CD38 genotype (rs1800561 (4693C > T): R140W)は新生児集中治療室への入院のリスク増加に関連する

BACKGROUNDS:Preterm birth (PTB)/admission to the neonatal intensive care unit (NICU) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. AIM:Given the role of CD38 in term delivery through oxytocin (OXT) release, we hypothesized that OXT signaling may play a role in the etiology of PTB/admission to the NICU. This study was designed to identify genetic variation in the CD38-oxytocin pathway associated with PTB/admission to the NICU. METHODS:To identify common genetic variants predisposing individuals to PTB/admission to the NICU, we genotyped two single nucleotide polymorphisms (SNPs) in the CD38-oxytocin pathway in 63 case mothers, 55 control mothers, and 188 female volunteers in Nara Medical University Hospital, Japan. RESULTS:Maternal genetic effect analysis of the SNP genotype data revealed a significant association between an SNP in CD38 (rs1800561 (4693C>T): R140W), which was reported to be correlated with diabetes and autism, and the risk of NICU admission. On the other hand, an SNP in the oxytocin receptor (OXTR) (rs2254298) showed no correlation with the risk of NICU admission. CONCLUSION:Our study points to an association between maternal common polymorphisms in the CD38 (rs1800561) gene in Japanese women and susceptibility to PTB/admission to the NICU. Future studies with larger sample sizes are needed to confirm the findings of this study.博士（医学）・甲第639号・平成27年11月27日Copyright © 2015 Elsevier B.V. All rights reserved

炎症性腸疾患におけるREG遺伝子ファミリーの発現と制御

The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all REG family genes in IBD is still unclear. Here, we analyzed expression of all REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in human colon cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (- 220 to - 211, - 179 to - 156, and - 146 to - 130) in REG Iα and the region (- 274 to- 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNAs for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.博士（医学）・乙第1438号・令和元年9月27日© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)

Field experiments to test the use of the normalized-difference vegetation index for phenology detection

Some previous studies have detected the timing of leaf expansion and defoliation using the normalized-difference vegetation index (NDVI), but to examine tree phenology using satellite data, NDVI results should be confirmed using ground-truthing. We examined the relationship between NDVI and tree phenology during leaf expansion and defoliation by simultaneously observing the spectral reflectance of the canopy surface and canopy surface images in a cool-temperate deciduous broad-leaved forest. To define the timing of leaf expansion and defoliation using NDVI, the index should meet three criteria: (1) NDVI should exhibit a monotonous increase or decrease (monotonicity). (2) The relationship between NDVI and the forest canopy\u27s status should be unique (uniqueness). (3) The method is robust against the systematic noise (bias) (robustness). In the spring, NDVI values of 0.2–0.3 (relative values: 0.15–0.28) and 0.6–0.7 (relative values: 0.65–0.78) satisfied all three criteria. NDVI values of 0.6–0.7 can serve as potential criteria for detecting the timing of leaf expansion. In autumn, no NDVI values satisfied all three criteria. Thus, NDVI does not appear to be useful for detecting the timing of defoliation. For an area where evergreen vegetation or snow covers the forest floor in winter, our results suggest that previous uses of NDVI to identify the timing of leaf expansion and defoliation on the basis of the date of the maximum rate of growth or reduction of NDVI and the date with a value midway between the year\u27s maximum and minimum values are misleading

Ultrafiltration attenuates cardiopulmonary bypass–induced acute lung injury in a canine model of single-lung transplantation

ObjectiveThe purpose of this study was to investigate the effects of cardiopulmonary bypass and ultrafiltration on graft function in a canine single-lung transplantation model.MethodsFifteen left single-lung transplantations were done in weight-mismatched canine pairs. The animals were divided into 3 groups: group 1, in which transplantation was done without cardiopulmonary bypass; group 2, in which transplantation was done with cardiopulmonary bypass and in which the cardiopulmonary bypass flow was decreased slowly with controlled pulmonary artery pressure; and group 3, in which transplantation was done with cardiopulmonary bypass and ultrafiltration. Hemodynamic parameters and lung function were monitored for 6 hours after reperfusion. The grafts were harvested for histologic studies, myeloperoxidase assay, and real-time quantitive reverse transcription–polymerase chain reaction of mRNA encoding interleukin 6.ResultsThe hemodynamic parameters were similar among the 3 groups. In group 1 Pao2 and alveolar to arterial gradient for O2 levels were excellent throughout the 6-hour observation period, but in group 2 they progressively deteriorated. However, ultrafiltration significantly (P = .02) improved the Pao2 level in group 3. On histology, interstitial edema and polynuclear cell infiltration were most marked in group 2 and significantly worse than in groups 1 and 3. Myeloperoxidase assay and real-time quantitative reverse transcription–polymerase chain reaction showed increased myeloperoxidase activity and interleukin 6 gene expression in group 2 grafts compared with group 1 grafts. Myeloperoxidase activity and interleukin 6 gene expression were suppressed with ultrafiltration.ConclusionsCardiopulmonary bypass had negative effects on the graft, but ultrafiltration attenuated acute lung dysfunction by reducing the inflammatory response

Expression of REG family genes in human inflammatory bowel diseases and its regulation

The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all REG family genes in IBD is still unclear. Here, we analyzed expression of all REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in human colon cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (− 220 to − 211, − 179 to − 156, and − 146 to − 130) in REG Iα and the region (− 274 to− 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNAs for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD

ヒト網膜色素上皮はヒドロキノンと最終糖化産物の共刺激により、VEGF遺伝子の発現上昇を伴って増殖する

Although recent research showed that advanced glycation endproduct (AGE) and hydroquinone (HQ) are related to the pathogenesis of age-related macular degeneration (AMD), the mechanism how AGE and HQ induce or accelerate AMD remains elusive. In the present study, we examined the effects of AGE and HQ on changes of human retinal pigment epithelial (RPE) cell numbers and found that the viable cell numbers were markedly reduced by HQ by apoptosis and that AGE prevented the decreases of HQ-treated cell numbers by increased replicative DNA synthesis of RPE cells without changing apoptosis. Real-time RT-PCR revealed that vascular endothelial growth factor (VEGF)-A mRNA was increased by HQ treatment and the addition of HQ+AGE resulted in a further increment. The increase of VEGF secretion was confirmed by ELISA, and inhibition of VEGF signaling by chemical inhibitors and small interfering RNA decreased the HQ+AGE-induced increases in RPE cell numbers. The deletion analysis demonstrated that −102 to −43 region was essential for the VEGF-A promoter activation. Site-directed mutaions of specificity protein 1 (SP1) binding sequences in the VEGF-A promoter and RNA interference of SP1 revealed that SP1 is an essential transcription factor for VEGF-A expression. These results indicate that HQ induces RPE cell apoptosis, leading to dry AMD, and suggest that AGE stimulation in addition to HQ enhances VEGF-A transcription via the AGE-receptor for AGE pathway in HQ-damaged cells. As a result, the secreted VEGF acts as an autocrine/paracrine growth factor for RPE and/or adjacent vascular cells, causing wet AMD.博士（医学）・甲第640号・平成27年11月27日Copyright © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Increase in Cytochorome c and a 11.9 kDa protein in Submerged Rice Seedlings after Exposure to Air

To examine the changes in cytocrome c content in submerged rice seedlings after exposure to air, antiserum was prepared against purified cytocrome c from rice bran. Western blottong analysis revealed that cytochrome c was detected 6 h after exposure to air, but not detected in submerged rice seedling. On a fresh weight basis, the same level of cytochrome c as that of the aerobic control was found in the 24-h-air adapted seedlings. judging from the high A408/A280 ratio (4.66),the cytochrome c preparation used as antigen was considered to be well purified. However, the antiserum reacted other several polypeptides. One of them reacted more strongly against the antisermu than cytochrome c and its molecular weight was estimated as 11.9 kDa. The polypeptide increased during air adaptation and the levels found in both submerged seedlings and aerobic control were lower than that in 24-h-air-adapted seedlings.イネ水中芽生えを空気に触れさせた後のチトクロムc含量の変動を調べるために、米ぬかから精製したチトクロムcを用いて抗チトクロムc血清を作成した。ウェスタンプロット分析によると、水中芽生えにはチトクロムcは検出されなかったが、空気に触れてから6時間以降に検出された。酸素適応24時間の芽生えには生重量あたりで好気対照と同レベルのチトクロムcが存在した。抗血清作成の抗原として用いたチトクロムc標品は、A408/A280比の値（4.66）が高いことから、よく精製されていると考えられるが、抗血清はいくつかの他のポリペプチドと反応した。そのうちの一つはチトクロムcよりも抗血清に強く反応し、その分子量は11.9kDaであった。このポリペプチドは酸素適応過程で増加し、水中芽生えや好気対照では24時間酸素適応芽生えよりも少なかった

妊娠高血圧症候群におけるRAGEの関与

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), high mobility group box 1 (HMGB1), and RAGE were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of IL-6 and CCL2 in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for RAGE (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly suggest that the elevated AGE, HMGB1, and LPS in pregnant women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.博士（医学）・乙第1451号・令和2年3月16日© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)