119 research outputs found
Alteration of Concanavalin A Binding Glycoproteins in Cerebrospinal Fluid and Serum of Alzheimer's Disease Patients
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. It is characterized pathologically by the formation of senile plaques and neurofibrilly tangles in the brain. Diagnostic markers for detecting earlier stages of AD are needed. We measured the intensity of concanavalin A (Con A) binding activities of glycoproteins of the cerebrospinal fluid (CSF) and serum of subjects to clarify the modification of core mannose since we expected that aberrant glycosylation of glycoproteins might be useful as a new biomarker for detecting AD. CSF samples were collected from 15 patients with probable AD (AD group), 5 patients with probable dementia with Lewy bodies (DLB) (DLB group) and 8 controls without dementia (control group), whereas serum samples from 20 patients with probable AD and 20 controls without dementia were also collected. Glycoproteins in the CSF and serum were detected by lectin blotting using Con A. In the CSF of the AD group, 2 Con A binding glycoproteins were significantly higher compared with the control group. Furthermore, using analysis of variance, 3 Con A binding glycoproteins detected from the CSF of the AD group showed significant differences among the 3 groups. The levels of 3 Con A binding glycoproteins were significantly lower than in non-dementia controls in the serum. These changes in Con A binding activities did not depend on the amount of proteins. Therefore, the data indicate that the aberrance of protein glycosylation relates to the pathology of AD, and has some promise as a new biomarker for the diagnosis of AD
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Identification of a Functional Variant in the <i>MICA</i> Promoter Which Regulates <i>MICA</i> Expression and Increases HCV-Related Hepatocellular Carcinoma Risk
Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10−5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.</p
PETREL for Astrophysics and Carbon Business
A multi-purpose 50kg class microsatellite hosting astrophysical mission and earth remote sensing, PETREL , will be launched in 2023. In the night side, PETREL observe the ultra-violet sky with a wide-field telescope covering 50 deg^2 for surveying transient objects related to supernovae, tidal disruption events, and gravitational wave events. Our UV telescope can detect the early phase UV emission from a neutron star merger occurred within 150 Mpc. In addition to the satellite observation, PETREL sends a detection alert including the coordinate and brightness of the UV transient to the ground via the real time communication network within several minutes after detection to conduct follow-up observations with the collaborating ground based observatories over the world. In the day side, PETREL observes the surface of the earth by using the tunable multi-spectral cameras and a ultra-compact hyperspectral camera. Our potential targets are the tropical forests (Green Carbon) and coastal zones (Blue Carbon) in the tropical areas to evaluating the global biological carbon strages. For this purpose PETREL will conduct multiple scale mapping collaborating with drones and small aircraft not only satellite. The obtained data will be used for academical research and for business applications. The technical difficulty of this satellite is that carries out multi-purpose with different requirements, such as astronomical observations which requires a quite high attitude stability and the earth observations requiring a high pointing accuracy, with limited resources. If it is possible, a novel small satellite system or a business style can be realized that can share the payload with academia and industry. PETREL has been adopted as Innovative Satellite Technology Demonstration Program No.3 led by JAXA, and development is underway with the aim of launching in FY2023
Hepatitis C Virus Infection Suppresses the Interferon Response in the Liver of the Human Hepatocyte Chimeric Mouse
BACKGROUND AND AIMS: Recent studies indicate that hepatitis C virus (HCV) can modulate the expression of various genes including those involved in interferon signaling, and up-regulation of interferon-stimulated genes by HCV was reported to be strongly associated with treatment outcome. To expand our understanding of the molecular mechanism underlying treatment resistance, we analyzed the direct effects of interferon and/or HCV infection under immunodeficient conditions using cDNA microarray analysis of human hepatocyte chimeric mice. METHODS: Human serum containing HCV genotype 1b was injected into human hepatocyte chimeric mice. IFN-α was administered 8 weeks after inoculation, and 6 hours later human hepatocytes in the mouse livers were collected for microarray analysis. RESULTS: HCV infection induced a more than 3-fold change in the expression of 181 genes, especially genes related to Organismal Injury and Abnormalities, such as fibrosis or injury of the liver (P = 5.90E-16∼3.66E-03). IFN administration induced more than 3-fold up-regulation in the expression of 152 genes. Marked induction was observed in the anti-fibrotic chemokines such as CXCL9, suggesting that IFN treatment might lead not only to HCV eradication but also prevention and repair of liver fibrosis. HCV infection appeared to suppress interferon signaling via significant reduction in interferon-induced gene expression in several genes of the IFN signaling pathway, including Mx1, STAT1, and several members of the CXCL and IFI families (P = 6.0E-12). Genes associated with Antimicrobial Response and Inflammatory Response were also significantly repressed (P = 5.22×10(-10)∼1.95×10(-2)). CONCLUSIONS: These results provide molecular insights into possible mechanisms used by HCV to evade innate immune responses, as well as novel therapeutic targets and a potential new indication for interferon therapy
The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection
DOCK2 is involved in the host genetics and biology of severe COVID-19
「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target
Characterization of MORN2 stability and regulatory function in LC3-associated phagocytosis in macrophages
Microtubule-associated protein A1/B1-light chain 3 (LC3)-associated phagocytosis (LAP) is a type of non-canonical autophagy that regulates phagosome maturation in macrophages. However, the role and regulatory mechanism of LAP remain largely unknown. Recently, the membrane occupation and recognition nexus repeat-containing-2 (MORN2) was identified as a key component of LAP for the efficient formation of LC3-recruiting phagosomes. To characterize MORN2 and elucidate its function in LAP, we established a MORN2-overexpressing macrophage line. At a steady state, MORN2 was partially cleaved by the ubiquitin-proteasome system. MORN2 overexpression promoted not only LC3-II production but also LAP phagosome (LAPosome) acidification during Escherichia coli uptake. Furthermore, the formation of LAPosomes containing the yeast cell wall component zymosan was enhanced in MORN2-overexpressing cells and depended on reactive oxygen species (ROS). Finally, MORN2-mediated LAP was regulated by plasma membrane-localized soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) such as SNAP-23 and syntaxin 11. Taken together, these findings demonstrate that MORN2, whose expression is downregulated via proteasomal digestion, is a limiting factor for LAP, and that membrane trafficking by SNARE proteins is involved in MORN2-mediated LAP
Effect of Pre-Gelatinization on the Physicochemical Properties of Dry Flours Produced from 5 Cassava Varieties of the Philippines
A New Content-Oriented Traffic Engineering for Content Distribution: CAR (Content Aware Routing)
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