Diabetes is a major public issue due to its high prevalence and long-term complications (1). The molecular pathogenesis of diabetes, however, remains largely unknown. The common forms of diabetes are syndromes with heterogeneous etiologies, each of which is influenced by polygenic and multiple environmental factors. Therefore, genetic and pathophysiologic analysis of diabetes remains a major challenge. On the other hand, recent progress in the identification of genetic alterations in monogenic disorders has provided clues for understanding the molecular pathogenesis of the common forms with similar phenotypes. There are several rare monogenic forms of diabetic syndromes, both in humans and in rodent models. In humans, there is a syndrome called maturity-onset diabetes of the young (MODY), which is inherited in an autosomal dominant mode (2). The primary lesions in these diseases are in the pancreatic β cells, resulting in decreased insulin secretion. The causal genes of some types of MODY were recently identified (3).In contrast, most of the monogenic diabetic syndromes in rodent models such as ob, db, agouti, tubby, and fat mice accompany obesity (4). The responsible genes are involved in the regulation of body weight, and their alterations result in increased insulin resistance in peripheral tissues, except in fat mice. Very recently, Yoshioka and colleagues established a monogenic diabetic model, called the Akita mouse (5). This model does not accompany either obesity or insulitis, but is accompanied by a notable pancreatic β-cell dysfunction, which distinguishes this mouse from the other well-characterized animal models. Diabetes in this mouse resembles that of human MODY in terms of early onset, an autosomal dominant mode of inheritance, and primary dysfunction of the β cells. The gene locus is named murine Mody and has been determined to be located on a distal end of Chromosome 7 by linkage analysis (5) and quantitative trait locus analysis (6).In this study, we demonstrate that the Mody mouse has a missense mutation of the insulin 2 gene (Ins2), which lies on a corresponding area of the Mody locus identified by the genetic analysis. This mutation completely cosegregates with the qualitative phenotype of diabetes in the Mody congenic lines, and it is therefore concluded to be responsible for diabetes in this mouse. The Mody mutation codes insulin 2, whose cysteine residue at the seventh amino acid of the A chain is replaced with tyrosine. This cysteine is involved in the formation of one of the Received for publication June 30, 1998, and accepted in revised form November 10, 1998.The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic β-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational chan...
Exfoliated graphite oxide (GO) sheets with hydroxyl groups and amine groups on the surface were prepared by modification of graphite. Atom transfer radical polymerization (ATRP) initiator molecules were grafted onto the GO sheets by reactions of 2-bromo-2-methylpropionyl bromide with hydroxyl groups and amine groups. Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chains on the surface of GO sheets were synthesized by in-situ ATRP. X-ray photoelectron spectroscopy, thermogravimetric analysis, and transmission electron microscopy (TEM) results all demonstrated that polymer chains were successfully produced. After grafting of PDMAEMA, the dispersity of GO sheets in solvents was improved significantly. Poly(ethylene glycol dimethacrylate-co-methacrylic acid) particles were deposited on GO sheets via hydrogen bonding between MAA units on polymer particles and amine groups of PDMAEMA. TEM and scanning electron microscopy were used to characterize the structure of the nanocomposites.
Lithium niobate (LN) microdisk resonators on a LN-silica-LN chip were fabricated using only conventional semiconductor fabrication processes. The quality factor of the LN resonator with a 39.6-μm radius and a 0.5-μm thickness is up to 1.19 × 10(6), which doubles the record of the quality factor 4.84 × 10(5) of LN resonators produced by microfabrication methods allowing batch production. Electro-optic modulation with an effective resonance-frequency tuning rate of 3.0 GHz/V was demonstrated in the fabricated LN microdisk resonator.
While Type I and Type II photosensitizers are often carefully tailored to achieve their respective advantages in treating different cancers, the identifications of the Type I and II mechanisms as such, the key reaction intermediates, and the consequent oxidation products of the substrates have never been easy. Using our unique home‐built field‐induced droplet ionization mass spectrometry (FIDI‐MS) method that selectively samples molecules at the air–water interface, here we show the facile determination of both Type I and II mechanisms of a poster‐child photosensitizer, temoporfin, without the addition of any probes. The unstable doublet radical resulting from the hydrogen abstraction by the triplet temoporfin through the Type I mechanism is captured, manifesting the in situ advantage of FIDI‐MS. We anticipate that the method developed in this study can be widely utilized in the future designs of novel photosensitizers and the screening of their photosensitization mechanisms.
[reaction: see text] Reaction of various aromatic aldehydes with 2,2'-dipyridyl ketone and ammonium acetate in hot acetic acid provides ready access to a series of substituted 1-pyridylimidazo[1,5-a]pyridines, a class of ligands possessing an N,N-bidentate feature, in good yields.
Background/Aims: The effects of zinc signaling on proliferation or apoptosis of leukemia cells remain elusive. In the present study, we used N, N, N’, N’-tetrakis-(2-pyridylmethyl)-ethylene-diamine (TPEN), a membrane-permeable zinc chelator, to evaluate the effect of zinc depletion on survival and apoptosis of NB4 acute promyelocytic leukemia (APL) cells. Methods: The pro-apoptotic effects of TPEN on NB4 cells were examined by flow cytometry, and observed using an optical microscope. Intracellular labile zinc, nitric oxide (NO) or reactive oxygen species (ROS) changes caused by TPEN were measured by flow cytometry. We then explored possible roles of the crosstalk between intracellular labile zinc signaling and nitric oxide signaling in TPEN-triggered apoptosis. Results: we found that TPEN induced apoptosis in NB4 APL cells in a dosage-dependent manner. We further demonstrated that TPEN triggered apoptosis by attenuating intracellular zinc and nitric oxide signaling in NB4 cells. Both exogenous zinc supplement and the nitric donor sodium nitroprusside (SNP) pre-incubation reversed TPEN-mediated inhibition of intracellular NO and Zn2+ signaling, and rescued NB4 cells from apoptosis. Conclusion: These results suggest for the first time that crosstalk between zinc signaling and nitric oxide pathway is essential for the survival of NB4 cells. TPEN induces apoptosis in NB4 cells via negatively regulating intracellular NO and Zn2+ signaling. Our in vitro data suggest that zinc depletion by TPEN may be a potential therapeutic strategy for APL.
Exploring the organic-to-aqueous phase transfer of quantum dots (QDs) is significant for achieving their versatile applications in biomedical fields. In this thematic issue, surface modification, size control, and biocompatibility of QDs and QDs-based nanocomposites are core problems. Herein, the new highly fluorescent tumor-targeted QDs-clusters consisting of ZnAgInSe/ZnS (ZAISe/ZnS) QDs and sulfobetaine-PIMA-histamine (SPH) polymer with the αβ integrin receptor cyclic RGD (c-RGD) were developed via ligand exchange and an accompanying self-assembly process. It was found that the structure of RGD-SPH QDs-clusters was propitious to reduce the capture of reticulo-endothelial system (RES) in virtue of external stealth ligands, and benefit to selectively accumulate at the tumor site after intravenous injection via active tumor targeting cooperated with the enhanced permeability and retention (EPR) effect. In the meantime, those clusters also recognized and enriched the cell surface when cocultured with the αβ integrin receptor overexpressed malignant cells (U87MG tumor). On the basis of the results, fabricating mutil-functional nanocomposites integrated with the long-term circulation and dual-targeting effects should be an interesting strategy for imaging cancer in vitro and in vivo.
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