1,724,642 research outputs found
Design of miR-34a mimics shifting the targetome towards HNF4
No full textmicroRNAs (miRNAs) regulate gene expression by inhibiting translation or inducing the degradation of messenger RNAs (mRNAs). miR-34a acts as a tumor suppressor, is predicted to have thousands of targets with more than hundreds of them are validated. Dysregulation of miR-34a has been implicated in various diseases.In this thesis, we investigated the structural and functional aspects of miRNA mediated repression, exploring how the structure governs the function of miRNA. We developed a structure-based design approach to increase specificity of miR- 34a. We than used this to design a series of miR-34a mimics aiming at specifically trapping a subset of the targets, centered around hepatocyte nuclear factor 4 alpha (HNF4a), which has been reported to be dysregulated in several cancer types. We used dual-luciferase reporter assay to measure the downregulation efficiency and RNA:RNA binding by SHAPE (RABS) to characterize the structural features. We found that the mimic with an altered tail region exhibited increased down-regulation activity for HNF4a specifically, while having little or no effect on the other targets in the luciferase reporter system. We highlight the critical importance of tail region of miR-34a, where three cytosines are located, with two of them being adjacent. We evaluated the overall effects of the designed miRNA mimics on the transcriptome via RNA sequencing and demonstrated that the mimics were able to capture mRNA targets sharing similar structural features with HNF4a. By designing a mimic to stabilize tail binding of miR-34a:target interaction, we successfully shifted miR-34a targetome, thus creating a specific yet broad interaction, which could provide insights for the design of miRNA-based drugs to treat multigenetic diseases.This thesis includes three projects. In Project I, we established a structural probing methodology RABS (RNA:RNA binding by SHAPE) to characterize the structural features of miRNA binding to its mRNA target. In project II, we investigated a specific miR-34a:HNF4a interaction and designed several miR-34a mimics to increase the specificity to HNF4a. In project III, we designed miRNA based small RNAs, which could shift miRNA targetome to a subset of target mRNAs. We showed the proof of concept for structure-activity relationship design of miRNA- based mimics to modulate target specificity, which may contribute to the concept of miRNA-based drug development.List of scientific papersI. Elnaz Banijamali, Lorenzo Baronti, Walter Becker, Joanna J Sajkowska-Kozielewicz, Ting Huang, Christina Palka, David Kosek, Lara Sweetapple, Juliane Müller, Michael D Stone, Emma R Andersson, Katja Petzold. RNA:RNA interaction in ternary complexes resolved by chemical probing. RNA. 2023 Mar;29(3):317-329 https://doi.org/10.1261/rna.079190.122II. Ting Huang, David Kosek, Rubin Dasgupta, Joanna J Sajkowska- Kozielewicz, Emma R Andersson, Katja Petzold. Design of miR-34a mimics shifting the targetome towards HNF4x for treatment of cancer [Manuscript]III. Ting Huang, Emma R Andersson, Katja Petzold. Design of small RNAs shifting the targetome of microRNA [Manuscript]</p
Address correspondence to: Yi Ting Huang What exactly do numbers mean?
No full textThe semantics of number words is a topic of much dispute in linguistics and of great relevance to understanding both the nature and development of number concepts and the division of labor between meaning and interpretation. Neo-Gricean theories posit that numbers, like scalar terms such as some, have lower-bounded semantics (two means “at least 2 and possibly more”) and receive exact interpretations via the pragmatic rule of scalar implicature. Other theorists propose that numbers have exact semantics (two means “exactly two”) and that apparent lower-bounded interpretations are achieved by contextual restriction or reference to subsets of the array. Prior findings that both children and adults strongly favor exact interpretations do not resolve this debate, because it is not clear whether this preference reflects an exact semantics or the calculation of a scalar implicature. We tested adults and 2- and 3-year-old children, with limited knowledge of number words, in a novel paradigm that teases apart semantic and pragmatic aspects of interpretation (the covered box task). Our findings establish that when scalar implicatures are cancelled in the critical trials of this task, both adults and children consistently give exact interpretations for number words. These results provide the first unambiguous evidence that number words have an exact semantics
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Chang_Supplemental_Table – Supplemental material for Delay Aversion, Temporal Processing, and N-3 Fatty Acids Intake in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
No full textSupplemental material, Chang_Supplemental_Table for Delay Aversion, Temporal Processing, and N-3 Fatty Acids Intake in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) by Jane Pei-Chen Chang, Li Jingling, Ya-Ting Huang, Yu-Ji Lu and Kuan-Pin Su in Clinical Psychological Science</p
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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