13 research outputs found
The impact of Thiosulfate sulfurtransferase (TST) on metabolic dysfunction-associated steatotic liver disease (MASLD) and the metabolic benefits of calorie restriction
No full textMetabolic dysfunction-associated steatotic liver disease (MASLD) affects 20-30% of adults in
western countries and is closely linked to obesity and type 2 diabetes. Hydrogen sulfide (H₂S),
once solely perceived as toxic, is now recognised for its role in various physiological and
pathological processes. H₂S donors have shown promise in treating fatty liver disease and
reducing blood pressure in animal models, but their therapeutic use is hindered by challenges
in H₂S pharmacokinetics. The sulphur oxidation pathway (SOP), which regulates H₂S levels
through its disposal, has been underexplored as a potential route to therapeutic H₂S elevation.
Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme, is part of the SOP and
metabolises H2S, indirectly, to prevent toxicity. Previous work leading up to this thesis showed
that TST mRNA levels were upregulated during the early steatosis stage of MASLD in humans.
Given the previously identified metabolic protective effect of adipose tissue TST elevation, I
hypothesised that elevation of hepatic TST in early MASLD was a protective mechanism,
counteracting declining liver function in MASLD. Improved metabolic health following
calorie restriction (CR) is mediated in part through increased hepatic production of H₂S. Tst⁻/⁻
mice exhibited elevated systemic H₂S levels, therefore I hypothesised they may have an
enhanced response to CR.
In chapters 3 and 4, I tested the hypothesis that elevated hepatic TST expression in MASLD
offered protection against MASLD development using a liver-specific overexpression mouse
model (Liv_hTST). Male and female C57BL/6J and Liv_hTST mice were fed either a control
diet or MASLD-inducing GAN diet for 20 weeks. Systemic and hepatic sulfide levels were
measured, fat and lean mass assessed, and glucose tolerance evaluated. In vitro, HepaRG cells
with TST overexpression were tested for lipid accumulation, oxidative stress, and
mitochondrial function. Results showed sex-specific effects on sulfide levels and glucose
tolerance, with protective effects against fibrosis in male mice in vivo, and a worsening of the
impaired lipid metabolism and mitochondrial function in vitro. This research addresses the gap
in understanding of the protective role ascribed to elevated TST expression against steatogenic
liver changes in MASLD and revealed novel sex-specific effects on systemic sulfide levels,
glucose tolerance, and fibrosis.
In chapter 5, I investigated whether Tst⁻/⁻ mice experienced enhanced metabolic benefits from
CR due to their elevated systemic sulfide. Ten-week-old male and female C57BL/6J and Tst⁻/⁻
mice underwent 4-week 30% CR. Indirect calorimetry, glucose tolerance, H₂S production, and
disposal (SOP) enzyme levels were assessed. Tst⁻/⁻ males had higher systemic but similar
hepatic sulfide levels compared to C57BL/6J males, confirming previous work. CR did not
affect sulfide levels but improved glucose tolerance in Tst⁻/⁻ males, despite their resistance to
fat mass loss. Energy expenditure and substrate utilisation were similar between genotypes.
Females were unaffected by the lack of TST and had lower levels of hepatic H₂S metabolism
enzymes. Our findings suggested mechanisms beyond hepatic sulfide modulation mediate CR
benefits. Understanding the novel role of elevated systemic H₂S and TST deficiency in
maintaining fat mass and concurrent metabolic benefits with CR may inform H₂S -targeted
therapeutic strategies in the future
The Establishment of Shaden and the Ritsuryo State
No full textapplication/pdf本稿は、神社社殿の成立時期について、律令国家との関係に注目しながら検討し、また、摂関期の国家と神社の関係についても論及するものである。
神社社殿がいつ、どうして成立したかについては、多く研究があるものの、これまでの研究成果を充分に消化しつつ、論じたものはあまり存在しないと思う。そこで❶章では、あらためて研究史整理を行い、神社社殿成立の時期について詳細に検討した。その結果、①律令国家の成立と神社社殿の成立はほぼ同時期であること、②律令国家成立以前の宗教施設には、大きく分類して、建築物を有しないモリと、建築物が付随するホクラがあること、以上二つの仮説を得た。
❷章では、ホクラと神社社殿の関係について、中国の「社」のあり方や平安時代の記録を用いて検証した。中国の宗教施設である「社」は建築物を伴わないことから、神社建築は中国の影響を受けない日本固有のものであると推測した。とすれば、七世紀以前に存在したホクラが神社建築に深く関係すると考えることもできよう。律令国家成立期、祈年祭を中心とした班幣制度を創始するにあたり、地方に幣帛を納める宗教施設として、建築物を伴う「神社」も創出されたのではないか。
❸章では、❶章の仮説①を検討するべく、律令国家が転換した十世紀以降における神社社殿と摂関期の国家・受領の関係について考えた。受領の神拝や神社修理について検討した結果、十世紀以降の神社社殿は、受領が社殿の繁栄や退転に大きく関係していることが判明した。律令期との相違は若干あるものの、摂関期の受領や国家などの支配者が神社社殿の維持に大きな役割を果たしたことは間違いないようである。
律令国家は、神社社殿成立に深く関与しており、また、摂関期においても受領が中心となって社殿を維持していたと結論づけた。This paper discusses the period of the establishment of shaden (shrine halls) by examining the relationship they had with the ritsuryo state as well as the relationship between the state and shrines during the Heian period.
Although considerable research has been carried out on when and how shaden came into being, there is little that addresses this topic while sufficiently assimilating the findings of past research.
Through a study of previous research, the first chapter examines in detail the period when shaden were built. As a result, the author arrived at two hypotheses: 1) the formation of the ritsuryo state and the establishment of shaden occurred almost simultaneously; and 2) before the formation of the ritsuryo state there were two main types of religious venue: mori with no buildings and hokura with buildings.
The second chapter examines the relationship between hokura and shaden by studying Chinese temples called “she” as well as using records from the Heian period. Because these Chinese religious venues did not have buildings, the author surmises that shrine buildings are peculiar to Japan and were not influenced by China. That being the case, we may also conclude that pre-7th century hokura are closely linked to shrine buildings. This suggests that around the time of the formation of the ritsuryo state and the establishment of the system of offerings for a bountiful harvest,“ shrines” with buildings were also built as regional religious venues.
In examining the first hypothesis presented in the first chapter, the third chapter considers the relationship between shaden and the state and provincial governors during the Heian period following the changes that occurred to the ritsuryo state in the 10th century. A study of worship by provincial governors and shrine repairs showed that from the 10th century the prosperity or decline of shaden had a lot to do with provincial governors. Despite slight differences between this period and the ritsuryo period, rulers and provincial governors played an important role in maintaining shaden.
In conclusion, the ritsuryo state was deeply involved in the establishment of shaden, and shaden were maintained chiefly through the role played by provincial governors in the Heian period as well.departmental bulletin pape
Effect of Weight Loss by Low-Calorie Diet on Cardiovascular Health in Type 2 Diabetes: An Interventional Cohort Study
No full textCardiovascular disease (CVD) remains a major problem for people with type 2 diabetes (T2DM), and the leading cause of death worldwide. We aimed to determine cardiovascular benefits of weight loss with or without remission of diabetes, and to assess utility of plasma biomarkers. 29 people with T2DM were studied at baseline and after dietary weight loss. Change in plasma adipokines and lipid related markers was examined in relation to weight loss, diabetes remission, 10-year cardiovascular risk (QRISK), and duration of diabetes. QRISK decreased markedly after weight loss (18.9 ± 2.2 to 11.2 ± 1.6%, p < 0.0001) in both responders and non-responders, but non-responders remained at higher risk (15.0 ± 2.0 vs. 5.8 ± 1.6%, p < 0.0001). At baseline, plasma GDF-15 was higher in longer diabetes duration (1.19 ± 0.14 vs. 0.82 ± 0.09 ng/mL, p = 0.034), as was the QRISK (22.8 ± 2.6 vs. 15.3 ± 3.4%, p = 0.031). Leptin, GDF-15 and FGF-21 decreased whereases adiponectin increased after weight loss in responders and non-responders. However, the level of FGF-21 remained higher in non-responders (0.58 [0.28–0.71] vs. 0.25 [0.15–0.42] ng/mL, p = 0.007). QRISK change correlated with change in plasma VLDL1-TG (r = 0.489, p = 0.007). There was a positive correlation between rise in HDL cholesterol and the decrease in leptin (r = 0.57, p = 0.001), or rise in adiponectin (r = 0.58, p = 0.001) levels. In conclusion, weight loss markedly decreases cardiometabolic risk particularly when remission of diabetes is achieved. Leptin, adiponectin, GDF-15 and FGF-21 changes were related to weight loss not remission of diabetes. Normalization of 10-year cardiovascular risk and heart age is possible after substantial dietary weight loss and remission of T2DM
Jerusalem: One City, Three Faiths (A Critical Historical Study of Karen Armstrong\u27s Book)
No full textReligious knowledge may hold greater value than some other forms of knowledge. Karen Armstrong, the researcher, worked diligently to gather information for her book, which was translated into Arabic from Jewish, Christian, and Islamic sources. She presented her perspective using a rich vocabulary, along with a comprehensive vision and subjectivity. Her book focuses on holy geography, highlighting the symbols that give certain places significant value. According to her book, the sacred feeling precedes the physical places and temples. After considerable effort, Karen sought to find a common link among the three Abrahamic religions. However, given the substantial amount of historical information presented by the author, it is possible that mistakes or generalizations occurred. Additionally, not all adherents of her religion or those of other faiths agree with her views. In this paper, the researcher aims to explore the different aspects of Karen’s book about Jerusalem, presenting information regarding the Jewish perspective on the city, as well as the viewpoints of Arab researchers. The researcher relied on various sources, with the most significant being Karen Armstrong\u27s book
Solar Geometry in Performance of the Built Environment: An Integrated Computational Design Method for High-Performance Building Massing Based on Attribute Point Cloud Information
No full textAs part of the passive design strategy, the development of computational solar envelopes plays a major role to construct a cooperative environmental performance exchange between new buildings and their local contexts. However, the state-of-the-art computational solar envelopes pose a great challenge in understanding site characteristics from a given context. Existing methods predominantly construct 3D context models based on basic architectural geometric shapes, which are often isolated from the surrounding properties of local contexts (i.e., vegetation, materials). Thus, they only focus on context-oriented buildings and energy quantities that unfortunately lack a contextual solar performance analysis. It is clear that this condition may result in a fragmented understanding of the local context during the design and simulation process. With the potential application of attribute point cloud information, it is necessary to consider relevant parameters such as surface and material properties of existing contexts during the simulation of solar geometries, which are currently absent in computational frameworks. As such, the new method is required to enable architects not only to measure specific performances of the local context but also to identify vulnerable areas that may affect the proposed design. This research focuses on exploring an integrated computational design method for solar geometry based on solar and shading envelopes, and geometric and radiometric information from point cloud data. In particular, two computational models consisting of SOLEN (Subtractive Solar Envelopes) and SHADEN (Subtractive Shading Envelopes) are developed, which are applied to temperate and tropical climates, respectively. In design practice, these models help architects to produce informed-design decisions towards high-performed building massing
Thiosulphate sulfurtransferase:Biological roles and therapeutic potential
No full textMitochondria are central to eukaryotic cell function, driving energy production, intermediary metabolism, and cellular homeostasis. Dysregulation of mitochondrial function often results in oxidative stress, a hallmark of numerous diseases, underscoring the critical need for maintaining mitochondrial integrity. Among mitochondrial enzymes, thiosulfate sulfurtransferase (TST) has emerged as a key regulator of sulfur metabolism, redox balance, and Fe-S protein maintenance. Beyond its well-known role in cyanide detoxification, TST facilitates hydrogen sulfide (H 2S) metabolism by catalyzing the transfer of sulfur from persulfides (R-SSH) to thiosulfate (S 2O 3 2-), promoting H 2S oxidation and preventing its toxic accumulation. Additionally, TST contributes to the thiol-dependent antioxidant system by regulating reactive sulfur species and sustaining mitochondrial functionality through its role in sulfide-driven bioenergetics. This review highlights the biochemical and therapeutic significance of TST in mitochondrial and cellular health, emphasizing its protective roles in diseases associated with oxidative stress and mitochondrial dysfunction. Dysregulation of TST has been implicated in diverse pathologies, including specific metabolic disorders, neurological diseases, cardiovascular conditions, kidney dysfunction, inflammatory bowel disease, and cancer. These associations underline TST's potential as a biomarker and therapeutic target. Therapeutic strategies to activate the TST pathway are explored, with a focus on sodium thiosulfate (STS), novel small molecule (Hit 2), and recombinant hTST protein. STS, an FDA-approved compound, has demonstrated antioxidant and anti-inflammatory effects across multiple preclinical models, mitigating oxidative damage and improving mitochondrial integrity. A slow-release oral formulation of STS is under development, offering promise for expanding its clinical applications. Small molecule activators like Hit 2 and hTST protein have shown efficacy in enhancing mitochondrial respiration and reducing oxidative stress, though both reagents need further in vitro and in vivo investigations. Despite promising advancements, TST-based therapies remain underexplored. Future research should focus on leveraging TST's interplay with pathways like NRF2 signaling, investigating its broader protective roles in cellular health, and developing targeted interventions. Enhancing TST activity represents an innovative therapeutic approach for addressing mitochondrial dysfunction, oxidative stress, and their associated pathologies, offering new hope for the treatment of diseases associated with mitochondrial dysfunction. </p
Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters
No full textBACKGROUND: Visceral leishmaniasis (VL) is a neglected tropical disease and is fatal if untreated. There is no vaccine available against leishmaniasis. The majority of patients with cutaneous leishmaniasis (CL) or VL develop a long-term protective immunity after cure from infection, which indicates that development of an effective vaccine against leishmaniasis is possible. Such protection may also be achieved by immunization with live attenuated parasites that do not cause disease. We have previously reported a protective response in mice, hamsters and dogs withLeishmania donovani centrin gene knock-out parasites (LdCen-/-), a live attenuated parasite with a cell division specific centrin1 gene deletion. In this study we have explored the effects of salivary protein LJM19 as an adjuvant and intradermal (ID) route of immunization on the efficacy of LdCen-/- parasites as a vaccine against virulent L. donovani. METHODOLOGY/PRINCIPAL FINDINGS: To explore the potential of a combination of LdCen-/- parasites and salivary protein LJM19 as vaccine antigens, LdCen-/- ID immunization followed by ID challenge with virulent L. donovaniwere performed in hamsters in a 9-month follow up study. We determined parasite burden (serial dilution), antibody production (ELISA) and cytokine expression (qPCR) in these animals. Compared to controls, animals immunized with LdCen-/- + LJM19 induced a strong antibody response, a reduction in spleen and liver parasite burden and a higher expression of pro-inflammatory cytokines after immunization and one month post-challenge. Additionally, a low parasite load in lymph nodes, spleen and liver, and a non-inflamed spleen was observed in immunized animals 9 months after the challenge infection. CONCLUSION: Our results demonstrate that an ID vaccination using LdCen-/-parasites in combination with sand fly salivary protein LJM19 has the capability to confer long lasting protection against visceral leishmaniasis that is comparable to intravenous or intracardial immunization. KEYWORDS: Hamsters, Parasitic Diseases, Spleen, Leishmania donovani, Immune Response, Lymph Nodes, Cytokines, Sand Flies, Diseases, Medicine and Health Science
Thiosulphate Sulfurtransferase: Biological Roles and Therapeutic Potential
No full textISTCTInternational audienceMitochondria are central to eukaryotic cell function, driving energy production, intermediary metabolism, and cellular homeostasis. Dysregulation of mitochondrial function often results in oxidative stress, a hallmark of numerous diseases, underscoring the critical need for maintaining mitochondrial integrity. Among mitochondrial enzymes, thiosulfate sulfurtransferase (TST) has emerged as a key regulator of sulfur metabolism, redox balance, and Fe-S protein maintenance. Beyond its well-known role in cyanide detoxification, TST facilitates hydrogen sulfide (H2S) metabolism by catalyzing the transfer of sulfur from persulfides (R-SSH) to thiosulfate (S2O32-), promoting H2S oxidation and preventing its toxic accumulation. Additionally, TST contributes to the thiol-dependent antioxidant system by regulating reactive sulfur species and sustaining mitochondrial functionality through its role in sulfide-driven bioenergetics.This review highlights the biochemical and therapeutic significance of TST in mitochondrial and cellular health, emphasizing its protective roles in diseases associated with oxidative stress and mitochondrial dysfunction. Dysregulation of TST has been implicated in diverse pathologies, including specific metabolic disorders, neurological diseases, cardiovascular conditions, kidney dysfunction, inflammatory bowel disease, and cancer. These associations underline TST’s potential as a biomarker and therapeutic target.Therapeutic strategies to activate the TST pathway are explored, with a focus on sodium thiosulfate (STS), novel small molecule (Hit 2), and recombinant hTST protein. STS, an FDA-approved compound, has demonstrated antioxidant and anti-inflammatory effects across multiple preclinical models, mitigating oxidative damage and improving mitochondrial integrity. A slow-release oral formulation of STS is under development, offering promise for expanding its clinical applications. Small molecule activators like Hit 2 and hTST protein have shown efficacy in enhancing mitochondrial respiration and reducing oxidative stress, though both reagents need further in vitro and in vivo investigations.Despite promising advancements, TST-based therapies remain underexplored. Future research should focus on leveraging TST’s interplay with pathways like NRF2 signaling, investigating its broader protective roles in cellular health, and developing targeted interventions. Enhancing TST activity represents an innovative therapeutic approach for addressing mitochondrial dysfunction, oxidative stress, and their associated pathologies, offering new hope for the treatment of diseases associated with mitochondrial dysfunction
Literary Bilingualism: Chinese Authors Writing in the Language of the Other in Sino-Anglophone Contexts, 1930s-1970s
No full textUniversity of Minnesota Ph.D. dissertation. August 2019. Major: Asian Literature, Culture & Media. Advisors: Joseph Allen, Shaden Tageldin. 1 computer file (PDF); v, 227 pages.This dissertation investigates the literary practice of bi-/multilingual Chinese writers within Sino-Anglophone contexts at different historical stages during the twentieth century. It proposes that writing in languages of the Other is a crucial part in the pursuit of modernity in (post)semi-colonial China. Through languages of the Other, Chinese authors’ representation and identification of Chineseness are put into dialogues, negotiations, and, at times, conflicts with heterolingual readerships of more diversified cultural, historical, and ideological backgrounds. Chinese modernity, I argue, is accomplished and continues to develop not on a monolingual and national level, but as part of a multilingual and global process. In a broader sense, this dissertation engages with questions in the fields of translation studies, bilingualism, transnationalism, and Asian American studies. Through the lens of the literary practice of bi-/multilingual Chinese writers, this study reconsiders such concepts as diasporic literature, literature of the exile, national literature, translingual practice, and above all, world literature. Chapter One examines the works of cosmopolitan liberal Chinese intellectuals in a Chinese-sponsored English-language journal, The China Critic. I display how the English language is creolized culturally and ideologically by Chinese authors in order to present their understanding of China-related issues to a non-Chinese audience in the 1920s and 1930s. Chapter Two analyzes Lin Yutang’s English-language texts of the 1930s and 1940s as well as his correspondence with his American editor and publisher. I show how the idea of world literature is negotiated and contested in Lin’s non-Chinese literary practice. Chapter Three investigates Eileen Chang’s English-language rewriting of her Chinese texts in the early 1950s. I examine the ways in which the theme of displacement is demonstrated through the practice of translingual rewriting itself as well as in Chang’s narratives. Chapter Four studies U.S.-based author Hualing Nieh’s experiments with the Chinese language as a language of the Other in a translingual context and the hetero-cultural reception of her novel Sangqing yu Taohong/Mulberry and Peach: Two Women of China. The Chinese language as well as the Chineseness embedded in it, I argue, are destabilized in Nieh’s writing and the cross-cultural adventures her work undertakes.Wang, Chen. (2019). Literary Bilingualism: Chinese Authors Writing in the Language of the Other in Sino-Anglophone Contexts, 1930s-1970s. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/224986
