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Description
V(D)J recombination is responsible for generating an enormous repertoire of immunoglobulins and T cell receptors, therefore it is a centerpiece to the formation of the adaptive immune system. The V(D)J recombination process proceeds through two steps, site-specific cleavage at RSS (Recombination Signal Sequence) site mediated by the RAG recombinase (RAG1/2) and the subsequent imprecise resolution of the DNA ends, which is carried out by the ubiquitous non-homologous end joining pathway (NHEJ). The V(D)J recombination reaction is obliged to be tightly controlled under all circumstances, as it involves generations of DNA double strand breaks, which are considered the most dangerous lesion to a cell. Multifaceted regulatory mechanisms have been evolved to create great diversity of the antigen receptor repertoire while ensuring genome stability. The RAG-mediated cleavage reaction is stringently regulated at both the pre-cleavage stage and the post-cleavage stage. Specifically, RAG1/2 first forms a pre-cleavage complex assembled at the boarder of RSS and coding flank, which ensures the appropriate DNA targeting. Subsequently, this complex initiates site-specific cleavage, generating two types of double stranded DNA breaks, hairpin-ended coding ends (HP-CEs) and blunt signal ends (SEs). After the cleavage, RAG1/2 proteins bind and retain the recombination ends to form post-cleavage complexes (PCC), which collaborates with the NHEJ machinery for appropriate transfer of recombination ends to NHEJ for proper end resolution. However, little is known about the molecular basis of this collaboration, partly attributed to the lack of sensitive assays to reveal the interaction of PCC with HP-CEs. Here, for the first time, by using two complementary fluorescence-based techniques, fluorescence anisotropy and fluorescence resonance energy transfer (FRET), I managed to monitor the RAG1/2-catalyzed cleavage reaction in real time, from the pre-cleavage to the post-cleavage stages. By examining the dynamic fluorescence changes during the RAG-mediated cleavage reactions, and by manipulating the reaction conditions, I was able to characterize some fundamental properties of RAG-DNA interactions before and after cleavage. Firstly, Mg2+, known as a physiological cofactor at the excision step, also promotes the HP-CEs retention in the RAG complex after cleavage. Secondly, the structure of pre-cleavage complex may affect the subsequent collaborations with NHEJ for end resolution. Thirdly, the non-core region of RAG2 may have differential influences on the PCC retention of HP-CEs and SEs. Furthermore, I also provide the first evidence of RAG1-mediated regulation of RAG2. Our study provides important insights into the multilayered regulatory mechanisms, in modulating recombination events in developing lymphocytes and paves the way for possible development of detection and diagnotic markers for defective recombination events that are often associated immunodeficiency and/or lymphoid malignancy.
ContributorsWang, Guannan (Author) / Chang, Yung (Thesis advisor) / Levitus, Marcia (Committee member) / Misra, Rajeev (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2012
Description
Intrinsic antibiotic resistance is of growing concern in modern medical treatment. The primary action of multidrug resistant strains is through over-expression of active transporters which recognize a broad range of antibiotics. In Escherichia coli, the TolC-AcrAB complex has become a model system to understand antibiotic efflux. While the structures of these three proteins (and many of their homologs) are known, the exact mechanisms of interaction are still poorly understood. By mutational analysis of the TolC turn 1 residues, a drug hypersensitive mutant has been identified which is defective in functional interactions with AcrA and AcrB. Antibiotic resistant revertants carry alterations in both TolC and AcrA act by stabilizing functional complex assembly and opening of the TolC aperture, as monitored by stability of a labile TolC mutant and sensitivity to vancomycin, respectively. Alterations in the AcrB periplasmic hairpin loops lead to a similar antibiotic hypersensitivity phenotype and destabilized complex assembly. Likewise, alterations in TolC which constitutively open the aperture suppress this antibiotic sensitivity. Suppressor alterations in AcrA and AcrB partially restore antibiotic resistance by mediating stability of the complex. The AcrA suppressor alterations isolated in these studies map to the three crystallized domains and it is concluded they alter the AcrA conformation such that it is permanently fixed in an active state, which wild type only transiently goes through when activated by AcrB. Through this genetic evidence, a direct interaction between TolC and AcrB which is stabilized by AcrA has been proposed. In addition to stabilizing the interactions between TolC and AcrB, AcrA is also responsible for triggering opening of the TolC aperture by mediating energy flow from AcrB to TolC. By permanently altering the conformation of AcrA, suppressor mutants allow defective TolC or AcrB mutants to regain functional interactions lost by the initial mutations. The data provide the genetic proof for direct interaction between AcrB and that AcrA mediated opening of TolC requires AcrB as a scaffold.
ContributorsWeeks, Jon William (Author) / Misra, Rajeev (Thesis advisor) / Stout, Valerie (Committee member) / Shi, Yixin (Committee member) / Clark-Curtiss, Josephine (Committee member) / Arizona State University (Publisher)
Created2012
Description
The discovery and development of novel antibacterial agents is essential to address the rising health concern over antibiotic resistant bacteria. This research investigated the antibacterial activity of a natural clay deposit near Crater Lake, Oregon, that is effective at killing antibiotic resistant human pathogens. The primary rock types in the deposit are andesitic pyroclastic materials, which have been hydrothermally altered into argillic clay zones. High-sulfidation (acidic) alteration produced clay zones with elevated pyrite (18%), illite-smectite (I-S) (70% illite), elemental sulfur, kaolinite and carbonates. Low-sulfidation alteration at neutral pH generated clay zones with lower pyrite concentrations pyrite (4-6%), the mixed-layered I-S clay rectorite (R1, I-S) and quartz.
Antibacterial susceptibility testing reveals that hydrated clays containing pyrite and I-S are effective at killing (100%) of the model pathogens tested (E. coli and S. epidermidis) when pH (< 4.2) and Eh (> 450 mV) promote pyrite oxidation and mineral dissolution, releasing > 1 mM concentrations of Fe2+, Fe3+ and Al3+. However, certain oxidized clay zones containing no pyrite still inhibited bacterial growth. These clays buffered solutions to low pH (< 4.7) and oxidizing Eh (> 400 mV) conditions, releasing lower amounts (< 1 mM) of Fe and Al. The presence of carbonate in the clays eliminated antibacterial activity due to increases in pH, which lower pyrite oxidation and mineral dissolution rates.
The antibacterial mechanism of these natural clays was explored using metal toxicity and genetic assays, along with advanced bioimaging techniques. Antibacterial clays provide a continuous reservoir of Fe2+, Fe3+ and Al3+ that synergistically attack pathogens while generating hydrogen peroxide (H2O¬2). Results show that dissolved Fe2+ and Al3+ are adsorbed to bacterial envelopes, causing protein misfolding and oxidation in the outer membrane. Only Fe2+ is taken up by the cells, generating oxidative stress that damages DNA and proteins. Excess Fe2+ oxidizes inside the cell and precipitates Fe3+-oxides, marking the sites of hydroxyl radical (•OH) generation. Recognition of this novel geochemical antibacterial process should inform designs of new mineral based antibacterial agents and could provide a new economic industry for such clays.
Antibacterial susceptibility testing reveals that hydrated clays containing pyrite and I-S are effective at killing (100%) of the model pathogens tested (E. coli and S. epidermidis) when pH (< 4.2) and Eh (> 450 mV) promote pyrite oxidation and mineral dissolution, releasing > 1 mM concentrations of Fe2+, Fe3+ and Al3+. However, certain oxidized clay zones containing no pyrite still inhibited bacterial growth. These clays buffered solutions to low pH (< 4.7) and oxidizing Eh (> 400 mV) conditions, releasing lower amounts (< 1 mM) of Fe and Al. The presence of carbonate in the clays eliminated antibacterial activity due to increases in pH, which lower pyrite oxidation and mineral dissolution rates.
The antibacterial mechanism of these natural clays was explored using metal toxicity and genetic assays, along with advanced bioimaging techniques. Antibacterial clays provide a continuous reservoir of Fe2+, Fe3+ and Al3+ that synergistically attack pathogens while generating hydrogen peroxide (H2O¬2). Results show that dissolved Fe2+ and Al3+ are adsorbed to bacterial envelopes, causing protein misfolding and oxidation in the outer membrane. Only Fe2+ is taken up by the cells, generating oxidative stress that damages DNA and proteins. Excess Fe2+ oxidizes inside the cell and precipitates Fe3+-oxides, marking the sites of hydroxyl radical (•OH) generation. Recognition of this novel geochemical antibacterial process should inform designs of new mineral based antibacterial agents and could provide a new economic industry for such clays.
ContributorsMorrison, Keith D (Author) / Williams, Lynda B (Thesis advisor) / Williams, Stanley N (Thesis advisor) / Misra, Rajeev (Committee member) / Shock, Everett (Committee member) / Anbar, Ariel (Committee member) / Arizona State University (Publisher)
Created2015
Description
How to play the advantages of network loan platform to reduce the financing costs of net loan platform both in theory and practice has important significance. In this paper, we use the method of qualitative and quantitative combination. First of all, through the interview of the net loan platform practitioners, the financing cost of the net loan platform comes from the internal and external parts. Part of the network loan platform should be righteous, but counterproductive human and material costs, credit costs, information efficiency, transaction costs and matching costs; part of the emerging industry as a challenge, compliance costs, technical costs and safety costs and other cost. And put forward the top design credit system, promote the credit system; build a unified development of regulatory policies to reduce compliance risks; increase investment in technology, share the improvement of technological progress bonuses. Through the establishment of the regression model, the paper analyzes the influence of various indexes of network loan platform on the cost of network reception. It is found that the background of net loan platform with shareholder and executive team as the proxy variable has significant influence on the cost of network loan platform. The effect is not significant. Risk control indicators on the net loan platform cost has a significant negative effect. The impact of operating capacity on the cost of net loan platform differentiation, the acquisition of the cost of positive relations, the other is negative relations. Policy compliance indicators of financial security on the net loan platform cost significantly, the other did not significantly affect the role of liquidity indicators of differentiation, the average borrowing period will significantly affect the net loan platform costs, liquidity is a negative impact. And finally put forward the policy and recommendations and research limitations and future direction.
ContributorsRen, Junxia (Author) / Gu, Bin (Thesis advisor) / Chang, Chun (Thesis advisor) / Qian, Jun (Committee member) / Arizona State University (Publisher)
Created2017
Description
This article can be divided into six parts.
The first chapter analyzes the background, theatrical and particle reasons of this research. The author argues that the management of law firm needs a set of good system. The first one is operating the law firm in scale, and the other on is corporate management model, which shall be constructed in detail in the paper and will be put into practice by the law firm in which the author is worked.
The second chapter will introduce modern management theory, combining the situation of management in our law firm to analyze, raising some reasonable suggestions and instructions to promote our law firm to achieve the corporate management.
In the third chapter, the first chapter, starting with the review of the development process of foreign and our law firms, listing the organizational forms and the characteristics of our law firm, analyzing the situation and the drawbacks of the law firm management.
The fourth and fifth chapter introduce he background, the connotation of the corporate management model, listing the development and successful experience of some typical cases in respect of corporate management.
In the last chapter, the construction of corporate management model will be introduced in terms of organization form, human resource management and informationizing development.
The corporate management model is not mature in china. Though it is not easy to reform the existing model, but it should be believed that the development benefiting the legal industry will be achieved.
The first chapter analyzes the background, theatrical and particle reasons of this research. The author argues that the management of law firm needs a set of good system. The first one is operating the law firm in scale, and the other on is corporate management model, which shall be constructed in detail in the paper and will be put into practice by the law firm in which the author is worked.
The second chapter will introduce modern management theory, combining the situation of management in our law firm to analyze, raising some reasonable suggestions and instructions to promote our law firm to achieve the corporate management.
In the third chapter, the first chapter, starting with the review of the development process of foreign and our law firms, listing the organizational forms and the characteristics of our law firm, analyzing the situation and the drawbacks of the law firm management.
The fourth and fifth chapter introduce he background, the connotation of the corporate management model, listing the development and successful experience of some typical cases in respect of corporate management.
In the last chapter, the construction of corporate management model will be introduced in terms of organization form, human resource management and informationizing development.
The corporate management model is not mature in china. Though it is not easy to reform the existing model, but it should be believed that the development benefiting the legal industry will be achieved.
ContributorsZhu, Ping (Author) / Gu, Bin (Thesis advisor) / Chang, Chun (Thesis advisor) / Zhu, Ning (Committee member) / Arizona State University (Publisher)
Created2017
Description
This dissertation focuses on risk prevention and regulatory issues of financial asset trading platforms, exploring the composition of a financial asset trading platform and its risks, formulating the general framework of platform risk prevention and regulation, and discussing the methodologies for monitoring and managing the risk of financial assets trading platform. The dissertation is divided into eight chapters. The first chapter is the introduction, which discusses the current status in this research field, the motivation and significance of the research topic. The second chapter discusses the transaction cost theory, information asymmetry theory, financial risk management theory, financial supervision theory and other related basic theories related to financial asset trading platform risk prevention and supervision. The third chapter presents the definition, the main types, the generating mechanism and the transmission mechanism of the financial asset trading platform. The fourth chapter elaborates theoretically on the general framework of financial asset trading platform risk prevention and supervision based on the aspects of basic principles, key tasks, applicable methods and constituent elements. The fifth chapter discusses the performance of financial asset trading business, asset return trading business, financing business and information coupling business on financial asset trading platforms, and analyzes the risk prevention of financial asset trading platforms from a business perspective. The sixth chapter discusses the development of financial asset trading platforms in developed countries, and summarizes the experience and practice of their risk prevention and supervision based on four categories of business lines. On this basis, the dissertation draws the inspiration and implications for the future development of the trading platforms in our country. The seventh chapter puts forward policy recommendations regarding risk prevention and supervision of financial asset trading platforms in five aspects: legal positioning, credit information system, protection of consumer rights, self-discipline management and business supervision.
ContributorsXu, Chaojun (Author) / Hwang, Yuhchang (Thesis advisor) / Yan, Hong (Thesis advisor) / Chang, Chun (Committee member) / Arizona State University (Publisher)
Created2017
Description
Lignocellulosic biomass represents a renewable domestic feedstock that can support large-scale biochemical production processes for fuels and specialty chemicals. However, cost-effective conversion of lignocellulosic sugars into valuable chemicals by microorganisms still remains a challenge. Biomass recalcitrance to saccharification, microbial substrate utilization, bioproduct titer toxicity, and toxic chemicals associated with chemical pretreatments are at the center of the bottlenecks limiting further commercialization of lignocellulose conversion. Genetic and metabolic engineering has allowed researchers to manipulate microorganisms to overcome some of these challenges, but new innovative approaches are needed to make the process more commercially viable. Transport proteins represent an underexplored target in genetic engineering that can potentially help to control the input of lignocellulosic substrate and output of products/toxins in microbial biocatalysts. In this work, I characterize and explore the use of transport systems to increase substrate utilization, conserve energy, increase tolerance, and enhance biocatalyst performance.
ContributorsKurgan, Gavin (Author) / Wang, Xuan (Thesis advisor) / Nielsen, David (Committee member) / Misra, Rajeev (Committee member) / Nannenga, Brent (Committee member) / Arizona State University (Publisher)
Created2018
Description财富管理是一个高度信息不对称的行业，因此投资人需要尽可能减少自身的不确定来做投资决策，通过文献整理，本文发现通过建立信任来消除不确定性是很多投资人都会选择的帮助投资决策的方法。纵观历史，美国2007-2008年的金融危机也恰恰导致金融市场投资人对于理财机构信任的严重缺失，相同的情况也可能发生在中国财富管理市场，因此本文将此选作研究重点，希望深入研究财富管理公司投资人对理财师的信任来得到一系列结论。本文最终发现就平台和理财师相比，投资人更看重平台的信誉度。 投资人大多认为平台的信誉度要高于理财师的信誉度，但是这并不意味着理财师不重要。本文进一步的分析发现，多数投资人会和理财师建立起一种私人联系，且该私人关系有助于加强客户和平台的联系。投资人认为行业经验、为人诚恳，说话可信以及责任心是加强这种私人关系的重要因素。最后，投资人对于钜派平台的信任主要由对于理财师的信任来维持，同时对于理财师的信任主要来自与情感信任。本文的发现对财富管理平台具有战略意义。
ContributorsWu, Qimin (Author) / Shen, Wei (Thesis advisor) / Chang, Chun (Thesis advisor) / Zhu, Hongquan (Committee member) / Arizona State University (Publisher)
Created2019
Description当前，上市公司的盈余管理问题已是我国资本市场中普遍存在的突出问题。一般来说，一些企业为了满足资本市场对于上市、增发等条件的要求,以及为有效推动企业的并购、重组等行为的顺利实现,甚至为了谋求公司管理层的个别利益,往往运用盈余管理等举措实施公司财报及关键指标的粉饰修正，让不知情的股民蒙受一定的损失。普遍分析显示，我国股市中民营企业比其他企业遭遇的问题和压力更多、更大、更突出,因此民营企业从客观上来说拥有更强的盈余管理动机。而从当前我国资本市场的实际情况来看，我国相关专家学者对盈余管理的系统性深入研究，一般都瞄准了上市企业群体或持续亏损企业，对盈余管理的研究不系统、不全面、不深入，这将对我国进一步提升盈余管理监管水平构成一定不利影响。当前，由于我国民企在自身管理及发展动力方面的特殊性,我国民企的管理、盈余管理特点和国外上市公司还存在着很大的不同,进一步深入研究我国民企上市公司自身管理方面的突出特点，以及其对企业盈余管理等方面的深层次影响,有助于监管层对症下药，更有针对性地研究出台全新的监管措施,进一步提升管理水平。这还可以为公司发展的决策层及相关会计信息使用人员提供一定的决策参考, 因此其拥有十分重要的意义。
本文首先认真总结分析了有关上市企业治理结构和盈余管理等方面的历史文献资料，依托当前资本市场上普遍运用的委托代理、内部人控制和契约等理论，系统研究了我国民企上市公司在自身治理结构方面的突出特征以及其对盈余管理方面所构成影响的深层次原理。在此基础上，本文通过2015-2017年我国上市企业数据，基于截面Jones模型对民营企业和非民营企业盈余管理程度进行测算和比较分析，发现民营企业盈余管理程度更高；从四个层面系统研究民企公司自身的治理结构突出特点,设立回归模型论证了民营企业独特的公司治理结构特征对盈余管理程度确实会产生影响；最后,本文进一步利用修正的费尔萨姆一奥尔森估价模型对民营上市公司盈余管理有公司价值的关系进行了验证，发现两者具有显著相关性。
本文首先认真总结分析了有关上市企业治理结构和盈余管理等方面的历史文献资料，依托当前资本市场上普遍运用的委托代理、内部人控制和契约等理论，系统研究了我国民企上市公司在自身治理结构方面的突出特征以及其对盈余管理方面所构成影响的深层次原理。在此基础上，本文通过2015-2017年我国上市企业数据，基于截面Jones模型对民营企业和非民营企业盈余管理程度进行测算和比较分析，发现民营企业盈余管理程度更高；从四个层面系统研究民企公司自身的治理结构突出特点,设立回归模型论证了民营企业独特的公司治理结构特征对盈余管理程度确实会产生影响；最后,本文进一步利用修正的费尔萨姆一奥尔森估价模型对民营上市公司盈余管理有公司价值的关系进行了验证，发现两者具有显著相关性。
ContributorsChen, Hui (Author) / Shen, Wei (Thesis advisor) / Chang, Chun (Thesis advisor) / Huang, Xiaochuan (Committee member) / Arizona State University (Publisher)
Created2019
Description随着中国经济过去30多年的高速发展，出现了一大批的高收入人群，他们更注重生活的品质，如追求自然、简约、低调的休闲生活方式，更看重健康生活、自身的身心修养，和提高自身修养的内涵式生活，以及注重子女的内涵气质教育。
同时，具有很强烈地获得心理认同的需求，参加各种以消费和交往为媒介和主体活动的社群或“社交圈子”，在心理和情感上自我获得与其在财富、生活方式以及生活品位等诸方面都类似的群体间的身份认同感和归属感；更看着与其社会阶层相匹配的身份地位、社交人脉、兴趣爱好等。
因此，从运营的角度来看，如何增加上述这些高净值人群对高净值社群的归属感，进而提高其对高净值社群的忠诚度，是高净值社群进一步可持续经营和发展的基石。本研究以上海嘉庭俱乐部为例，在对问卷调查的基础上，通过实证研究，探讨影响高净值社群归属感与忠诚度的关键因素，高净值社群中会员的归属感与忠诚度的关系，会员生活型态的差异使得归属感与忠诚度的影响关系呈现显著的不同。
实证研究表明，“时尚流行”会员较为理性，其更注重休闲风尚；而“优雅休闲与享受尊荣”的会员则偏感性，其相当注重心灵感受与宁静舒适的感觉，强调全家共享以及纯封闭式的会员享受，能够更多地认识到与个人品味和品位相同的人，如对生活品质的追求、价值观、子女教育等；内心更开放、所接受教育程度更高的家庭，在嘉庭会感受到的归属感意识更高、其忠诚度也更高。
同时，具有很强烈地获得心理认同的需求，参加各种以消费和交往为媒介和主体活动的社群或“社交圈子”，在心理和情感上自我获得与其在财富、生活方式以及生活品位等诸方面都类似的群体间的身份认同感和归属感；更看着与其社会阶层相匹配的身份地位、社交人脉、兴趣爱好等。
因此，从运营的角度来看，如何增加上述这些高净值人群对高净值社群的归属感，进而提高其对高净值社群的忠诚度，是高净值社群进一步可持续经营和发展的基石。本研究以上海嘉庭俱乐部为例，在对问卷调查的基础上，通过实证研究，探讨影响高净值社群归属感与忠诚度的关键因素，高净值社群中会员的归属感与忠诚度的关系，会员生活型态的差异使得归属感与忠诚度的影响关系呈现显著的不同。
实证研究表明，“时尚流行”会员较为理性，其更注重休闲风尚；而“优雅休闲与享受尊荣”的会员则偏感性，其相当注重心灵感受与宁静舒适的感觉，强调全家共享以及纯封闭式的会员享受，能够更多地认识到与个人品味和品位相同的人，如对生活品质的追求、价值观、子女教育等；内心更开放、所接受教育程度更高的家庭，在嘉庭会感受到的归属感意识更高、其忠诚度也更高。
ContributorsLi, Hailin (Author) / Gu, Bin (Thesis advisor) / Chen, Xinlei (Thesis advisor) / Chang, Chun (Committee member) / Arizona State University (Publisher)
Created2019