Active Notch1 confers a transformed phenotype to primary human melanocytes

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.

Youth Alcohol and Drug Practice Guide 3 : Practice Strategies and Interventions

This guide canvasses a range of practice strategies and interventions utilised by workers and services who engage with young people experiencing problematic AOD use whilst also exploring the many and varied challenges associated with this type of work.

Thoughts make the world

Thoughts Make the World is a synchronised two-channel video with sound. On the right-hand screen, a young man and woman exchange timeworn philosophical phrases and existential questions. On the left-hand screen, a guitarist plays a soundtrack that slowly builds over time. As the actors’ quest for meaning struggles toward an unresolved end, the guitarist launches into a climactic, liberating solo, eclipsing their somewhat-labored attempts to understand existence. By contrasting these verbal and non-verbal signifiers of self-reflection and self-expression, Thoughts Make the World questions how and where to grapple with enduring existential problems in a context dominated by the pre-packaged formats of popular culture and ironic modes of individualised response.

Vertically aligned ZnO nanorods on flexible substrates for multifunctional device applications: Easy and cost-effective route

Zinc oxide nanorods (ZnO NRs) have been synthesized on flexible substrates by adopting a new and novel three-step process. The as-grown ZnO NRs are vertically aligned and have excellent chemical stoichiometry between its constituents. The transmission electron microscopic studies show that these NR structures are single crystalline and grown along the < 001 > direction. The optical studies show that these nanostructures have a direct optical band gap of about 3.34 eV. Therefore, the proposed methodology for the synthesis of vertically aligned NRs on flexible sheets launches a new route in the development of low-cost flexible devices. (C) 2014 Elsevier B.V. All rights reserved.

Symmetrical 2-D Hermite-Gaussian square launch for high bit rate transmission in multimode fiber links

A 2-D Hermite-Gaussian square launch is demonstrated to show improved systems capacity over multimode fiber links. It shows a bandwidth improvement over both center and offset launches and exhibits ±5 μm misalignment tolerance. © 2011 Optical Society of America.

Primary cosmic-ray positrons and negatrons in 1968 at energies between 11 and 204 MeV

The cosmic-ray positron and negatron spectra between 11 and 204 MeV have been measured in a series of 3 high-altitude balloon flights launched from Fort Churchill, Manitoba, on July 16, July 21, and July 29, 1968. The detector system consisted of a magnetic spectrometer utilizing a 1000-gauss permanent magnet, scintillation counters, and a lucite Čerenkov counter.

Launches were timed so that the ascent through the 100 g/cm² level of residual atmosphere occurred after the evening geomagnetic cutoff transition. Data gathered during ascent are used to correct for the contribution of atmospheric secondary electrons to the flux measured at float altitude. All flights floated near 2.4 g/cm².

A pronounced morning intensity increase was observed in each flight. We present daytime positron and negatron data which support the interpretation of the diurnal flux variation as a change in the local geomagnetic cutoff. A large diurnal variation was observed in the count rate of positrons and negatrons with magnetic rigidities less than 11 MV and is evidence that the nighttime cutoff was well below this value.

Using nighttime data we derive extraterrestrial positron and negatron spectra. The positron-to-total-electron ratio which we measure indicates that the interstellar secondary, or collision, source contributes ≾50 percent of the electron flux within this energy interval. By comparing our measured positron spectrum with the positron spectrum calculated for the collision source we derive the absolute solar modulation for positrons in 1968. Assuming negligible energy loss during modulation, we derive the total interstellar electron spectrum as well as the spectrum of directly accelerated, or primary, electrons. We examine the effect of adiabatic deceleration and find that many of the conclusions regarding the interstellar electron spectrum are not significantly altered for an assumed energy loss of up to 50 percent of the original energy.

Cicatrizes de leitura: um aparte do peso do conhecimento em Fausto de Fernando Pessoa

A presente dissertação toma como propósito compreender de que forma a ideia do peso do conhecimento é apresentada no Fausto de Fernando Pessoa. A expressão peso do conhecimento, cunhada pelo filósofo Stanley Cavell, surge como forma de apresentação da tragédia na modernidade. O Fausto de Fernando Pessoa, mediante a sua queda na mente, relata, no encontro com a Morte, a figuração máxima de todo e qualquer conhecimento; a afetação trágica que o consome. Esse trabalho, portanto, inaugura a perspectiva que visa explorar, como forma de compreensão da obra pessoana, a ideia de que a tragédia moderna é o peso do conhecimento. E, ao mesmo tempo, sustenta a hipótese de que o peso do conhecimento pressupõe o reconhecimento de que toda vida do conhecedor termina num tipo de tragédia shakespeariana. Assim, a obra de Fernando Pessoa se apropria de uma longa tradição que se inicia com Hamlet e, com ela, delineia, a partir do problema do peso do conhecimento, a teatralidade da escrita dos versos de Fausto, cuja apresentação do dilema entre a Vida e o Conhecimento pressupõe a cena imediata de uma figura, Fausto (ou Hamlet

O Barão de Lavos: do belo ao grotesco: uma análise comparativista

Esta pesquisa tem por objetivo, em perspectiva comparada, analisar o encontro de duas artes: a literatura e a pintura, observado na obra O Barão de Lavos (1891), de Abel Botelho. O romance naturalista, com traços decadentistas, do escritor Abel Botelho que abre a série intiulada Patologia Social (1891) nos mostra, como diz José Carlos Seabra Pereira, um tempo em se convegiam o romantismo,o realismo e pretensões de modernidade baudealiriana (mais ou menos satanistas) (PEREIRA, 1995) e onde as diversas categorias das artes se encontram e se conjugam. Nesse cenário caótico, mas profícuo, temos este romance que estabelece a arte plástica como ponto focal dentro do texto. Analisa, sobretudo, o processo da escrita onde foi possível constatar a deformação do belo em grotesco ao longo do romance. Investiga a questão imagética encontrada no texto botelhiano, caracterizada através da gravura Rapto de Ganimedes; litografia de grande simbologia dentro dessa obra literária, pois representa o ideal estético idealizado pelo próprio Barão, e tudo de significativo que compõe a trajetória e as emoções de D. Sebastião ao longo de sua vida, portanto permeando e atravessando toda narrativa

Symmetrical 2-D hermite-gaussian square launch for high bit rate transmission in multimode fiber links

A 2-D Hermite-Gaussian square launch is demonstrated to show improved systems capacity over multimode fiber links. It shows a bandwidth improvement over both center and offset launches and exhibits ±5 ìm misalignment tolerance. © OSA/OFC/NFOEC 2011.

高山峡谷地区大跨度桥梁岸坡稳定性分析、趋势预测及应用研究

In order to realize fast development of the national economy in a healthy way and coordinate progress with whole society, the country has implemented the strategy of development of the western region. An important action of finishing this strategic task is to accelerate the highway construction in the western region, join the western region and places along the coast, the river, the border with goods and materials, technology, and personnel interchanges, and then drive development of the local economy.The western region was influenced by the Himalaya Tectonization in Cenozoic, and the crust rose and became the plateau. In the course of rising, rivers cut down sharply to form a lot of high mountains and gorges.Because of topography and geomorphology, bridges in the traffic construction in the alpine gorge area are needed. Rivers have characteristics of large flow, fast velocity and high and steep river valley, so building a pier in the river is not only very difficult, but also making the cost increase. At the same time, the impact that the pier is corroded and the bridge base that is drawn to be empty by flow are apt to cause destruction of the pier. For those reasons, suspending bridge and cable-stay bridge are usually adopted with the single and large span. For the large span bridge, the pier foundation could receive ten thousand and more vertical strength, bending moment and near kiloton horizontal thrust.Because bank slope in the alpine gorge district is cut deeply and unsettled big, natural stability is worse under endogenic and exogenic force. When bank slope bears heavy vertical strength, bending moment and horizontal thrust facing the river, it will inevitably make the balance state of rock and soil mass change, bridge bank slope deform, and even destroyed. So the key problem at the time of the large span's bridge construction in the alpine gorge area is how to make it stable.So based on the spot investigation, the Engineering Geology Analysis Method is very important to grasp the bank slope stability. It can provide the bank slope stability macroscopic ally and qualitatively, and reference to the indoor calculation. The Engineering Geology Analysis Method is that by way of analyzing and investigating terms of bank slope instability, stability development trend, the ancient rock slide and devolution in the site, stability comprehensive evaluation primarily, current and future stability of bank slope is gotten, realizing the intention to serving the concrete engineering.After the Engineering Geology Analysis Method is applied to project instances of BeiPan River Bridge and BaLin River Bridge, results are accord with bank slope actual conditions, which proves sites are suited to building bridges from site stability.we often meet bank slope stability issues in the traffic construction in the alpine gorge areao Before the evaluation of the bank slope stability, the engineering geological condition is investigated first. After that, the next exploration target and geology measures are decided. So, the Engineering Geology Analysis Method that the investigation of the engineering geological condition is the main content is quite important in practice. The other evaluations of the bank slope stability are based on it. Because foundation receives very heavy load, for the big span's bridge in the alpine gorge area, a long pile of the large diameter (D^0.8m) is usually selected. In order to reflect rock mass's deformation properties under rock-socketed pile function, the author has used the FLAG30 software for rock and soil mass and done many numerical simulations. By them, the author launches the further investigation on deformation properties of bank slope under different slope angle, pile length, diameter, elastic modulus, load, bank slope's structure, etc. Some conclusion meaningful to the design and produce are obtained.

The VITEWRITE Model of Handwriting Production

This article describes the VITEWRITE model for generating handwriting movements. The model consists of a sequential controller, or motor program, that interacts with a trajectory generator to move a hand with redundant degrees of freedom. The neural trajectory generator is the Vector Integration to Endpoint (VITE) model for synchronous variable-speed control of multijoint movements. VITE properties enable a simple control strategy to generate complex handwritten script if the hand model contains redundant degrees of freedom. The controller launches transient directional commands to independent hand synergies at times when the hand begins to move, or when a velocity peak in the outflow command to a given synergy occurs. The VITE model translates these temporally disjoint synergy commands into smooth curvilinear trajectories among temporally overlapping synergetic movements. Each synergy exhibits a unimodal velocity profile during any stroke, generates letters that are invariant under speed and size rescaling, and enables effortless connection of letter shapes into words. Speed and size rescaling are achieved by scalar GO and GRO signals that express computationally simple volitional commands. Psychophysical data such as the isochrony principle, asymmetric velocity profiles, and the two-thirds power law relating movement curvature and velocity arise as emergent properties of model interactions.

A Neural Network Model for Cursive Script Production

This article describes a neural network model, called the VITEWRITE model, for generating handwriting movements. The model consists of a sequential controller, or motor program, that interacts with a trajectory generator to move a. hand with redundant degrees of freedom. The neural trajectory generator is the Vector Integration to Endpoint (VITE) model for synchronous variable-speed control of multijoint movements. VITE properties enable a simple control strategy to generate complex handwritten script if the hand model contains redundant degrees of freedom. The proposed controller launches transient directional commands to independent hand synergies at times when the hand begins to move, or when a velocity peak in a given synergy is achieved. The VITE model translates these temporally disjoint synergy commands into smooth curvilinear trajectories among temporally overlapping synergetic movements. The separate "score" of onset times used in most prior models is hereby replaced by a self-scaling activity-released "motor program" that uses few memory resources, enables each synergy to exhibit a unimodal velocity profile during any stroke, generates letters that are invariant under speed and size rescaling, and enables effortless. connection of letter shapes into words. Speed and size rescaling are achieved by scalar GO and GRO signals that express computationally simple volitional commands. Psychophysical data concerning band movements, such as the isochrony principle, asymmetric velocity profiles, and the two-thirds power law relating movement curvature and velocity arise as emergent properties of model interactions.

MarcoPolo-R near earth asteroid sample return mission

MarcoPolo-R is a sample return mission to a primitive Near-Earth Asteroid (NEA) proposed in collaboration with NASA. It will rendezvous with a primitive NEA, scientifically characterize it at multiple scales,and return a unique sample to Earth unaltered by the atmospheric entry process or terrestrial weathering. MarcoPolo-R will return bulk samples (up to 2 kg) from an organic-rich binary asteroid to Earth for laboratory analyses, allowing us to: explore the origin of planetary materials and initial stages of habitable planet formation; identify and characterize the organics and volatiles in a primitive asteroid; understand the unique geomorphology, dynamics and evolution of a binaryNEA. This project is based on the previous Marco Polo mission study,which was selected for the Assessment Phase of the first round of Cosmic Vision. Its scientific rationale was highly ranked by ESA committees andit was not selected only because the estimated cost was higher than theallotted amount for an M class mission. The cost of Marco Polo-R will be reduced to within the ESA medium mission budget by collaboration withAPL (John Hopkins University) and JPL in the NASA program for coordination with ESA's Cosmic Vision Call. The baseline target is a binary asteroid (175706) 1996 FG3, which offers a very efficient operational and technical mission profile. A binary target also providesenhanced science return. The choice of this target will allow newinvestigations to be performed more easily than at a single object, andalso enables investigations of the fascinating geology and geophysics ofasteroids that are impossible at a single object. Several launch windows have been identified in the time-span 2020-2024. A number of otherpossible primitive single targets of high scientific interest have beenidentified covering a wide range of possible launch dates. The baselinemission scenario of Marco Polo-R to 1996 FG3 is as follows: a singleprimary spacecraft provided by ESA, carrying the Earth Re-entry Capsule, sample acquisition and transfer system provided by NASA, will be launched by a Soyuz-Fregat rocket from Kourou into GTO and using two space segment stages. Two similar missions with two launch windows, in 2021 and 2022 and for both sample return in 2029 (with mission durationof 7 and 8 years), have been defined. Earlier or later launches, in 2020 or 2024, also offer good opportunities. All manoeuvres are carried out by a chemical propulsion system. MarcoPolo-R takes advantage of three industrial studies completed as part of the previous Marco Polo mission (see ESA/SRE (2009)3, Marco Polo Yellow Book) and of the expertise of the consortium led by Dr. A.F. Cheng (PI of the NASA NEAR Shoemaker mission) of the JHU-APL, including JPL, NASA ARC, NASA LaRC, and MIT.

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

The host launches an antimicrobial defense program upon infection. A long-held belief is that pathogens prevent host recognition by remodeling their surface in response to different host microenvironments. Yet direct evidence that this happens in vivo is lacking. Here we report that the pathogen Klebsiella pneumoniae modifies one of its surface molecules, the lipopolysaccharide, in the lungs of mice to evade immune surveillance. These in vivo-induced changes are lost in bacteria grown after isolation from the tissues. These lipopolysaccharide modifications contribute to survival in vivo and mediate resistance to colistin, one of the last options to treat multidrug-resistant Klebsiella. This work opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.

O tempo das reformas : o papel da companhia de Jesus no enfrentamento com ideais protestantes na Europa do Sul : uma proposta pedagógica

Relatório da prática de ensino supervisionada, Mestrado em Ensino da História e da Geografia no 3º Ciclo do Ensino Básico e no Ensino Secundário, Universidade de Lisboa, 2014