The guanine nucleotide exchanger Vav2 interacts with c-ErbB-2 and induces alveolar morphogenesis of mammary epithelial cells

Die Familie der ErbB-Rezeptor-Tyrosinkinasen besteht aus vier Mitgliedern, dem EGF-Rezeptor (ErbB-1), ErbB-2, ErbB-3 und ErbB-4. ErbB-Rezeptoren spielen eine wichtige Rolle bei der Entwicklung des Nervensystems, des Herzens und der Brustdrüsen. Ein Teil dieser Differenzierungsvorgänge läßt sich in vitro nachvollziehen: so ist zum Beispiel die Aktivierung des ErbB-2 Rezeptors ausreichend für alveoläre Morphogenese der Brustdrüsenepithelzellinie EpH4. Intrazelluläre Moleküle, die dieses ErbB2-Signal übertragen, sind allerdings noch unbekannt. Mit Hilfe eines neuen, modifizierten Hefe-2-Hybrid-Systems wurde in der vorliegenden Arbeit Vav2 als neuer Interaktionspartner von ErbB-2 identifiziert. Vav2 assoziiert mit aktiviertem ErbB-2 über eine SH2-Domäne. Die Interaktion ist direkt und ist von zwei Phosphotyrosinen in ErbB-2 abhängig. Vav2 kann den GDP/GTP-Austausch bei GTPasen der Rho-Familie vermitteln. Dadurch kann der Umbau des Zytoskeletts und Veränderungen der Transkription sowie Zelltransformation induziert werden. In einem dreidimensionalen Zellkultursystem kann aktiviertes Vav2 in EpH4 Zellen die Bildung von alveolären Zellaggregaten induzieren. In diesen Alveolen umgibt eine Schicht polarisierter milchproduzierender Zellen ein zentrales Lumen. Diese Vav2-vermittelte Morphogenese ist abhängig von der katalytischen GDP/GTP-Austausch Aktivität von Vav2. Katalytisch-inaktives Vav2 kann die morphogenetische Aktivität von ErbB-2 in EpH4-Zellen verhindern, ohne die mitogene Aktivität von ErbB-2 zu beeinflussen. Vav2 ist mit ErbB-2 coexprimiert und interagiert mit dem Rezeptor in Brustdrüsenzellen schwangerer Mäuse. Diese Untersuchungen deuten darauf hin, dass Vav2 eine wichtige Funktion bei der durch ErbB-2 induzierten alveolären Morphogenese der Brustdrüse spielt.The ErbB receptor tyrosine kinases constitute a subfamily of four structurally related members, the EGF receptor (ErbB-1), ErbB-2, ErbB-3 and ErbB-4. ErbB receptor tyrosine kinases are critical for embryonic development of central and peripheral neural structures and heart. In addition, ErbB receptors play an important role in the postnatal development of the mammary gland. Previous studies showed that activated ErbB-2 receptor induces alveolar morphogenesis of EpH4 mammary epithelial cells that are cultured on a three-dimensional matrix (termed Matrigel). However, the downstream signaling proteins that mediate this biological activity of ErbB-2 were unknown. In this work, Vav2 was identified as a direct interaction partner of tyrosine-phosphorylated ErbB receptors using the yeast two-hybrid system. Vav2 is a member of a family of guanine nucleotide exchange factors that induce cytoskeletal rearrangements, transcriptional alterations, and have oncogenic potential when activated. To test the ability of Vav2 to mediate morphogenic signals of ErbB-2, EpH4 cells overexpressing Vav2 protein were cultured on Matrigel. Indeed, Vav2 induces alveolar morphogenesis of EpH4 cells when activated either by oncogenic mutation or tyrosine phosphorylation by ErbB-2. The morphogenic activity of Vav2 requires the Dbl homology domain, which mediates GDP/GTP exchange. Dominant-negative Vav2 specifically blocks the morphogenic signals of ErbB-2 in EpH4 cells without interfering with ErbB2-induced mitogenesis. Importantly, Vav2 is co-expressed and interacts with ErbB-2 in the mammary glands of pregnant mice. Taken together, these results point to Vav2 as a candidate to mediate ErbB-2 signals for alveolar morphogenesis in vivo, which is a relevant step in the development of the mammary gland during pregnancy

“A growing excitement that ‘something was happening’”: A Rhetorical History of Gay Liberation and Socialist Feminism in the New American Movement between 1970 and 1980

This project charts a rhetorical history of the New American Movement’s (NAM) organizational debates on gay liberation and socialist feminism between 1970 and 1980. NAM was a socialist feminist organization active across the 1970s in the United States that sought to create a mass movement through a conception of a particularly “American Socialism.” Through a periodization of NAM’s archival history, I highlight how NAM members were able to work in coalition with a wide range of individuals and groups both within and outside of the organization to build a socialist feminist conception of gay liberation. Drawing on original archival research performed at four archives in the United States in collections of speeches, internal memos, personal and organizational correspondence, newsletters, and discussion notes, I argue that NAM’s adoption of a socialist feminist approach to gay liberation augments “siloed” rhetorical approaches to social movements in the 1970s in as much as NAM members, as well as their theories and practice, worked out of, within, and with autonomous liberation movements. This project also intervenes in histories of gay liberation, feminism, and socialism in the 1970s by centering NAM’s, largely unaddressed in scholarship, work which challenges the seemingly stable lines between each movement

A Performance Guide To Prokofiev: Romeo And Juliet For Solo Tuba

As the most recent brass instrument to be added to the standard orchestra, the tuba’s solo repertoire is relatively new compared to other orchestral instruments. Ralph Vaughan Williams composed the first major concerto for tuba in 1954, over 100 years after the tuba’s creation in 1835 by Wilhelm Friedrich Wieprecht and Johann Gottfried Moritz. Though many composers — including Bruce Broughton, Eric Ewazen, Paul Hindemith, Gunther Schuller, and John Williams — have written solos for the tuba since Vaughan Williams, performers rely on arrangements and transcriptions of existing works to fill gaps in the repertoire. In 2011, Chicago Symphony Orchestra’s bass trombonist Charles Vernon arranged ten movements of Sergei Prokofiev’s ballet Romeo and Juliet for the Chicago Symphony Orchestra’s Principal Tuba, Gene Pokorny. Sergei Prokofiev is one of the most well-known composers of the 20th century. His works include concerti, chamber music, orchestral music, operas, and ballets; one of his most popular works is the ballet Romeo and Juliet, William Shakespeare’s timeless story of star-crossed lovers. He also used material from the ballet to create three orchestral suites. This performance guide serves as a detailed resource for Prokofiev’s Romeo and Juliet Suite No. 1, Op. 64, arranged for Tuba and Piano by Charles Vernon. There are many resources that provide historical details and context on the life and works of Sergei Prokofiev, but there are few performance guides for tuba solos, let alone transcriptions of his works. Though the breadth of literature on tuba solos is limited, what is available will be referenced as best as possible. This paper fills a gap in tuba performance guides and provides a needed resource for tubists. There have been transcriptions of Romeo and Juliet movements for other instruments, including trombone, piano, and viola, but no performance guide or literature can be found for tuba. Since Romeo and Juliet was written for orchestra, there are many things to consider when performing a transcription. The player should know what instrument the original melody was written for to inform musical decisions, what character is represented by the theme they are playing, and what drama is accompanying that movement. This arrangement is for solo tuba and piano, so important orchestral lines are played by the piano. This guide helps decipher when the “solo” voice has the melody and is playing a background role. There are also technical challenges since the piece was not originally written for the tuba. In addition to the analysis of the transcription itself, the tuba player will run into technically challenging aspects of the music. The included practice guide gives the tubist a path toward working through the difficulties with various methods, techniques, and practice tools to aid in learning the piece. The first resources referenced in this paper are books, dissertations, and articles related to the composer Sergei Prokofiev and his music. These are used for historical context and biographical context. These also provide information on his ballets, including Romeo and Juliet. Performance guides for other solos are also examined to illustrate past approaches and ideas. The second methodology predominately used in this paper are musical scores of the original orchestral parts to Romeo and Juliet and the Charles Vernon tuba solo. Scores of Prokofiev’s earlier works are also cited in order to understand how he usually wrote for the tuba in an orchestral setting. Analysis of the original ballet score alongside the Vernon arrangement provides important information for the performer on the similarities and differences between the two

Synergistic qualities of form and space

None provided

System Response Time and User Satisfaction: An Experimental Study of Browser-based Applications

With rapid advances in hardware speed and data communication bandwidth, one might not expect to have to deal with issues such as response time and system performance. But these issues remain a very real concern today. Lengthy system response times may cause lower satisfaction and poor productivity among users. Lowered user satisfaction may lead to discontinued use of an application, especially in discretionary applications such as those found on the Internet. The intent of this experimental research is to (1) substantiate that slow system response time leads to dissatisfaction; (2) assess the point at which users may become dissatisfied with system response time; (3) determine a threshold at which dissatisfaction may lead to discontinued use of the application, and (4) determine if experience influences response time tolerance. The results showed that indeed satisfaction does decrease as response time increases. However, instant response was not perceived as making the system easier to use or learn. It also showed that for discretionary applications, there appears to be a level of intolerance in the 12-second response range

Impulsivity Relates to Relative Preservation of Mesolimbic Connectivity in Patients with Parkinson Disease.

IntroductionThe relationship between Parkinson Disease (PD) pathology, dopamine replacement therapy (DRT), and impulse control disorder (ICD) development is still incompletely understood. Given the sensorimotor-lateral substantia nigra (SN) selective degeneration associated with PD, we posit that a relative sparing of the limbic-medial SN in the context of DRT drives impulsive, reward-seeking behavior in PD patients with recent history of severe impulsivity.MethodsImpulsive and control participants were selected from a consecutive list of PD patients receiving pre-operative deep brain stimulation (DBS) planning scans including 3T structural MRI and 64 direction diffusion tensor imaging (DTI). Using previously identified substantia nigra (SN) subsegment network connectivity profiles to develop classification targets, split-hemisphere target-based SN segmentation with probabilistic tractography was performed. The relative subsegment volumes and strength of connectivity between the SN and the limbic, associative, and motor network targets were compared.ResultsOur results show that there is greater probability of connectivity between the SN and limbic network targets relative to motor and associative network targets in PD patients with recent history of severe impulsivity as compared to PD patients without impulsivity (P = 0.0075). We did not observe relative volumetric subsegment differences across groups.ConclusionFirstly, our results suggest that fine-grained, atlas-derived classification targets may be used in PD to parcellate and classify functionally distinct subsegments of the SN, with the apparent preservation of previously reported topographical limbic-medial SN, associative-ventral SN, and sensorimotor-lateral SN orientation. We suggest that relative, as opposed to absolute, degeneration amongst SN-associated dopaminergic networks relates to the impulsivity phenotype in PD

Investigation of Carbon Reduction from Overnight Lighting in Non-Domestic Building Stock

The use of electricity, specifically through overnight lighting in non-domestic buildings, is a cause for increasing carbon dioxide emissions. Through our project, we developed and implemented a new methodology for nighttime observations of overnight lighting in non-domestic buildings. Analysis of our data has led to a more robust image of overnight lighting which Carbon Reduction in Buildings can combine with existing data to develop a socio-technical model for estimating carbon dioxide emissions in the United Kingdom

Imputation, Estimation and Missing Data in Finance

Suppose X is a diffusion process, possibly multivariate, and suppose that there are various segments of the components of X that are missing. This happens, for example, if X is the price of various assets and these prices are only observed at specific discrete trading times. Imputation (or conditional simulation) of the missing pieces of the sample paths of X is discussed in several settings. When X is a Brownian motion the conditioned process is a tied down Brownian motion or a Brownian bridge process. In the special case of Gaussian stochastic processes the problem is simplified since the conditional finite dimensional distributions of the process are multivariate Normal. For more general diffusion processes, including those with jump components, an acceptance-rejection simulation algorithm is introduced which enables one to sample from the exact conditional distribution without appealing to approximate time step methods such as the popular Euler or Milstein schemes. The method is referred to as pathwise imputation. Its practical implementation relies only on the basic elements of simulation while its theoretical justification depends on the pathwise properties of stochastic processes and in particular Girsanov's theorem. The method allows for the complete characterization of the bridge paths of complicated diffusions using only Brownian bridge interpolation. The imputation methods discussed are applied to estimation, variance reduction and exotic option pricing

L'architettura dell'illusione a Palazzo Poggi

Il lavoro svolto per l’elaborazione di questa tesi si basa sulla raffigurazione dell’architettura nel genere della quadratura, un tipo di pittura illusoria, raffiguranti architetture, che utilizza la tecnica della prospettiva per creare l’illusione di uno spazio tridimensionale su un piano o una superficie voltata. Lo sfondato prospettico preso in esame consiste nell'affresco rappresentante “la caduta di Fetonte” realizzato da Pellegrino Tibaldi a Palazzo Poggi a Bologna nel 1551. E' stato eseguito un rilevo digitale della sala, mediante laser scanner a differenza di fase CAM2 Focus3D, a cui è seguita la redazione di elaborati grafici (utili per comprendere gli aspetti geometrici della sala), lo studio di trattati prospettici in un periodo storico compreso dal XVI al XVII e un'analisi della superficie pittorica (riferimenti geometrici quali assi, individuazione del punto “riguardante”). E' stata infine ricostruita, con software di modellazione tridimensionale, l'architettura illusoria rappresentata nella quadratura