トランスナショナルな公共圏とメディアの可能性に関する考察 : 1970年代～80年代における「日韓連帯運動」を事例に

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 林 香里, 東京大学教授 真鍋 祐子, 東京大学教授 北田 暁大, 東京大学名誉教授 姜 尚中, 慶應義塾大学教授 小熊 英二University of Tokyo(東京大学

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable.

Novel Pyrrolopyrimidine-Based α-Helix Mimetics: Cell- Permeable Inhibitors of Protein-Protein Interactions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja108230s.There is considerable interest in developing nonpeptidic, small molecule α-helix mimetics to disrupt α-helix-mediated protein-protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid phase synthetic route, which is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics

Low Temperature Synthesis of Hexagonal Shaped α

This study demonstrates the low temperature synthesis of α-Al2O3 by solvothermal method using gibbsite alumina precursor in 1, 4-butanediol solvent according to various pH conditions. In acidic solution, an orthorhombic boehmite (AlOOH) structure was obtained after solvothermal reaction. A significant result in this study was that the solvothermally synthesized alumina in pH=9 at 300 °C for 36 h represented a rhombohedral α-Al2O3 structure hexagonal shaped with about 1.5~2.0 μm of particle size. Otherwise, the α-Al2O3 structure was rather changed to the mixture of a boehmite and α-Al2O3 structures above pH=11. In the case of α-Al2O3 synthesized at pH=9, the specific surface area was 26.18 m2/g, and the particles that were stable in acidic solution resulted in 61.80 mV of zeta potential

Synthesis of Octahedral-Shaped NiO and Approaches to an Anode Material of Manufactured Solid Oxide Fuel Cells Using the Decalcomania Method

Micrometer-sized and octahedral-shaped NiO particles were synthesized by microwave thermal treatment at 300 watt power for 15 min in a microwave chamber to be used as an anode material in solid oxide fuel cells. SEM image and particle size distribution revealed near-perfect octahedral NiO microparticle with sizes ranging from 4.0~11.0 μm. The anode functional layer (AFL, 60 wt% NiO synthesized: commercial 40 wt% YSZ), electrolyte (commercial Yttria-stabilized zirconia, YSZ), and cathode (commercial La0.8Sr0.2MnO3, LSM) layers were manufactured using the decalcomania method on a porous anode support, sequentially. The sintered electrolyte at 1450°C for 2 h using the decalcomania method was dense and had a thickness of about 10 μm. The cathode was sintered at 1250°C for 2 h, and it was porous. Using humidified hydrogen as a fuel, a coin cell with a 15 μm thick anode functional layer exhibited maximum power densities of 0.28, 0.38, and 0.65 W/cm2 at 700, 750, and 800°C, respectively. Otherwise, when a commercial YSZ anode functional layer was used, the maximum power density was 0.55 W/cm2 at 800°C

The experience of unmarried mothers raising their children in residential facilities: a phenomenological qualitative study

Background : Birth outside of marriage has been gradually increasing in Korea. However, social perception of unmarried mothers is still negative, and a number of them are not accepted by their family. Therefore, the Korean government has implemented a policy to provide financial aid and communal residence to unmarried mothers who cannot raise children with their family, or afford residence. Unmarried young mothers who rely on this government policy have low economic independence and social adaptation skills. Additionally, they have a high chance of encountering numerous challenges in raising children due to their living conditions in residential facilities and social prejudice. This study was conducted to gain an in-depth understanding of the lived experience of unmarried mothers raising children in residential facilities. Methods : Data were collected through in-depth interviews with nine unmarried mothers living in residential facilities with their children. An interpretative phenomenological analysis was conducted to analyze the data. Results : The findings revealed that unmarried mothers struggled with various difficulties given the limitations of living in the facility, but attempted to navigate their uncertain future with the determination to be good mothers. Three main themes and eight sub-themes emerged: (1) adaptation to the identity of “unmarried mother”, (2) willingly undertaking the heavy burden of childrearing, (3) indispensable but insufficient supports from facilities. Participants had childrearing responsibilities, and tried to be good mothers for their children while struggling to adapt to their new identities. However, their self-doubt as a “good mother” and the absence of the child's father made them feel sorry for their child. Their daily experiences raising children and simultaneously preparing for their own independence were exhausting. The supports from the facilities were helpful but unsatisfactory and led to various psychosocial difficulties such as anxiety, depression, fear, guilty, and anger in unmarried mothers. Conclusions : Besides information and resources for parenting and independence, active approaches are needed to improve the psychological stability of unmarried mothers raising their children in facilities, and sustain a long-term socioeconomic support system. Thoughtful services tailored to mothers and children are also needed, instead of standardized services.This work was supported by the National Research Foundation of Korea (NRF) under grant by the Korea government (MSIT) (No. NRF-2019R1A2B5B01070519)

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.N