Targeting the actin cytoskeleton in HER2+ metastatic cancer cells using a macrolide toxin

Breast and ovarian cancers are among the leading causes of cancer related deaths in women worldwide. In a subset of these cancers, dysregulation of the human epidermal growth factor receptor 2 (HER2) leads to overexpression of the receptor on the cell surface. Previous studies have found that these HER2+ cancers show high rates of progression to metastatic disease. Metastasis is driven by cytoskeletal rearrangements that produce filamentous actin (F-actin) based structures that penetrate and degrade extracellular matrix to facilitate tumour invasion. Advancements in targeted therapy have made F-actin an attractive target for the development of new cancer therapies. In this thesis, we tested the actin-depolymerizing macrolide toxin, Mycalolide B (MycB), as a potential warhead for a novel antibody drug conjugate (ADC) to target highly metastatic HER2+ breast and ovarian cancers. We found that MycB treatment of HER2+ breast (SKBR3, MDA-MB-453) and ovarian (SKOV3) cancer cells led to loss of viability (IC50 values ≤ 64 nM). Sub-lethal doses of MycB treatment caused potent suppression of leading edge protrusions, migration and invasion potential of HER2+ cancer cells (IC50 ≤ 32 nM). In contrast, other F-actin based processes such as receptor endocytosis were less sensitive to MycB treatment. MycB treatment skewed the size of endocytic vesicles, which may reflect defects in F-actin based vesicle motility or maturation. Given that HER2+ cancers have been effectively targeted by Trastuzumab and Trastuzumab-based ADCs, we tested the effects of a combination of Trastuzumab and MycB on cell migration and invasion. We found that MycB/ Trastuzumab combination treatments inhibited motility of SKOV3 cells to a greater degree than either treatment alone. Altogether, our results provide proof-of-principle that actin toxins such as MycB can be used as a novel class of warheads for ADCs to target and combat highly metastatic cancers.

miRNAs as therapeutic agents in neurodegeneration, a pilot study

L’échec des différents essais cliniques souligne la nécessité de développer des nouvelles thérapies pour la maladie d’Alzheimer (MA), la cause la plus commune de démence. Les microARNs (miARNs) sont les ARNs non-codants les plus étudiés et ils jouent un rôle important dans la modulation de l’expression des gènes et de multiples voies de signalisation. Des études antérieures, dont celles de mon laboratoire d’accueil, ont permis de développer l’hypothèse que certains membres de la famille miR-15/107 (c.-à-d. miR-15ab, miR-16, miR-195, miR-424, and miR-497) pourraient être utilisés comme agents thérapeutiques dans MA. En effet, cette famille avait le potentiel de réguler de multiples gènes associés à MA, tels que la protéine précurseur de l’amyloïde (APP), la β-secrétase (BACE1), et la protéine Tau. Tel que démontré dans ce projet de thèse, j’ai choisi miR-16 comme cible thérapeutique potentielle pour MA parmi tous les membres de la famille. L’essai luciférase dans ce projet confirme que miR-16 peut réguler simultanément APP et BACE1, directement par une interaction avec la région non-codante en 3’ de l’ARNm). Notamment, nous observons aussi une réduction de la production des peptides amyloïdes et de la phosphorylation de Tau après une augmentation de miR-16 en cellule. J’ai ensuite validé mes résultats in vivo dans la souris en utilisant une méthode de livraison de miR-16 via une pompe osmotique implanté dans le cerveau. Dans ce cas, l’expression des protéines d’intérêts (APP, BACE1, Tau) a été mesurée par immunobuvardage et PCR à temps réel. Après validation, ces résultats ont été complémentés par une étude protéomique (iTRAQ) du tronc cérébral et de l’hippocampe, deux régions associées à la maladie. Ces données m’ont permis d’identifier d’autres protéines régulées par miR-16 in vivo, incluant α-Synucléine, Transferrine receptor1, et SRm300. Une autre observation intéressante : les voies régulées par miR-16 in vivo sont directement en lien avec le stress oxydatif et la neurodégénération. En résumé, ce travail démontre l’efficacité et la faisabilité d’utiliser un miARN comme outil thérapeutique pour la maladie d’Alzheimer. Ces résultats rentrent dans un cadre plus vaste de découvrir de nouvelles cibles pour MA, et en particulier la forme sporadique de la maladie qui représente plus de 95% de tous les cas. Évidemment, la découverte d’une molécule pouvant cibler simultanément les deux pathologies de la maladie (plaques amyloïdes et hyper phosphorylation de tau) est nouvelle et intéressante, et ce domaine de recherche ouvre la porte aux autres petits ARNs non-codants dans MA et les maladies neurodégénératives connexes.

Efficient entanglement distillation without quantum memory

Entanglement distribution between distant parties is an essential component to most quantum communication protocols. Unfortunately, decoherence effects such as phase noise in optical fibres are known to demolish entanglement. Iterative (multistep) entanglement distillation protocols have long been proposed to overcome decoherence, but their probabilistic nature makes them inefficient since the success probability decays exponentially with the number of steps. Quantum memories have been contemplated to make entanglement distillation practical, but suitable quantum memories are not realised to date. Here, we present the theory for an efficient iterative entanglement distillation protocol without quantum memories and provide a proof-of-principle experimental demonstration. The scheme is applied to phase-diffused two-mode-squeezed states and proven to distil entanglement for up to three iteration steps. The data are indistinguishable from those that an efficient scheme using quantum memories would produce. Since our protocol includes the final measurement it is particularly promising for enhancing continuous-variable quantum key distribution.

The Southeast Indian Ridge between 88°E and 118°E: Gravity anomalies and crustal accretion at intermediate spreading rates

Although slow spreading ridges characterized by a deep axial valley and fast spreading ridges characterized by an axial bathymetric high have been extensively studied, the transition between these two modes of axial morphology is not well understood. We conducted a geophysical-survey of the intermediate spreading rate Southeast Indian Ridge between 88 degrees E and 118 degrees E, a 2300-km-long section of the ridge located between the Amsterdam hot spot and the Australian-Antarctic Discordance where satellite gravity data suggest that the Southeast Indian Ridge (SEIR) undergoes a change from an axial high in the west to an axial valley in the east. A basic change in axial morphology is found near 103 degrees 30'E in the shipboard data; the axis to the west is marked by an axial high, while a valley is found to the east. Although a well-developed axial high, characteristic of the East Pacific Rise (EPR), is occasionally present, the more common observation is a rifted high that is lower and pervasively faulted, sometimes with significant (> 50 m throw) faults within a kilometer of the axis. A shallow axial valley (< 700 m deep) is observed from 104 degrees E to 114 degrees E with a sudden change to a deep (>1200 m deep) valley across a transform at 114 degrees E. The changes in axial morphology along the SEIR are accompanied by a 500 m increase in near-axis ridge flank depth from 2800 m near 88 degrees E to 3300 m near 114 degrees E and by a 50 mGal increase in the regional level of mantle Bouguer gravity anomalies over the same distance, The regional changes in depth and mantle Bouguer anomaly (MBA) gravity can be both explained by a 1.7-2.4 km change in crustal thickness or by a mantle temperature change of 50 degrees C-90 degrees C. In reality, melt supply (crustal thickness) and mantle temperature are linked, so that changes in both may occur simultaneously and these estimates serve as upper bounds. The along-axis MBA gradient is not uniform. Pronounced steps in the regional level of the MBA gravity occur at 103 degrees 30'E-104 degrees E and at 114 degrees E-116 degrees E and correspond to the changes in the nature of the axial morphology and in the amplitude of abyssal hill morphology suggesting that the different forms of morphology do not grade into each other but rather represent distinctly different forms of axial (s)tructure and tectonics with a sharp transition between them. The change from an axial high to an axial valley requires a threshold effect in which the strength of the lithosphere changes quickly. The presence or absence of a quasi-steady state magma chamber may provide such a mechanism. The different forms of axial morphology are also associated with different intrasegment MBA gravity patterns. Segments with an axial high have an MBA low located at a depth minimum near the center of the segment, At EPR-like segments, the MBA low is about 10 mGal with along-axis gradients of 0.15-0.25 mGal/km, similar to those observed at the EPR, Rifted highs have a shallower low and lower gradients suggesting an attenuated composite magma chamber and a reduced and perhaps episodic melt supply. Segments with a shallow axial valley have very flat along-axis MBA profiles with little correspondence between axial depth and axial MBA gravity.

Igual consideração e respeito, independência ética e liberdade de expressão em Dworkin : uma reconciliação entre igualdade e liberdade e a possibilidade do discurso do ódio em um ordenamento coerente de princípios

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Direito, Pós-Graduação Stricto Sensu em Direito, 2016.

A fiber-compatible spectrally encoded imaging system using a 45° tilted fiber grating

We propose and demonstrate, for the first time to our best knowledge, the use of a 45° tilted fiber grating (TFG) as an infiber lateral diffraction element in an efficient and fiber-compatible spectrally encoded imaging (SEI) system. Under proper polarization control, the TFG has significantly enhanced diffraction efficiency (93.5%) due to strong tilted reflection. Our conceptually new fiber-topics-based design eliminates the need for bulky and lossy free-space diffraction gratings, significantly reduces the volume and cost of the imaging system, improves energy efficiency, and increases system stability. As a proof-of-principle experiment, we use the proposed system to perform an one dimensional (1D) line scan imaging of a customer-designed three-slot sample and the results show that the constructed image matches well with the actual sample. The angular dispersion of the 45° TFG is measured to be 0.054°/nm and the lateral resolution of the SEI system is measured to be 28 μm in our experiment.

Impedancias basales registradas durante la denervación renal por radiofrecuencia en pacientes con hipertensión arterial resistente

Objetivo: Determinar diferencias en las impedancias basales registradas durante los procedimientos de denervación renal por radiofrecuencia de los pacientes sometidos a este procedimiento en la Fundación Cardioinfantil de Bogotá durante los años 2012 a 2015. Materiales y métodos: Estudio observacional, analítico de corte retrospectivo, donde se analizaron todas las impedancias basales medidas durante los procedimientos de denervación renal, buscando diferencias significativas entre los segmentos de las arterias intervenidas, estratificados en proximal, medio distal y superior, lateral, inferior u ostial. Con seguimiento a los pacientes a tres, seis y doce meses en cuanto a presión arterial de consultorio. Resultados: Se evaluaron 150 puntos de denervación renal exitosos, correspondientes a 23 arterias renales de 11 procedimientos. La mediana de edad fue 56 años. Al realizar un modelo de regresión lineal no se encontró ninguna diferencia estadísticamente significativa entre las impedancias de ninguno de los segmentos de las arterias ni sitios anatómicos. Se documentó disminución de presión arterial sistólica a tres meses, seis meses y doce meses de 14 mmHg (RIQ 10-33mmHg), 21 mmHg (RIQ 12-42mmHg) y 19 mmHg (RIQ 11-42 mmHg) respectivamente

Pluralismo y derechos fundamentales en el estado social de derecho: la situación de las poblaciones indígenas en Colombia en 2014

Este es un estudio sobre la garantía y aplicabilidad de los derechos humanos de las poblaciones indígenas colombianas durante los primeros cuatro años de mandato de la administración Santos. La investigación busca explicar la manera en que las adversas condiciones socio económicas que caracterizan el desarrollo de las poblaciones indígenas, denotan la incapacidad del Estado Social de Derecho para garantizar la protección y aplicabilidad de los derechos fundamentales de estas comunidades. Las disposiciones constitucionales han tenido un desarrollo truncado debido a las escasas medidas proferidas por diferentes gobiernos frente a las necesidades de estos grupos en particular. En razón de lo anterior, el estudio se inscribe dentro del marco teórico referente al neo constitucionalismo debido al alto valor explicativo que ofrecen los postulados de Gustavo Zagrebelsky y Luigi Ferrajoli en relación al fenómeno que se pretende analizar. Se concluye que frente a la persistencia de los factores que afectan el desarrollo de las poblaciones indígenas, el reconocimiento constitucional debe ser complementado por una efectiva normatividad que asegure la aplicabilidad de los derechos fundamentales por parte de las administraciones políticas: no debe existir un desfase entre las nociones de principio y la ley.

Da intervenção da Santa Casa da Misericórdia de Évora: a qualidade das respostas sociais e satisfação percebida dos utentes internos da SCMÉ

O Relatório de estágio tem por desígnio, compreender e analisar, o statu quo das dimensões da satisfação (Contemplando o seu bem-estar pessoal e social) dos utentes das valências da Santa Casa da Misericórdia de Évora, por conseguinte, analisando e compreendendo a qualidade de vida desses mesmos utentes, debruçando-se, pois, sobre as potenciais e/ou evidentes necessidades institucionais por suprimir, e problemas sociais por erradicar. O levantamento da actual informação obteve-se através de dois instrumentos metodológicos de recolha de dados: inquérito por questionário de aplicação directa auto-administrada (utentes), e por intermédio de entrevistas semi-estruturadas (diretores técnicos das valências). Relativamente, aos métodos de tratamento de dados, no primeiro instrumento utilizou-se IBM SPSS 22, já no segundo análise de conteúdo. Após a detecção das necessidades existentes, procedeu-se a elaboração de uma proposta de intervenção sócio-organizacional, por forma a solucionar essas mesmas necessidades existentes. O presente documento estrutura-se em 4 eixos: o Eixo 1 – Componente teórica - ; o Eixo 2 – Componente metodológica - ; Eixo 3 – Componente dos resultados - ; Eixo 4 – Componente de intervenção sócio- organizacional; Abstract: Intervention of the Holy House of Mercy of Evora - The quality of the Social Responses and satisfaction perceived Internal SCME of users -. This work is to design, understand and analyze the status quo of the dimensions of satisfaction (Contemplating their personal and social welfare) of users of the valences of the Holy House of Mercy of Evora, therefore, analyzing and understanding the quality life of these same users, addressing therefore, on potential and / or obvious institutional needs to suppress and eradicate social problems. The survey of current information was obtained through two methodological tools for data collection: survey by self-administered direct application questionnaire (users), and through semi-structured interviews (technical directors of valences). With regard to the data processing methods, the first instrument was used SPSS 22, in the second content analysis. After detection of the needs, it proceeded to draw up a proposal for social and organizational intervention in order to solve these same existing needs. This document is divided into four axes: Axis 1 - Theoretical component -; Axis 2 - methodological component -; Axis 3 - Component of results -; Axis 4 - socio-organizational intervention component.

Coflow jets with large velocity difference - a new aerodynamic principle of flame stabilization and combustion intensification

A new aerodynamic principle of flame stabilization and combustion intensification, the coflow jets with large velocity difference, is described. One or more small high-velocity jets of air or steam, injected off the axis and in the same direction as the low-velocity main fuel-air flow into the combustor, create a large recirculation zone of high turbulence intensity in which the combustibles and high temperature gases are effectively mixed, so that stable and intensive combustion can be maintained even for fuels with poor ignition. A pulverized coal combustor based on the principle mentioned above is shown to be characteristic of excellent combustoom and a simple structure. A number of precombustors of this type are in operation at some power stations and industrial boilers of China. Using such precombustor, successtul startups and part-load operation of the boilers have become available under conditions of unpreheated air and low-grade coal with volatiles as low as 15% and ash content as high as 30%. This principle shows good promise as an attractive new technology of combustion.

On the behavior of pliable plate dynamics in wind : application to vertical axis wind turbines

Numerous studies have shown that flexible materials improve resilience and durability of a structure. Several studies have investigated the behavior of elastic plates under the influence of a free stream, such as studies of the fluttering flag and others of shape reconfiguration, due to a free stream.

The principle engineering contribution of this thesis is the design and development of a vertical axis wind turbine that features pliable blades which undergo various modes of behavior, ultimately leading to rotational propulsion of the turbine. The wind turbine design was tested in a wind tunnel and at the Caltech Laboratory for Optimized Wind Energy. Ultimately, the flexible blade vertical axis wind turbine proved to be an effective way of harnessing the power of the wind.

In addition, this body of work builds on the current knowledge of elastic cantilever plates in a free stream flow by investigating the inverted flag. While previous studies have focused on the fluid structure interaction of a free stream on elastic cantilever plates, none had studied the plate configuration where the trailing edge was clamped, leaving the leading edge free to move. Furthermore, the studies presented in this thesis establish the geometric boundaries of where the large-amplitude flapping occurs.

Double refraction and reflection of sequential crystal interfaces with arbitrary orientation of the optic axis and application to optimum design

The general formulation of double refraction or internal double reflection for any directions of incidence and arbitrary orientation of the optic axis in a uniaxial crystal is analysed in terms of Huygens' principle. Then double refraction and double reflection along the sequential interfaces in a crystal are discussed. On this basis, if the parameters of the interface are chosen appropriately, the range of angular separation between the ordinary ray and extraordinary ray can be much greater, It is useful for crystal element design. Finally, as an example, an optimum design of the Output end interface for a 2 x 2 electro-optic switch is given.

A stochastic principle behind polar properties of condensed molecular matter

A statistical mechanics view leads to the conclusion that polar molecules allowed to populate a degree of freedom for orientational disorder in a condensed phase thermalize into a bi-polar state featuring zero net polarity. In cases of orientational disorder polar order of condensed molecular matter can only exist in corresponding sectors of opposite average polarities. Channel type inclusion compounds, single component molecular crystals, solid solutions, optically anomalous crystals, inorganic ionic crystals, biomimetic crystals and biological tissues investigated by scanning pyroelectric and phase sensitive second harmonic generation microscopy all showed domains of opposite polarities in their final grown state. For reported polar molecular crystal structures it is assumed that kinetic hindrance along one direction of the polar axis is preventing the formation of a bi-polar state, thus allowing for a kinetically controlled mono-domain state. In this review we summarize theoretical and experimental findings leading to far reaching conclusions on the polar state of solid molecular matter. “… no stationary state … of a system has an electrical dipole moment.” P. W. Anderson, Science, 1972, 177, 393.

Magnetic properties of ODP Hole 109-670A

Magnetic fabrics of serpentinized peridotites are related to anisomorphic magnetite formed during serpentinization. In the less serpentinized facies they are, however, mainly mimetic of the high temperature deformation prior to serpentinization. In more serpentinized peridotites, the magnetic fabrics, related to magnetite veins which are more developed in this case, are superimposed on mimetic fabrics. Remanent properties, hysteresis loop parameters, and Curie temperatures were measured. Natural remanent magnetizations (NRM) have crystallization remanent magnetic (CRM) origin. Measured magnetic parameters suggest that pseudo-single domain (PSD) grains of magnetite are present in samples with low degree of serpentinization. The samples with high degree of serpentinization contain mainly multi-domain (MD) magnetite grains.