The Role of Smc3 in Mouse Embryonic and Adult Hematopoiesis

Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by recurrent genetic mutations. Mutations in the cohesin complex are one of the 8 functional categories of mutations in AML. SMC3 encodes a subunit of the cohesin complex, which has important roles in chromosome segregation, genome instability, and gene expression. In the first chapter of the dissertation, we discuss the genetics of AML, normal functions of the cohesin complex, and the interplay between cohesin mutations and myeloid malignancies. SMC3 is recurrently mutated in AML and other myeloid malignancies. In the second chapter of the dissertation, we compare the consequences of Smc3 deficient and haploinsufficient mouse models to determine whether the heterozygous missense mutations in SMC3 might have dominant-negative effects or phenocopy loss-of-function effects. We found that homozygous deletion of Smc3 during embryogenesis or in adult mice resulted in hematopoietic failure. SMC3 missense mutations are therefore unlikely to be associated with simple dominant negative phenotypes due to incompatibility with hematopoiesis. Smc3 haploinsufficiency, in contrast, was tolerated during embryonic and adult hematopoiesis. Under steady-state conditions, Smc3 haploinsufficiency did not alter colony forming capacity ex vivo and led to modest transcriptional and chromatin accessibility changes in Lin-cKit+ progenitor cells. However, following tamoxifen-induced deletion in competitive transplantations, we observed a significant hematopoietic competitive disadvantage in Smc3 haploinsufficient bone marrow cells across myeloid and lymphoid lineages and within the stem/progenitor compartments. The competitive disadvantage was not affected by different conditions of hematopoietic stresses, but was partially abrogated by concurrent Dnmt3a haploinsufficiency, suggesting that antecedent mutations may be the prerequisites to realize the leukemogenic potential of Smc3 mutations. In the third chapter of the dissertation, we present a case of an older women that initially appeared to be treatment-related AML following non-cytotoxic all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) therapy for acute promyelocytic leukemia (APL), but upon further analysis found to be more consistent with secondary AML. Exome sequencing revealed a TET2-mutated dominant clonal process that preceded the APL diagnosis, persisted, and gave rise to an AML-associated new subclone with a NPM1 mutation. Review of additional cytogenetic abnormalities observed in APL patients showed that cytogenetic abnormalities commonly occur as subclones of the APL clone, although one rare case with del(7) independent of the APL clone was identified. These results demonstrated that APL may emerge within the context of clonal hematopoiesis and caution must be exercised when interpreting the development of tAML after ATRA/ATO therapy, especially in older patients

Function and dynamics of aptamers: A case study on the malachite green aptamer

Aptamers are short single-stranded nucleic acids that can bind to their targets with high specificity and high affinity. To study aptamer function and dynamics, the malachite green aptamer was chosen as a model. Malachite green (MG) bleaching, in which an OH- attacks the central carbon (C1) of MG, was inhibited in the presence of the malachite green aptamer (MGA). The inhibition of MG bleaching by MGA could be reversed by an antisense oligonucleotide (AS) complementary to the MGA binding pocket. Computational cavity analysis of the NMR structure of the MGA-MG complex predicted that the OH- is sterically excluded from the C1 of MG. The prediction was confirmed experimentally using variants of the MGA with changes in the MG binding pocket. This work shows that molecular reactivity can be reversibly regulated by an aptamer-AS pair based on steric hindrance. In addition to demonstrate that aptamers could control molecular reactivity, aptamer dynamics was studied with a strategy combining molecular dynamics (MD) simulation and experimental verification. MD simulation predicted that the MG binding pocket of the MGA is largely pre-organized and that binding of MG involves reorganization of the pocket and a simultaneous twisting of the MGA terminal stems around the pocket. MD simulation also provided a 3D-structure model of unoccupied MGA that has not yet been obtained by biophysical measurements. These predictions were consistent with biochemical and biophysical measurements of the MGA-MG interaction including RNase I footprinting, melting curves, thermodynamic and kinetic constants measurement. This work shows that MD simulation can be used to extend our understanding of the dynamics of aptamer-target interaction which is not evident from static 3D-structures. To conclude, I have developed a novel concept to control molecular reactivity by an aptamer based on steric protection and a strategy to study the dynamics of aptamer-target interaction by combining MD simulation and experimental verification. The former has potential application in controlling metabolic reactions and protein modifications by small reactants and the latter may serve as a general approach to study the dynamics of aptamer-target interaction for new insights into mechanisms of aptamer-target recognition

Augmented Reality in Sports Event Videos: A Qualitative Study on Viewer Experience

Augmented reality (AR) has been widely used in sports broadcasting. However, little is known about viewer experience with AR in sports event videos. To identify key AR features as well as its advantages and drawbacks in sports event videos, this research conducted a qualitative study through a semi-structured interview with 30 participants. Content analysis on the interview transcript identified four salient features of AR in the sports event video context, i.e., informativeness, novelty, vividness, and telepresence. It also revealed three key advantages of AR to sports audiences, including game comprehension, enjoyment, and fan socialization, as well as two drawbacks, including distraction and inauthenticity. The qualitative study provides a theory-building process and results in a conceptual model, which, based on the net valence approach, postulates the relationships between AR features and viewers’ behavioral intentions through the mediation of perceived advantages and drawbacks

Exploring the Persuasion Effects of Threatening Content in COVID-19 Advertising: The Roles of Threat Intensity and Sensation Seeking on Consumer Attitudes

The COVID-19 pandemic has resulted in a wave of advertising activities advocating care for the community in a time of crisis. These COVID-19 ads often feature threatening depictions of the crisis as a persuasion strategy. Hence, the present study explores the persuasion effects of COVID-19 advertising by focusing on threat persuasion. Specifically, by adopting an online experiment with 724 U.S. participants, this study investigates how the threat intensity of crisis depictions featured in COVID-19 ads (low vs. medium vs. high) interact with individual differences in sensation-seeking in order to impact ads and brand attitudes, through the mediating pathways of positive moral emotions (warmth and gratitude) and corporate social responsibility (CSR) authenticity. The results reveal that the high-threat crisis depiction generates the lowest warmth and ad attitudes, whereas the medium-threat crisis depiction yields the strongest gratitude and better brand attitudes than the low-threat crisis depiction, but only for low sensation seekers (LSS). Also, for LSS, exposure to the medium-threat (versus low-threat) crisis depiction increases their gratitude, which leads to higher CSR authenticity, and, eventually results in more favorable ad or brand attitudes. On the contrary, for high sensation seekers, threat intensity does not have an indirect effect on the ad or brand attitudes via warmth, gratitude, and CSR authenticity

Who Teaches in Rural Schools in Underdeveloped Areas? An Investigation Based on a Survey of 5,554 Teachers from 117 Towns in H Province in Wuling Mountains Zone, China

Teacher shortage is a major hindrance to China’s rural education growth in underdeveloped areas, as well as one of the main causes of educational injustice. We conducted a survey of 5,554 teachers from 117 towns in H province in the Wuling Mountains Zone to investigate the issue of rural school teacher supply. From geographical, emotional, and institutional perspectives, we used a polynomial logit model to examine the validity of the “hometown effects” hypothesis. The findings showed that hometown effects exist in China in all three dimensions. The institutional hometown effects are the most pronounced; when compared to open recruitment, teachers sourced through teacher supply augmentation programs (such as the Secondary Normal Graduates Program, Special Position Program, and Targeted Position Program) are more likely to teach in rural schools, particularly more disadvantaged village primary schools or teaching sites. China’s policy of increasing teacher supply has had a considerable positive influence on rural school staffing. Students from rural areas make better teacher candidates; feelings for hometowns should be encouraged among normal school or university students in pre-service education; and the implementation of teacher support policies should be emphasized to retain rural teachers and improve their teaching quality

A Meta-Study on E-Collaboration

Collaborative activities across organizations are common when conducting business online. There have been numerous research results on different aspects of inter-organization collaborations through electronic means or in an electronic environment. However, the term ‘collaboration’ in Information Systems research literature often has different meanings. Also, a wide spectrum of technologies has been labeled as collaborative technology. In order to make the knowledge of the new research field cohesive and accumulative, the paradigm of electronic collaboration (e-Collaboration) has yet to be established. Thus this paper aims to provide a framework for e-Collaboration from the perspective different levels of involvements of inter-organization interactions. The framework differentiates the types of the ‘collaboration’ in a cohesive manner, and underlines the core characteristics of e-Collaboration - joint intellectual efforts. Moreover, a content analysis on the existing related literatures is conducted, using the framework proposed. Future research directions in the field are also discussed