Phd Degree / Doktora
Permanent URI for this collectionhttps://hdl.handle.net/11147/2869
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Doctoral Thesis Molecular Characterization of Long Non Coding Rnas That Mediate Apoptosis in Human(Izmir Institute of Technology, 2019) Sweef, Osama Abdel Hady Biaomy; Akgül, BünyaminApoptosis is an evolutionarily form of programmed cell death for development and tissue homeostasis. Apoptosis is regulated by protein-coding genes and plays an important role in a wide range of biological processes. We aimed to identify and characterize differentially expressed lncRNAs in apoptosis. HeLa cells were used as a model system to identify the lncRNAs. The total RNAs was subjected to deep sequencing by next-generation sequencing. OmicsBOX Bioinformatics tools were used for differential expression analysis of lncRNAs that are apoptosis-induced. Gene set enrichment analysis (GSEA) was used to profile the miRNAs targeting lncRNAs. Cytoscape software was used to reconstruct lncRNA-miRNA targeting networks. RT-qPCR was used to validate miRNAs and their targets of lncRNAs and it was found that the overexpression of miR-519d-3p causes downregulation of lncRNAs RAB22A-202, PARD3-211, and AC027237.1-210. Also, the overexpression of miR-124-3p down-regulates the expression level of APEX2-202 and CD59-209. GTF2A1-AS, TNFRSF10B-AS, and CAMTA1-DT were detected in the nucleus and have no poly (A) tail and they belong to TATA-less promoter genes. TNFRSF10B-AS has a coding probability of 0.99 and alignment to High-scoring Segment Pair (HSP) clarifies one hit to Q9UBN6 protein. ChIRP clarifies that TNFRSF10B-AS binds to a protein (25 kDa). miR-519d-3p and miR-124-3p interact with lncRNA targets by miRNA-mediated lncRNA degradation pattern under apoptosis conditions. TNFRSF10B-AS has a putative regulatory function in the nucleus during apoptosis via binding specifically to the ribonucleoprotein partner.Doctoral Thesis Sensitization of Philadelphia Positive Acute Lymphoblastic Leukemia Cells Resistant To Imatinib by Targeting Sphingolipid Metabolism(Izmir Institute of Technology, 2019) Kiraz, Yağmur; Baran, YusufPhiladelphia positive acute lymphoblastic leukemia (Ph+ALL) is a common subtype of ALL and characterized by having BCR/ABL translocation. Tyrosine kinase inhibitors (TKI) such as imatinib are used for the treatment in Ph+ALL, however, 60-75% of the patients can develop resistance against the TKIs. Bioactive sphingolipids are a group of lipids that play roles in various cellular mechanisms. Previous studies showed that sphingolipids and genes in the pathway were involved in response to TKI treatment in Ph+ALL. Here, we investigated the roles of SPL on the growth inhibitory effects of imatinib and exploit sphingolipid metabolism by majorly inhibiting glucosylceramide synthase (GCS) to accumulate ceramide or sphingosine to further sensitize cells to imatinib and/or overcome resistance to imatinib in Ph+ALL. Firstly, we detected that, sphingosine kinase-1 (SK-1) a well-studied SPL enzyme inhibition did not contribute to cytotoxic effects of imatinib in SD-1 Ph+ALL cells. Moreover, we determined that imatinib is inducing de novo synthesis pathway of SPL and increasing the levels of ceramide, sphingosine, hexosylceramides and sphingomyelin in SD-1 cells. Interestingly, newly generated imatinib-resistant cell line SD-1R was detected to have an aberration in this pathway resulting in development of resistance. Combination treatment with eliglustat (GCS inhibitor) resulted in a significant increase in ceramide and sphingosine levels and reflected on cell growth and sensitized cells to imatinib. Taken together, it was shown for the first time in the literature that the cytotoxic effects of imatinib was due to induction of de novo synthesis pathway of sphingolipids and inhibition of GCS together with imatinib has synergistic cytotoxic effects on imatinib resistant Ph+ALL cells. As a conclusion, increasing the intracellular levels of ceramide (and/or sphingosine) can be a novel approach to sensitize drug resistant Ph+ALL cells.Doctoral Thesis Understanding the Biological Role of Sialidase Neu3 in Tay-Sachs Disease Mouse Model(Izmir Institute of Technology, 2019) Akyıldız Demir, Seçil; Seyrantepe, VolkanTay-Sachs disease is a severe lysosomal storage disorder characterized by mutations in the lysosomal ß-Hexosaminidase A (HEXA) enzyme which converts GM2 to GM3 ganglioside. The GM2 ganglioside accumulation is observed predominantly in the neurons. The infants appear normal in their inborn time, but the progressive accumulation of undegraded GM2 results with death. Hexa-/- mice were created. However, they have a normal lifespan with no obvious neurological impairment until one year. It was thought that stored GM2 catabolized to GA2 using sialidase(s), which is further processed by HEXB. To determine the contribution of sialidase NEU3 to degradation of GM2, a mouse with combined deficiencies of Hexa and Neu3 genes was generated. The Hexa-/-Neu3-/- mice were healthy at birth, but they died between 1.5 and 5 months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa-/-Neu3-/- mice revealed the abnormal accumulation of GM2. The progressive GM2 accumulation was also verified on testes, liver, and kidney of Hexa-/- Neu3-/- mice. GM2 accumulation in the brain leads to increased lysosomes with membranous cytoplasmic bodies, Purkinje cell depletion, cytoplasmic vacuolization, astrogliosis, and age-dependent lessening in neurons and oligodendrocytes. These mice have prominent disorders such as growth impairment, skeletal bones abnormalities, slow movement, tremors, anxiety and age-dependent loss in both memory and muscle strength. Consequently, the Hexa-/-Neu3-/- mice mimic the pathological, biochemical and clinical abnormalities of the Tay-Sachs patients, and useful model for the future understanding of cellular pathologies that drive the progression of the disease. They are a suitable model for the future pre-clinical testing of possible treatments.Doctoral Thesis Discourse of Publicness in the Discussions of Art Museums Since the 1990s(Izmir Institute of Technology, 2019) Kılıç, Pınar; Çil, ElaThe 1990s was an important scene for art museums. Such that, not only an increase in art museums’ construction numbers began, but also their publicness occurred as an issue in the discourse. From the 1960s and onwards critics including artists and curators had been criticizing art museums’ institutional and operational strategies and they had been demanding a democratized art museum institution that could foster a strong and comprehensive publicness for multiple publics in society. It is interesting that since the 1990s publicness has also demanded by art museum institutions as well. As a result of the foundation of art museums’ publicness as an issue in the discourse, today we are witnessing that discussions on art museums’ publicness are high on the agenda of the art world. This dissertation aims to understand what the publicness of art museums could tell us. By considering this aim, this research is focusing on the questions, why publicness has been an issue in the discourse on art museums since the 1990s, and how and which aspects of publicness have been discussed in relation to art museums since the 1990s in the discourse.Doctoral Thesis Biochemical and Mechanical Cues for Osteogenic Induction of Stem Cells on Paper Based Scaffolds(Izmir Institute of Technology, 2019) Karadaş, Özge; Özçivici, Engin; Özhan Baykan, Hatice GüneşTissue engineering aims to produce functional constructs with living cells that can fully integrate with the tissue when inserted into the body. Design of the scaffold and the choice of cell type that will be used for production of the tissue engineering construct are very important for the success of the application. For bone tissue engineering, incorporation of substances with antimicrobial properties can supply additional benefits. This dissertation seeks answers for two discrete questions in different chapters: Do carnosol and carnosic acid, phenolic antimicrobial compounds extracted from plants have cytotoxic effect on bone tissue derived cells and do the culture conditions (monolayer or 3D) effect the response of cells (Chapter 2); and how do application of a single type of mechanical force (vibration) and a combination of two forces (vibration plus fluid shear) affect the osteogenesis of tissue engineering constructs (Chapters 3 and 4)? The results of this research demonstrated that carnosol and carnosic acid had bacteriostatic effect at 60 µg/mL but this concentration value was highly cytotoxic for bone tissue derived cells. Nevertheless, when the same cells were incubated under 3D culture conditions their cytotoxic tolerance was higher. The supportive role of mechanical forces on osteogenic differentiation of stem cells on 3D scaffolds prepared by using filter paper, on the other hand, was demonstrated with the increase in osteoblastic gene expression, immunocytochemical staining and detection of mineralization by Alizarin red S staining and quantification. In conclusion this research showed the importance of biochemical and biomechanical cues on osteogenesis.Doctoral Thesis Development of Plasmonic Nanostructures for Photothermal Therapy of Prostate and Breast Cancer(Izmir Institute of Technology, 2019) Tomak, Aysel; Bulmuş, Volga; Şahin, HasanThe aim of this thesis is to synthesize gold nanorods (AuNRs) and lipid-stabilized nanobubbles containing AuNRs and investigate the potential of these plasmonic nanostructures as photothermal therapy agents for breast and prostate cancer through in vitro cell culture experiments. For this aim, firstly, AuNRs were synthesized at varying aspect ratios (ARs) and characterized via several techniques including UV-Vis/NIR spectroscopy, scanning electron microscopy (SEM), atomic force microscopy (AFM), inductively coupled plasma-mass spectroscopy (ICP-MS), electrophoretic light scattering (ELS) and X-ray photoelectron spectroscopy (XPS). The surface of AuNRs was modified with a biocompatible polymer, poly(ethylene glycol) (PEG), via ligand exchange method. Cytotoxicity, cell uptake and photothermal effects of AuNRs were investigated via in vitro cell culture experiments using human prostate cancer (DU 145) and epithelial (RWPE-1), breast cancer (MCF7) and epithelial (MCF 10A) cell lines. It was concluded that AuNRs (AR=4.0) were superior than AuNRs (AR=7.0) in terms of cell viability and photothermal effect. Separately, a non-commercial antibody (Ab) targeting a specific sialic acid derivative on the plasma membrane of DU 145 and MCF7 cancer cells was conjugated to AuNRs. Conjugations were characterized with the same techniques and investigated via in vitro cytotoxicity and cell uptake experiments. The Ab-conjugated AuNRs displayed the capability of selective targeting prostate cancer cells. Additionally, lipid-stabilized AuNRs and lipid-stabilized nanobubbles containing AuNRs (AuNBs) were synthesized for the first time and characterized using UV-Vis/NIR spectroscopy, SEM, ICP-MS and ELS techniques. Lipid-stabilized AuNRs were successfully synthesized using varying lipid mixtures instead of cationic, toxic surfactant. Separately, AuNBs were synthesized by combining PEG modified AuNRs with DPPC: DSPE-PEG lipid film under sonication and gas stream. AuNBs showed the same or significantly lower toxicity depending on the cell types and the same photothermal effect with respect to AuNRs (AR=4.0) upon irradiation under laser at 808 nm.Doctoral Thesis Thermal Retrofitting on Traditional Building With Exterior Hall (sofa): Urban and Rural Houses of Muğla(Izmir Institute of Technology, 2019) Timur, Barış Ali; İpekoğlu, Başak; Başaran, TahsinSustaining functional continuity of historical buildings is a commonly acknowledged conservation strategy and thermal retrofitting interventions applied on these buildings has complemental potentials to this strategy as these interventions can be designed to increase the thermal satisfaction of occupants. The aim of this thesis is to examine the thermal behavior of a common historical building type in Anatolia, the traditional houses with exterior hall, and to determine enhancement potentials of possible thermal interventions which will not cause loss of heritage values. Method of the study consists of on-site thermal measurements and transient thermal analysis of case studies utilizing the software DesignBuilder. Case studies were selected from both urban and rural sub-settlements of Muğla City in order to detect possible effects of prevailing microclimates. With the results obtained, it was demonstrated the retrofitting interventions of thermal insulation works in roofs and floors between storeys, airtightness measures, addition of secondary glazing to window frames and the addition of closed circulation corridors provide significant improvements in thermal performance of the cases. According to simulation analyses, it was specified that these interventions would save 38.0% of the total building energy use in the urban and 49.4% in the rural subsettlements. These improvement percentages can even be increased to more than 80% when the integration of a new HVAC system such as ground-source heat pump is implemented. Consequently, it was determined the traditional houses with exterior hall have significant potentials for thermal enhancements which renders the application of thermal interventions as a capable conservation strategy.Doctoral Thesis Increasing Stability of Microbubbles Under Ultrasound(Izmir Institute of Technology, 2019) Ayaz, İlyas Umur; Özdemir, Ekrem; Seçil, MustafaMicrobubbles are used as effective contrast agents in ultrasound imaging. However, low stability of the microbubbles limits their use for prolonged period of time in medical applications. The aim of this dissertation is to increase the stability of microbubbles under ultrasound. The stability and acoustic response of microbubbles were investigated under ultrasound as a function of their shell composition. Microbubbles were fabricated using combinations of phospholipid (DSPC) and an emulsifier (PEG40St) in different molar ratios. It was found that adding the emulsifier decreased the microbubble stability under ultrasound; however, the echogenicity of microbubbles was shown to increase with increasing emulsifier content. A method was developed to estimate the concentration of microbubbles with ultrasound. Hydrostatic pressure studies showed that the microbubbles recovered their spherical structures at low pressure pulses, in contrast, disappeared in a very short time at high pressure pulses. B-mode ultrasound intensity of microbubbles was investigated at different ultrasound powers under Doppler ultrasonography, and for the first time, a model was developed to relate the intensity to effective bubble concentration. We calculated acoustic energy thresholds and explained a possible mechanism for the destruction of microbubbles under ultrasound. The effect of shell loadings on the acoustic response and stability of microbubbles were investigated under ultrasound. It was found that both the echogenicity and stability of microbubbles increased with increasing mass of the loadings on microbubble shell. In-vivo studies showed that the acoustic performance of in-house made microbubbles was comparable to that of commercial standard Vevo MicroMarker® contrast agents.Doctoral Thesis Exploring Lysozyme-Nisin Antimicrobial Synergy at Different Conditions for Novel Food Applications(Izmir Institute of Technology, 2019) Sözbilen, Gözde Seval; Yemenicioğlu, AhmetThe main objective of this thesis is to explore lysozyme-nisin antimicrobial synergy in combination with refrigeration, mild heating or edible packaging for novel food applications. The thesis is based on the following four chapters: (1) Characterization of biochemical properties of lysozyme at different conditions; (2) Lysozyme-nisin synergy in combination with mild heating against Listeria innocua: test of findings in inoculated raw-milk (3) Lysozyme-nisin synergy in combination with chitosan coating against Listeria innocua: test of findings on coated inoculated sprouting seeds; (4) Lysozyme-nisin synergy in combination with refrigeration against lactic acid bacteria (LAB): test of findings in boza, a traditional fermented beverage. The results of this thesis clearly showed that the use of lysozyme-nisin synergy in combination with mild heating at 50 ºC or in combination with edible chitosan coating could be employed to reduce risk of listeriosis from raw-milk and sprouted seeds, respectively. It is also clearly demonstrated that the lysozyme-nisin synergy in combination with refrigeration could be used to delay acidic spoilage of boza without reducing LAB below 106 CFU/mL. This thesis clearly showed the high potential of using lysozyme-nisin synergy against pathogenic or spoilage bacteria as an effective hurdle.Doctoral Thesis Data-Driven Modelling of Daylight Redirecting Fenestration at Variable Directional Resolution(Izmir Institute of Technology, 2019) Grobe, Lars Oliver; Kazanasmaz, Tuğçe; Wittkopf, StephenDaylight Redirecting Fenestration (DRF) aims at the optimal utilisation of daylight in buildings striving for high visual comfort standards. Daylight simulation allows to assess whether this objective is met in architectural context, and guides decisions in building design as well as the development of DRF. The daylight simulation suite Radiance allows to employ data-driven models of variable resolution to accurately replicate the irregular light scattering by DRF. In this context, this research provides methods to improve DRFs’ integration in daylight assessments. The thesis consolidates a series of publications that address particular problems in the generation and application of data-driven models, with a focus on accurate image synthesis for visual comfort assessments. First, the parametrisation of model generation from gonio-photometric measurements is tested. Second, a novel extension of the instrumentation allows to characterise and subsequently model retro-reflection by an innovative coating. Applied in DRF, the coating controls solar gains and glare, while maintaining a view to the outside. Third, to assemble accurate data-driven models of fenestration layers into descriptions of the entire DRF, an approach employing matrix calculations is adapted and tested. Finally, the Photon Map implementation in Radiance is modified for efficient image synthesis with data-driven models, and employed in a simplified but accurate approach to Climate-Based Daylight Modelling that demonstrates the potential of retro-reflection to efficiently control glare and maintain view with static DRF. The research contributes to the applicability of data-driven models, and confirms the potential of DRF to reconcile diverging daylight performance targets such as glare control and view.