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 Density Grid Based Stream Clustering Algorithm(Izmir Institute of Technology, 2019) Ahmed, Rowanda Daoud; Ayav, Tolga; Ayav, Tolga; Dalkılıç, GökhanRecently as applications produce overwhelming data streams, the need for strategies to analyze and cluster streaming data becomes an urgent and a crucial research area for knowledge discovery. The main objective and the key aim of data stream clustering is to gain insights into incoming data. Recognizing all probable patterns in this boundless data which arrives at varying speeds and structure and evolves over time, is very important in this analysis process. The existing data stream clustering strategies so far, all suffer from different limitations, like the inability to find the arbitrary shaped clusters and handling outliers in addition to requiring some parameter information for data processing. For fast, accurate, efficient and effective handling for all these challenges, we proposed DGStream, a new online-offline grid and density-based stream clustering algorithm. We conducted many experiments and evaluated the performance of DGStream over different simulated databases and for different parameter settings where a wide variety of concept drifts, novelty, evolving data, number and size of clusters and outlier detection are considered. Our algorithm is suitable for applications where the interest lies in the most recent information like stock market, or if the analysis of existing information is required as well as cases where both the old and the recent information are all equally important. The experiments, over the synthetic and real datasets, show that our proposed algorithm outperforms the other algorithms in efficiency.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 Single-Photon Generation From Defects and Manipulation With Nanostructures(Izmir Institute of Technology, 2019) Özçeri İyikanat, Elif; Aygün, Gülnur; Tarhan, Enver; Tarhan, Enver; Aygün Özyüzer, GülnurSingle-photon sources are essential components for several applications in the field of quantum information technologies, such as quantum cryptology and quantum computation. To this aim, efficient generation and detection of single-photons are the crucial to be achieved. Among single-photon sources that are extensively studied in the literature, defect centers in solid are very promising due to their room temperature operation and their stability. The aim of this thesis is to generate single photons at room temperature and control their optical properties by nanostructures. Single-photon emission from TMDCs originates from localized weakly bound excitons at cryogenic temperatures due to their small exciton binding energies. However, room temperature SP emission from WS2 can be obtained by creatingWO3 defects. In our study, room temperature emission from defects in WO3 was investigated. Density functional theory calculations showed that the source of the emission can be oxygen defects. Additionally, the emission was brightened by plasmonic gold nanoparticles. Furthermore, defects in two-dimensional (2D) hexagonal boron nitride (hBN) is offered as an efficient room temperature SPS. HBN is a wide bandgap 2D material, in which defect centers create discrete energy level to generate single photons. In our study, reversible single-photon emission control from defects in hBN was demonstrated by Förster-like resonance energy transfer between the single-photon emitter and a graphene layer. To this aim an ionic liquid based device structure was used.