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Metal-organic frameworks as intracellular delivery vectors
Metal-organic frameworks (MOFs) have emerged as interesting candidates for intracellular carrier-based delivery. These hybrid materials are constituted of metal clusters linked together by organic ligands. The possibility to tune their physical and chemical properties both in the bulk and at the surface allows for the design of biocompatible delivery systems with high loading capacities and targeting abilities, combining the benefits of both organic and inorganic materials. The following dissertation focuses on developing and evaluating MOFs as intracellular delivery systems.
In the first instance, a zirconium-based MOF, UiO-66, was synthesised and utilised as an intracellular delivery vector for trehalose, a disaccharide with cryoprotective properties when present in the cytosol. This MOF demonstrated very high trehalose weight loadings compared to other trehalose delivery systems (up to ca. 50 wt %), release of the sugar from the framework over 5 h, and appropriate biocompatibility. To assess the delivery system’s impact on cryopreservation, the viability of cells cryoprotected with trehalose-loaded UiO-66 was tested at 0 h, 24 h, and 48 h post-thaw, and showed no improvement compared to cells frozen with free trehalose or growth media alone. The absence of cryoprotective effect was hypothesised to be due to endosomal entrapment of the delivery system after cellular uptake through endocytosis.
The final fate of particles taken up by cells depends on the endocytosis pathways they go through. In order to confirm the hypothesis of MOF endosomal entrapment, the endocytosis of MOF particles was studied. In particular, the effects of surface chemistry of Zr-based MOFs on their endocytosis mechanisms were investigated. It was found that MOF surface chemistry had an important effect on cellular uptake behaviour, whereas particle size played a less important role. In particular, Zr-based MOFs synthesised using naphthalene-2,6-dicarboxylic acid and 4,4′-biphenyldicarboxylic acid as organic ligands, and UiO 66 particles surface-decorated with folic acid and PEG, promoted entry through the caveolin-pathway. This allowed the particles to potentially avoid endosomal entrapment and reach the cytosol, enhancing their therapeutic activity when loaded with drugs.
Equipped with an understanding of the cellular uptake of MOF particles, a range of mitochondrially-targeted UiO-66 particles capable of bypassing endosomal entrapment was prepared and tested. The UiO-66 particles were loaded with dichloracetic acid (DCA), a small chemotherapeutic drug molecule that acts on mitochondria, and surface-functionalised with triphenylphosphonium, a known mitochondrial targeting agent. The system demonstrated a dramatic increase in efficacy, allowing a reduction in DCA effective dose of ca. 100-fold compared to the free drug, and ca. 10-fold compared to non-targeted, DCA-loaded UiO-66. Confocal microscopy revealed a distribution of the targeted nanoparticles around mitochondria. Super-resolution microscopy of cells treated with the system revealed important mitochondrial morphology changes associated with cell death as soon as 30 minutes after incubation. A whole transcriptome analysis of cells treated with the system indicated widespread changes in gene expression compared to both untreated cells and to cells treated with non-targeted, DCA-loaded UiO-66.
In summary, these studies demonstrated the advantages of MOFs as targeted intracellular delivery vectors. The ease with which their physicochemical properties can be tuned allows for the design of delivery systems able to bypass the critical drug delivery bottlenecks of endosomal entrapment and non-specific delivery
Using The Instructional Congruence Model To Change A Science Teacher\u27s Practices And English Language Learners\u27 Attitudes And Achievement In Science
The purpose of the current study was to examine the effects of adapting the instructional congruence model on the English Language Learners\u27 (ELL) attitudes and achievement in science. Changes in teacher\u27s views and practices were documented. The mixed-method approach was adapted. Data sources were the Attitude Towards Science survey, VNOS-C questionnaire, Luykx and Lee (2007) observational instrument, Gee (1997) discussion categories, video recordings, and pre- and post-tests. A science teacher and a class of 24 ELL female students in a charter school participated in this research. The results of this study indicated that student achievement increased significantly and students\u27 attitudes improved in all contexts. At the conclusion of the study, all teacher\u27s views on NOS were reported to be informed, teacher\u27s practices were rated higher, and different classroom interactions increased significantly. The instructional congruence model in science education has been successful in reaching different learners, improving students\u27 attitudes and achievement in science and enhancing teacher\u27s views and practices. This model has significant potential for meeting the challenging goals of reformed science education
An enhanced semi-analytical estimation of tool-chip interface temperature in metal cutting
An accurate estimation of the temperature distribution on tool surfaces is of great industrial importance; without it, a reliable prediction of tool wear in machining, especially thermally-induced wear mechanisms such as dissolution-diffusion and oxidation, is deemed impossible. This has promoted the development of semi-analytical models for simulation of the tool-chip interface temperature, which are less time-intensive and reasonably accurate. This study aims to present an enhanced prediction of the tool-chip interface temperature within the context of the available semi-analytical solutions of the heat conduction-advection problem with a moving heat source. A novel approach is presented to obtain the variable heat flux along the tool-chip interface based on a non-uniform contribution of generated heat in the sticking and sliding zones during chip flow. The capability of the enhanced model to simulate the temperature distribution is demonstrated for machining C45 and C50 plain carbon steels using uncoated carbide tools. The predictions are validated against the results of experimental orthogonal cutting tests for the same cutting conditions. A comparative analysis is then performed to underline the importance of incorporating the variable heat flux for reliable predictions of the maximum interface temperature and its location on the rake face. The outlook for future developments is also highlighted
Debe llegarse a tiempo a los municipios, por aire, tierra o en camioncitos : el cambio institucional del ejército nacional de Colombia durante el gobierno Uribe Vélez (2002-2010)
Este documento estudia aspectos generales del fortalecimiento del Ejército Nacional de Colombia en el período 2002-2011. Para esto, se plantearán, en primera instancia, los parámetros en virtud de los cuales se evalúa la noción de fortalecimiento. Luego se observará la concepción del fortalecimiento de las Fuerzas Militares a través de su coincidencia con la Política de Seguridad Democrática y la Política de Consolidación de la Seguridad Democrática. Enseguida, se analizarán los cambios iniciales que ha suscitado la llegada al poder del presidente Santos para, como cuarto punto, evaluar con todos los elementos esbozados el fortalecimiento institucional del Ejército Nacional a la luz de indicadores que expresan una mejora en su legitimidad, capacidad1, y bienestar. Finalmente, se presentarán las conclusiones del trabajoPregrad
Examining Students’ Perceptions About an Adaptive-Responsive Online Homework System and its Influence on Motivation and Learning
Advances in technological education have made online homework an integral part of science courses in general which is especially true for general chemistry courses. Online homework, if used correctly, has the potential to improve students’ experience, and learning and performance in general chemistry courses. The purpose of this research investigation is to study students’ levels of perceptions about an adaptive-responsive online homework in terms of (1) examining students’ motivation, learning, and understanding of concepts, (2) determining the aspects of adaptive-responsive online homework that are useful to students’ learning, and (3) understanding the features in online homework that causes improvement in students’ motivation. The investigation took place at an urban, commuter, minority serving, and public college. The study subjects were recruited from student enrolled in general chemistry courses consisting of 207 research participants (N = 207). Our data suggest that students display positive levels of perceptions about the adaptive-responsive online homework and its use. Students also hold perceptions that show positive attitudes towards the online homework system and that it positively affected their motivation. Also, students list several useful aspects of the online homework system such as explanations of concepts, knowledge checks, review questions for tests, and tutorials. The adaptive-responsive online homework, according to the participants in our study, helped motivate students by helping them learn the concepts, continuously assessing their learning, checking their knowledge, and updating the topics accordingly
POWER OF CANTILEVER DESIGN IN THE CONTEMPORARY ARCHITECTURE
Cantilever is a structural form that extends horizontally and is supported by one end and free on the other while the load is distributed equally, initiated by the use of bridges and balconies in the buildings. The power of Cantilevers with its different designs is spreading throughout the world via various perspectives since it increases the ability of design creativity and gives proper solutions. However, from that point forward, a research gap that has been found missing relating the structural challenges and how it affects the design and the decisions taken by the clients/ owners paying budgets on such type of structural additions that may not achieve the 100% building safety. Lack of knowing the proper building technologies may lead to reduce limits of innovation, that resulted in building repetitive traditional prototype without remarkable decisions. This paper therefore aims to detect the new building technologies that enable architects to design a cantilever in their projects, helping the design and the load carrying problems and highlight the exceptional designs that challenges the attractive force and establish a flying structure. In order to achieve the mentioned aim, the paper will start presenting a literature review based on a desk research theories and methods of construction were used to clearly explains our topic “the power of cantilevers in contemporary arch.” Supported with diverse analysis of Frank Lloyd Wright, Zaha Hadid, and Knight Architects
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