Publications by authors named "Ayako Hashimoto"

64 Publications

Intraspecific variations of the cytoplasmic male sterility genes and in Brassica maurorum and Moricandia arvensis, and the specificity of the mRNA processing.

Genome 2021 Jun 15. Epub 2021 Jun 15.

Dept. Biotech., Fac. Eng., Kyoto Sangyo Univ., Motoyama, Kamigamo, Kyoto, Kyoto, Japan, 603-8555;

The mitochondrial gene co-transcribed with and causes cytoplasmic male sterility in crops, is widely distributed across wild species and genera of . However, intraspecific variations in the presence of have not yet been studied, and the mechanisms for the wide distribution of the gene remain unclear. We analyzed the presence and sequence variations of in two wild species, and . After polymerase chain reaction amplification of the 5' region of and the coding sequence of , we determined the DNA sequences. and showed variations for the presence of or () both between and within accessions, and were not fixed to the mitochondrial type having the male sterile genes. Sequencing of the amplicons clarified that has instead of . Sequencing also indicated mitochondrial heteroplasmy in the two species; particularly, in , one plant possessed both the and sequences. The results suggested that substoichiometric shifting of the mitochondrial genomes leads to the acquisition or loss of . Furthermore, fertility restorer genes of the two species were involved in the processing of the mRNA of the male sterility genes at different sites.
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http://dx.doi.org/10.1139/gen-2021-0011DOI Listing
June 2021

Development of a Gas Environmental Heating Specimen Holder System Using Differential Pumping.

Microscopy (Oxf) 2021 May 28. Epub 2021 May 28.

In-situ Characterization Technique Development Group, National Institute for Materials Science, 1-2-1 Sengen, Tsukuba, 305-0047, Japan.

We developed a gas environmental heating specimen holder system by applying differential pumping effect to a specimen holder for the in-situ transmission electron microscopy observation and electron energy loss spectroscopy (EELS) analysis of catalytic materials. In the in-situ experiments, using two small orifices and O-rings, the maximum formed gas pressure was ~20 Pa. Also, using a heater membrane, the maximum obtained heating temperature was ~1000°C. We could actually observe/analyze the Pt and Ni nanoparticles with an atomic scale using a double-aberration corrected microscope and an EELS instrument in the reaction gases at high temperatures.
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http://dx.doi.org/10.1093/jmicro/dfab019DOI Listing
May 2021

A single nucleotide substitution in the coding region of Ogura male sterile gene, orf138, determines effectiveness of a fertility restorer gene, Rfo, in radish.

Mol Genet Genomics 2021 May 26;296(3):705-717. Epub 2021 Mar 26.

Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo, Kita, Kyoto, 603-8555, Japan.

Cytoplasmic male sterility (CMS) observed in many plants leads defect in the production of functional pollen, while the expression of CMS is suppressed by a fertility restorer gene in the nuclear genome. Ogura CMS of radish is induced by a mitochondrial orf138, and a fertility restorer gene, Rfo, encodes a P-type PPR protein, ORF687, acting at the translational level. But, the exact function of ORF687 is still unclear. We found a Japanese variety showing male sterility even in the presence of Rfo. We examined the pollen fertility, Rfo expression, and orf138 mRNA in progenies of this variety. The progeny with Type H orf138 and Rfo showed male sterility when their orf138 mRNA was unprocessed within the coding region. By contrast, all progeny with Type A orf138 were fertile though orf138 mRNA remained unprocessed in the coding region, demonstrating that ORF687 functions on Type A but not on Type H. In silico analysis suggested a specific binding site of ORF687 in the coding region, not the 5' untranslated region estimated previously, of Type A. A single nucleotide substitution in the putative binding site diminishes affinity of ORF687 in Type H and is most likely the cause of the ineffectiveness of ORF687. Furthermore, fertility restoration by RNA processing at a novel site in some progeny plants indicated a new and the third fertility restorer gene, Rfs, for orf138. This study clarified that direct ORF687 binding to the coding region of orf138 is essential for fertility restoration by Rfo.
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http://dx.doi.org/10.1007/s00438-021-01777-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144145PMC
May 2021

Appearance of male sterile and black radishes in the progeny of cross between and .

Breed Sci 2020 Dec 5;70(5):637-641. Epub 2020 Nov 5.

Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo, Kita, Kyoto 603-8555, Japan.

In addition to Ogura cytoplasmic male sterility (CMS), which is used extensively for F hybrid seed production in Brassicaceae crops, two other CMS systems, NWB CMS and DCGMS, have also been identified. The causal gene for the latter two CMS systems has been identified as a novel chimeric gene, . We previously reported that is specific to black radish cultivars and that it is present in line 'RS-5' of ; however, the sequence in 'RS-5' differed from that of black radish cultivars. Though, with an sequence identical to that found in black radish cultivars was recently identified. We therefore sought to determine whether the gene in line 'RS-5' induces CMS in radishes. We crossed 'RS-5' as a female parent with a cultivated radish, 'Uchiki-Gensuke', as a male parent, and examined the gross plant morphology and pollen fertility of the resulting progeny. The F population contained both male sterile plants and plants with black roots. The findings showed that contains two types of genes that induce CMS, and that the origin of black radishes could be attributed to having gene.
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http://dx.doi.org/10.1270/jsbbs.20081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878931PMC
December 2020

Impact of exosome-mediated feto-maternal interactions on pregnancy maintenance and development of obstetric complications.

J Biochem 2021 Mar;169(2):163-171

School of Life Science and Technology, Tokyo Institute of Technology, Nagatsuta-cho 4259, Midori-ku, Yokohama-shi, Kanagawa 226-8501, Japan.

Pregnancy is an immunological paradox, a phenomenon in which the foetus and the placenta, containing foreign antigens to the mother, develop without inducing rejection by the maternal immune system. Cell-to-cell communication between the foetus and the mother is mediated by secreted factors such as cytokines, hormones and extracellular vesicles (EVs) for a successful pregnancy and to avoid rejection. Exosomes, the smallest of EVs, are released extracellularly, where they are taken up by proximal or distant recipient cells. Here, we discuss the role of EVs, especially exosomes in feto-maternal communication during pregnancy. This review will provide an overview of the functional roles exosomes may play during embryo implantation, modulating immune responses during pregnancy and the onset of labour. Moreover, we will discuss exosomal function in obstetric pathology, and the development of pregnancy-associated complications such as preeclampsia and preterm birth as well as the biomarker potential of exosomes for detecting such conditions.
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http://dx.doi.org/10.1093/jb/mvaa137DOI Listing
March 2021

Polyhydramnios is associated with postnatal dysphagia determining short-term prognosis of the newborn with 22q11.2 deletion syndrome - A case series analysis.

Taiwan J Obstet Gynecol 2020 Sep;59(5):744-747

Department of Obstetrics and Gynecology, Faculty of Medicine, Japan.

Objective: We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios, and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on dysphagia.

Case Report: A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios. After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and 22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retrospective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and no major complications.

Conclusion: Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-term prognostic outcomes in newborns with 22qDS.
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http://dx.doi.org/10.1016/j.tjog.2020.07.021DOI Listing
September 2020

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

Cell 2020 08 13;182(4):1044-1061.e18. Epub 2020 Aug 13.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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http://dx.doi.org/10.1016/j.cell.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522766PMC
August 2020

Low energy intake and dietary quality are associated with low objective sleep quality in young Japanese women.

Nutr Res 2020 08 6;80:44-54. Epub 2020 Jun 6.

School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address:

Literature reports suggest that subjective sleep quality is associated with nutrient intake in elderly people and workers. However, few studies have suggested an association between objective sleep quality and dietary intake in adolescents and young women. We hypothesized that objective sleep quality is associated with dietary intake in adolescents and young women. We evaluated the association between energy and nutrient intake and objective sleep quality in adolescents and young Japanese women. In a cross-sectional study of 80 women aged 18-27 years, dietary intake was assessed using the self-administered diet history questionnaire. Objective sleep quality was assessed by actigraphy. Lifestyle characteristics, dietary habits, and mental health were assessed using specific questionnaires. Subjects were classified into 3 groups according to sleep efficiency (SE <80%, 80%-85%, and ≥85%), and the relationships between dietary intake and objective sleep quality were statistically evaluated. No significant differences occurred in lifestyle characteristics, physical activity levels, eating behavior, and mental health status among the 3 SE groups. Energy intake was significantly lower in the low-SE group than in the middle- (P = .004) and high- (P = .015) SE groups. Protein intake was significantly lower in the low-SE group than in the high-SE group (P = .034). The mean energy-adjusted intakes of vitamin K, vitamin B, potassium, magnesium, iron, zinc, copper, and tryptophan were significantly lower in the low-SE group than in the high-SE group. Adequate energy intake and a high-quality diet including vitamins, minerals, and tryptophan may result in high sleep quality and help prevent sleep problems.
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http://dx.doi.org/10.1016/j.nutres.2020.06.002DOI Listing
August 2020

Congenital extracardiac venous system anomaly in two siblings with normal karyotype and increased nuchal translucency thickness: a case report.

Oxf Med Case Reports 2020 Jun 13;2020(6):omaa034. Epub 2020 Jun 13.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Previous studies have reported that congenital heart diseases (CHDs) develop in patients with genetic and environmental predisposition. Compared to CHDs, the significance of hereditary factors in the pathogenesis of congenital venous system anomalies remains unclear. Additionally, reports describing the pathogenic relationship between venous system anomalies and increased nuchal translucency (NT) are few. We report sibling recurrence of congenital venous system anomalies. In the prenatal periods of both siblings, increased NT without aneuploidy was confirmed. In the first sibling, the absence of ductus venosus (ADV) and umbilical vein-coronary sinus anastomosis was detected using prenatal ultrasonography. In the second sibling, abnormality of the pulmonary vein was suspected prenatally, leading to a final diagnosis of infracardiac total anomalous pulmonary venous return (TAPVR). This is the first report of extracardiac venous anomaly-associated recurrence of increased NT among siblings. We conclude that a hereditary factor may be responsible for the development of ADV and TAPVR.
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http://dx.doi.org/10.1093/omcr/omaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293141PMC
June 2020

Comparison of the Intestinal Drug Permeation and Accumulation Between Normal Human Intestinal Tissues and Human Intestinal Tissues With Ulcerative Colitis.

J Pharm Sci 2020 04 20;109(4):1623-1626. Epub 2019 Dec 20.

Quality Assurance Section, Quality Assurance Department, Headquarters for Product Safety and Quality Assurance, Otsuka Pharmaceutical Co. Ltd., Matsudani Itano-cho, Itano-gun, Tokushima 779-0195, Japan.

The purpose of this study was to examine drug absorption profile utilizing human intestinal tissues from ulcerative colitis (UC) patients and to compare with normal tissues from intestinal cancer patients. Human intestinal tissues from UC and cancer patients mounted in a mini-Ussing chamber were used to evaluate the permeation of drugs, including FD-4, a very low permeable marker, rebamipide, a low permeable marker, and metoprolol, a high permeable marker. The transport index, an index of sum of permeated and tissue-accumulated molecules, of the model drugs was in accordance with their absorption rank order, and was almost kept constant irrespective of autopsy grade based on tissue fibrosis. On the other hand, UC tissues of grade 2 showed the decreased X, an index of permeated amount of molecules and increased T, an index of tissue-accumulated molecules for every tested compound. Our finding of the transport characteristics in intestinal tissues of severe UC patients in mini-Ussing chamber system demonstrated that autopsy grade of UC patients did not drastically change membrane permeability of the tested compounds. Furthermore, it was suggested that morphological changes of intestinal tissues caused by fibrosis led to limited permeation and subsequently increased accumulation with little change of total absorption.
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http://dx.doi.org/10.1016/j.xphs.2019.12.015DOI Listing
April 2020

Reversible low-temperature redox activity and selective oxidation catalysis derived from the concerted activation of multiple metal species on Cr and Rh-incorporated ceria catalysts.

Phys Chem Chem Phys 2019 Oct 13;21(37):20868-20877. Epub 2019 Sep 13.

Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. and Research Center for Materials Science (RCMS) & Integrated Research Consortium on Chemical Sciences (IRCCS), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.

The ceria-based catalyst incorporated with Cr and a trace amount of Rh (CrRhCeO) was prepared and the reversible redox performances and oxidation catalysis of CO and alcohol derivatives with O at low temperatures (<373 K) were investigated. In situ X-ray absorption fine structure (XAFS), ambient-pressure X-ray photoelectron spectroscopy (AP-XPS), high angle annular dark-field scanning transmission electron microscopy (HAADF-STEM)-EDS/EELS and temperature-programmed reduction/oxidation (TPR/TPO) revealed the structures and redox mechanisms of three metals in CrRhCeO: dispersed Rh species (<1 nm) and CrO nanoparticles (∼1 nm) supported on CeO in CrRhCeO were transformed to Rh nanoclusters, Cr(OH) species and CeO with two Ce-oxide layers at the surface in a concerted activation manner of the three metal species with H.
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http://dx.doi.org/10.1039/c9cp04625aDOI Listing
October 2019

Mesoporous Rh Emerging from Nanophase-separated Rh-Y Alloy.

Chem Asian J 2019 Aug 19;14(16):2802-2805. Epub 2019 Jul 19.

National Institute for Materials Science, Namiki 1-1, Tsukuba, Ibaraki, 305-0044, Japan.

Mesoporous precious metals with abundant active sites and high surface area have been widely recognized as high-performance catalytic materials. However, the templated synthesis is complex and costly. Herein, we report a mesoporous rhodium (m-Rh) that can be readily synthesized from entangled nanofibres of Rh and Y O without templates. The entangled nanofibres, prepared from uniform Rh-Y alloys under redox atmosphere, were the key precursor in the synthesis processes. Moreover, the m-Rh efficiently catalyzed carbon dioxide reforming of methane (DRM) at a low reaction temperature of 683 K. Further, electrochemical methods of CO electro-oxidation were innovatively used to demonstrate the stability of CO and oxygen species for the DRM reaction.
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http://dx.doi.org/10.1002/asia.201900542DOI Listing
August 2019

Management of a pregnant woman with hypouricemia: a case report.

Oxf Med Case Reports 2019 May 31;2019(5):omz035. Epub 2019 May 31.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Renal hypouricemia is associated with urinary calculi and severe acute renal failure after exercise. The epidemiology of renal hypouricemia is not yet sufficiently understood, and there is no report of it occurring during pregnancy. We report the case of a pregnant woman with renal hypouricemia. At her first pregnancy, she developed preeclampsia with severe features at the 34th week of gestation. After parturition, she developed acute renal failure and was diagnosed with renal hypouricemia. During the second pregnancy, when she was referred to our hospital, care was taken to ensure adequate hydration by infusion of liquids and water at the time of labour. Consequently, she did not have onset of renal hypouricemia. We suggest that acute renal failure may be avoided in pregnant women with renal hypouricemia by preventing dehydration via drinking enough during pregnancy postpartum period and by infusion during labour.
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http://dx.doi.org/10.1093/omcr/omz035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544418PMC
May 2019

Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease.

Nat Commun 2019 05 8;10(1):2110. Epub 2019 May 8.

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden.

Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
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http://dx.doi.org/10.1038/s41467-019-10100-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506521PMC
May 2019

Topologically immobilized catalysis centre for long-term stable carbon dioxide reforming of methane.

Chem Sci 2019 Apr 13;10(13):3701-3705. Epub 2019 Feb 13.

National Institute for Materials Science , 1-1 Namiki , Tsukuba , Ibaraki 305-004 , Japan . Email: ; Email:

Methane reforming at low temperatures is of growing importance to mitigate the environmental impact of the production of synthesis gas, but it suffers from short catalyst lifetimes due to the severe deposition of carbon byproducts. Herein, we introduce a new class of topology-tailored catalyst in which tens-of-nanometer-thick fibrous networks of Ni metal and oxygen-deficient YO are entangled with each other to form a rooted structure, , Ni#YO. We demonstrate that the rooted Ni#YO catalyst stably promotes the carbon-dioxide reforming of methane at 723 K for over 1000 h, where the performance of traditional supported catalysts such as Ni/YO diminishes within 100 h due to the precluded mass transport by accumulated carbon byproducts. TEM demonstrates that the supported Ni nanoparticles are readily detached from the support surface in the reaction atmosphere, and migrate around to result in widespread accumulation of the carbon byproducts. The long-term stable methane reforming over the rooted catalyst is ultimately attributed to the topologically immobilized Ni catalysis centre and the synergistic function of the oxygen-deficient YO matrix, which successfully inhibits the accumulation of byproducts.
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http://dx.doi.org/10.1039/c8sc04965cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461125PMC
April 2019

Hunter Syndrome Diagnosed by Otorhinolaryngologist.

Case Rep Otolaryngol 2018 13;2018:4252696. Epub 2018 May 13.

Department of Otorhinolaryngology, Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Hunter syndrome is a lysosomal disease characterized by deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). It has an estimated incidence of approximately 1 in 1,62,000 live male births. We report a case of Hunter syndrome diagnosed by an otorhinolaryngologist. To our knowledge, this is the first study diagnosed by an otorhinolaryngologist despite the fact that otorhinolaryngological symptoms manifest at a young age in this disease. The patient was a 4-year-old boy. He underwent adenotonsillectomy. Intubation was difficult, and he had some symptoms which are reasonable as a mucopolysaccharidosis. The otorhinolaryngologist should play an integral role in the multidisciplinary approach to the diagnosis and management of many children with MPS (mucopolysaccharidoses) disorders.
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http://dx.doi.org/10.1155/2018/4252696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971261PMC
May 2018

An infant case of intraoral penetrating injury with a toothbrush causing retropharyngeal and upper mediastinal emphysema.

J Indian Soc Pedod Prev Dent 2017 Apr-Jun;35(2):181-183

Department of Acute Critical Care Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan.

A 2-year-old male child who was running and fell with a toothbrush in his mouth suffered an injury to the inside of his right cheeks. His mother noticed that the toothbrush had impaled his mouth, and removed it. On arrival, a wound was observed on the right cheeks and palate. His general condition was good. However, computed tomography revealed emphysema from the left side of epipharynx to the upper mediastinum. This patient shows the importance of not only checking the medical history and performing a physical examination but also performing an imaging examination.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_114_16DOI Listing
March 2018

One-atom-thick 2D copper oxide clusters on graphene.

Nanoscale 2017 Mar;9(11):3980-3985

Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8573, Japan. and National Institute for Materials Science, Tsukuba, 305-0047, Japan.

The successful isolation and remarkable properties of graphene have recently triggered investigation of two-dimensional (2D) materials from layered compounds; however, one-atom-thick 2D materials without bulk layered counterparts are scarcely reported. Here we report the structure and properties of novel 2D copper oxide studied by experimental and theoretical methods. Electron microscopy observations reveal that copper oxide can form monoatomic layers with an unusual square lattice on graphene. Density functional theory calculations suggest that oxygen atoms at the centre of the square lattice stabilizes the 2D Cu structure, and that the 2D copper oxide sheets have unusual electronic and magnetic properties different from 3D bulk copper oxide.
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http://dx.doi.org/10.1039/c6nr06874jDOI Listing
March 2017

Adenomyosis and adverse perinatal outcomes: increased risk of second trimester miscarriage, preeclampsia, and placental malposition.

J Matern Fetal Neonatal Med 2018 Feb 9;31(3):364-369. Epub 2017 Feb 9.

a Department of Obstetrics and Gynecology, Faculty of Medicine , University of Tokyo , Tokyo , Japan.

Objective: To evaluate the potential impact of adenomyosis on the pregnancy outcomes by retrospectively investigating adenomyosis-complicated pregnancy cases.

Methods: We performed a retrospective case-control study. Forty-nine singleton pregnancy cases complicated with adenomyosis were included in this study. The controls (n = 245) were singleton pregnant women without adenomyosis and were frequency matched to adenomyosis cases by age, parity, and the need for assisted reproductive technology for this conception. The incidence of obstetrical complications and delivery and neonatal outcomes were examined.

Results: Patients in the adenomyosis group were significantly more likely to have a second trimester miscarriage (12.2% versus 1.2%, odds ratio (OR): 11.2, 95% confidence interval (95% CI): 2.2-71.2), preeclampsia (18.3% versus 1.2%, OR: 21.0, 95% CI: 4.8-124.5), placental malposition (14.2% versus 3.2%, OR: 4.9, 95% CI: 1.4-16.3), and preterm delivery (24.4% versus 9.3%, OR: 3.1, 95% CI: 1.2-7.2), compared with the control group.

Conclusion: Adenomyosis was associated not only with an increased incidence of preterm delivery, as previously reported, but also with an increased risk of second trimester miscarriage, preeclampsia, and placental malposition, which could lead to poor perinatal outcomes.
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http://dx.doi.org/10.1080/14767058.2017.1285895DOI Listing
February 2018

The Effect of Cage Shape on Nanoparticle-Based Drug Carriers: Anticancer Drug Release and Efficacy via Receptor Blockade Using Dextran-Coated Iron Oxide Nanocages.

Nano Lett 2016 12 10;16(12):7357-7363. Epub 2016 Nov 10.

Department of Chemistry, Hunter College, City University of New York , 695 Park Avenue, New York, New York 10065, United States.

Although a range of nanoparticles have been developed as drug delivery systems in cancer therapeutics, this approach faces several important challenges concerning nanocarrier circulation, clearance, and penetration. The impact of reducing nanoparticle size on penetration through leaky blood vessels around tumor microenvironments via enhanced permeability and retention (EPR) effect has been extensively examined. Recent research has also investigated the effect of nanoparticle shape on circulation and target binding affinity. However, how nanoparticle shape affects drug release and therapeutic efficacy has not been previously explored. Here, we compared the drug release and efficacy of iron oxide nanoparticles possessing either a cage shape (IO-NCage) or a solid spherical shape (IO-NSP). Riluzole cytotoxicity against metastatic cancer cells was enhanced 3-fold with IO-NCage. The shape of nanoparticles (or nanocages) affected the drug release point and cellular internalization, which in turn influenced drug efficacy. Our study provides evidence that the shape of iron oxide nanoparticles has a significant impact on drug release and efficacy.
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http://dx.doi.org/10.1021/acs.nanolett.6b02577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610656PMC
December 2016

Chronic active EBV infection with features of granulomatosis with polyangiitis.

Pediatr Int 2016 Jul 8;58(7):639-42. Epub 2016 Mar 8.

Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Herein, we report the case of a 13-year-old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein-Barr virus (EBV)-encoded RNA (EBER) in most lymphocytes in the same sample. The EBER-positive lymphocytes were mainly CD4-positive T cells. The EBV-DNA load in the peripheral blood was also abnormally increased (1.0 × 10(4) copies/μg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA.
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http://dx.doi.org/10.1111/ped.12892DOI Listing
July 2016

Properties of Zip4 accumulation during zinc deficiency and its usefulness to evaluate zinc status: a study of the effects of zinc deficiency during lactation.

Am J Physiol Regul Integr Comp Physiol 2016 Mar 23;310(5):R459-68. Epub 2015 Dec 23.

Department of Science of Food Function and Health, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan;

Systemic and cellular zinc homeostasis is elaborately controlled by ZIP and ZnT zinc transporters. Therefore, detailed characterization of their expression properties is of importance. Of these transporter proteins, Zip4 functions as the primarily important transporter to control systemic zinc homeostasis because of its indispensable function of zinc absorption in the small intestine. In this study, we closely investigated Zip4 protein accumulation in the rat small intestine in response to zinc status using an anti-Zip4 monoclonal antibody that we generated and contrasted this with the zinc-responsive activity of the membrane-bound alkaline phosphatase (ALP). We found that Zip4 accumulation is more rapid in response to zinc deficiency than previously thought. Accumulation increased in the jejunum as early as 1 day following a zinc-deficient diet. In the small intestine, Zip4 protein expression was higher in the jejunum than in the duodenum and was accompanied by reduction of ALP activity, suggesting that the jejunum can become zinc deficient more easily. Furthermore, by monitoring Zip4 accumulation levels and ALP activity in the duodenum and jejunum, we reasserted that zinc deficiency during lactation may transiently alter plasma glucose levels in the offspring in a sex-specific manner, without affecting homeostatic control of zinc metabolism. This confirms that zinc nutrition during lactation is extremely important for the health of the offspring. These results reveal that rapid Zip4 accumulation provides a significant conceptual advance in understanding the molecular basis of systemic zinc homeostatic control, and that properties of Zip4 protein accumulation are useful to evaluate zinc status closely.
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http://dx.doi.org/10.1152/ajpregu.00439.2015DOI Listing
March 2016

Interactions between C and Cu atoms in single-layer graphene: direct observation and modelling.

Nanoscale 2016 Jan;8(1):529-35

Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8573, Japan. and Surface Physics and Structure Unit, National Institute for Materials Science, Tsukuba, 305-0047, Japan.

Metal doping into the graphene lattice has been studied recently to develop novel nanoelectronic devices and to gain an understanding of the catalytic activities of metals in nanocarbon structures. Here we report the direct observation of interactions between Cu atoms and single-layer graphene by transmission electron microscopy. We document stable configurations of Cu atoms in the graphene sheet and unique transformations of graphene promoted by Cu atoms. First-principles calculations based on density functional theory reveal a reduction of energy barrier that caused rotation of C-C bonds near Cu atoms. We discuss two driving forces, electron irradiation and in situ heating, and conclude that the observed transformations were mainly promoted by electron irradiation. Our results suggest that individual Cu atoms can promote reconstruction of single-layer graphene.
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http://dx.doi.org/10.1039/c5nr05913eDOI Listing
January 2016

Mg, Zn and Cu Transport Proteins: A Brief Overview from Physiological and Molecular Perspectives.

J Nutr Sci Vitaminol (Tokyo) 2015 ;61 Suppl:S116-8

The Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University.

Essential major and trace elements, including magnesium (Mg), zinc (Zn) and copper (Cu), are involved in numerous physiological processes. These elements are important components for maintaining proper protein structure and function. They are also used as catalytic cofactors for enzymes and as mediators in signaling cascades. Thus, systemic homeostasis of these metals is sophisticatedly regulated at a molecular level. A balance between absorption and excretion of these metals is critical, and transport proteins play a key role in this balance. In particular, transport proteins in intestinal epithelial cells are indispensable and ensure adequate metal absorption. Regulation of the expression and activity of these proteins is complicated. Thus, dysfunction of these proteins causes an imbalance in the systemic homeostasis of corresponding metals, and thus likely links to disease pathogenesis. In this review, we briefly describe the importance of mammalian metal transport proteins, including Mg channels, and Zn and Cu transporters, focusing on their roles in the absorption process in intestinal epithelial cells. Specifically, TRPM6 channels in Mg absorption, ZIP4 and ZnT1 transporters for Zn absorption, and CTR1 and ATP7A for Cu absorption are overviewed.
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http://dx.doi.org/10.3177/jnsv.61.S116DOI Listing
September 2016

Tumour exosome integrins determine organotropic metastasis.

Nature 2015 Nov 28;527(7578):329-35. Epub 2015 Oct 28.

Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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http://dx.doi.org/10.1038/nature15756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788391PMC
November 2015

Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling.

EMBO J 2015 Nov 5;34(21):2703-19. Epub 2015 Oct 5.

Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

Degradation of mitochondria via selective autophagy, termed mitophagy, contributes to mitochondrial quality and quantity control whose defects have been implicated in oxidative phosphorylation deficiency, aberrant cell differentiation, and neurodegeneration. How mitophagy is regulated in response to cellular physiology remains obscure. Here, we show that mitophagy in yeast is linked to the phospholipid biosynthesis pathway for conversion of phosphatidylethanolamine to phosphatidylcholine by the two methyltransferases Cho2 and Opi3. Under mitophagy-inducing conditions, cells lacking Opi3 exhibit retardation of Cho2 repression that causes an anomalous increase in glutathione levels, leading to suppression of Atg32, a mitochondria-anchored protein essential for mitophagy. In addition, loss of Opi3 results in accumulation of phosphatidylmonomethylethanolamine (PMME) and, surprisingly, generation of Atg8-PMME, a mitophagy-incompetent lipid conjugate of the autophagy-related ubiquitin-like modifier. Amelioration of Atg32 expression and attenuation of Atg8-PMME conjugation markedly rescue mitophagy in opi3-null cells. We propose that proper regulation of phospholipid methylation is crucial for Atg32-mediated mitophagy.
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http://dx.doi.org/10.15252/embj.201591440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641534PMC
November 2015

Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.

Biochem J 2015 Dec 18;472(2):183-93. Epub 2015 Sep 18.

Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans.
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http://dx.doi.org/10.1042/BJ20150862DOI Listing
December 2015

Cilostazol Induces PGI2 Production via Activation of the Downstream Epac-1/Rap1 Signaling Cascade to Increase Intracellular Calcium by PLCε and to Activate p44/42 MAPK in Human Aortic Endothelial Cells.

PLoS One 2015 16;10(7):e0132835. Epub 2015 Jul 16.

First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima-shi, Tokushima, Japan.

Background: Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells.

Methods And Results: Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) γ, and phospholipase C (PLC) ε, suppressed cilostazol-induced PGI2 synthesis.

Conclusions: The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCε/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kγ, resulting in synergistically induced PGI2 synthesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504471PMC
April 2016

Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation.

Nat Commun 2015 Jul 6;6:7527. Epub 2015 Jul 6.

Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London SE5 9NU, UK.

Damaged mitochondria are removed by mitophagy. Although Atg32 is essential for mitophagy in yeast, no Atg32 homologue has been identified in mammalian cells. Here, we show that Bcl-2-like protein 13 (Bcl2-L-13) induces mitochondrial fragmentation and mitophagy in mammalian cells. First, we hypothesized that unidentified mammalian mitophagy receptors would share molecular features of Atg32. By screening the public protein database for Atg32 homologues, we identify Bcl2-L-13. Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy in HEK293 cells. In Bcl2-L-13, the BH domains are important for the fragmentation, while the WXXI motif facilitates mitophagy. Bcl2-L-13 induces mitochondrial fragmentation in the absence of Drp1, while it induces mitophagy in Parkin-deficient cells. Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy. Bcl2-L-13 induces mitophagy in Atg32-deficient yeast cells. Induction and/or phosphorylation of Bcl2-L-13 may regulate its activity. Our findings offer insights into mitochondrial quality control in mammalian cells.
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http://dx.doi.org/10.1038/ncomms8527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501433PMC
July 2015

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism.

Physiol Rev 2015 Jul;95(3):749-84

Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.
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http://dx.doi.org/10.1152/physrev.00035.2014DOI Listing
July 2015
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