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ANALYSIS OF THE UPSTREAM SIGNALLING PATHWAY CONTROLLING DELTANP63ALPHA PROTEIN STABILITY AND FUNCTION
No full text1. Abstract
The p63 transcription factor, homolog to the p53 tumor suppressor, plays a crucial role in epidermal and limb development. Dominant mutations in the p63 gene give rise to several human congenital syndromes characterized by skin, craniofacial and limb defects. One of the syndromes caused by p63 mutations is the Split-Hand/Foot Malformation-IV (SHFM-IV) syndrome, characterized by the loss of central rays of hands and feet. These developmental defects are due to failure of Apical Ectodermal Ridge (AER) development. The correct limb outgrowth and patterning is guarantee by the expression of key molecules including Fybroblast Growth Factor 8 (FGF8), p63 and the DLX5 and DLX6 transcription factors. In this context, the study of the molecular mechanisms regulating p63 stability and function is fundamental for understanding the molecular bases of the SHFM-IV pathogenesis: indeed p63 as been proposed to be one of the crucial regulators of limb and epidermal development.
Little is known on the post-translational modifications and the upstream signalling pathway controlling ΔNp63α functions, one of the most expressed p63 isoform in epithelial tissues and in the AER cells. The projects performed during my PhD thesis achieved to the identification of FGF8 as a crucial regulator of ΔNp63α stability and activity in human osteosarcoma and keratinocyte cell lines. FGF8 determined also ΔNp63α protein stabilization in mice embryonic limb buds put in culture at Embryonic day 10.5 (E10.5). In particular, treatments with FGF8 of human osteosarcoma cell lines (U2OS) and human keratinocytes (HaCat), activate the tyrosine kinase c-Abl, leading to ΔNp63α phosphorylation and consequent acetylation by the p300 acetyl-transferase, promoting ΔNp63α stabilization and transcriptional activation. Moreover, I have found that p300 interacts with ΔNp63α determing its acetylation on lysine K193E, in vitro. Interestingly, this regulatory cascade is not active on the natural ΔNp63αK193E mutant associated to the SHFM-IV syndrome. Indeed, the ΔNp63αK193E mutant displays promoter specific altered DNA binding activity that results in altered expression of ΔNp63α target genes involved in limb development (like Perp, Ikkα and DLX5 gene) (Manuscript in preparation).
One of the mechanism by which FGF8 promotes ΔNp63α stability and activation, is inhibiting its interaction with Pin1, a prolyl isomerase known to positively regulate p53 and p73 in response to DNA damage stress. In particular, PIN1 has an opposite effect on ΔNp63α respect to p53 and p73: it promotes ΔNp63α degradation through the proteasome pathway. Moreover, ΔNp63α mutant proteins, associated with SHFM-IV or EEC syndromes, characterized by limb defects, are not degraded by PIN1 overexpression. These data were confirmed also by in vivo experiments on PIN1 Knock-Out (KO) mice, where lack of PIN1 expression caused the accumulation of p63 in the embryonic limbs and ectoderm compared to wild-type littermates. Moreover, I found that FGF8 is a downstream target of the transcription factor Dlx5. Indeed, in the limb buds of both p63 and DLX5;DLX6 KO mice, the AER is poorly stratified and FGF8 expression is severely reduced. All these data suggest that DLX5, ΔNp63α, FGF8 and PIN1 participate in a regulatory loop essential for AER stratification, normal patterning and morphogenesis of the limb buds (1).
The work performed during my PhD contributes to a better understanding of the regulatory mechanisms controlling ΔNp63α function and stability. We have identified FGF8 as a crucial upstream signal required for ΔNp63α activation and stabilization during limb development: mutations or altered expression of regulators in this pathway leads to abnormal limb development and onset of pathogenesis
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
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
Information Capacity Regret Bounds for Bandits with Mediator Feedback
Full text linkThis work addresses the mediator feedback problem, a bandit game where the decision set consists of a number of policies, each associated with a probability distribution over a common space of outcomes. Upon choosing a policy, the learner observes an outcome sampled from its distribution and incurs the loss assigned to this outcome in the present round. We introduce the policy set capacity as an information-theoretic measure for the complexity of the policy set. Adopting the classical EXP4 algorithm, we provide new regret bounds depending on the policy set capacity in both the adversarial and the stochastic settings. For a selection of policy set families, we prove nearly-matching lower bounds, scaling similarly with the capacity. We also consider the case when the policies' distributions can vary between rounds, thus addressing the related bandits with expert advice problem, which we improve upon its prior results. Additionally, we prove a lower bound showing that exploiting the similarity between the policies is not possible in general under linear bandit feedback. Finally, for a full-information variant, we provide a regret bound scaling with the information radius of the policy set
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
Considerations on the steady-state modeling of methanol synthesis fixed-bed reactor
No full textThis paper proposes and compares different steady-state models for the methanol synthesis fixed-bed reactor. The main goal is to indicate the pros and cons of these alternative models, to highlight their peculiarities in providing accurate and reliable estimations, and to warn the reader about possible risks involved in certain modeling assumptions. The Lurgi-type shell and tube boiler-reactor mathematical modeling is also laid out, before more complex issues and research, such as dynamic simulation or PDE-based predictive control, are broached
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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