<p>Tidigare forskning kring funktionshindrade elevers skolgång och behov har oftast kretsat runt föräldrarnas eller andra vuxnas perspektiv. Barn och unga med funktionshinder har setts med vuxnas ögon. Röster och erfarenheter från barn och ungdomar med funktionshinder har i stort saknats i utredningar och betänkanden. Detta trots att Sverige förbundit sig att efterleva FN:s konvention om barnets rättigheter och inlemma barn och unga i beslutsprocesser. Med utgångspunkt från artikel 12 i FN:s barnkonvention, om barns rätt att höras och bli hörda och den nyligen initierade utredningen om bland annat behovet av en specialskola för elever i gymnasieålder, samt kommunernas möjlighet att anordna utbildning för elever med vissa funktionshinder, var syftet med den aktuella studien att belysa funktionshindrade barn och ungdomars erfarenheter och upplevelser av sin skolsituation. Metoden som använts i denna studie är kvalitativ och med hjälp av en relativt ny och kreativ teknik som kallas ”höringar” försökte vi kartlägga och fördjupa kunskaperna om hörselskadade och döva ungdomars skollinje och erfarenheter från olika skolformer. Utifrån ett barnperspektiv försökte vi besvara dessa frågeställningar; Hur upplever RGD/RGH-elever sin nuvarande skolsituation? Hur gestaltar sig deras erfarenheter av tidigare skolformer? Är ”höringar” en användbar teknik för att få fram de döva och hörselskadades röster? Målgruppen för den aktuella studien består av nio döva och hörselskadade ungdomar som går på riksgymnasiet för döva och hörselskadade i Örebro. Avsikten med studien har inte varit att utröna vilken skolform som kan anses mest lämplig för döva och hörselskadade elever. Studiens litteraturgenomgång berörde centrala begrepp och definitioner på funktionshinder, från de döva och hörselskadades perspektiv. Det svenska teckenspråkets ställning, förhållandet mellan barnperspektiv och barns perspektiv samt internationella politiska styrdokument låg till grund för denna studie. Resultaten från höringarna presenterades i enlighet med modellen i text och bild, så tolkningsfritt som möjligt. Av resultaten framkom det att ungdomarnas upplevelser och erfarenheter låg i linje med den litteratur som granskats i denna studie. Studien visade att ungdomarna upplevelser av RGD/RGH i stort är positiv när det gäller boende-skola-fritid i Örebro. Slutsatsen blev att, för att kartlägga funktionshindrades upplevelser och erfarenheter med ett barnperspektiv utifrån barnkonventionen, så är tekniken ”höring” en passande metod.</p> / <p>Earlier research concerning disabled children’s school attendance or needs often did focus from the parent’s or other adult’s point of view. Disabled youths and children has been seen through the eyes of the adults. Views and experiences of disabled youth and children has clearly been missing in inquiries and reports. Even though that Sweden has undertaken to live up to UN:s Convention about the Rights of Children and involve young people in the decision-making. Setting out from the UNCRC, article 12, about children’s rights to be heard and the recently proposed inquiry of the need of a special upper secondary school for students with disabilities, and the ability of the municipalities to organize education for students with certain disabilities, the purpose of this study was to shed light upon disabled youths and children’s experiences of their school situation. The method used in this study is qualitative, and with this new and creative technique called ”hearings” we tried to map out and engross the knowledge about the line of school for deaf and heaing impaired youth and their views on these different types of schools. Attempts were made to answer these questions from a child’s perspective; how do RGD/RGH-students find their present schoolsituation? What shapes have their experiences from earlier schools they attended? Was ”hearings” a useful technique to express the views of the young deaf and the hearing impareds? The target group in this study consisted of nine deaf and hearing impared youths attending the national upper secondary school for the deaf and hearing impared in Örebro. The purpose of this study was not to find out what would be the best kind of school for the deaf and hearing impared students. The litterature review in the study touched upon central concepts and definitions on disabilities, from the perspective of deaf and hearing impared. Status of the Swedish sign language, relationship between childperspective/ children’s perspective and international political treaties and document was the basis of this study. The results from the ”hearings” was presented accordingly to this techique in texts and pictures, as free from interpretations as possible. The study concluded that the experiences of these youths were in line with the literature review being used in this study. The study shows that their experiences are of the positive kind concerning housing-school-leisure in Örebro. The study also concluded that, in order to map out the experiences of disabled people from a children’s point of view according to the UNCRC, ”hearing” as a technique is suitable.</p>

Tidigare forskning kring funktionshindrade elevers skolgång och behov har oftast kretsat runt föräldrarnas eller andra vuxnas perspektiv. Barn och unga med funktionshinder har setts med vuxnas ögon. Röster och erfarenheter från barn och ungdomar med funktionshinder har i stort saknats i utredningar och betänkanden. Detta trots att Sverige förbundit sig att efterleva FN:s konvention om barnets rättigheter och inlemma barn och unga i beslutsprocesser. Med utgångspunkt från artikel 12 i FN:s barnkonvention, om barns rätt att höras och bli hörda och den nyligen initierade utredningen om bland annat behovet av en specialskola för elever i gymnasieålder, samt kommunernas möjlighet att anordna utbildning för elever med vissa funktionshinder, var syftet med den aktuella studien att belysa funktionshindrade barn och ungdomars erfarenheter och upplevelser av sin skolsituation. Metoden som använts i denna studie är kvalitativ och med hjälp av en relativt ny och kreativ teknik som kallas ”höringar” försökte vi kartlägga och fördjupa kunskaperna om hörselskadade och döva ungdomars skollinje och erfarenheter från olika skolformer. Utifrån ett barnperspektiv försökte vi besvara dessa frågeställningar; Hur upplever RGD/RGH-elever sin nuvarande skolsituation? Hur gestaltar sig deras erfarenheter av tidigare skolformer? Är ”höringar” en användbar teknik för att få fram de döva och hörselskadades röster? Målgruppen för den aktuella studien består av nio döva och hörselskadade ungdomar som går på riksgymnasiet för döva och hörselskadade i Örebro. Avsikten med studien har inte varit att utröna vilken skolform som kan anses mest lämplig för döva och hörselskadade elever. Studiens litteraturgenomgång berörde centrala begrepp och definitioner på funktionshinder, från de döva och hörselskadades perspektiv. Det svenska teckenspråkets ställning, förhållandet mellan barnperspektiv och barns perspektiv samt internationella politiska styrdokument låg till grund för denna studie. Resultaten från höringarna presenterades i enlighet med modellen i text och bild, så tolkningsfritt som möjligt. Av resultaten framkom det att ungdomarnas upplevelser och erfarenheter låg i linje med den litteratur som granskats i denna studie. Studien visade att ungdomarna upplevelser av RGD/RGH i stort är positiv när det gäller boende-skola-fritid i Örebro. Slutsatsen blev att, för att kartlägga funktionshindrades upplevelser och erfarenheter med ett barnperspektiv utifrån barnkonventionen, så är tekniken ”höring” en passande metod. / Earlier research concerning disabled children’s school attendance or needs often did focus from the parent’s or other adult’s point of view. Disabled youths and children has been seen through the eyes of the adults. Views and experiences of disabled youth and children has clearly been missing in inquiries and reports. Even though that Sweden has undertaken to live up to UN:s Convention about the Rights of Children and involve young people in the decision-making. Setting out from the UNCRC, article 12, about children’s rights to be heard and the recently proposed inquiry of the need of a special upper secondary school for students with disabilities, and the ability of the municipalities to organize education for students with certain disabilities, the purpose of this study was to shed light upon disabled youths and children’s experiences of their school situation. The method used in this study is qualitative, and with this new and creative technique called ”hearings” we tried to map out and engross the knowledge about the line of school for deaf and heaing impaired youth and their views on these different types of schools. Attempts were made to answer these questions from a child’s perspective; how do RGD/RGH-students find their present schoolsituation? What shapes have their experiences from earlier schools they attended? Was ”hearings” a useful technique to express the views of the young deaf and the hearing impareds? The target group in this study consisted of nine deaf and hearing impared youths attending the national upper secondary school for the deaf and hearing impared in Örebro. The purpose of this study was not to find out what would be the best kind of school for the deaf and hearing impared students. The litterature review in the study touched upon central concepts and definitions on disabilities, from the perspective of deaf and hearing impared. Status of the Swedish sign language, relationship between childperspective/ children’s perspective and international political treaties and document was the basis of this study. The results from the ”hearings” was presented accordingly to this techique in texts and pictures, as free from interpretations as possible. The study concluded that the experiences of these youths were in line with the literature review being used in this study. The study shows that their experiences are of the positive kind concerning housing-school-leisure in Örebro. The study also concluded that, in order to map out the experiences of disabled people from a children’s point of view according to the UNCRC, ”hearing” as a technique is suitable.

Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for high mortality worldwide. In this theses the computer-aided design of new anti-thrombotic agents able to inhibit two types of receptors located on the surface of the platelets has been applied. The first one - αIIbβ3 - is responsible for the interaction of activated platelets with fibrinogen to form clots, whereas the second one - thromboxane A2 - is responsible for platelet activation by one of agonists excreted by activated platelets. To achieve this, different types of models have been developed using experimentally available information and structure of protein-ligand complexes. This concerns: QSAR models, structure-based and ligand-based 3D pharmacophore models, 2D pharmacophore models, shape-based and molecular field-based models. The ensemble of the developed models were used in virtual screening. This study resulted in suggestion of new potential antagonists of αIIbβ3 and thromboxane A2 receptors. Suggested antagonists of αIIbβ3 able to bind either open or closed form of the receptor have been synthesized and tested experimentally. Experiments show that they display high activity; moreover some of theoretically designed compounds are more efficient than Tirofiban - the commercialized drug molecule. The recommended antagonists of thromboxane A2 receptor have been already synthesized but biological tests have not been completed yet.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-03-09T22:56:49Z No. of bitstreams: 1 KyviaBezerraMota_TESE.pdf: 5202658 bytes, checksum: 44dd9aeba607843c325d09b4d48f945d (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-03-13T23:39:17Z (GMT) No. of bitstreams: 1 KyviaBezerraMota_TESE.pdf: 5202658 bytes, checksum: 44dd9aeba607843c325d09b4d48f945d (MD5) / Made available in DSpace on 2017-03-13T23:39:17Z (GMT). No. of bitstreams: 1 KyviaBezerraMota_TESE.pdf: 5202658 bytes, checksum: 44dd9aeba607843c325d09b4d48f945d (MD5) Previous issue date: 2016-10-07 / Essa tese trata de duas pesquisas com diferentes naturezas conceituais no campo da modelagem molecular, por?m baseadas em semelhantes princ?pios te?ricos da f?sica qu?ntica e da qu?mica computacional. No primeiro estudo, as estabilidades dos sistemas ER?-OHT (Receptor ? de Estr?geno-Hidroxitamoxifeno), ER?-RAL (Receptor ? de Estr?geno-Raloxifeno) e Integrina ?v?3-Cilengitide foram determinadas em termos energ?ticos a partir da t?cnica de fracionamento molecular com capuzes conjugados (MFCC) e no escopo da teoria do funcional da densidade (DFT) seguindo o esquema GGA-PBE-Grimme para calcular a intera??o energias dos sistemas estudados. No primeiro estudo, foi poss?vel predizer a relev?ncia individual dos amino?cidos Glu, Asp, Arg, Lys no sistema com o Tamoxifeno e Glu, Asp e Lys com o Raloxifeno. Para isso ser poss?vel, as for?as de atra??o e repuls?o dos res?duos que comp?em os sistemas foram calculadas. Cada um desses res?duos apresentou uma energia de intera??o que variou dependendo da natureza qu?mica da sua cadeia lateral, do ambiente de microsolvata??o que o envolve e dos contatos intermoleculares que estabelece. O estudo pioneiro da estabilidade conformacional em termos energ?ticos de uma regi?o livre de amino?cidos incitar? pesquisas centradas no desenvolvimento e s?ntese de novos antagonistas utilizados no tratamento de diversas patologias comuns na popula??o geral. No segundo estudo, foram determinadas as propriedades energ?ticas do sistema Integrina ?V?3-Cilengitide, cuja estrutura cristalogr?fica apresenta c?tions Mn+2. Observou-se a import?ncias dos amino?cidos Ser, Asp, Leu, Arg, Lys, Ala e Pro na intera?ao da integrina com o fragmento RGD (R: arginina; G: glicina; D: ?cido asp?rtico) do cilengitide. A import?ncia da integrina com o fragmento RGD no mecanismo de ades?o de diversas c?lulas envolvidas nas doen?as cancer?genas e tamb?m na implanta??o embrion?ria permitir? o desenvolvimento de novas terapias impactantes na sobrevida de pacientes portadores de diversas neoplasias e na reprodu??o humana. / This thesis deals with two researches with different conceptual nature in the field of molecular modeling based on similar theoretical principles of quantum physics and computational chemistry. In the first study the stabilities of ER?-OHT (Receptor ? Estrogen co-crystalyzed with Hydroxytamoxifen), ER?-RAL (?-Estrogen Receptor co-crystalyzed with Raloxifene) and integrin ?v?3 co-crystalyzed with cilengitide systems were determined in terms of energy from the Molecular Fractionation Technique Caps Conjugates (MFCC), and the scope of the Density Functional Theory (DFT) following GGA-PBE-Grimme scheme for calculating the interaction energy of the systems studied. In the first study, it was possible to predict the relevance of individual amino acids Glu, Asp, Arg, Lys in the system with Tamoxifen and Glu, Asp and Lys in Raloxifene system. For this to be possible, the attraction and repulsion forces of the residues that comprise the systems were calculated. Each of these residues had an energy of interaction that varied depending on the chemical nature of the side chain, the microsolvation environment that surrounds and intermolecular contacts establishing. The pioneer study of conformational stability in terms of energy of free amino acid region will encourage research focusing on the development and synthesis of new antagonists used in the treatment of several common diseases in the general population. In the second study, we determined the energetic properties of Integrin ?V?3-cilengitide system, whose crystallographic structure has Mn+2 cations. It was noted the importance of amino acids Ser, Asp, Leu, Arg, Lys, Ala and Pro in integrin interaction with the RGD fragment (R: arginine; G: glycine; D: aspartic acid) of cilengitide. The importance of integrin with the RGD fragment in the adhesion mechanism of various cells involved in cancers and in embryo implantation allows the development of new therapies impacting on survival of patients with various forms of neoplasms and in human reproduction.

No description available.

No description available.

Specific interactions of ligands with receptors is one of the approaches for active targeting of anticancer drugs to cancer cells. Over expression of integrin receptors is a physiological manifestation in several cancers and is associated with cancer progression and metastasis, which makes it an attractive target for cancer chemotherapy. The peptide sequence for this integrin recognition is the Arg-Gly-Asp (RGD). Self-assembly offers a unique way of presenting ligands to target receptors for recognition and binding. This study focuses on development of integrin specific peptide amphiphile self-assemblies as carriers for targeted delivery of paclitaxel to α v β 3 integrin overexpressing cancers. Amphiphiles composed of conjugates of different analogs of RGD (linear, cyclic or glycosylated) and aliphatic fatty acid with or without 8-amino-3,6-dioxaoctanoic acid (ADA) as linker were synthesized and characterized. The amphiphiles exhibited Critical Micellar Concentration in the range of 7-30 μM. Transmission electron microscopy images revealed the formation of spherical micelles in the size range of 10-40 nm. Forster Resonance Energy Transfer studies revealed entrapment of hydrophobic dyes within a tight micellar core and provided information regarding the cargo exchange within micelles. The RGD micelles exhibited competitive binding with 55% displacement of a bound fluorescent probe by the cyclic RGD micelles. The internalization of fluorescein isothiocynate (FITC) loaded RGD micelles was significantly higher in A2058 melanoma cells compared to free FITC within 20 minutes of incubation at 37°C. The same micelles showed significantly lower internalization at 4°C and on pretreatment with 0.45M sucrose confirming endocytotic uptake of the RGD micellar carriers. The IC50 of paclitaxel in A2058 melanoma cells was lower when treated within RGD micelles as compared to treatment of free drug. On the other hand, IC50 values increased by 2 to 9 fold for micellar treatment in comparison to free drug in Detroit 551 cells. In A2058 melanoma xenograft mice model, the Paclitaxel-RGD micelles exhibited a significant inhibition of tumor growth in comparison to control treatment for both alternate day and twice weekly treatments. The studies showed the feasibility of using the non covalent peptide based self-assemblies as vehicles for targeted delivery in cancer.

Calcific aortic valve disease (CAVD) is one of the most common causes of cardiovascular disease in North America. Mechanical factors have been closely linked to the pathogenesis of CAVD and may contribute to the disease by actively regulating the mechanobiology of valve interstitial cells (VICs). Mechanical forces affect VIC function through interactions between the VIC and the extracellular matrix (ECM). Studies have shown that the transfer of mechanical stimulus during cell-ECM interaction depends on the local material properties at hierarchical length scales encompassing tissue, cell and cytoskeleton. In this thesis, biomechanical tools were developed and applied to investigate hierarchical cell-ECM interactions, using VICs and valve tissue as a model system. Four topics of critical importance to understanding VIC-ECM interactions were studied: focal biomechanical material properties of aortic valve tissue; viscoelastic properties of VICs; transduction of mechanical deformation from the ECM to the cytoskeletal network; and the impact of altered cell-ECM interactions on VIC survival. To measure focal valve tissue properties, a micropipette aspiration (MA) method was implemented and validated. It was found that nonlinear elastic properties of the top layer of a multilayered biomaterial can be estimated by MA by using a pipette with a diameter smaller than the top layer thickness. Using this approach, it was shown that the effective stiffness of the fibrosa layer is greater than that of the ventricularis layer in intact aortic valve leaflets (p<0.01). To characterize the viscoelastic properties of VICs, an inverse FE method of single cell MA was developed and compared with the analytical half-space model. It was found that inherent differences in the half-space and FE models of single cell MA yield different cell viscoelastic material parameters. However, under particular experimental conditions, the parameters estimated by the half-space model are statistically indistinguishable from those predicted by the FE model. To study strain transduction from the ECM to cytoskeleton, an improved texture correlation algorithm and a uniaxial tension release device were developed. It was found that substrate strain fully transfers to the cytoskeletal network via focal adhesions in live VICs under large strain tension release. To study the effects of cell-ECM interactions on VIC survival, two mechanical stimulus systems that can simulate the separate effects of cell contraction and cell monolayer detachment were developed. It was found that cell sheet detachment and disrupted cell-ECM signaling is likely responsible for the apoptosis of VICs grown in culture on thin collagen matrices, leading to calcification. The studies presented in this thesis refine existing biomechanical tools and provide new experimental and analytical tools with which to study cell-ECM interactions. Their application resulted in an improved understanding of hierarchical valve biomechanics, mechanotransduction, and mechanobiology.

Calcific aortic valve disease (CAVD) is one of the most common causes of cardiovascular disease in North America. Mechanical factors have been closely linked to the pathogenesis of CAVD and may contribute to the disease by actively regulating the mechanobiology of valve interstitial cells (VICs). Mechanical forces affect VIC function through interactions between the VIC and the extracellular matrix (ECM). Studies have shown that the transfer of mechanical stimulus during cell-ECM interaction depends on the local material properties at hierarchical length scales encompassing tissue, cell and cytoskeleton. In this thesis, biomechanical tools were developed and applied to investigate hierarchical cell-ECM interactions, using VICs and valve tissue as a model system. Four topics of critical importance to understanding VIC-ECM interactions were studied: focal biomechanical material properties of aortic valve tissue; viscoelastic properties of VICs; transduction of mechanical deformation from the ECM to the cytoskeletal network; and the impact of altered cell-ECM interactions on VIC survival. To measure focal valve tissue properties, a micropipette aspiration (MA) method was implemented and validated. It was found that nonlinear elastic properties of the top layer of a multilayered biomaterial can be estimated by MA by using a pipette with a diameter smaller than the top layer thickness. Using this approach, it was shown that the effective stiffness of the fibrosa layer is greater than that of the ventricularis layer in intact aortic valve leaflets (p<0.01). To characterize the viscoelastic properties of VICs, an inverse FE method of single cell MA was developed and compared with the analytical half-space model. It was found that inherent differences in the half-space and FE models of single cell MA yield different cell viscoelastic material parameters. However, under particular experimental conditions, the parameters estimated by the half-space model are statistically indistinguishable from those predicted by the FE model. To study strain transduction from the ECM to cytoskeleton, an improved texture correlation algorithm and a uniaxial tension release device were developed. It was found that substrate strain fully transfers to the cytoskeletal network via focal adhesions in live VICs under large strain tension release. To study the effects of cell-ECM interactions on VIC survival, two mechanical stimulus systems that can simulate the separate effects of cell contraction and cell monolayer detachment were developed. It was found that cell sheet detachment and disrupted cell-ECM signaling is likely responsible for the apoptosis of VICs grown in culture on thin collagen matrices, leading to calcification. The studies presented in this thesis refine existing biomechanical tools and provide new experimental and analytical tools with which to study cell-ECM interactions. Their application resulted in an improved understanding of hierarchical valve biomechanics, mechanotransduction, and mechanobiology.

Indiana University-Purdue University Indianapolis (IUPUI) / Insulin-like Growth Factor I (IGF-I) is a growth factor that stimulates both mitogenic and anabolic responses in articular chondrocytes. While it has been shown that exogenous IGF-I can regulate chondrocyte integrins, little is known regarding regulatory effects of IGF-I produced from a transiently expressed plasmid based adeno-associated virus (pAAV) vector. Because chondrocytes are using cellular machinery to overexpress IGF-I, it is of interest to see whether or not pAAV IGF-I will significantly upregulate or downregulate chondrocyte integrins. Additionally, it is of interest to know whether chondrocyte adhesion through integrins will have any regulatory effects on the production of IGF-I from the transgene. Therefore, this study will ascertain if pAAV IGF-I will have similar effects that exogenous IGF-I has on integrin regulation and if integrin silencing mechanisms will affect the production of IGF-I from the transgene. To test these hypotheses, adult articular chondrocytes were doubly transfected with the pAAV vector for IGF-I and short interference ribonucleic acid (siRNA) for integrins beta 1 and alpha V. Gene products were monitored at the transcriptional levels using quantitative real time polymerase chain reactions (qPCR) and IGF-I protein production was monitored at the translational level using enzyme linked immunoabsorbant assays (ELISAs). Adult articular chondrocytes doubly transfected were encapsulated in a three dimensional hydrogel system to simulate an in vivo environment. Samples were collected for analysis at days 2, 4, and 6 post encapsulation. Results show that IGF-I treatment with the pAAV vector does not cause significant changes in the transcriptional regulation of the beta 1 integrin in a three dimensional hydrogel system. The pAAV IGF-I vector did not cause significant regulatory changes on integrin alpha V at any time point during the experiment. Additionally, by knocking down the expression levels of integrins by using siRNA, it was shown that integrin knockdown does not have a significant regulatory effect on transcriptional or translational expression levels of IGF-I from the pAAV vector.