Production of Transgenic Cloned Miniature Pigs with Membrane-bound Human Fas Ligand (FasL) by Somatic Cell Nuclear Transfer

Cell-mediated xenograft rejection, including NK cells and CD8+ CTL, is a major obstacle in successful pig-to-human xenotransplantation. Human CD8+ CTL and NK cells display high cytotoxicity for pig cells, mediated at least in part by the Fas/FasL pathway. To prevent cell-mediated xenocytotoxicity, a membrane-bound form of human FasL (mFasL) was generated as an inhibitor for CTL and NK cell cytotoxicity that could not be cleaved by metalloproteinase to produce putative soluble FasL. We produced two healthy transgenic pigs harboring the mFasL gene via somatic cell nuclear transfer (SCNT). In a cytotoxicity assay using transgenic clonal cell lines and transgenic pig ear cells, the rate of CD8+ CTL-mediated cytotoxicity was significantly reduced in transgenic pig's ear cells compared with that in normal minipig fetal fibroblasts. Our data indicate that grafts of transgenic pigs expressing membrane-bound human FasL control the cellular immune response to xenografts, creating a window of opportunity to facilitate xenograft survival

A Case of Cogan's Syndrome With Angina

Cogan's syndrome is a rare systemic inflammatory disease and can be diagnosed on the basis of typical inner ear and ocular involvement with the presence of large vessel vasculitis. We report a case of Cogan's syndrome with stable angina resulting from coronary ostial stenosis caused by aortitis

The effecet of UNCL inactivation on the expression of mechanical stress related genes in cultured human PDL fibroblasts

A mutation of UNCL, an inner nuclear membrane RNAbinding protein, has been found to eliminate mechanotransduction in Drosophila. UNCL is expressed in human periodontal tissue including in periodontal ligament (PDL) fibroblasts. However, it is unclear how a mechanical stimulus is translated into cellular responses in PDL fibroblasts. The aim of this study was to evaluate the effect of UNCl on mechanical stress related genes in PDL fibroblasts in response to mechanical stress. The mRNA of TGF-β, COX-2, and MMP-2 was up-regulated after UNCL inactivation in PDL fibroblasts under the compression force. Under the tensile force, inactivation of UNCL decreased the expression of Biglycan, RANKL, MMP-2, and TIMP-2 mRNAs while it increased the expression of TIMP-1. p38-MAPK was expressed in PDL fibroblasts under compression forces whereas phospho-ERK1/2, p65- NFkB, and c-fos were expressed under tension forces. The expression and phosphorylation of the mechanical stress related genes, kinases, and transcription factors were changed according to the types of stress. Furthermore, most of them were regulated by the inactivation of UNCL. This suggests that UNCL is involved in the regulation of mechanical stress related genes through the signaling pathway in PDL fibroblasts

Paradoxical response during antituberculous therapy in a patient discontinuing infliximab: a case report

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Data Assimilation of AOD and Estimation of Surface Particulate Matters over the Arctic

In this study, more accurate information on the levels of aerosol optical depth (AOD) was calculated from the assimilation of the modeled AOD based on the optimal interpolation method. Additionally, more realistic levels of surface particulate matters over the Arctic were estimated using the assimilated AOD based on the linear relationship between the particulate matters and AODs. In comparison to the MODIS observation, the assimilated AOD was much improved compared with the modeled AOD (e.g., increase in correlation coefficients from −0.15–0.26 to 0.17–0.76 over the Arctic). The newly inferred monthly averages of PM10 and PM2.5 for April–September 2008 were 2.18–3.70 μg m−3 and 0.85–1.68 μg m−3 over the Arctic, respectively. These corresponded to an increase of 140–180%, compared with the modeled PMs. In comparison to in-situ observation, the inferred PMs showed better performances than those from the simulations, particularly at Hyytiala station. Therefore, combining the model simulation and data assimilation provided more accurate concentrations of AOD, PM10, and PM2.5 than those only calculated from the model simulations

Data Assimilation of AOD and Estimation of Surface Particulate Matters over the Arctic

In this study, more accurate information on the levels of aerosol optical depth (AOD) was calculated from the assimilation of the modeled AOD based on the optimal interpolation method. Additionally, more realistic levels of surface particulate matters over the Arctic were estimated using the assimilated AOD based on the linear relationship between the particulate matters and AODs. In comparison to the MODIS observation, the assimilated AOD was much improved compared with the modeled AOD (e.g., increase in correlation coefficients from −0.15–0.26 to 0.17–0.76 over the Arctic). The newly inferred monthly averages of PM10 and PM2.5 for April–September 2008 were 2.18–3.70 μg m−3 and 0.85–1.68 μg m−3 over the Arctic, respectively. These corresponded to an increase of 140–180%, compared with the modeled PMs. In comparison to in-situ observation, the inferred PMs showed better performances than those from the simulations, particularly at Hyytiala station. Therefore, combining the model simulation and data assimilation provided more accurate concentrations of AOD, PM10, and PM2.5 than those only calculated from the model simulations

Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS-and Aβ-induced neuroinflam-matory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 mi-croglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proin-flammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflam-masome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroin-flammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphol-ogy, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and mor-phology. Taken together, our findings indicate that donepezil significantly downregulates LPS-and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.1