Browsing by Subject "identification"
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Item Open Access A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins(2010) Ensterö, Mats; Akerborg, Orjan; Lundin, Daniel; Wang, Bei; Furey, Terrence S; Ohman, Marie; Lagergren, JensBackground: Several bioinformatic approaches have previously been used to find novel sites of ADAR mediated A-to-I RNA editing in human. These studies have discovered thousands of genes that are hyper-edited in their non-coding intronic regions, especially in alu retrotransposable elements, but very few substrates that are site-selectively edited in coding regions. Known RNA edited substrates suggest, however, that site selective A-to-I editing is particularly important for normal brain development in mammals. Results: We have compiled a screen that enables the identification of new sites of site-selective editing, primarily in coding sequences. To avoid hyper-edited repeat regions, we applied our screen to the alu-free mouse genome. Focusing on the mouse also facilitated better experimental verification. To identify candidate sites of RNA editing, we first performed an explorative screen based on RNA structure and genomic sequence conservation. We further evaluated the results of the explorative screen by determining which transcripts were enriched for A-G mismatches between the genomic template and the expressed sequence since the editing product, inosine (I), is read as guanosine (G) by the translational machinery. For expressed sequences, we only considered coding regions to focus entirely on re-coding events. Lastly, we refined the results from the explorative screen using a novel scoring scheme based on characteristics for known A-to-I edited sites. The extent of editing in the final candidate genes was verified using total RNA from mouse brain and 454 sequencing. Conclusions: Using this method, we identified and confirmed efficient editing at one site in the Gabra3 gene. Editing was also verified at several other novel sites within candidates predicted to be edited. Five of these sites are situated in genes coding for the neuron-specific RNA binding proteins HuB and HuD.Item Open Access Burkholdines 1097 and 1229, Potent Antifungal Peptides from Burkholderia ambifaria 2.2N(2010) Tawfik, Kamilia A; Jeffs, Peter; Bray, Brian; Dubay, George; Falkinham, Joseph O; Mesbah, Mostafa; Youssef, Diaa; Khalifa, Sherief; Schmidt, Eric WPotent antifungal cyclic lipopeptides, burkholdines (Bk), were isolated from a culture of Burkholderia ambifaria 2.2N. Bk-1229 (1) and Bk-1097 (2) are octapeptides comprised of nonproteinogenic amino acids, including beta-hydroxytyrosine, beta-hydroxyasparagine, and a new fatty acyl amino acid. 1 and 2 are fungicidal against a panel of fungi with potencies 2-60-fold better than amphotericin B control.Item Open Access Detection of Alternative Splice Variants at the Proteome Level in Aspergillus flavus(2010) Chang, Kung-Yen; Georgianna, D Ryan; Heber, Steffen; Payne, Gary A; Muddiman, David CIdentification of proteins from proteolytic peptides or intact proteins plays an essential role in proteomics. Researchers use search engines to match the acquired peptide sequences to the target proteins. However, search engines depend on protein databases to provide candidates for consideration. Alternative splicing (AS), the mechanism where the exon of pre-mRNAs can be spliced and rearranged to generate distinct mRNA and therefore protein variants, enable higher eukaryotic organisms, with only a limited number of genes, to have the requisite complexity and diversity at the proteome level. Multiple alternative isoforms from one gene often share common segments of sequences. However, many protein databases only include a limited number of isoforms to keep minimal redundancy. As a result, the database search might not identify a target protein even with high quality tandem MS data and accurate intact precursor ion mass. We computationally predicted an exhaustive list of putative isoforms of Aspergillus flavus proteins from 20 371 expressed sequence tags to investigate whether an alternative splicing protein database can assign a greater proportion of mass spectrometry data. The newly constructed AS database provided 9807 new alternatively spliced variants in addition to 12 832 previously annotated proteins. The searches of the existing tandem MS spectra data set using the AS database identified 29 new proteins encoded by 26 genes. Nine fungal genes appeared to have multiple protein isoforms. In addition to the discovery of splice variants, AS database also showed potential to improve genome annotation. In summary, the introduction of an alternative splicing database helps identify more proteins and unveils more information about a proteome.Item Open Access Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium.(Antibiotics (Basel, Switzerland), 2020-12) Arastehfar, Amir; Gabaldón, Toni; Garcia-Rubio, Rocio; Jenks, Jeffrey D; Hoenigl, Martin; Salzer, Helmut JF; Ilkit, Macit; Lass-Flörl, Cornelia; Perlin, David SThe high clinical mortality and economic burden posed by invasive fungal infections (IFIs), along with significant agricultural crop loss caused by various fungal species, has resulted in the widespread use of antifungal agents. Selective drug pressure, fungal attributes, and host- and drug-related factors have counteracted the efficacy of the limited systemic antifungal drugs and changed the epidemiological landscape of IFIs. Species belonging to Candida, Aspergillus, Cryptococcus, and Pneumocystis are among the fungal pathogens showing notable rates of antifungal resistance. Drug-resistant fungi from the environment are increasingly identified in clinical settings. Furthermore, we have a limited understanding of drug class-specific resistance mechanisms in emerging Candida species. The establishment of antifungal stewardship programs in both clinical and agricultural fields and the inclusion of species identification, antifungal susceptibility testing, and therapeutic drug monitoring practices in the clinic can minimize the emergence of drug-resistant fungi. New antifungal drugs featuring promising therapeutic profiles have great promise to treat drug-resistant fungi in the clinical setting. Mitigating antifungal tolerance, a prelude to the emergence of resistance, also requires the development of effective and fungal-specific adjuvants to be used in combination with systemic antifungals.Item Open Access Settling institutional uncertainty: Policing Chicago and New York, 1877–1923(Criminology, 2023-01-01) Koehler, J; Cheng, TWe show how both the Chicago Police Department and the New York Police Department sought to settle uncertainty about their propriety and purpose during a period when abrupt transformations destabilized urban order and called the police mandate into question. By comparing annual reports that the Chicago Police Department and the New York Police Department published from 1877 to 1923, we observe two techniques in how the police enacted that settlement: identification of the problems that the police believed themselves uniquely well equipped to manage and authorization of the powers necessary to do so. Comparison of identification and authorization yields insights into the role that these police departments played in convergent and divergent constructions of disorder and, in turn, into Progressivism's varying effects in early urban policing.Item Open Access The psychology of legitimacy: Implications for organizational leadership and change(2010) Tost, Leigh PlunkettThree distinct chapters explore the individual-level dynamics of legitimacy judgments and support for leaders and their initiatives. Chapter 1 develops a theoretical framework for understanding the content of legitimacy judgments and the process by which those judgments develop and change over time. Chapter 2 explores the role of group orientation in moderating the impact of instrumental, relational, and moral concerns in determining support for leaders. Chapter 3 explores the role of power in moderating leaders' assumptions about the types of behaviors that will elicit support for followers.
In Chapter 1, I build on institutional, social psychological, and sociological theory to develop a theoretical framework that specifies both the content underlying judgments of the legitimacy of social entities and a model of the process by which these judgments develop and change over time. With respect to the content of legitimacy judgments, I argue that individual-level judgments of the legitimacy of social entities are based on perceptions and beliefs about the entity that fall along three key dimensions: instrumental, relational, and moral. With respect to the process by which legitimacy judgments develop and change over time, I specify three modes of the legitimacy judgment process (evaluative, passive, and socialization), and I explain which of these modes is likely to predominate as individuals move through the stages of the legitimacy judgment process. The model specifies the circumstances under which the legitimacy of existing institutions is likely to be either challenged or bolstered. I conclude by discussing the implications of this framework for advancing a more detailed understanding of the micro-level dynamics of critical areas of inquiry in organizational studies.
In Chapter 2, I present a series of three studies demonstrating that individuals' intrinsic or extrinsic orientation toward their group moderates their responsiveness to different types of behaviors and appeals, such that individuals who have an intrinsic orientation (such as high identifiers and individuals who feel a high level of group belongingness) are more responsive to moral behaviors and appeals, while individuals with an extrinsic orientation (such as low identifiers and individuals who feel a low level of group belongingness) are more responsive to instrumental behaviors and appeals.
In Chapter 3, four studies demonstrate that subjective feelings of social power impact leaders' assumptions about the bases of their legitimacy with followers, which in turn impacts leaders' decisions about what types of leadership behaviors and tactics to engage. Study 1 demonstrates that leaders who feel a high level of power within their group or organization perceive support from followers as stemming primarily from their instrumental rather than relational behaviors, while leaders who feel a low level of power perceive that the support they receive from followers stems primarily from their relational rather than instrumental behaviors. Study 2 is a vignette study in which individuals primed with high power report greater expectations of support in response to decisions made on instrumental rather than relational bases, while individuals primed with low power report greater expectations of support in response to decisions made on relational rather than on instrumental bases. Study 3 replicates this interaction and shows that the effect is mediated by leaders' assumptions about the types of behaviors that followers prefer. Study 4 demonstrates that leaders primed with power are more likely to engage in instrumental behaviors in their attempts to persuade followers, while individuals primed with low power are more likely to engage in relational behaviors in their attempts to persuade followers. Theoretical and practical implications are discussed.
Chapter 4 describes a final study that integrates the findings from Chapters 2 and 3. Specifically, Chapter 4 demonstrates that there is a positive effect of leader power on support for the leader among low, but not high, identifying groups. The findings further indicate that this effect is mediated by followers' perceptions of the leader's instrumental behaviors. Implications, limitations, and future directions of the research are discussed.