲ型分泌系統(tǒng)內(nèi)蛋白相互作用及LcrG調(diào)控的研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2009年

5 李蓓;鼠疫耶爾森氏菌候選疫苗靶標(biāo)的篩選與初步驗(yàn)證[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2008年

6 譚亞芳;鼠疫耶爾森氏菌Ⅲ型分泌系統(tǒng)效應(yīng)蛋白YopK在致病機(jī)制中的作用研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2011年

7 戴二黑;鼠疫耶爾森氏菌基因分型與適應(yīng)性微進(jìn)化研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2005年

8 畢玉晶;鼠疫耶爾森氏菌YscW對(duì)小鼠巨噬細(xì)胞生物效應(yīng)的研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2008年

9 柯躍華;鼠疫菌蛋白YpkA和人蛋白VASP的相互作用和功能研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2011年

10 曲識(shí);鼠疫菌毒力調(diào)節(jié)因子Hfq及CRP作用機(jī)制的研究[D];吉林大學(xué);2014年

相關(guān)碩士學(xué)位論文 前10條

1 楊明新;近代福建鼠疫研究[D];福建師范大學(xué);2006年

2 劉軼然;示蹤鼠疫菌構(gòu)建及吞噬細(xì)胞對(duì)其吞噬能力的觀察[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2011年

3 姜慧;1942年河套地區(qū)鼠疫研究[D];內(nèi)蒙古大學(xué);2012年

4 王娜;中國鼠疫菌單核苷酸多態(tài)性研究[D];中國疾病預(yù)防控制中心;2011年

5 尤敬民;1911年直隸鼠疫防治研究[D];河北師范大學(xué);2012年

6 陳雙艷;一株大腸桿菌O104的表型及基因型鑒定[D];大理學(xué)院;2013年

7 張建山;利用重組工程技術(shù)標(biāo)記鼠疫菌染色體基因[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2006年

8 張蓉;云南省鼠疫菌多位點(diǎn)可變數(shù)目串聯(lián)重復(fù)序列分型及流行病學(xué)意義[D];大理學(xué)院;2013年

9 羅張;鼠疫菌重要調(diào)控蛋白的表達(dá)純化及其DNA結(jié)合活性分析[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2011年

10 汪潔英;鼠疫雙組分疫苗的免疫學(xué)評(píng)價(jià)[D];福建醫(yī)科大學(xué);2011年

，

本文編號(hào)：1800107