Proper development and activation of cells of the myeloid lineage are critical for supporting innate immunity. This myelopoiesis is orchestrated by interdependent interactions between cytokine receptors, transcription factors and, as recently described, microRNAs (miRNAs). miRNAs contribute to normal and dysregulated myelopoiesis. Alterations in myelopoiesis underlie myeloid-derived suppressor cell (MDSC) expansion, a poorly understood heterogeneous population of immature and suppressive myeloid cells that expand in nearly all diseases where inflammation exists. MDSCs associated with inflammation often have immunosuppressive properties, but molecular mechanisms responsible for MDSC expansion are unclear. Emerging data implicate miRNAs in MDSC expansion. This review focuses on miRNAs that contribute to myeloid lineage differentiation and maturation under physiological conditions, and introduces the concept that altered miRNA expression my underlie expansion and accumulation of MDSCs. We divide our miRNAs into those with potential to promote MDSC expansion and two with known direct links to MDSC expansion, miR-223 and miR-494.

According to the World Health Organization (WHO) depression is the leading cause of disability worldwide with more than 300 million patients affected. Current antidepressants have a delayed onset of action and moreover, only two-thirds of patients suffering from depressive disorder respond to antidepressant drug treatment. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of this thesis was to investigate the molecular mechanism of ketamine and its major metabolites at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). As the pathophysiology of depression correlates with decreased adult neurogenesis, I aimed to investigate the molecular effects of ketamine on neural progenitor cell proliferation using a human-based iPSC-model. The findings from this thesis substantially contribute to an enhanced understanding of the molecular mode of action of ketamine as a novel signaling pathway involved in ketamine-induced effects was identified. Ketamine induced proliferation of human iPSC-derived NPCs and bioinformatic analysis of RNA-Seq data revealed significant upregulation of insulin-like growth factor2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 hours after ketamine treatment. In line with this, ketamine dependent proliferation was significantly impaired after IGF2 knockdown. Moreover, ketamine was able to enhance cAMP signaling in NPCs and both, cell proliferation as well as IGF2 expression, were reduced after protein kinase A (PKA)-inhibition. Noteworthy, the Nestin-expressing NPCs do not express functional NMDA receptors, suggesting that the proproliferative effect of ketamine in NPCs is NMDA receptor-independent. Furthermore, 24 hours post administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

Detecting changes in land cover through time using remotely sensed imagery is a powerful application that has seen increased use as imagery has become more widely available and inexpensive. Before a time series of remotely sensed imagery can be used for change detection, images must first be standardized for effects outside of real surface change. This thesis established a validation protocol to evaluate the effectiveness of an automated technique for normalizing temporally separate but spatially coincident imagery. Using the concept of pseudo-invariant features between master-slave image pairs, spatially coincident dark and bright points are identified from images and a regression equation is calculated to normalize slave images to a master. I used two sets of imagery to test the performance of the standardization process, a spatially coincident, but temporally variable time series, and spatially and temporally variable images. I tested the underlying statistical assumptions of this approach, and performed simple image subtraction to validate the reduction of master-slave differences using invariant locations. In addition I tested the possibility of reducing between-sensor differences by applying simple linear regression to comparable bands of MSS and TM sensors. Image subtraction showed decreases in master-slave differences as a result of the standardization process, and the process behaved appropriately when there should be no difference between master and slave images (adjacent, but temporally identical imagery). I also found that comparable bands between MSS and TM sensors are similar enough that linear regression may not significantly reduce between-sensor differences.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18149号 / 医博第3869号 / 新制||医||1002(附属図書館) / 31007 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福田 和彦, 教授 渡邉 大, 教授 河野 憲二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19595号 / 医博第4102号 / 新制||医||1014(附属図書館) / 32631 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 瀬原 淳子, 教授 前川 平 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20253号 / 医博第4212号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 戸井 雅和, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24792号 / 医博第4984号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 辻川 明孝, 教授 山中 伸弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The synthesis and characterization of porous SiCN ceramics produced by the method of polymer-derived ceramics were studied in this work. The polymer-to-ceramic conversion technique is a novel revolution in the methods for fabricating porous materials with controlled morphologies and tailored properties. The porous SiCN ceramics can be successfully prepared from thermal decomposition of polymeric precursors (polysilazane) and the pore former (polyvinyl alcohol (PVA)). The fabrication procedures involved the mixing of the pre-ceramic precursor with appropriate concentration of the PVA, curing, pyrolysis and subsequent PVA removal, leaving pores in the ceramic matrix. The material obtained revealed a homogeneous amorphous microstructure consisting of Si, C and N elements. The effects of the concentration and the particle size of PVA on the bulk density, open porosity, line shrinkage, microstructure, pore size, permeability, mechanical behavior, oxidation behavior and thermal stability were examined in this thesis. An increase in both concentration and particle size of PVA contribute to a decrease in the bulk density and an increase in the open porosity and line shrinkage. The morphology development, in particular, was investigated by scanning electron microscopy (SEM). The properties in terms of the pore size and permeability were measured by the water expulsion method. The mechanical behavior of the porous SiCN ceramic was characterized by the three- point bending strength test, thermal shock strength test and hertzian indentation strength test. The flexural strength and hertzian indentation strength of these porous ceramics at room temperature decrease with an increase in porosity. However, the flexural strength after thermal shock was significantly improved by increasing the temperature change. The oxidation behavior and thermal stability of porous SiAlCN ceramics were also explored by the mass change versus oxidation time and temperature. The phase evolution at different temperatures was also investigated by XRD analysis.

No description available.