No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23802号 / 医博第4848号 / 新制||医||1058(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 永井 洋士, 教授 羽賀 博典, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Municipal electorates across America are vocal, unrepresentative networks. With lower turnout rates than state and national elections, the local electoral process disproportionately elects white, older, home-owning officials. Voting and elected bodies align demographically, thus leading to a policy that disproportionately reflects the interests of white, older, home-owning voters (Levine Einstein, Ornstein, & Palmer, 2019). This cycle is problematic because it halts the passage of policy that reflects the interest of historically underrepresented voters: young people and people of color. I argue that, for local races, campaign methods disproportionately mobilize the social networks that white, older, home-owning voters belong to. Members of these groups disproportionately occupy low-density housing-building types that can be accessed and mobilized by all campaigns. I suggest a relationship exists between housing density and turnout, with voters residing in low-density housing participating at higher rates in local elections. Therefore, local races have smaller budgets and fewer reserves to invest in mobilizing voters residing in high-density housing. To assess this relationship, I compare housing density - whether a voter lives in low density or high-density housing - and individual voting records from 2017 to 2021 across four municipalities in Massachusetts: Cambridge, Boston, Somerville, and Worcester. I expect to find that compared to voters living in low-density housing, those residing in high-density housing - disproportionately young voters and voters of color - are turning out at lower rates in local elections than in the 2018 Midterm and 2020 Presidential Elections. To change this cycle, scholars must pay more attention to the role housing density plays in inhibiting local mobilization efforts, and campaigns must collaborate to mobilize voting members of all social networks, especially those residing in high-density housing.

Synthetic antioxidants have traditionally been added directly to food products in a single initial dose to protect against oxidation of lipids and generation of free radicals. Natural antioxidants have been shown to undergo loss of activity and become prooxidants at high concentrations; therefore, a need exists to develop active packaging which can gradually deliver antioxidants in a controlled manner. The objectives of this research were to (1) form and characterize cyclodextrin inclusion complexes with the natural antioxidants, alpha-tocopherol and quercetin, (2) incorporate cyclodextrin inclusion complexes of natural antioxidants into linear low density polyethylene (LLDPE), and (3) measure the release kinetics of inclusion complexes of natural antioxidants from LLDPE into a model food system. Cyclodextrin inclusion complexes of alpha-tocopherol and quercetin were formed by the coprecipitation method and characterized in the solid state by NMR, IR spectroscopy, and thermal analyses. Solid inclusion complex products of alpha-tocopherol:beta-cyclodextrin and quercetin:gamma-cyclodextrin had molar ratios of 1.7:1 as determined by UV spectrophotometry, which were equivalent to 18.1% (w/w) alpha-tocopherol and 13.0% (w/w) quercetin. Free and cyclodextrin complexed antioxidant additives were compounded with a twin-screw mixer into two LLDPE resin types followed by compression molding into films. Release of alpha-tocopherol and quercetin from LLDPE films into coconut oil at 30 °C was quantified by HPLC during 4 weeks of storage. The total release of alpha-tocopherol after 4 weeks was 70% from the free form and 8% from the complexed form averaged across both LLDPE resins. The mechanism by which alpha-tocopherol was released was modified due to its encapsulation inside the beta-cyclodextrin cavity within the LLDPE matrix as indicated by its diffusion coefficient decreasing by two orders of magnitude. Molecular encapsulation of natural antioxidants using cyclodextrins may be used as a controlled release mechanism within polymer food packaging to gradually deliver an effective antioxidant concentration to a food product, thereby, limiting oxidation, maintaining nutritional quality, and extending shelf life. / Ph. D.

The present architectural proposal aims to foster engagement, support independence, and promote a sense of meaning, comfort, and safety for dementia residents of care facilities. The proposed Iron Heart Memory Village aims to improve the quality of life for dementia residents by redesigning healthcare facilities and integrating everyday lifestyles into their living spaces. Dementia, characterized by cognitive decline and functional impairments, poses significant challenges to individuals and their caregivers. By reimagining program spaces within low-density housing and providing access to public amenities, entertainment, and natural environments, healthcare facilities can emulate familiar everyday settings. In terms of design, Iron Heart Memory Village offers a setting that prioritizes interactions between residents, healthcare professionals, and visitors through low-density residences, individual courtyards designed for the different stages of dementia, shopping, cooking, entertainment, public amenities, and simple living. This proposal considers the proposed site's history, climate, site, demographics, economics, and other factors to best design a building that serves not only dementia residents but also the neighborhood. The proposal addresses the multifaceted needs of dementia residents and their caregivers through sustainable architecture and construction. Innovative architecture, such as green roofs, solar panels, locally sourced materials, open designs, and more, are some of the elements used to enhance mobility, stimulate mental abilities, and create environments conducive to holistic well-being. Through a deeper understanding of dementia as a condition influenced by various factors, including brain damage and other underlying conditions, this project underscores the importance of design and architecture as a means to alleviate symptoms and improve overall outcomes for individuals affected by dementia. / Master of Architecture / Dementia is a big challenge for people, families, and healthcare systems worldwide because it affects memory and everyday activities. As more people get older, dementia is becoming more common. This means we need new ideas to help those with dementia. Many traditional healthcare places struggle to help people with dementia properly, which can make life harder for them and their caregivers. However, new research shows that changing how healthcare buildings are designed and including things from everyday life can make a big difference for people with dementia. This sets the stage for a proposal to improve healthcare places for people with dementia by redesigning them to feel like regular homes. The proposal suggests making healthcare buildings more like real homes by adding things like places to hang out, entertainment options, and nature views. It also suggests activities people enjoy, like shopping and cooking, to help them stay social. Plus, it includes changes to make the buildings easier to get around for people with mobility issues. Overall, the goal is to make life better for people with dementia by making healthcare places feel more like home and helping them stay active and independent. This could also make things easier for their caregivers. The proposal is a plan for this and could be a model for future dementia care.

Individer med homozygot familjär hyperkolesterolemi(FH), har höga halter av Low Density Lipoprotein (LDL) vilket leder till ökad risk för kardiovaskulära sjukdomar. Behandling av dessa individer kan göras med extrakorporal elimination av LDL med hjälp av specifika reningskolonner. Syftet med studien var att utvärdera några agarosmodifierade adsorbenter för denna applikation. Adsorbenterna, modifierad polyakrylat (DALI), agaros (Zetaros), direkt sulfateradZetarose och taurin immobiliserad Zetarose, inkuberades med humant plasma spädd med PBS, och en volyms förhållande mellan matris och plasman på 1:5. Inkubering utfördes i rumstemperatur under 60 min med kontinuerlig blandning i rotator. Efter inkubation centrifugerades proverna och LDL bestämdes i såväl supernatant som pellet. Totalmängd adsorberade proteiner analyserades också i eluat från erhållen pellet. LDL bestämdes indirekt med hjälp av Friedewaldsformel (LDL = totalkolesterol (TC) –highdensitylipoprotein (HDL) - (0,45 x Triglycerider(TG)). TC och TG bestämdes enzymatiskt medan HDL kvantifierades som TC efter utfällning av LDL med dextransulfat. Resultaten visar tydligt att DALI har god adsorptionsförmåga.Dock uppvisar de modifierade Zetaroserna begränsad adsorptionskapacitet för LDL. Vid desorption av adsorbenterna visar SDS en bättre elueringsförmåga än NaCl relaterad till protein, vilket tyder hydrofoba proteiner. Metodiken som används i studien är lämplig för vidare studier av andra adsorbenter som förväntas användas i kliniska applikationer för elimination av LDL hos FH patienter. / Individuals that suffer from homozygote Familiar Hyperkolesterolemia (FH), has increased amounts of Low Density Lipoproteins (LDL) which leads to a higher risk of cardiovascular diseases. Treatment of these individuals can be achieved by extracorporeal elimination of LDL using specific columns. The aim of this study was to evaluate different agarose-modified adsorbents ability to adsorb LDL from human plasma. The adsorbents (DALI, Zetarose, sulphonated Zetarose and taurine immobilized onto Zetarose) were incubated for 60 minutes with human plasma diluted with PBS, in a ratio of 1:5 between the matrix and the plasma during rotation with a rotator. After incubation the samples were centrifuged and the LDL content was determined in both the supernatant and the pellet. The amount proteins adsorbed were assayed by eluting the pellets. LDL was determined indirectly using Friedwalds equation; LDL= Total cholesterol (TC) - High density lipoprotein (HDL)-(0,45x Triglycerides (TG). The values of TC and TG in the sample were determined enzymatically, whilst HDL was quantified as TC after LDL-precipitation by dextran sulfate. The results clearly show that DALI has good adsorption capacity, but none of the modified Zetaroses shows any capacity to absorb LDL from human plasma. Desorption of the adsorbents using SDS gave higher amounts of eluated protein compared to NaCl elution, indicating hydrofobic proteins. However, the methods used in this study could be used to evaluate new adsorbents for LDL-elimination applications in patients with chronic hyperlipemia.

Os tumores malignos apresentam um aumento da expressão dos receptores de lipoproteínas, devido ao aceleramento da proliferação celular com consequente aumento da necessidade de lípides para a síntese das membranas celulares. Esse aumento da expressão dos receptores de LDL no câncer pode ser utilizado para concentrar fármacos de ação antineoplásica em tecido tumoral, utilizando lipoproteínas ou nanoemulsões semelhantes a lipoproteínas como veículo. No presente estudo, foram investigados os efeitos da quimioterapia convencional na expressão dos receptores de LDL e LRP-1 em 16 pacientes com carcinoma de mama estádios II ou III, não candidatas à cirurgia conservadora e com indicação de tratamento quimioterápico neoadjuvante. A expressão dos receptores LDLR e LRP-1 foi avaliada por imunoistoquimica em tecido mamário normal e em tecido neoplásico antes e depois da quimioterapia neoadjuvante. Quatro pacientes que apresentaram resposta completa à quimioterapia foram retiradas da análise da expressão de receptores por não existir tumor no fragmento cirúrgico. Em relação ao LDLR, a expressão desse receptor no tecido neoplásico foi maior em comparação ao tecido normal em 8 das 11 pacientes. Após a quimioterapia, a expressão do receptor de LDL diminuiu em 6, aumentou em 4 e não se alterou em 2 pacientes. Do mesmo modo, a expressão do receptor LRP-1 no tecido tumoral estava aumentada em relação ao tecido normal em 4 pacientes das 12 avaliadas. Em comparação com o tecido tumoral antes da quimioterapia, a expressão do receptor LRP-1 diminuiu em 6, aumentou em 4 e permaneceu inalterada em 2 pacientes após a quimioterapia. Esses dados mostram que o efeito da quimioterapia na expressão dos receptores de lipoproteínas foi heterogêneo. A redução da expressão dos receptores não foi o padrão observado, o que indica que o uso de sistemas de carreamento de fármacos via receptores de LDL para o tratamento do câncer pode ser de grande importância. Esses resultados podem contribuir para o desenho de futuros estudos clínicos / Proliferative tumor cells present a high expression of LDL receptors due to accelerated mitosis rates which takes to increased need of lipids internalization for building new membranes. Upregulation of LDL receptors may be used as a gate to deliver anticancer drugs to tumor tissues using lipoproteins or artificial nanoemulsions as vehicle. This study investigated the effects of conventional chemotherapy on the expression of LDL and LRP-1 receptors in 16 patients with breast cancer in stage II or III who were not candidates to conservative surgery and with indication of neo-adjuvant chemotherapy. Expression of LDL and LRP-1 receptor was evaluated by immunohistochemistry in normal and neoplastic breast tissue before and after chemotherapy. For absence of tumor in the surgical fragments, 4 patients who presented complete response to chemotherapy were excluded from this analysis. In relation of LDLR, the expression in neoplastic tissue was higher than in normal tissue in 8 of 11 patients. After chemotherapy, LDL receptor expression diminished in 6, increased in 4 and unchanged in 2 patients. Expression of LRP-1 in tumor tissue was higher in 4 of 12 patients when compared to normal tissue. After chemotherapy, the expression of LRP-1 diminished in 6, increased in 4 and showed no difference in 2 patients. These data show that the chemotherapy effects on the tumor expression of LDL receptors were very heterogeneous. The diminution of the receptor expression is not the post-chemotherapy pattern, allowing the use of drug carrier systems that target cancer cells via the LDL receptor pathway. These results may contribute for the design of future clinical assays

Os tumores malignos apresentam um aumento da expressão dos receptores de lipoproteínas, devido ao aceleramento da proliferação celular com consequente aumento da necessidade de lípides para a síntese das membranas celulares. Esse aumento da expressão dos receptores de LDL no câncer pode ser utilizado para concentrar fármacos de ação antineoplásica em tecido tumoral, utilizando lipoproteínas ou nanoemulsões semelhantes a lipoproteínas como veículo. No presente estudo, foram investigados os efeitos da quimioterapia convencional na expressão dos receptores de LDL e LRP-1 em 16 pacientes com carcinoma de mama estádios II ou III, não candidatas à cirurgia conservadora e com indicação de tratamento quimioterápico neoadjuvante. A expressão dos receptores LDLR e LRP-1 foi avaliada por imunoistoquimica em tecido mamário normal e em tecido neoplásico antes e depois da quimioterapia neoadjuvante. Quatro pacientes que apresentaram resposta completa à quimioterapia foram retiradas da análise da expressão de receptores por não existir tumor no fragmento cirúrgico. Em relação ao LDLR, a expressão desse receptor no tecido neoplásico foi maior em comparação ao tecido normal em 8 das 11 pacientes. Após a quimioterapia, a expressão do receptor de LDL diminuiu em 6, aumentou em 4 e não se alterou em 2 pacientes. Do mesmo modo, a expressão do receptor LRP-1 no tecido tumoral estava aumentada em relação ao tecido normal em 4 pacientes das 12 avaliadas. Em comparação com o tecido tumoral antes da quimioterapia, a expressão do receptor LRP-1 diminuiu em 6, aumentou em 4 e permaneceu inalterada em 2 pacientes após a quimioterapia. Esses dados mostram que o efeito da quimioterapia na expressão dos receptores de lipoproteínas foi heterogêneo. A redução da expressão dos receptores não foi o padrão observado, o que indica que o uso de sistemas de carreamento de fármacos via receptores de LDL para o tratamento do câncer pode ser de grande importância. Esses resultados podem contribuir para o desenho de futuros estudos clínicos / Proliferative tumor cells present a high expression of LDL receptors due to accelerated mitosis rates which takes to increased need of lipids internalization for building new membranes. Upregulation of LDL receptors may be used as a gate to deliver anticancer drugs to tumor tissues using lipoproteins or artificial nanoemulsions as vehicle. This study investigated the effects of conventional chemotherapy on the expression of LDL and LRP-1 receptors in 16 patients with breast cancer in stage II or III who were not candidates to conservative surgery and with indication of neo-adjuvant chemotherapy. Expression of LDL and LRP-1 receptor was evaluated by immunohistochemistry in normal and neoplastic breast tissue before and after chemotherapy. For absence of tumor in the surgical fragments, 4 patients who presented complete response to chemotherapy were excluded from this analysis. In relation of LDLR, the expression in neoplastic tissue was higher than in normal tissue in 8 of 11 patients. After chemotherapy, LDL receptor expression diminished in 6, increased in 4 and unchanged in 2 patients. Expression of LRP-1 in tumor tissue was higher in 4 of 12 patients when compared to normal tissue. After chemotherapy, the expression of LRP-1 diminished in 6, increased in 4 and showed no difference in 2 patients. These data show that the chemotherapy effects on the tumor expression of LDL receptors were very heterogeneous. The diminution of the receptor expression is not the post-chemotherapy pattern, allowing the use of drug carrier systems that target cancer cells via the LDL receptor pathway. These results may contribute for the design of future clinical assays

Abstract Carbamylation of proteins in vivo occurs by cyanate, non-enzymatically when urea is dissociated, and by myeloperoxidase-catalyzed oxidation from thiocyanate. Carbamylation of low-density lipoprotein is suggested to enhance atherogenesis in patients with with chronic kidney disease and uremia. This thesis study assessed the questions of whether healthy humans or uremic patients under enhanced carbamylation have antibodies recognizing carbamyl-epitopes in plasma, and what is their role in vivo. Also, humoral immune response to carbamyl-LDL immunization and its impact on atherogenesis in LDLR-/- mice was investigated. In this thesis study, plasma antibodies to carbamylated proteins were detected in humans, and IgG antibodies to carbamylated proteins were associated with uremia and smoking, conditions with enhanced carbamylation. The human IgG and IgM antibodies binding to carbamyl-epitopes were associated with oxidation-specific epitopes in plasma. Monoclonal Fab antibodies with characteristics of a natural antibody and ability to bind both carbamyl- and malondialdehyde-derived epitopes were cloned from healthy humans. An investigated Fab antibody was able to bind epitopes found in atherosclerotic lesions and inhibit the uptake of modified LDL by macrophages. Human plasma antibodies and the monoclonal Fab bound to epitopes found on apoptotic cells. Human B-cells secreted antibodies with similar cross-reactive binding properties between carbamyl- and malondialdehyde adducts and apoptotic cells in vitro. Immunization with mouse carbamyl-LDL without adjuvant resulted in specific IgG immune response in LDLR-/- mice, but also a cross-reaction with malondialdehyde-adducts was observed. Carbamyl-LDL immunized mice had enhanced plasma antibody binding to apoptotic cells. Carbamyl-LDL immunization did not affect atherogenesis in mice. This thesis demonstrates that IgG antibodies to carbamyl-epitope might serve as a novel indicator of carbamylation in vivo in uremic patients or smokers. The cross-reactivity between antibodies binding to carbamylated and oxidation-specific epitopes, and apoptotic cells may have a role in explaining the link between enhanced atherogenesis and kidney disease. / Tiivistelmä Proteiinien karbamylaatiota tapahtuu syanaatin vaikutuksesta. Sitä muodostuu urean hajotessa tai myeloperoksidaasin katalysoimana tiosyanaatin hapettuessa. Low-density lipoproteiinin eli LDL:n karbamylaation on esitetty edistävän valtimonkovettumataudin eli ateroskleroosin kehittymistä munuaisten vajaatoimintaa sairastavilla ureemisilla potilailla. Väitöskirjatyössä tutkittiin, onko terveillä ihmisillä ja ureemisilla potilailla karbamyyli-epitooppeja tunnistavia vasta-aineita, ja mikä niiden merkitys on elimistössä. Humoraalista immuunivastetta karbamyyli-LDL-immunisaation jälkeen sekä sen vaikutusta ateroskleroosin kehittymiseen tutkittiin LDL-reseptoripuutteellisilla hiirillä. Tutkimuksessa osoitettiin, että ihmisillä on plasmassa karbamyloituja proteiineja tunnistavia vasta-aineita. IgG-luokan vasta-aineet ovat yhteydessä uremiaan ja tupakointiin, joissa karbamylaatio on lisääntynyt. Karbamyyli- ja hapettuneita epitooppeja tunnistavien plasman IgG- ja IgM-vasta-aineiden välillä havaittiin olevan yhteys. Työssä kloonattiin terveistä ihmisistä monoklonaalisia Fab-vasta-aineita, joilla on luonnollisten vasta-aineiden kaltaisia ominaisuuksia ja kyky sitoutua sekä karbamyyli- että malonidialdehydi-epitooppeihin. Yksi tutkittu Fab-vasta-aine sitoutui valtimonkovettumataudin ateroomissa oleviin epitooppeihin ja esti muuntuneen LDL:n sisäänoton makrofagi-soluihin. Ihmisen plasman vasta-aineet ja monoklonaalinen Fab-vasta-aine sitoutuivat apoptoottisten solujen pinnalla oleviin rakenteisiin. Soluviljelyolosuhteissa ihmisen B-solut tuottivat vasta-aineita, joilla oli samanlaisia ristireaktio-ominaisuuksia karbamyyli- ja malonidialdehydi-epitooppeja sekä apoptoottisia soluja kohtaan. Karbamyyli-LDL-immunisaatio sai aikaan IgG-immuunivasteen hiirillä karbamyyli-LDL:a kohtaan, mutta myös ristireaktio malonidialdehydi-rakenteita sekä apoptoottisia soluja kohtaan havaittiin. Karbamyyli-LDL-immunisaatio ei vaikuttanut ateroskleroosin kehittymiseen hiirillä. Tutkimus osoittaa, että IgG-vasta-aineet karbamyyli-epitooppeja kohtaan voivat olla uudenlainen karbamylaation merkkiaine elimistössä ureemisilla potilailla ja tupakoitsijoilla. Karbamyloituneiden ja hapettuneiden epitooppien sekä apoptoottisten solujen välillä havaituilla vasta-aineiden ristireaktioilla voi olla merkitystä valtimonkovettumataudin etenemiseen munuaisten vajaatoiminnassa.