A study of mammalian microRNA-mediated repression of gene expression by ribosome profiling

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2011.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.All cells in a multicellular organism carry the same genes, yet these same genes direct the differentiation of many different cell types. This is facilitated by differential gene expression, the control of which can be exerted at the transcriptional, as well as post-transcriptional, level. MicroRNAs (miRNAs) are -22- nucleotide small RNAs that mediate post-transcriptional regulation of gene expression by base pairing to their target mRNAs to direct repression. In animals, this repression is usually mediated through translational repression and/or mRNA destabilization. In studies that investigate miRNA-mediated repression with reporter constructs or individual endogenous genes, translational repression and mRNA destabilization have been observed to contribute variably to the overall level of repression. This led to the question of whether the same was true for endogenous targets at a genome-wide level. While changes in mRNA levels can be easily captured by microarray measurements, it is harder to measure translational repression on a genome-wide scale. To address this gap, we used ribosome profiling to measure effects on protein production and compared these to simultaneously measured effects on mRNA levels. The latter were also quantified by a deep-sequencing approach (mRNA-Seq). This enabled us to obtain a snapshot of changes in translational efficiency at the genome-wide level. For both ectopic and endogenous miRNA regulatory interactions, we observed that lowered mRNA levels account for most (>84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output. The slight reduction in translational efficiency is likely mediated by an inhibition of translation initiation. For studying miRNA repression in an endogenous system, we had initially used in vitro differentiated neutrophils from mir-223 knockout mice and compared these to cells from wild-type mice. Because neutrophils have a shorter lifespan than most differentiated cell types, we selected another endogenous system, antigen-stimulated B cells from mir-155 knockout mice, and similarly compared these to cells from wild-type mice. In addition to mRNA-Seq and ribosome profiling, we made parallel proteomics measurements. Our results show that miR- 155 in antigen-stimulated B cells primarily mediates mRNAlevel changes, though the contribution from changes in translational efficiency was larger than previously observed. In addition, we observed widespread translation of upstream open reading frames initiated from canonical and non-canonical start codons. These upstream open reading frames are also translationally repressed by miR-155.by Huili Guo.Ph.D

Stochastically Ultimate Boundedness and Global Attraction of Positive Solution for a Stochastic Competitive System

A stochastic competitive system is investigated. We first show that the positive solution of the above system does not explode to infinity in a finite time, and the existence and uniqueness of positive solution are discussed. Later, sufficient conditions for the stochastically ultimate boundedness of positive solution are derived. Also, with the help of Lyapunov function, sufficient conditions for the global attraction of positive solution are established. Finally, numerical simulations are presented to justify our theoretical results

The association between the rs11196218A/G polymorphism of the TCF7L2 gene and type 2 diabetes in the Chinese Han population: a meta-analysis

Transcription factor 7-like 2 has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups in recent years. In the Chinese Han population in particular, numerous studies have evaluated the association between the rs11196218A/G polymorphism of the transcription factor 7-like 2 gene and type 2 diabetes mellitus. However, the results have been inconsistent, so we performed a meta-analysis to assess the association. Odds ratio and 95% confidence interval values were calculated using a random-effects model or a fixed-effects model based on heterogeneity analysis. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Subgroup analyses were conducted based on conformity with Hardy-Weinberg equilibrium in the control group as well as on other variables, such as age, sex and body mass index. Sensitivity analysis was also performed to detect heterogeneity and to assess the stability of the results. In total, 10 case-control studies comprising 7,491 cases and 12,968 controls were included in this meta-analysis. The combined analysis indicated that the rs11196218A/G polymorphism was not associated with type 2 diabetes mellitus (G vs. A, OR=1.04, 95% CI=0.97–1.13, p=0.28). The subgroup analyses also did not show any association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus. Furthermore, the results of the subgroup analyses indicated that the absence of an association was not influenced by age, sex or body mass index. The results of the sensitivity analysis verified the reliability and stability of this meta-analysis. In conclusion, this study indicated that there is no significant association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus in the Chinese Han population

Modeling 3-D permeability distribution in alluvial fans using facies architecture and geophysical acquisitions

Alluvial fans are highly heterogeneous in hydraulic properties due to complex depositional processes, which make it difficult to characterize the spatial distribution of the hydraulic conductivity (K). An original methodology is developed to identify the spatial statistical parameters (mean, variance, correlation range) of the hydraulic conductivity in a three-dimensional (3-D) setting by using geological and geophysical data. More specifically, a large number of inexpensive vertical electric soundings are integrated with a facies model developed from borehole lithologic data to simulate the log10(K) continuous distributions in multiplezone heterogeneous alluvial megafans. The Chaobai River alluvial fan in the Beijing Plain, China, is used as an example to test the proposed approach. Due to the non-stationary property of the K distribution in the alluvial fan, a multiplezone parameterization approach is applied to analyze the conductivity statistical properties of different hydrofacies in the various zones. The composite variance in each zone is computed to describe the evolution of the conductivity along the flow direction. Consistently with the scales of the sedimentary transport energy, the results show that conductivity variances of fine sand, medium-coarse sand, and gravel decrease from the upper (zone 1) to the lower (zone 3) portion along the flow direction. In zone 1, sediments were moved by higher-energy flooding, which induces poor sorting and larger conductivity variances. The composite variance confirms this feature with statistically different facies from zone 1 to zone 3. The results of this study provide insights to improve our understanding on conductivity heterogeneity and a method for characterizing the spatial distribution of K in alluvial fans

Expression and prognostic relevance of Cyclophilin A and matrix metalloproteinase 9 in esophageal squamous cell carcinoma

AIMS: To guide clinicians in selecting treatment options for esophageal squamous cell carcinoma (ESCC) patients, reliable markers predictive of clinical outcome are desirable. This study analyzed the correlation of cyclophilin A (CypA) and matrix metalloproteinase 9 (MMP9) in ESCC and their relationships to clinicopathological features and survival. METHODS: We immunohistochemically investigated 70 specimens of ESCC tissues using CypA and MMP9 antibodies. Then, the correlations between CypA and MMP9 expression and clinicopathological features and its prognostic relevance were determined. RESULTS: Significant correlations were only found in high level of CypA and MMP9 expression with tumor differentiation and lymph node status. Significant positive correlations were found between the expression status of CypA and that of MMP9. Overexpression of CypA and metastasis were significantly associated with shorter progression free survival times in univariate analysis. Multivariate analysis confirmed that CypA expression was an independent prognostic factor. CONCLUSIONS: CypA might be correlated with the differentiation, and its elevated expression may be an adverse prognostic indicator for the patients of ESCC. CypA/MMP9 signal pathway may be attributed to the malignant transformation of ESCC, and attention should be paid to a possible target for therapy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1166551968105508

A Study of the Impact of Micro-Blog Marketing on Consumers’ Brand Loyalty

Micro-blog marketing has developed rapidly in our country, its commercial value is getting more and more attention by the enterprises. This paper regards the enterprise micro-blog marketing as the research context, placing the authenticity, the professional, the humanity, the brand trust and brand loyalty into a frame, setting up a theory model, putting forward the research hypothesis. In the end, this paper makes some conclusions and puts forward some suggestions on enterprise micro-blog marketing through the empirical analysis. Key words: Micro-blog marketing; Brand trust; Brand loyalt

Research on the Brand Niche Overlap of the B2C Websites: A Case of four Online Cosmetics Stores

This paper uses theories in ecology for resource competition to study the brand competition in business. It provides a quantitative method to measure brand breadth and brand overlap and examines their relationships with brand competition. Four Chinese online Cosmetics stores are used as examples to illustrate the utility of the proposed method in evaluating their degree of competition. This study can help companies identify main competitors in the industry and the main aspects that they are competing in. Key words: Brand niche; Brand niche breadth; Brand niche overlap; Online cosmetics stores bran

Discrete Event Simulation Models for CT Examination Queuing in West China Hospital

In CT examination, the emergency patients (EPs) have highest priorities in the queuing system and thus the general patients (GPs) have to wait for a long time. This leads to a low degree of satisfaction of the whole patients. The aim of this study is to improve the patients’ satisfaction by designing new queuing strategies for CT examination. We divide the EPs into urgent type and emergency type and then design two queuing strategies: one is that the urgent patients (UPs) wedge into the GPs’ queue with fixed interval (fixed priority model) and the other is that the patients have dynamic priorities for queuing (dynamic priority model). Based on the data from Radiology Information Database (RID) of West China Hospital (WCH), we develop some discrete event simulation models for CT examination according to the designed strategies. We compare the performance of different strategies on the basis of the simulation results. The strategy that patients have dynamic priorities for queuing makes the waiting time of GPs decrease by 13 minutes and the degree of satisfaction increase by 40.6%. We design a more reasonable CT examination queuing strategy to decrease patients’ waiting time and increase their satisfaction degrees

S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling

Hydrogen sulfide (H2S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H2S in the pathogenesis of doxorubicin-induced cardiomyopathy

Low Serum Vitamin D Is Associated with Anti-Thyroid-Globulin Antibody in Female Individuals

Objectives. Some evidence has pointed out that vitamin D plays a significant role in reducing the incidence of autoimmune diseases, especially autoimmune thyroid diseases. The authors aimed to examine the relationship between circulating 25-hydroxyvitamin D and thyroid autoantibody in a population-based health survey of Xinjiang Chinese population. Subjects and Methods. A total of 1714 Chinese adults were analyzed. 25(OH)D, anti-thyroid antibodies, and thyroid function were measured. Results. The prevalence of vitamin D insufficiency was 28.3% in Hans and 9.3% in Uyghurs, and the prevalence of vitamin D deficiency was 61.6% in Hans and 87.6% in Uyghurs. Overall prevalence of TgAb positivity was 6.2% (0.9% males; 5.3% females). In female subjects, mean serum 25(OH)D levels were significantly lower in Hans and Uyghurs compared with males, and the difference was statistically significant. Importantly, after adjusting for age and ethnicity, a negative correlation (r=-0.121, P=0.014) was recognized between 25(OH)D and TgAb levels only in female subjects. Conclusion. Vitamin D insufficiency and deficiency are prevalent among Chinese adults. Low serum 25(OH)D is related to the presence of TgAb in females. The causal effect of low vitamin D level on thyroid autoimmunity should be studied further more