98 research outputs found
The discovery of small-molecule inhibitors of keap1-nrf2 interaction with homogeneous fluorescence-based high throughput screening assays
No full textKeap1-Nrf2 interaction is a key protein-protein interaction involved in the activation of antioxidant response element which regulates the expression of cytoprotective enzymes in response to oxidative stress conditions. To identify direct inhibitors of Keap1-Nrf2 interaction, a series of fluorescently-labeled Nrf2 peptides were synthesized and evaluated as tracers in the development of a fluorescence polarization (FP) assay. The optimized tracer, FITC-9mer Nrf2 amide, was determined to have the highest binding affinity and dynamic range of all tracers evaluated. The FP assay has considerable tolerance towards DMSO and was capable of distinguishing the inhibitory Nrf2 peptides with a Z'-factor of 0.70 as determined under the FP assay conditions. Taken together, these results demonstrate that the FP assay is suitable for application in high-throughput screening (HTS). In addition, a series of novel lanthanide chelates were designed, synthesized, and evaluated for the development of a time-resolved fluorescence resonance energy transfer (TR-FRET) assay using an in situ labeling approach. The cyclam and EDTA-based tris-NTA were found to have the strongest affinity to the His6-tag of Keap1 Kelch domain with a Kd of 1.6 nM and 2.2 nM, respectively. Among the tris-NTA conjugates evaluated as donors of TR-FRET, the EDTA-tris-NTA Acp6-linker conjugate was found to have the highest TR-FRET signal. The in situ labeling technique was also evaluated for Eu(III) chelate and through biotin-streptavidin interaction, increasing the choice of fluorophores and extending the application of the assay to biotinylated biomolecules. Thus, the novel labeling reagent provides an excellent solution for facile development of TR-FRET assays in drug discovery. The FP assay was adapted for HTS of the NIH MLPCN library. Eight confirmed hits were obtained and one of the promising hits (LH602) was targeted for preliminary structure-activity relationship (SAR) studies. Among the synthesized compounds, 2,4,6-trimethylbenzenesulfonamide substituted analog 81 showed the highest affinity to Keap1 Kelch domain. However, LH602 was found to be unstable due to its naphthoquinone structure with a half-life of 6 hours in the assay buffer. Further SAR studies are needed to improve the binding affinity as well as stability of the compound in our effort to identify potent inhibitors of Keap1-Nrf2 interaction.Ph.D.Includes bibliographical referencesby Daigo Inoyam
Memorialized in Verse: Hideyoshi's Daigo Hanami of 1598
No full textAuthor Institution: University of Virgini
A new proof of the Bondal-Orlov reconstruction using Matsui spectra
No full textIn 2005, Balmer defined the ringed space for a given tensor triangulated category, while in 2023, the
second author introduced the ringed space for a given triangulated category. In the algebro-geometric
context, these spectra provided several reconstruction theorems using derived
categories. In this paper, we prove that
is an open
ringed subspace of for
a quasi-projective variety . As an application, we provide a new proof of
the Bondal-Orlov and Ballard reconstruction theorems in terms of these spectra.
Recently, the first author introduced the Fourier-Mukai locus
for a smooth projective
variety , which is constructed by gluing Fourier-Mukai partners of
inside . As another
application of our main theorem, we demonstrate that
can be viewed as an
open ringed subspace of . As a result, we show that all the Fourier-Mukai partners of an abelian
variety can be reconstructed by topologically identifying the Fourier-Mukai
locus within .Comment: 17 pages, Comments welcome
Plasma proteins as potential biomarkers of aging of single tissue and cell type
No full textPlasma proteins serve as biomarkers of aging and various age-related diseases. While a number of plasma proteins have been identified that increase or decrease with age, the interpretation of each protein is challenging. This is due to the nature of plasma, which is a mixture of factors secreted by many different tissues and cells. Therefore, the catalog of age-related proteins secreted by a single cell type in a single tissue would be useful for understanding tissue-specific aging patterns. In this study, the author addressed this challenge by integrative data mining of the Human Protein Atlas and the recently published result of large-scale aging proteomics research. Finally, we identified the 17 age-related proteins produced by a single tissue and a single cell type: MBL2 and HP in the liver (hepatocytes), SFTPC in the lung (type II alveolar cells), PRL and POMC in the pituitary (anterior cells), GCG, CUZD1 and CPA2 in the pancreas (pancreatic cells), MYBPC1 in skeletal muscle (myocytes), PTH in the parathyroid gland (glandular cells), LPO and AMY1A in the salivary gland (glandular cells), INSL3 in the male testis (Leydig cells), KLK3 and KLK4 in the male prostate (glandular cells), MPO and ACP5 in immune cells. This list of proteins would be potentially useful for understanding age-related changes in the plasma proteome and inter-tissue networks
Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.
No full textAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease
Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis
No full textNeutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis
Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients
No full text東京女子医科大学博士(医学)博士(医学) 乙第3045号(主論文の要旨、要約、審査結果の要旨、本文)，著者名:Yuiko KAMEI・Daigo KAMEI・Ken TSUCHIYA・Michio MINESHIMA・Kosaku NITTA，タイトル:Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients，掲載誌:PloS one(1932-6203)，巻・頁・年:13巻8号 p.e0201591(2018)，著作権関連情報:© 2018 Kamei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.，DOI:10.1371/journal.pone.0201591doctoral thesi
Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients
No full text博士(医学) 乙第3045号(主論文の要旨、要約、審査結果の要旨、本文)，著者名:Yuiko KAMEI・Daigo KAMEI・Ken TSUCHIYA・Michio MINESHIMA・Kosaku NITTA，タイトル:Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients，掲載誌:PloS one(1932-6203)，巻・頁・年:13巻8号 p.e0201591(2018)，著作権関連情報:© 2018 Kamei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.，DOI:10.1371/journal.pone.020159
Formy przenikania się sfery sacrum i władzy w przestrzeni miejskiej Kioto
No full textKyōto, as a former capital city of Japan, is a perfect place to study the forms of urban coexistence of elements of the sacrum and of secular power. The author distinguishes several such forms, and explores examples to show that the basis of the phenomenon can be found in city planning, as well as in the approach to establishing temples. Among the different forms, we may encounter the transformation of imperial villas into Buddhist temples, the erection of commemorative Shintō shrines and temples dedicated to certain people (such as Sugawara Michizane, or Emperor Go‑Daigo), and the installation of particular elements in temple precincts. Another form consists of unplanned modifications to the temple areas or buildings resulting from political conflicts. All of the various forms show the dynamic nature of the relations obtaining between sacrum and power in Japan over the centuries.Paweł F. Nowakowsk
Author Correction: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis
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