A Functional Analysis of the Role of SHP-2 in Vertebrate Heart Development

SHP-2 is a protein tyrosine phosphatase that has been shown to be required for proper vertebrate embryogenesis. Loss of function studies demonstrate roles for SHP-2 in gastrulation, cell migration, and the maintenance of trophoblast stem cells and results in lethality prior to or during gastrulation. In addition to the requirement for SHP-2 during early vertebrate development, there is also a requirement for SHP-2 during heart development which is supported by studies showing patients with Noonan syndrome often having mis-sense mutations in Shp-2. To date the mechanism leading to abnormal cardiac development in Noonan syndrome patients has not been determined. We have examined the effects of SHP-2 inhibition and of human mis-sense mutations of Shp-2 on early heart development using Xenopus. We find that in the absence of SHP-2 signaling, cardiac progenitor cells down-regulate genes associated with early heart development and fail to initiate cardiac differentiation. We further show that this requirement for SHP-2 is restricted to cardiac precursor cells undergoing active proliferation. By demonstrating that SHP-2 is phosphorylated on Y542/Y580 and that it binds to FRS-2, an effector of FGF signaling, we place SHP-2 in the FGF pathway during early embryonic heart development. Furthermore, we demonstrate that inhibition of FGF signaling mimics the cellular and biochemical effects of SHP-2 inhibition and that these effects can be rescued by constitutively active/Noonan syndrome associated forms of SHP-2. We also find that N308D, a Shp-2 mutation associated with Noonan Syndrome, leads to cardiac abnormalities in Xenopus. Characterization of the phenotypic defects in these hearts show that they are reduced in size and display delayed morphological movements. These cardiac abnormalities appear to be associated with alterations in the actin cytoskeleton. In addition, we also observed a dramatic increase in the number of cells in M-phase of the cell cycle without an increase in cell number. These defects appear to reflect lengthening of the cardiac cell cycle. Collectively, these results show that SHP-2 functions within the FGF/MAPK pathway to maintain survival of proliferating populations of cells and that Shp-2 N308D function primarily to alter actin muscle development which ultimately leads to defects in cardiac morphogenesis

Decorum in portraits of Medici women at the court of Cosimo I, 1537-1574. (Volumes I and II).

Leonardo's precept 'decoro', provided a sixteenth-century model for analysis of portraits of Medici women. Its distinctive elements offered guidelines for the artist to effect portrayals, emphasizing appropriate dignity of rank, sex, age, setting and circumstances, with corresponding dress and 'action'. Decorum's connotations and its pertinence to portraiture were assessed. Pino and Dolce expressed it as a sine qua non for artists by mid century, and its axioms inform de Hollanda's pioneer treatise for the court portraitist in 1549. Its ends were consistently held to be rhetorical. Leonardo's writings circulated in Florentine circles. Moreover, in Chapters III to VII, the portrait studies, his artistic legacy was manifest in Bronzino's work. Norms of appropriateness for women were sought in books of manners, poetry, and artistic theory by court satellites--Firenzuola, Bronzino, Varchi, Cattani di Diacetto, Vasari and Danti included. Rich layers of symbolic meaning were exposed, with Bronzino's dynastic Eleonora di Toledo with her son Giovanni at the core of the inquiry. Distinctions of pose, color, illumination, modeling, and perspective were proposed by de Hollanda to advance decorum. Florentine artistic dialog, promoted by Benedetto Varchi, revealed similar implications. The portraits testified that the artist's task was construction of an exemplary persona. Medici women were portrayed at portentous moments as paragons of chastity and, regardless of age, legitimacy, and rank, their portraits were vehicles for current Medici propaganda. Decorum proved to have diagnostic value. Incongruity with its norms demanded rejection of some traditional identifications, and a revised chronology of Pontormo's late portraits ensued. Circumstances expressed in Pontormo's and Bronzino's portraits reflect Cosimo's Ficinesque and Petrarchan revival. AIlori's portraits--some newly identified--testify that Tridentine ideals of demystification rapidly took root from 1560, reflecting a new papal alliance and patronage by IsabelIa de' Medici. Indirectly, workshop procedures were illuminated. 'Fresher', bustlength portraits always preceded large, formal, state portraits. Death masks were used for posthumous works, and copies proliferated. Stringent rules existed. Assessment of women's portraiture as a distinct genre is explicit in 'decoro', but related studies could include portraits of men; reexamination of Bronzino's early portraits of women; and reassessment of erotic private portraits of both sexes.Ph.D.Art historyCommunication and the ArtsLanguage, Literature and LinguisticsModern literatureSocial SciencesWomen's studiesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128890/2/9226948.pd

Pontormo and Medici Lineages: Maria Salviati, Alessandro, Giulia and Giulio de’ Medici

Le portrait de Pontormo à Baltimore que l’on croyait être, depuis 1940, celui de Maria Salviati et son fils Cosimo serait plutôt celui de la jeune femme et Giulia de’ Medici, reprenant ainsi la description avec « una puttina » de l’inventaire Riccardi de 1612. La grande ressemblance entre la fillette et son père Alessandro de’ Medici que l’on peut observer dans un portrait exécuté par Pontormo en 1534-35 (Philadelphie), et dans un second de Lucca, identifié récemment comme celui d’Alessandro de’ Medici, jeune homme permet d’identifier Giulia avec certitude. L’âge de la jeune fille, les signes de la maladie qui emportèrent Maria Salviati et les circonstances de la commande permettent d’avancer la date de 1540 pour le portrait de Baltimore. Ce portrait a une fonction politique évidente. Il affirme le rôle de Cosimo comme « gardien légal » de la branche aînée de la famille Médicis contre les intrigues du frère de Giulia pour le titre de Cosimo. La représentation de Maria Salviati vient probablement du portrait Castello (perdu) de Pontormo de 1537. Cet article analysera aussi les relations intimes entre Giulia et Cosimo et leurs ancêtres médicéens dans un portrait d’Alessandro Allori, la Dame au camée, exécuté en 1559, (Offices) où, âgée de vingt-cinq ans environ, elle est représentée en veuve

A cluster randomised controlled feasibility study of nurse-initiated behavioural strategies to manage interruptions during medication administration

Objectives To examine the feasibility of a behavioural e-learning intervention to support nurses to manage interruptions during medication administration. Design A cluster randomised feasibility trial. Setting The cluster trial included four intervention and four control wards randomly selected across four metropolitan hospitals in Sydney, Australia. Participants We observed 806 (402 pre-intervention and 404 post-intervention) medication events, where nurses prepared and administered medications to patients within the cluster wards. Main Outcome Measures The primary outcome measured was the observed number of interruptions occurring during administration, with secondary outcomes being the number of clinical errors and procedural failures. Changes in the use of behavioural strategies to manage interruptions, targeted by the e-learning intervention, were also assessed. Results No significant differences were found in the number of interruptions (P = 0.82), procedural failures (P = 0.19) or clinical errors per 100 medications (P = 0.32), between the intervention and control wards. Differences in the use of specific behavioural strategies (engagement and multitasking) were found in the intervention wards. Conclusion This behavioural e-learning intervention has not been found to significantly reduce interruptions, however, changes in the use of strategies did occur. Careful selection of clinical settings where there is a high number of predictable interruptions is recommended for further research into the impact of the behavioural e-learning intervention. An increase in the intensity of this intervention is recommended with training undertaken away from the clinical setting. Further research on additional consumer-sensitive interventions is urgently needed