3,184 results on '"Nakata, A."'
Search Results
2. Low serum albumin concentration is associated with increased risk of osteoporosis in postmenopausal patients with rheumatoid arthritis
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Jun Hashimoto, Hideki Tsuboi, Yoshio Nagayama, Kosuke Ebina, Hideki Yoshikawa, Ken Nakata, Seiji Okada, and Makoto Hirao
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medicine.medical_specialty ,Osteoporosis ,Serum albumin ,Gastroenterology ,Bone remodeling ,Arthritis, Rheumatoid ,Absorptiometry, Photon ,Bone Density ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,Serum Albumin ,Osteoporosis, Postmenopausal ,Aged ,Retrospective Studies ,Femoral neck ,Bone mineral ,Lumbar Vertebrae ,biology ,business.industry ,medicine.disease ,Postmenopause ,medicine.anatomical_structure ,Rheumatoid arthritis ,Propensity score matching ,Prednisolone ,biology.protein ,Female ,Surgery ,business ,medicine.drug - Abstract
The risk of osteoporosis in patients with rheumatoid arthritis (RA) is frequently overlooked, and investigating a simple indicator in routine care may be beneficial to motivate osteoporosis examination. The aim of this retrospective, case-controlled study was to identify the correlation between serum albumin concentrations and the prevalence of osteoporosis in postmenopausal patients with RA.This study enrolled 197 patients who underwent dual-energy X-ray absorptiometry of lumbar spine (LS) and proximal femur without osteoporosis treatment [mean age, 67.5 years; disease duration, 12.8 years; Disease Activity Score assessing 28 joints with C-reactive protein, 2.0; prednisolone dose, 4.9 mg/day (usage, 42.6%); and LS T-score, -1.9]. Patients were classified into 2 groups: osteoporosis, defined as ≥ 1 part bone mineral density T-score ≤ -2.5 or history of fragility fracture of the vertebra or proximal femur (121 patients), and non-osteoporosis (76 patients). Groups were then matched by propensity score using clinical backgrounds affecting bone metabolism.In non-matched model, serum albumin concentration was significantly associated with osteoporosis-related factors such as aging, inflammation, physical disability, and glucocorticoid dose. Multivariate logistic regression revealed that serum albumin concentration was independently and significantly associated with osteoporosis risk (odds ratio = 0.22, 95% confidence interval = 0.08, 0.61, p = 0.0033). After propensity score matching, 57 patients for each group showed that in addition to the LS and femoral neck T-scores (p 0.001), serum albumin concentrations (p = 0.01) remained lower in the osteoporosis group compared to non-osteoporosis group. Receiver operating characteristic curve analysis in non-matched model revealed that when cut-off value of serum albumin concentration for indicating osteoporosis was set at 4.2 g/dl, the area under the curve was 0.69, sensitivity 0.74, and specificity 0.58.Low serum albumin concentration was significantly and independently associated with the prevalence of osteoporosis, which may be considered as one of the osteoporosis-related factors in postmenopausal patients with RA.
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- 2022
3. Reproductive biology of the introduced red-swamp crayfish Procambarus clarkii (Girard, 1852) (Decapoda: Astacidea: Cambaridae) in western Japan.
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Luong, Quang-Tuong, Shiraishi, Rika, Kawai, Tadashi, Katsuhara, Koki R, and Nakata, Kazuyoshi
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PROCAMBARUS clarkii ,CRAYFISH ,DECAPODA ,BENTHIC plants ,BIOLOGY ,BENTHIC animals - Abstract
The red swamp crayfish Procambarus clarkii (Girard, 1852) has been responsible for negative impacts on native benthic fauna and flora in invaded freshwater ecosystems around the world, including Japan. We need to clarify the reproductive biology in the invaded habitats as basic information to effectively control the introduced populations, but the reproductive biology of P. clarkii in Japan (especially in western Japan) has not been well studied. We conducted monthly samplings of P. clarkii from November 2015 to November 2016 in a pond (which does not freeze, even in winter) in Okayama, western Japan, both by using shrimp cage traps and by hand nets to examine aspects of the reproduction, including a form alternation (i.e. Form I and II). We also reared spawning females in the laboratory and calculated the accumulated water temperature during the period to Stage-3 juveniles after spawning. The total number of individuals caught throughout the study period was 6,319 (2,601 males and 2,777 females, with eight of unknown sex and 933 juveniles). The males were all Form I with a breeding status from September to November 2016. We first found ovigerous females in July 2016 and females carrying hatchlings in October 2016, even in January 2016. The form alternation in males was confirmed not only in the cheliped length, but in the hook length. In laboratory observations, approximately 52 days with approximately 1,222 °C degree-days of the accumulated water temperature were necessary to Stage-3 juveniles after spawning. Our results indicate that P. clarkii can reproduce within approximately five months of hatching. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Pyogenic Spondylitis Caused by Staphylococcus schleiferi in a Patient with Crohn's Disease
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Yuji Nadatani, Rieko Nakata, Yasuhiro Fujiwara, Naoko Sugita, Toshio Watanabe, Fumio Tanaka, Shusei Fukunaga, Shuhei Hosomi, Noriko Kamata, Koichi Taira, Yasuaki Nagami, Yu Nishida, Koji Fujimoto, and Koji Otani
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medicine.medical_specialty ,Crohn's disease ,Neck pain ,biology ,medicine.diagnostic_test ,business.industry ,Neurological examination ,General Medicine ,biology.organism_classification ,medicine.disease ,Dermatology ,medicine.anatomical_structure ,Parenteral nutrition ,Port (medical) ,Staphylococcus schleiferi ,Internal Medicine ,medicine ,medicine.symptom ,Vein ,business ,Spondylitis - Abstract
Staphylococcus schleiferi has rarely been reported to cause pyogenic spondylitis. A 42-year-old man had been treated for Crohn's disease with immunosuppressive agents and home parenteral nutrition via a central vein (CV) port. The patient was admitted to our hospital, presenting with neck pain and a fever. A neurological examination showed slight weakness in his left-hand muscles, and he was diagnosed with pyogenic spondylitis of C6 and C7 vertebral bodies due to catheter-related blood stream infection caused by S. schleiferi. An early diagnosis by magnetic resonance imaging, CV port removal and antibiotic therapy targeting S. schleiferi improved his symptoms.
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- 2022
5. A case of multiple systemic thrombosis including cerebral infarction associated with SARS-CoV-2, in which PCR test for SARS-CoV-2 was negative but antibody test was positive
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Kyoko Higashida, Jyunichi Iida, Syuichi Nakata, Yuichiro Oba, Mikito Shimizu, Manabu Sakaguchi, Ryo Tamaki, Hideyuki Ito, Yuki Shimada, Kanako Asai, Satoshi Fujimi, Isao Fukasaka, Nozomi Nagashima, Taku Hoshi, Hiroyuki Sumikura, and Takeshi Nishida
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medicine.medical_specialty ,biology ,business.industry ,Cerebral infarction ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Systemic embolism ,medicine.disease ,Thrombosis ,Mechanical thrombectomy ,Pcr test ,Internal medicine ,biology.protein ,Cardiology ,Medicine ,Antibody ,business ,Large vessel occlusion - Published
- 2022
6. Potential drug–drug interactions in the era of integrase strand transfer inhibitors: a cross-sectional single-center study in Japan
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Ryosuke Matamura, Tomoko Kimyo, Hiromasa Nakata, Masayoshi Kobune, Manabu Kitagawa, Satoshi Fujii, Hiroshi Ikeda, Masahide Fukudo, Yusuke Kunimoto, and Atsushi Miyamoto
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Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Pharmacology (nursing) ,Pharmacy ,RM1-950 ,Potential drug–drug interaction ,Integrase strand transfer inhibitors ,Pharmacotherapy ,Pharmacy and materia medica ,Internal medicine ,medicine ,Clinical endpoint ,Pharmacology (medical) ,media_common ,Polypharmacy ,biology ,business.industry ,Incidence (epidemiology) ,HIV ,Integrase ,Antiretroviral therapy ,RS1-441 ,Concomitant ,biology.protein ,Therapeutics. Pharmacology ,business ,Research Article - Abstract
Background Potential drug–drug interactions (PDDIs) commonly occur because of aging and comorbidities in people living with human immunodeficiency virus (HIV; PLWH). Protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been reported to cause PDDIs in these patients. However, there are few reports of PDDIs in the era of treatment using integrase strand transfer inhibitors. Therefore, we investigated PDDIs in Japanese PLWH receiving antiretroviral drugs (ARVs). Methods This was a cross-sectional observational study conducted in Japanese outpatients. All eligible patients who had received ARV therapy for at least 48 weeks were enrolled. The primary endpoint was the incidence of PDDIs detected using the Lexicomp® interface. Results Of the 71 eligible patients, 51 (71.8%) were prescribed concomitant non-ARV medications. In 21 patients (29.6%), PDDIs with the potential to reduce the effects of ARVs occurred, although the HIV load was suppressed in all cases. Polypharmacy (the use of ≥5 non-ARVs) was observed in 25 patients (35.2%). There was a significantly higher median number of non-ARV medications in the PDDI group than in the non-PDDI group (6 vs. 3, P P Conclusions The incidence of PDDIs is relatively high in Japanese PLWH, even in the era of treatment using integrase strand transfer inhibitors. Therefore, it is important for patients and health care providers to be constantly aware of PDDIs associated with ARV treatment.
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- 2021
7. Human papillomavirus detected in sperm of Japanese infertile males affects reproductive parameters
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Masashi Iijima, Yoshifumi Kadono, Kouji Izumi, Shohei Kawaguchi, Yuki Kato, Hiroki Nakata, Kazuyoshi Shigehara, Kazufumi Nakashima, Tomomi Nakagawa, and Atsushi Mizokami
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Microbiology (medical) ,Male ,HPV ,Sperm infection ,Prevalence ,Semen ,Infectious and parasitic diseases ,RC109-216 ,Alphapapillomavirus ,Infertile men ,law.invention ,Superoxide dismutase ,Andrology ,Japan ,law ,medicine ,Humans ,Papillomaviridae ,Sperm motility ,Polymerase chain reaction ,biology ,urogenital system ,Papillomavirus Infections ,HPV infection ,virus diseases ,General Medicine ,medicine.disease ,Sperm ,Spermatozoa ,female genital diseases and pregnancy complications ,Sperm concentration ,Infectious Diseases ,biology.protein ,Reproductive parameters ,Nested polymerase chain reaction - Abstract
Objectives The effects of human papillomavirus (HPV) infection on male reproductive parameters are currently a matter of controversy. In order to clarify the issue in Japanese infertile men, the prevalence and localization of HPV in semen, sperm parameters, and superoxide dismutase (SOD) activity in seminal plasma were examined in 216 Japanese infertile men. Methods DNA was extracted from liquid-based cytological semen samples. The β-globin gene was amplified by polymerase chain reaction (PCR), and HPV-DNA was amplified using nested PCR with MY09/MY11 as outer primers and GP5+/GP6+ as inner primers. HPV genotyping was performed in the HPV-positive samples. In addition, SOD levels in seminal plasma were analysed quantitatively. In-situ hybridization (ISH) was performed to localize HPV-DNA in sperm from HPV-positive samples. Results Any-risk and high-risk prevalence rates of HPV in semen were 12.5% and 6.9%, respectively. No significant difference in the prevalence of HPV was observed between azoospermic and non-azoospermic subjects. Among non-azoospermic patients, those with HPV detected in semen had significantly lower sperm motility and concentration compared with subjects without HPV detected in semen. SOD levels in seminal plasma were significantly higher in HPV-positive patients compared with HPV-negative patients. ISH analysis of HPV-positive samples revealed that HPV-DNA was localized to the head and mid-piece of sperm. HPV-DNA was present in the sperm of young infertile men. Conclusion HPV infection of sperm was associated with reduced sperm motility and concentration, and resulted in an increase in seminal SOD activity.
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- 2021
8. Three-dimensional morphological analysis of spermatogenesis in aged mouse testes
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Kazuyoshi Shigehara, Hiroaki Iwamoto, Shohei Kawaguchi, Takahiro Nohara, Yoshifumi Kadono, Suguru Kadomoto, Hiroshi Yaegashi, Kouji Izumi, Masashi Iijima, Atsushi Mizokami, Taito Nakano, and Hiroki Nakata
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Male ,Aging ,Urology ,Science ,Vacuole ,Biology ,Article ,Male infertility ,Andrology ,Mice ,Rete testis ,Testis ,medicine ,Animals ,Spermatogenesis ,Multidisciplinary ,Seminiferous Tubules ,Sertoli cell ,medicine.disease ,Epithelium ,Spermatogonia ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Tubule ,Seminiferous Epithelium ,Morphological analysis ,Medicine ,Anatomy - Abstract
Spermatogenesis, which is a continuous process from undifferentiated spermatogonia to spermatozoa in the seminiferous tubules, declines with age. To investigate changes in spermatogenesis with aging, we reconstructed the seminiferous tubules of 12 mice aged 12 to 30 months from serial sections and examined age-related and region-specific alterations in the seminiferous epithelium and spermatogenic waves in three dimensions. The basic structure of the seminiferous tubules, including the numbers of tubules, terminating points, branching points, and total tubule length, did not change with age. Age-related alterations in spermatogenesis, primarily assessed by the formation of vacuoles in Sertoli cells, were detected in the seminiferous tubules at 12 months. The proportion of altered tubule segments with impaired spermatogenesis further increased by 24 months, but remained unchanged thereafter. Altered tubule segments were preferentially distributed in tubule areas close to the rete testis and those in the center of the testis. Spermatogenic waves became shorter in length with age. These results provide a basis for examining the decline of spermatogenesis not only with aging, but also in male infertility.
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- 2021
9. Tumor PD-L1 and VEGF Expression, and CD8 T Cell Infiltration Predict Clinical Response to Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer
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Katsuhiko Shimizu, Yuji Nojima, Takeshi Kurosaki, Shinsuke Saisho, Mikio Oka, Toru Oga, Koji Kurose, Masao Nakata, and Ai Maeda
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Adult ,Male ,Vascular Endothelial Growth Factor A ,Cancer Research ,Lung Neoplasms ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,chemistry.chemical_compound ,Lymphocytes, Tumor-Infiltrating ,Carcinoma, Non-Small-Cell Lung ,PD-L1 ,Tumor Microenvironment ,Humans ,Medicine ,Cytotoxic T cell ,Lung cancer ,Receptor ,Immune Checkpoint Inhibitors ,Aged ,Aged, 80 and over ,biology ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Vascular endothelial growth factor ,Oncology ,chemistry ,Disease Progression ,biology.protein ,Cancer research ,Biomarker (medicine) ,Immunohistochemistry ,Female ,business ,CD8 - Abstract
Background/aim We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME. Materials and methods Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy. Results Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types. Conclusion The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy.
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- 2021
10. Biodiversity and succession of lactic microbiota involved in Brazilian buffalo mozzarella cheese production
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Luana Faria Silva, Juliano De Dea Lindner, Tássila Nakata Sunakozawa, Daniel Mathias Fuzette Amaral, Tiago Casella, Ana Lúcia Barretto Penna, Mara Corrêa Lelles Nogueira, Universidade Estadual Paulista (UNESP), Universidade Federal de Santa Catarina (UFSC), and FAMERP - São José Do Rio Preto Medical School
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Cheese biodiversity ,Buffaloes ,medicine.disease_cause ,Microbiology ,chemistry.chemical_compound ,Microbial ecology ,Cheese ,Leuconostoc citreum ,RNA, Ribosomal, 16S ,Media Technology ,medicine ,Animals ,Food microbiology ,Food science ,biology ,Microbiota ,Raw milk ,food and beverages ,Autochthonous bacteria ,Biodiversity ,biology.organism_classification ,Random Amplified Polymorphic DNA Technique ,Lactic acid ,Milk ,chemistry ,Leuconostoc mesenteroides ,Food Microbiology - Research Paper ,Food Microbiology ,Restriction fragment length polymorphism ,Lactic acid bacteria identification ,Bacteria - Abstract
Made available in DSpace on 2022-05-01T09:47:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The biodiversity and succession of lactic acid bacteria (LAB) involved in the production and storage of Brazilian buffalo mozzarella cheese were evaluated. The isolates were characterized by Gram staining and catalase test, by the ability to grow at different conditions: temperatures, pH, concentrations of NaCl, and production of CO2 from glucose. The biodiversity and succession of 152 LAB isolated during cheese production were evaluated by 16S rRNA gene sequencing, Random Amplified Polymorphic DNA (RAPD-PCR), and Restriction Fragment Length Polymorphism (RFLP-PCR) techniques. Most of the strains grow well at 30 °C and are tolerant to 6.5% of NaCl, and in general, the best pH for growing was 9.6. Leuconostoc mesenteroides, Lacticaseibacillus casei, Limosilactobacillus fermentum, and Enterococcus sp. were prevalent and present in almost all steps of production. The LAB strains are typically found in the traditional Italian cheese, except the Leuconostoc citreum species. Sixty clusters were obtained by RAPD-PCR with 85% of similarity (114 isolates) while most of the LAB was clustered with 100% of similarity by the RFLP-PCR technique. The applied techniques enabled a valuable elucidation of the LAB biodiversity and succession, contributing to a better understanding of the specific microbial cultures with a technological aptitude of this cheese. Food Engineering and Technology Department UNESP - São Paulo State University, Rua Cristóvão Colombo, 2265, SP Food Science and Technology Department UFSC - Federal University of Santa Catarina, SC Center for Microorganisms Investigation FAMERP - São José Do Rio Preto Medical School, SP Food Engineering and Technology Department UNESP - São Paulo State University, Rua Cristóvão Colombo, 2265, SP FAPESP: 2008/56667-5 FAPESP: 2011/11922-0
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- 2021
11. Structural insights into the enhanced thermostability of cysteine substitution mutants of L-histidine decarboxylase from Photobacterium phosphoreum
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Hiroshi Miyano, Kunio Nakata, Oda Yuki, Toshimi Mizukoshi, Hiroki Yamaguchi, and Tatsuki Kashiwagi
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chemistry.chemical_classification ,biology ,Photobacterium ,Stereochemistry ,Photobacterium phosphoreum ,Mutant ,General Medicine ,Histidine Decarboxylase ,biology.organism_classification ,Biochemistry ,Histidine decarboxylase ,Amino acid ,Hydrophobic effect ,Enzyme ,chemistry ,Histidine ,Cysteine ,Molecular Biology ,Thermostability - Abstract
Enzymatic amino acid assays are important in physiological research and clinical diagnostics because abnormal amino acid concentrations in biofluids are associated with various diseases. L-histidine decarboxylase from Photobacterium phosphoreum (PpHDC) is a pyridoxal 5′-phosphate-dependent enzyme and a candidate for use in an L-histidine quantitation assay. Previous cysteine substitution experiments demonstrated that the PpHDC C57S mutant displayed improved long-term storage stability and thermostability when compared with those of the wild-type enzyme. In this study, combinational mutation experiments of single cysteine substitution mutants of PpHDC were performed, revealing that the PpHDC C57S/C101V/C282V mutant possessed the highest thermostability. The stabilizing mechanism of these mutations was elucidated by solving the structures of PpHDC C57S and C57S/C101V/C282V mutants by X-ray crystallography. In the crystal structures, two symmetry-related PpHDC molecules form a domain-swapped homodimer. The side chain of S57 is solvent exposed in the structure, indicating that the C57S mutation eliminates chemical oxidation or disulfide bond formation with a free thiol group, thereby providing greater stability. Residues 101 and 282 form hydrophobic interactions with neighboring hydrophobic residues. Mutations C101V and C282V enhanced thermostability of PpHDC by filling a cavity present in the hydrophobic core (C101V) and increasing hydrophobic interactions.
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- 2021
12. Small regulatory RNAs of oral streptococci and periodontal bacteria
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Yuichi Oogai and Masanobu Nakata
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Messenger RNA ,biology ,Periodontal pathogens ,Streptococcus ,RK1-715 ,Computational biology ,Review Article ,biology.organism_classification ,Non-coding RNA ,Antisense RNA ,Oral bacteria ,Dentistry ,Gene expression ,Transfer RNA ,Adaptation ,Small regulatory RNA ,General Dentistry ,Gene ,Bacteria - Abstract
Small regulatory RNAs (sRNAs) belong to a family of non-coding RNAs, and many of which regulate expression of genes via interaction with mRNA. The recent popularity of high-throughput next generation sequencers have presented abundant sRNA-related data, including sRNAs of several different oral bacterial species. Some sRNA candidates have been validated in terms of their expression and interaction with target mRNAs. Since the oral cavity is an environment constantly exposed to various stimuli, such as fluctuations in temperature and pH, and osmotic pressure, as well as changes in nutrient availability, oral bacteria require rapid control of gene expression for adaptation to such diverse conditions, while regulation via interactions of sRNAs with mRNA provides advantages for rapid adaptation. This review summarizes methods effective for identification and validation of sRNAs, as well as sRNAs identified to be associated with oral bacterial species, including cariogenic and periodontal pathogens, together with their confirmed and putative target genes.
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- 2021
13. Mouse resources at the RIKEN BioResource Research Center and the National BioResource Project core facility in Japan
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Keiji Mochida, Noriko Hiraiwa, Atsuo Ogura, Toshihiko Shiroishi, Hatsumi Nakata, Atsushi Yoshiki, Toshiaki Nakashiba, Shinya Ayabe, Fumio Ike, Yuichi Obata, Masaru Tamura, Hiroshi Masuya, Saori Mizuno-Iijima, and Shoko Kawamoto
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Government ,Genome ,Resource (biology) ,Library science ,Biology ,Information Centers ,Article ,Government Programs ,Core Facility ,Resource center ,Mice ,Experimental animal ,Japan ,Research community ,Genetics ,Added value ,Animals ,Research center - Abstract
The RIKEN BioResource Research Center (BRC) was established in 2001 as a comprehensive biological resource center in Japan. The Experimental Animal Division, one of the BRC infrastructure divisions, has been designated as the core facility for mouse resources within the National BioResource Project (NBRP) by the Japanese government since FY2002. Our activities regarding the collection, preservation, quality control, and distribution of mouse resources have been supported by the research community, including evaluations and guidance on advancing social and research needs, as well as the operations and future direction of the BRC. Expenditure for collection, preservation, and quality-control operations of the BRC, as a national core facility, has been funded by the government, while distribution has been separately funded by users’ reimbursement fees. We have collected over 9000 strains created mainly by Japanese scientists including Nobel laureates and researchers in cutting-edge fields and distributed mice to 7000 scientists with 1500 organizations in Japan and globally. Our users have published 1000 outstanding papers and a few dozen patents. The collected mouse resources are accessible via the RIKEN BRC website, with a revised version of the searchable online catalog. In addition, to enhance the visibility of useful strains, we have launched web corners designated as the “Mouse of the Month” and “Today’s Tool and Model.” Only high-demand strains are maintained in live colonies, while other strains are cryopreserved as embryos or sperm to achieve cost-effective management. Since 2007, the RIKEN BRC has built up a back-up facility in the RIKEN Harima branch to protect the deposited strains from disasters. Our mice have been distributed with high quality through the application of strict microbial and genetic quality control programs that cover a globally accepted pathogens list and mutated alleles generated by various methods. Added value features, such as information about users’ publications, standardized phenotyping data, and genome sequences of the collected strains, are important to facilitate the use of our resources. We have added and disseminated such information in collaboration with the NBRP Information Center and the NBRP Genome Information Upgrading Program. The RIKEN BRC has participated in international mouse resource networks such as the International Mouse Strain Resource, International Mouse Phenotyping Consortium, and Asian Mouse Mutagenesis and Resource Association to facilitate the worldwide use of high-quality mouse resources, and as a consequence it contributes to reproducible life science studies and innovation around the globe.
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- 2021
14. Three‐dimensional reconstruction of testis cords/seminiferous tubules
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Hiroki Nakata, Shoichi Iseki, and Atsushi Mizokami
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reconstruction ,QH471-489 ,Age differences ,Reproduction ,3d analysis ,3D reconstruction ,Reviews ,Cell Biology ,Serial section ,Anatomy ,Review ,Biology ,RC648-665 ,testis cord ,Diseases of the endocrine glands. Clinical endocrinology ,Seminiferous tubule ,medicine.anatomical_structure ,Reproductive Medicine ,Paraffin section ,medicine ,serial section ,seminiferous tubule ,3D - Abstract
Background Due to the development of novel equipment for the acquisition of two‐dimensional serial images and software capable of displaying three‐dimensional (3D) images from serial images, the accurate 3D reconstruction of organs and tissues has become possible. Methods Based on published studies, this review summarizes techniques for the 3D reconstruction of the testis cords/seminiferous tubules, with special reference to our method using serial paraffin sections and 3D visualization software. Main findings The testes of mice, rats, and hamsters of various ages were 3D reconstructed and species and age differences in the structures of the testis cords/seminiferous tubules were analyzed. Our method is advantageous because conventional paraffin‐embedded normal and pathological specimens may be utilized for the 3D analysis without the need for complicated and expensive equipment. Conclusion By further decreasing the time and labor required for the procedure and adding information on molecular localization, the technique for 3D reconstruction will contribute to the elucidation of not only the structures, but also the functions of various organs, including the testis., The testes of mice, rats, and hamsters of various ages were 3D reconstructed and species and age differences in the structures of the testis cords/seminiferous tubules were analyzed. Our method is advantageous because conventional paraffin‐embedded normal and pathological specimens may be utilized for the 3D analysis without the need for complicated and expensive equipment.
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- 2021
15. Glutathione S-transferase gene polymorphisms in association with susceptibility to lead toxicity in lead- and cadmium-exposed children near an abandoned lead-zinc mining area in Kabwe, Zambia
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John Yabe, Mayumi Ishizuka, Yoshinori Ikenaka, Haruya Toyomaki, Kaampwe Muzandu, Kennedy Choongo, Hokuto Nakata, Andrew Kataba, Shouta M.M. Nakayama, and Yared B. Yohannes
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Cadmium ,Health, Toxicology and Mutagenesis ,chemistry.chemical_element ,General Medicine ,Glutathione ,Biology ,Pollution ,Molecular biology ,GSTP1 ,chemistry.chemical_compound ,Glutathione S-transferase ,chemistry ,Polymorphism (computer science) ,Genetic variation ,Toxicity ,Genotype ,biology.protein ,Environmental Chemistry - Abstract
Interindividual genetic variations determine human's susceptibility to heavy metal-induced toxicity. Thus, we analyzed blood concentrations of lead (Pb) and cadmium (Cd) in 140 lead-exposed children. Genotyping of the glutathione S-transferase (GST) genes, GSTM1, GSTT1, and GSTP1 genes, was carried out to investigate their possible association with heavy metal concentrations and the risk of susceptibility to Pb toxicity. Exposure to both heavy metals was prevalent among the children. The blood Pb level ranged from 3.30 to 74.0 μg dL-1 with an average value of 26.8 μg dL-1 that is five times above its reference level. The average Cd level (0.22 μg L-1) was below its reference level. The metal-gene interaction showed positive correlation between GSTT1 null genotype and Pb and Cd levels (β = 0.11; p = 0.02 and β = 0.10; p = 0.01, respectively). More pronounced effects (β = 0.19; p < 0.01 and β = 0.25; p = 0.04) were found for the mixture of the three putative genes with blood Pb concentration. The susceptibility analysis using 10 μg dL-1 as blood Pb cutoff level showed a high risk of Pb toxicity (OR = 2.54; 95% CI: 1.02-6.32, p = 0.04) for children carrying the GSTP1 Ile/Val genotype. Further, the combined effect of GSTP1 Ile/Val with GSTT1 null genotype was more pronounced and showed an increased risk of susceptibility to Pb toxicity (OR = 11.7; 95% CI: 1.36-102.1, p = 0.02). In summary, this study suggests that GSTT1 null and GSTP1 Ile/Val genotypes are the main genetic factors, and individual and specific combinations of GSTP1 Ile/Val with GSTM1 and GSTT1 GST polymorphisms are associated with susceptibility to Pb toxicity.
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- 2021
16. Relationship between body colour and microhabitat breadth in an orb-web spider
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Kensuke Nakata
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Orb (astrology) ,Spider ,Zoology ,Body colour ,Biology ,Ecology, Evolution, Behavior and Systematics - Abstract
Habitat use often differs among intraspecific individuals, and the degree to which individual animals use specific habitats, i.e. microhabitat breadth, can also vary. Variation in body colour sometimes emerges as dark vs. bright coloration, which can be related to habitat selectivity. The aim of this study was to examine whether darker animals prefer shady sites to avoid overheating from direct sunlight exposure, whereas brighter animals would use both shady and open sites. Orb-web spiders, Cyclosa argenteoalba, have a silver dorsal abdomen with black markings; the proportion of these black markings varies between 20 and 100% among individuals. In summer, there was less variation in the duration of direct sunlight hitting the webs of darker spiders compared with that of brighter spiders. This indicated a narrower microhabitat range for darker spiders, which preferred shady sites. This pattern was not observed in spring and autumn, when thermal conditions were less severe. These results are consistent with the hypothesis that when the temperature is high, darker animals are microhabitat specialists, whereas brighter animals are generalists. A previous study found that darker spiders capture more prey than brighter spiders, and the amount of black markings is considered to be a trade-off between foraging success and microhabitat availability.
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- 2021
17. Three‐dimensional analysis of mesonephric tubules remodeling into efferent tubules in the male mouse embryo
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Hiroki Nakata, Masahiro Itoh, and Takuya Omotehara
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Epididymis ,Male ,Mesonephric tubules ,endocrine system ,Rete Testis ,Sex Differentiation ,Efferent ,Efferent ducts ,Embryo ,Anatomy ,Biology ,Embryo, Mammalian ,Spermatozoa ,Mesonephric duct ,Mice ,medicine.anatomical_structure ,Rete testis ,Testis ,medicine ,Animals ,Duct (anatomy) ,Process (anatomy) ,Developmental Biology - Abstract
Background Spermatozoa are transported to the epididymal duct through efferent tubules. Although the origin of the efferent tubules is thought to be mesonephric tubules, their detailed developmental process, for example, where the rete testis and efferent tubules are connected, is unclear. We investigated the structural changes of the mesonephric tubules in the male mouse embryo using a three-dimensional reconstruction method. Results Three-six mesonephric tubules were connected to the Wolffian duct, and some of them branched, resulting in five-nine tips. Rete cells contacted the three-six tips. The mesonephric tubules showed a folded shape when the gonadal fate was determined. After the testis development started, they became short and straight but emerged as long and twisting by birth. Before birth, the efferent duct was composed of mesonephric tubules and a cranial portion of the folded Wolffian duct. Conclusions The contact between the rete testis and efferent tubules is possibly established at the tip of each mesonephric tubule. The mesonephric tubules regress after gonadal fate is determined but is remodeled to the twisting efferent tubules by birth. The efferent tubules are composed of the MTs but also a cranial portion of the folded Wolffian duct in the mouse. This article is protected by copyright. All rights reserved.
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- 2021
18. Stabilization and structural changes of 2D DNA origami by enzymatic ligation
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Takashi Morii, Eiji Nakata, Amulya Giridasappa, Arivazhagan Rajendran, and Kirankumar Krishnamurthy
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DNA Ligases ,AcademicSubjects/SCI00010 ,Intercalation (chemistry) ,02 engineering and technology ,Biology ,Microscopy, Atomic Force ,Nucleic Acid Denaturation ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Chemical Biology and Nucleic Acid Chemistry ,Ethidium ,DNA nanotechnology ,Genetics ,DNA origami ,Thermal stability ,Phosphorylation ,Electrophoresis, Agar Gel ,chemistry.chemical_classification ,DNA ligase ,Temperature ,DNA ,021001 nanoscience & nanotechnology ,Nanostructures ,0104 chemical sciences ,Kinetics ,chemistry ,Biophysics ,Nucleic Acid Conformation ,Thermodynamics ,0210 nano-technology ,Ligation ,Ethidium bromide - Abstract
The low thermal stability of DNA nanostructures is the major drawback in their practical applications. Most of the DNA nanotubes/tiles and the DNA origami structures melt below 60°C due to the presence of discontinuities in the phosphate backbone (i.e., nicks) of the staple strands. In molecular biology, enzymatic ligation is commonly used to seal the nicks in the duplex DNA. However, in DNA nanotechnology, the ligation procedures are neither optimized for the DNA origami nor routinely applied to link the nicks in it. Here, we report a detailed analysis and optimization of the conditions for the enzymatic ligation of the staple strands in four types of 2D square lattice DNA origami. Our results indicated that the ligation takes overnight, efficient at 37°C rather than the usual 16°C or room temperature, and typically requires much higher concentration of T4 DNA ligase. Under the optimized conditions, up to 10 staples ligation with a maximum ligation efficiency of 55% was achieved. Also, the ligation is found to increase the thermal stability of the origami as low as 5°C to as high as 20°C, depending on the structure. Further, our studies indicated that the ligation of the staple strands influences the globular structure/planarity of the DNA origami, and the origami is more compact when the staples are ligated. The globular structure of the native and ligated origami was also found to be altered dynamically and progressively upon ethidium bromide intercalation in a concentration-dependent manner.
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- 2021
19. Identification of mouse helper epitopes for WT1-specific CD4+ T cells
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Akihiro Tsuboi, Haruo Sugiyama, Shinji Sogo, Naoki Hosen, Kanako Imafuku, Kana Hasegawa, Sumiyuki Nishida, Soyoko Morimoto, Keiko Udaka, Kazuki Isokawa, Fumihiro Fujiki, Jun Nakata, Yusuke Oji, Hiroko Nakajima, Yoshiko Hashii, Hiromu Hayashibara, and Yoshihiro Oka
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,biology ,urogenital system ,Helper T lymphocyte ,Immunology ,CD44 ,chemical and pharmacologic phenomena ,urologic and male genital diseases ,female genital diseases and pregnancy complications ,Epitope ,Cell biology ,CTL ,Oncology ,Antigen ,Peptide vaccine ,biology.protein ,Immunology and Allergy ,Cytotoxic T cell ,CD8 - Abstract
Helper T lymphocytes (HTLs) play a central role in cancer immunity because they can not only help the induction and proliferation of cytotoxic T lymphocytes (CTLs) but also their differentiation into cytotoxic CD4+ T cells and directly kill the target cells.This study describes the identification of three novel mouse Th epitope peptides, WT135-52, WT186-102 and WT1294-312, derived from WT1 protein, which is the most potent tumor-associated antigen. Compared to immunization with WT1 CTL peptide alone, immunization with the addition of these WT1-specific Th peptides strongly induced WT1-specific CTLs, continued to maintain them, and efficiently rejected the challenge of WT1-expressing tumor cells. Importantly, the majority of WT1-specific CTLs induced by the co-immunization with WT1 CTL and the WT1-specific Th peptides were CD44+CD62L- effector memory CD8+ T cells, which played a central role in tumor rejection. Establishment of mouse models suitable for the analysis of the detailed mechanism of these functions of HTLs is very important. These results clearly showed that WT1-specific HTLs perform an essential function in WT1-specific tumor immunity. Therefore, the WT1-specific Th peptides identified here should make a major contribution to elucidation of the mutual roles of WT1-specific CTLs and HTLs in cancer immunity in in vivo mouse models.
- Published
- 2021
20. Chirality matters: stereo-defined phosphorothioate linkages at the termini of small interfering RNAs improve pharmacology in vivo
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Anna Bisbe, Martin Maier, Tuyen Nguyen, Martin Egli, Jennifer L. S. Willoughby, Muthiah Manoharan, Ivan Zlatev, Masaaki Akabane-Nakata, Matt Hettinger, Shigeo Matsuda, Hartmut Jahns, Christopher R. Brown, Nate Taneja, Rajar M. Manoharan, Kallanthottathil G. Rajeev, and Klaus Charisse
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0301 basic medicine ,Exonuclease ,Small interfering RNA ,Stereochemistry ,RNA Stability ,In silico ,010402 general chemistry ,01 natural sciences ,Mice ,03 medical and health sciences ,Isomerism ,RNA interference ,In vivo ,Genetics ,Animals ,RNA, Small Interfering ,RNA, Double-Stranded ,biology ,Diastereomer ,Argonaute ,Organophosphates ,0104 chemical sciences ,030104 developmental biology ,Phosphodiester bond ,biology.protein ,RNA Interference - Abstract
A critical challenge for the successful development of RNA interference-based therapeutics therapeutics has been the enhancement of their in vivo metabolic stability. In therapeutically relevant, fully chemically modified small interfering RNAs (siRNAs), modification of the two terminal phosphodiester linkages in each strand of the siRNA duplex with phosphorothioate (PS) is generally sufficient to protect against exonuclease degradation in vivo. Since PS linkages are chiral, we systematically studied the properties of siRNAs containing single chiral PS linkages at each strand terminus. We report an efficient and simple method to introduce chiral PS linkages and demonstrate that Rp diastereomers at the 5′ end and Sp diastereomers at the 3′ end of the antisense siRNA strand improved pharmacokinetic and pharmacodynamic properties in a mouse model. In silico modeling studies provide mechanistic insights into how the Rp isomer at the 5′ end and Sp isomer at the 3′ end of the antisense siRNA enhance Argonaute 2 (Ago2) loading and metabolic stability of siRNAs in a concerted manner.
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- 2021
21. CD271+CD51+PALLADIN− Human Mesenchymal Stromal Cells Possess Enhanced Ossicle-Forming Potential
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Motohiko Oshima, Subinoy Biswas, Atsushi Iwama, Nobukazu Okamoto, Sayuri Nakata, Nicole Pui Yu Ho, Shuhei Koide, Maiko Sezaki, Takeshi Miyamoto, and Hitoshi Takizawa
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0301 basic medicine ,Stromal cell ,Palladin ,Mesenchymal stem cell ,food and beverages ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Biology ,Chondrogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Ossicle ,Cancer research ,medicine ,Low-affinity nerve growth factor receptor ,Bone marrow ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Human mesenchymal stem/stromal cells (hMSCs), when engrafted into immunodeficient mice, can form ectopic bone organs with hematopoietic stem cell (HSC) supportive functions. However, the ability to...
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- 2021
22. Destruction and restoration processes of fossil oyster reef influenced by repeated large-scale waves: An example of Holocene Crassostrea gigas shellbeds around Pashukurutou Lagoon, eastern Hokkaido, northeast Japan
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Akiko Nakata, Hisao Ando, Futoshi Nanayama, Yasuo Kondo, Ryuta Furukawa, Yoshiharu Yokoyama, Yui Sasajima, Masayuki Ishii, and Kiyoyuki Shigeno
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Oceanography ,biology ,Scale (ratio) ,Crassostrea ,General Materials Science ,biology.organism_classification ,Oyster reef ,Geology ,Holocene - Published
- 2021
23. The outstanding rooting1 mutation gene maintains shoot growth and grain yield through promoting root development in rice under water deficit field environments
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Hiroaki Samejima, Mayumi Kikuta, Daniel Makori Menge, Cornelius Mbathi Wainaina, John Munji Kimani, Akira Yamauchi, Tomomi Hasegawa, Emily Gichuhi, Mana Kano-Nakata, Ruth Nzisa Musila, Nonawin Lucob-Agustin, Daigo Makihara, Yoshiaki Inukai, and Akihide Shibata
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Drought stress ,Agronomy ,Shoot ,Grain yield ,Plant Science ,Gene mutation ,Biology ,Agronomy and Crop Science - Published
- 2021
24. Relationships among wintering ability, fructan content, and allelic variation of fructan metabolic enzyme genes in Japanese barley cultivars
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Hideyuki Aoki, Masako Seki, Masaru Nakata, and Takashi Nagamine
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Genetics ,Variation (linguistics) ,Fructan ,Metabolic enzymes ,General Medicine ,Cultivar ,Allele ,Biology ,Gene - Published
- 2021
25. Comprehensive analysis of bacteriocins in Streptococcus mutans
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Junzo Hisatsune, Miki Kawada-Matsuo, Mi Nguyen-Tra Le, Masanobu Nakata, Hitoshi Komatsuzawa, Yuichi Oogai, Shouichi Miyawaki, Atsuko Watanabe, Motoyuki Sugai, and Yoshio Nakano
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0301 basic medicine ,Science ,030106 microbiology ,Microbial communities ,Microbial Sensitivity Tests ,Regulatory Sequences, Nucleic Acid ,Biology ,Genome ,Article ,Microbiology ,Streptococcus mutans ,03 medical and health sciences ,Bacteriocins ,Bacteriocin ,Antibiosis ,Bacteriology ,Humans ,Amino Acid Sequence ,Promoter Regions, Genetic ,Gene ,Multidisciplinary ,Strain (chemistry) ,Gene Expression Regulation, Bacterial ,biology.organism_classification ,Anti-Bacterial Agents ,030104 developmental biology ,Mutation ,Medicine ,Antibacterial activity ,Bacteria - Abstract
Streptococcus mutans produces bacteriocins that show antibacterial activity against several bacteria. However, comprehensive analysis of these bacteriocins has not been well done. In this study, we isolated 125 S. mutans strains from volunteers and determined their whole genome sequence. Based on the genome analysis, the distribution of each bacteriocin gene (mutacins I-IV, K8 and Smb) was investigated. We found 17, 5, and 2 strains showing 100% matches with mutacin I, mutacin II and mutacin III, respectively. Five mutacin III-positive strains had 2 mismatches compared to mature mutacin III. In 67 mutacin IV-positive strains, 38 strains showed 100% match with mutacin IV, while 29 strains showed some variations. In 23 mutacin K8- and 32 mutacin Smb-positive strains, all except one mutacin K8-positive strain showed 100% match with the mature peptides. Among 125 strains, 84 (65.1%), 26 (20.2%), and 5 (3.9%) strains were positive for one, two and three bacteriocin genes, respectively. Then, the antibacterial activity against oral streptococci and other oral bacterial species was investigated by using bacteriocin gene single-positive strains. Each bacteriocin gene-positive strain showed a different pattern of antibacterial activity. These results speculate that individual S. mutans strains may affect the bacterial composition of dental plaques.
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- 2021
26. Gemella haemolysans inhibits the growth of the periodontal pathogen Porphyromonas gingivalis
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Nobuo Yoshinari, Tomohiro Miyoshi, Akihiro Yoshida, Reiko Kousaka, Shogo Oge, Satoshi Nakata, Yuki Miura, Hidehiko Ukita, and Yuji Ueno
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0301 basic medicine ,Adult ,Male ,Saliva ,Science ,030106 microbiology ,Hemolysis ,Article ,Microbiology ,Periodontal pathogen ,03 medical and health sciences ,chemistry.chemical_compound ,Antibiosis ,Gemella ,Medicine ,Humans ,Symbiosis ,Clinical microbiology ,Pathogen ,Porphyromonas gingivalis ,Periodontal Diseases ,Aged ,Periodontitis ,Mouth ,Multidisciplinary ,biology ,business.industry ,Middle Aged ,biology.organism_classification ,medicine.disease ,Bacterial Typing Techniques ,stomatognathic diseases ,030104 developmental biology ,chemistry ,Case-Control Studies ,Female ,Oral Microbiome ,Growth inhibition ,business ,Bacteria - Abstract
The oral microbiome plays an important role in the human microbial community and in maintaining the health of an individual. Imbalances in the oral microbiome may contribute to oral and systemic diseases. The progression of periodontal disease is closely related to the growth of bacteria, such as Porphyromonas gingivalis, in the oral cavity. However, the pathogen growth mechanism specific to periodontal disease remains unknown. This study aimed to identify bacteria associated with periodontal health by focusing on hemolytic bacteria. Unstimulated saliva samples were collected from ten periodontitis patients and five healthy subjects to detect and identify the presence of hemolytic bacteria. The saliva of healthy subjects contained a higher proportion of G. haemolysans than saliva samples from patients with periodontitis. Growth inhibition assays indicated that the protein components contained in the culture supernatant of G. haemolysans directly suppressed the growth of P. gingivalis. This study shows that the presence of G. haemolysans in saliva is associated with periodontal health and that it inhibits the growth of P. gingivalis in vitro.
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- 2021
27. Survival of young, dense Betula ermanii stands after wildfire at top soil removal sites
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Yasutaka Nakata, Masato Hayamizu, and Hiroyuki Torita
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0106 biological sciences ,Topsoil ,010504 meteorology & atmospheric sciences ,Betula ermanii ,Forestry ,Biology ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,0105 earth and related environmental sciences - Abstract
A forest fire in a cool-temperate broadleaved forest in northern Japan, from 26 May to 19 June 2019, provided an opportunity to examine the post-fire dynamics of young, dense birch (Betula ermanii Cham.) stands that had previously undergone top soil removal through soil scarification. To characterize the post-fire responses (survival and resprouting) of birch trees, we set up two plots, 6 months after the fire. We investigated the trunk diameter at breast height and burn marks on the trunks (scorch height and bole charring percentage) of all B. ermanii trees in both plots. Survival and resprouting of each tree were monitored over a 10-month period (6 and 16 months after the fire). To quantify post-fire vegetation recovery of the forest floor, we manually mapped the dominant understory plant, dwarf bamboo (i.e. Sasa kurilensis (Rupr.) Makino et Shibata), from orthomosaic images obtained using an unmanned aircraft vehicle, and estimated the recovery rate in the second year after the fire. Additionally, the seedlings of woody species were counted in both plots. A logistic generalized linear model revealed that the size-dependent survival rates of the plants in each plots were similar in the first year after fire. All B. ermanii trees died without resprouting in the second year after the fire, indicating the lethal effects of fire on young birch trees in top soil removal sites. Moreover, a high recovery rate of dwarf bamboo over 2 years in both plots and limited woody seedling establishment of woody plants suggest that the fire resulted in the regeneration failure of young stands in the top soil removal sites. Based on these findings, we suggest that the vulnerability of young trees can lead to the rapid change in vegetation from young forest to dense dwarf bamboo cover after a fire.
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- 2021
28. Molecular Epidemiological Insights into Transmission Trends in Nagoya Area Based on SARS-CoV-2 Genome Sequencing (Mar-Oct, 2020)
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Yoshihiro Nakata, Miho Nakasuji, Yasumasa Iwatani, Mayumi Imahashi, Kazuhiro Matsuoka, Hirotaka Ode, Yoshiyuki Yokomaku, Mikiko Mori, Mai Kubota, and Masakazu Matsuda
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Whole genome sequencing ,Genetics ,Genetic diversity ,Molecular epidemiology ,viruses ,General Medicine ,Biology ,medicine.disease_cause ,Genome ,GenBank ,Genotype ,medicine ,Clade ,Coronavirus - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease (COVID-19) which has spread rapidly worldwide to cause a global pandemic. The SARS-CoV-2 genome shows a lower mutation rate than other RNA viruses. However, because of the ongoing rapid worldwide transmission among humans, the genetic diversity of the SARS-CoV-2 genome has increased. In Japan, a previous study suggested that the distinct viral clades L, S, G and GR of SARS-CoV-2 had been imported from overseas and begun to circulate domestically by April 2020. However, little is known about molecular epidemiology of SARS-CoV-2 since then, because of the lack of sufficient information on the viral genome sequence information in Japan. Herein, to probe the molecular epidemiological trends in Japan, we determined the full genome sequences of SARS-CoV-2 (n=55) derived from patients admitted to our hospital and performed a comparative analysis with domestic and international sequence information available from GISAID and GenBank. The results showed that the dominant domestic genotypes, including our determined sequences, had shifted from clades S and L to clades G and GR, and dispersed widely during the first infection peak period (March to April). In contrast, all the SARS-CoV-2 genotypes after May 2020 are highly clustered as unique clade GR genotypes that are not detected outside Japan. This genetic clustering occurred during the period under which restrictions were placed on overseas travel in Japan. Similar trends of viral genotype clustering have also been observed worldwide, with regional disparities. Under these circumstances, we should adopt adequate preventive measures to prevent the viral genetic diversity from increasing, and also further extend the molecular epidemiological survey of SARS-CoV-2 genotypes in Japan. These efforts will aid in ensuring successful use of the novel vaccines and antiviral drugs in the near future.
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- 2021
29. Classification of patients with esophageal eosinophilia by patterns of sensitization revealed by a diagnostic assay for multiple allergen-specific IgEs
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Yasuaki Nagami, Akinobu Nakata, Koichi Taira, Fumio Tanaka, Yasuhiro Fujiwara, Koji Otani, Shusei Fukunaga, Toshio Watanabe, Yuji Nadatani, Shuhei Hosomi, and Noriko Kamata
- Subjects
Adult ,Male ,medicine.medical_specialty ,アレルゲン ,medicine.disease_cause ,Immunoglobulin E ,Gastroenterology ,Statistics, Nonparametric ,Allergic sensitization ,03 medical and health sciences ,0302 clinical medicine ,Allergen ,Japan ,Internal medicine ,medicine ,Humans ,Eosinophilia ,免疫グロブリンE ,Eosinophilic esophagitis ,Sensitization ,Diagnostic panel ,Retrospective Studies ,biology ,business.industry ,Sensitization patterns ,Middle Aged ,respiratory system ,Allergens ,medicine.disease ,Dysphagia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cohort ,好酸球性食道炎 ,biology.protein ,Female ,Immunization ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
Eosinophilic esophagitis (EoE) is considered to be an immunoglobulin E (IgE)-mediated allergic disorder. Our goal was to examine IgE-mediated allergic sensitization patterns in patients with esophageal eosinophilia (EE). We enrolled subjects with EE who underwent evaluation with a diagnostic panel to document multiple allergen-specific IgEs. Statistically significant groups were identified by cluster analysis. We also defined allergens based on their characteristics including outdoor, indoor, plant, and animal allergens. We classified patients with EE into 3 distinct groups, including cluster 1 (n = 62) who were minimally sensitized to most allergens except pollen and house dust, cluster 2 (n = 30) who were hypersensitized to outdoor and plant allergens, and cluster 3 (n = 15) who were hypersensitized to most allergens, most notably to indoor and animal allergens. Dysphagia reported among those in clusters 1, 2, and 3 at 35.5%, 46.7%, and 73.3%, respectively, (p = 0.028) and EoE endoscopic reference scores (EREFS) at 3.0, 6.0, and 8.0, respectively, (p
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- 2021
30. Evaluation of antixenosis in soybean against Spodoptera litura by dual-choice assay aided by a statistical analysis model: Discovery of a novel antixenosis in Peking
- Author
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Hajime Ono, Ryu Nakata, Takato Inoue, Naoki Mori, Yutaka Okumoto, Mariko Yano, Masayoshi Teraishi, and Naoko Yoshinaga
- Subjects
Glycine max ,Health, Toxicology and Mutagenesis ,Maximum likelihood ,fungi ,Spodoptera litura ,food and beverages ,Regular Article ,Biology ,biology.organism_classification ,Cutworm ,Horticulture ,Statistical criterion ,Insect Science ,antixenosis ,Instar ,Statistical analysis ,Cultivar - Abstract
The method for evaluating soybean (Glycine max) antixenosis against the common cutworm (Spodoptera litura) was developed based on a dual-choice assay aided by a statistical analysis model. This model was constructed from the results of a dual-choice assay in which Enrei, a soybean cultivar susceptible to S. litura, was used as both a standard and a test leaf disc for 2nd-5th instar larvae. The statistical criterion created by this model enabled the evaluation of the presence of antixenosis. This method was applied to four soybean varieties, including Tamahomare (susceptible), Himeshirazu (resistant), IAC100 (resistant), and Peking (unknown), as well as Enrei. Subsequently, the degrees of antixenosis were also compared by F-test, followed by maximum likelihood estimation (MLE). According to the results, the antixenosis of Tamahomare, Himeshirazu, and IAC100 was statistically reevaluated and Peking exhibited a novel antixenosis, which was stronger for 3rd-5th instar larvae than for 2nd instar.
- Published
- 2021
31. Eradication of the mongoose is crucial for the conservation of three endemic bird species in Yambaru, Okinawa Island, Japan
- Author
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Tomoki Nakaya, Katsushi Nakata, Tsutomu Yagihashi, Shin Ichi Seki, and Nobuhiko Kotaka
- Subjects
0106 biological sciences ,Ecology ,biology ,Logging ,biology.organism_classification ,Dendrocopos ,010603 evolutionary biology ,01 natural sciences ,Mongoose ,Biodiversity hotspot ,Invasive species ,010605 ornithology ,Okinawa woodpecker ,biology.animal ,Seasonal breeder ,Endemism ,Ecology, Evolution, Behavior and Systematics - Abstract
Okinawa Island, Japan, is a globally important biodiversity hotspot. Three endemic bird species, Okinawa rail (Hypotaenidia okinawae), Okinawa woodpecker (Dendrocopos noguchii), and Okinawa robin (Larvivora namiyei), are found only in the Yambaru region of the northern part of Okinawa Island. In order to conserve endemic species, it is important to determine the effect of alien species on endemic species. We conducted playback surveys four times every three years from 2007 to 2016 to evaluate the recent distribution of these three forest-dwelling bird species during the breeding season. Then, the association between the numbers of detections of these three species with the invasive mongoose density and the hardwood forest area was evaluated with a generalized additive mixed model (GAMM). The results showed that the distribution areas of these bird species have been recovering since the 2007 within the small Indian mongoose (Urva auropunctata) controlled area. The GAMM results showed that these bird species were abundant in areas with fewer small Indian mongooses and larger areas of hardwood forests. Thus, the mongoose had a negative impact not only on the flightless rails but also on the woodpeckers and the robins. In recent years, most of the old-growth forests have been designated as protected forests, and large-scale logging is no longer taking place in Yambaru. Eradication of the mongoose is particularly important for the conservation of these three endemic bird species.
- Published
- 2021
32. T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy
- Author
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Akane Okuda, Maki Miyazaki, Naoki Hosen, Soyoko Morimoto, Haruo Sugiyama, Saeka Ogawa, Atsushi Kumanogoh, Yusuke Oji, Akihiro Tsuboi, Hiroko Nakajima, Eriko Ueda, Ayako Isotani, Akiko Katsuhara, Jun Nakata, Yoshihiro Oka, Fumihiro Fujiki, Masahito Ikawa, and Sumiyuki Nishida
- Subjects
Effector ,Cellular differentiation ,medicine.medical_treatment ,T cell ,Immunology ,Retinoic acid ,Tretinoin ,Biology ,Cell biology ,Retinoic acid receptor ,chemistry.chemical_compound ,Alcohol Oxidoreductases ,Memory T Cells ,medicine.anatomical_structure ,Cancer immunotherapy ,chemistry ,T cell differentiation ,Neoplasms ,medicine ,Immunology and Allergy ,Immunotherapy ,Vitamin A ,Memory T cell - Abstract
Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T- cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh10 deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.
- Published
- 2022
33. NOTE ON THE UNIQUENESS OF AN ENDEMIC EQUILIBRIUM OF AN EPIDEMIC MODEL WITH BOOSTING OF IMMUNITY
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Yukihiko Nakata and Liu Yang
- Subjects
0303 health sciences ,Boosting (machine learning) ,Ecology ,animal diseases ,Applied Mathematics ,chemical and pharmacologic phenomena ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Biology ,01 natural sciences ,Agricultural and Biological Sciences (miscellaneous) ,010101 applied mathematics ,Vaccination ,03 medical and health sciences ,Immunity ,Immunology ,bacteria ,Uniqueness ,0101 mathematics ,Epidemic model ,030304 developmental biology - Abstract
For some diseases, it is recognized that immunity acquired by natural infection and vaccination subsequently wanes. As such, immunity provides temporal protection to recovered individuals from an infection. An immune period is extended owing to boosting of immunity by asymptomatic re-exposure to an infection. An individual’s immune status plays an important role in the spread of infectious diseases at the population level. We study an age-dependent epidemic model formulated as a nonlinear version of the Aron epidemic model, which incorporates boosting of immunity by a system of delay equations and study the existence of an endemic equilibrium to observe whether boosting of immunity changes the qualitative property of the existence of the equilibrium. We establish a sufficient condition related to the strength of disease transmission from subclinical and clinical infective populations, for the unique existence of an endemic equilibrium.
- Published
- 2021
34. Flight behavior of four species of Holotrichia chafer (Coleoptera: Scarabaeidae) with different habitat use
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Shogo Kan, Toshiyuki Nakata, Wataru Kojima, and Masahiro Harada
- Subjects
0106 biological sciences ,0301 basic medicine ,Scarabaeidae ,Entomology ,biology ,Zoology ,Interspecific competition ,Nocturnal ,Spatial distribution ,biology.organism_classification ,01 natural sciences ,Insect flight ,010602 entomology ,03 medical and health sciences ,030104 developmental biology ,Habitat ,Insect Science ,Holotrichia - Abstract
Insect flight behavior varies among species and selective pressures underlying the diversification of flight performance remain to be fully elucidated. Comparisons of flight behavior among congeners with differing ecologies can contribute to gaining a better understanding of the mechanisms underlying the diversification of insect flight behavior. In this study, we compared the laboratory arena flight performance of four species of nocturnal Holotrichia black chafers (Coleoptera: Scarabaeidae) based on three-dimensional reconstructions of flight trajectories. Principal component analysis was applied to six kinematic parameters to summarize the flight performance of each species. We found that the flight of H. parallela, which feeds on the leaves of hardwood species, was faster and higher than that of the other three species (H. kiotonensis, H. picea, and H. convexopyga), which typically feed on herbaceous plants. However, maneuverability (rotational component) did not differ significantly among the four species. We further compared the flight velocities of H. parallela and H. kiotonensis using a tethered flight mill system. Similar to the free-flight observations, the velocity of H. parallela flights was significantly greater than that of H. kiotonensis. The interspecific difference in velocities may be associated with differences in spatial distribution of their host plants.
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- 2021
35. Nationwide survey of intrauterine blood transfusion for fetal anemia in Japan
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Masahiko Nakata, Keisuke Ishii, Ryo Yamamoto, Seiji Wada, Masahito Mizuuchi, Takeshi Murakoshi, Jun Murotsuki, Haruhiko Sago, Yuichiro Takahashi, and Jun Sasahara
- Subjects
medicine.medical_specialty ,Blood Transfusion, Intrauterine ,Umbilical cord ,03 medical and health sciences ,Monochorionic Diamniotic Twin Pregnancy ,0302 clinical medicine ,Japan ,Fetal anemia ,Pregnancy ,Surveys and Questionnaires ,Parvovirus B19, Human ,medicine ,Humans ,Intrauterine blood transfusion ,Adverse effect ,Retrospective Studies ,030219 obstetrics & reproductive medicine ,biology ,Cesarean Section ,Parvovirus ,Obstetrics ,business.industry ,Infant, Newborn ,Obstetrics and Gynecology ,Anemia ,Retrospective cohort study ,Perioperative ,biology.organism_classification ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Aim The present study investigated the current situation regarding intrauterine blood transfusion (IUT) for fetal anemia in Japan. Methods We conducted a nationwide, multicenter, retrospective cohort questionnaire survey for cases that underwent IUT from 2011 to 2015. The questionnaire required perioperative information, indications, details of the procedure, procedure-related complications, and neonatal morbidity. Results A total of 100 IUT procedures were performed in 66 cases at 19 institutions during the study period. The most frequent indication of IUT was complicated monochorionic diamniotic (MCDA) twins in 28 (42.4%) cases, followed by 16 (24.2%) cases of red-cell alloimmunization, and 10 (15.2%) cases of parvovirus B19 infection. IUT was performed through the umbilical cord in the vast of majority cases (92%). Bleeding from the IUT site was the most common adverse event (40%). Two cases (2%) underwent emergency cesarean section after the procedure. There were no cases of rupture of membrane or intrauterine infection after IUT. The neonatal survival rate was 77.3% in the 66 total cases and 64% in the hydrops cases. The neonatal survival rates in MCDA twins, red-cell alloimmunization, and parvovirus B19 infection were 75%, 93.8%, and 70%, respectively. Conclusions IUT was performed for mainly three indications in Japan: MCDA twins, red-cell alloimmunization, and parvovirus B19 infection. The incidences of severe adverse events seemed very low. The outcomes after IUT were favorable with variations in survival rates according to indications. However, further studies with long-term follow-up will be required to assess the effectiveness of IUT, especially for complicated MCDA twins.
- Published
- 2021
36. miR-34a-5p might have an important role for inducing apoptosis by down-regulation of SNAI1 in apigenin-treated lung cancer cells
- Author
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Yuho Obata, Kaoru Yoshida, Kazunori Okano, Hiromi Hagiwara, Rieko Aida, Kyoko Nakata, Takahiro Yamashita, and Keitaro Hagiwara
- Subjects
Lung Neoplasms ,Cell Survival ,Down-Regulation ,Apoptosis ,Biology ,Models, Biological ,chemistry.chemical_compound ,miR-34a-5p ,Downregulation and upregulation ,Human lung cancer cell A549 ,microRNA ,Genetics ,medicine ,Humans ,RNA, Messenger ,Apigenin ,Lung cancer ,Molecular Biology ,A549 cell ,Microarray analysis techniques ,General Medicine ,medicine.disease ,SNAI1 (SNAIL) ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,chemistry ,A549 Cells ,SNAI1 ,Cancer research ,Original Article ,Snail Family Transcription Factors - Abstract
Apigenin is a flavonoid with antioxidant and anticancer effects. It has been reported that apigenin inhibits proliferation, migration, and invasion and induces apoptosis in cultured lung cancer cells. However, there is little information on the involvement of microRNAs (miRNAs) in its effects. miRNA microarray analysis and polymerase-chain-reaction analysis of miRNAs revealed that treatment of human lung cancer A549 cells with apigenin up-regulated the level of miR-34a-5p. Furthermore, mRNA microarray analysis and the results of three microRNA target prediction tools showed that Snail Family Transcriptional Repressor 1 (SNAI1), which inhibits the induction of apoptosis, had its mRNA expression down-regulated in A549 cells treated with apigenin. Our findings suggest that apigenin might induce apoptosis by down-regulation of SNAI1 through up-regulation of miR-34a-5p in A549 cells.
- Published
- 2021
37. Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need
- Author
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Chika Miyoshi, Hiromasa Funato, Seiya Mizuno, Minjeong Park, Kanako Iwasaki, Noriko Hotta-Hirashima, Satoru Takahashi, Fumihiro Sugiyama, Manabu Abe, Kenji Sakimura, Masashi Yanagisawa, Aya Ikkyu, Tomoyuki Fujiyama, Shinya Nakata, and Miyo Kakizaki
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cell type ,Mutation ,medicine.diagnostic_test ,General Neuroscience ,Biology ,Electroencephalography ,medicine.disease_cause ,Sleep in non-human animals ,03 medical and health sciences ,Sleep deprivation ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Wakefulness ,medicine.symptom ,Allele ,030217 neurology & neurosurgery ,Homeostasis - Abstract
Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-functionSleepy(Slp) mutation in thesalt-inducible kinase 3(Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. SinceSik3Slpmice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype inSik3Slpmice remain to be elucidated. Here, we generated two mouse lines,synapsin1CreERT2andSik3ex13floxmice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen tosynapsin1CreERT2mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in malesynapsin1CreERT2; Sik3ex13flox/+mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.SIGNIFICANCE STATEMENTThe propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show thatSik3Slpallele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep.
- Published
- 2021
38. CITROBACTER KOSERI INFECTION DERIVED FROM PLATELET TRANSFUSION FOR SEVERE APLASTIC ANEMIA
- Author
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Toshimitsu Ueki, Fumio Shiratori, Taro Nakajima, Hikaru Kobayashi, Yuki Hiroshima, Takayoshi Tokutake, Masahiko Sumi, and Shohei Nakata
- Subjects
medicine.medical_specialty ,Platelet transfusion ,biology ,business.industry ,Internal medicine ,Medicine ,Citrobacter koseri ,business ,biology.organism_classification ,Gastroenterology ,Severe Aplastic Anemia - Published
- 2021
39. siRNAs containing 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2′-F-NMC NTPs
- Author
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Mark K Schlegel, Derek K O'Flaherty, Maja M. Janas, Jason A. Gilbert, Namrata D. Erande, Ivan Zlatev, Shigeo Matsuda, Yongfeng Jiang, June Qin, Pawan Kumar, Rohan Degaonkar, Martha Mendez, Masaaki Akabane-Nakata, Muthiah Manoharan, Martin Egli, and Lauren Blair Woods
- Subjects
Models, Molecular ,Small interfering RNA ,AcademicSubjects/SCI00010 ,DNA polymerase ,010402 general chemistry ,01 natural sciences ,Mitochondrial Proteins ,Mice ,03 medical and health sciences ,Organophosphorus Compounds ,Chemical Biology and Nucleic Acid Chemistry ,RNA interference ,Chlorocebus aethiops ,Genetics ,Animals ,Prealbumin ,Gene silencing ,Nucleotide ,RNA, Small Interfering ,Uridine ,Cells, Cultured ,Polymerase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Nucleotides ,Kinase ,RNA ,DNA-Directed RNA Polymerases ,DNA Polymerase gamma ,Mitochondria ,0104 chemical sciences ,Biochemistry ,chemistry ,Argonaute Proteins ,COS Cells ,biology.protein ,Pyrimidine Nucleotides ,RNA Interference - Abstract
We recently reported the synthesis of 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides, which are based on a bicyclo[3.1.0]hexane scaffold. Here, we analyzed RNAi-mediated gene silencing activity in cell culture and demonstrated that a single incorporation of 2′-F-NMC within the guide or passenger strand of the tri-N-acetylgalactosamine-conjugated siRNA targeting mouse Ttr was generally well tolerated. Exceptions were incorporation of 2′-F-NMC into the guide strand at positions 1 and 2, which resulted in a loss of the in vitro activity. Activity at position 1 was recovered when the guide strand was modified with a 5′ phosphate, suggesting that the 2′-F-NMC is a poor substrate for 5′ kinases. In mice, the 2′-F-NMC-modified siRNAs had comparable RNAi potencies to the parent siRNA. 2′-F-NMC residues in the guide seed region position 7 and at positions 10, 11 and 12 were well tolerated. Surprisingly, when the 5′-phosphate mimic 5′-(E)-vinylphosphonate was attached to the 2′-F-NMC at the position 1 of the guide strand, activity was considerably reduced. The steric constraints of the bicyclic 2′-F-NMC may impair formation of hydrogen-bonding interactions between the vinylphosphonate and the MID domain of Ago2. Molecular modeling studies explain the position- and conformation-dependent RNAi-mediated gene silencing activity of 2′-F-NMC. Finally, the 5′-triphosphate of 2′-F-NMC is not a substrate for mitochondrial RNA and DNA polymerases, indicating that metabolites should not be toxic.
- Published
- 2021
40. Long‐term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation‐positive lung adenocarcinoma
- Author
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Toshiyuki Sumi, Hisashi Nakata, Naoki Shijubou, Yuji Mori, Hirofumi Chiba, Takeyuki Sawai, Yuichi Yamada, and Koki Kamada
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Afatinib ,afatinib ,Adenocarcinoma of Lung ,Case Report ,Case Reports ,lcsh:RC254-282 ,elderly ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Stomatitis ,Aged, 80 and over ,biology ,business.industry ,Standard treatment ,Common Terminology Criteria for Adverse Events ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Primary tumor ,ErbB Receptors ,lung cancer ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Adenocarcinoma ,business ,medicine.drug - Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%–23% of EGFR mutation‐positive NSCLC. The treatment of uncommon EGFR mutation‐positive NSCLCs is controversial. Here, we present the case of an 81‐year‐old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation‐induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions., A large number of compound mutations have been observed in patients with uncommon EGFR mutation‐positive NSCLC. Compound mutation‐induced cells are most susceptible to afatinib, suggesting the efficacy of afatinib in clinical practice. Afatinib may be administered to elderly patients with appropriate dose adjustments
- Published
- 2021
41. Quick validation of genetic quality for conditional alleles in mice
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Hatsumi Nakata, Atsushi Yoshiki, and Tomomi Hashimoto
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endocrine system ,conditional mice ,media_common.quotation_subject ,genetic quality ,Flp‐FRT ,Computational biology ,Biology ,Genome ,Polymerase Chain Reaction ,03 medical and health sciences ,Genetics ,Animals ,Quality (business) ,Allele ,Gene ,reproducibility ,Gene knockout ,Alleles ,030304 developmental biology ,media_common ,DNA Primers ,0303 health sciences ,Base Sequence ,Brief Report ,Reproducibility of Results ,Cell Biology ,Mice, Inbred C57BL ,Restriction enzyme ,Brief Reports ,Cre-Lox recombination ,Cre‐loxP ,Primer (molecular biology) - Abstract
Site‐specific conditional inactivation technologies using Cre‐loxP or Flp‐FRT systems are becoming increasingly important for the elucidation of gene function and disease mechanism in vivo. A large number of gene knockout mouse models carrying complex conditional alleles have been generated by global community efforts and made available for biomedical researchers. The structures of conditional alleles in these mice are becoming increasingly complex and sophisticated, and so the validation of the genetic quality of these alleles is likewise becoming a laborious task for individual researchers. To ensure the reproducibility of conditional experiments, the researcher should confirm that loxP or FRT is integrated at the correct positions in the genome prior to start of the experiments. We report the successful design of universal PCR primers specific to loxP and FRT for the quick validation of conditional floxed and Flrted alleles. The primer set consists of forward and reverse primers complimentary to the loxP or FRT sequences with partial modifications at the 5ʹ end containing 6‐base restriction endonuclease recognition sites. The universal primer set was tested to detect genomic intervals between a pair of cis‐integrated loxP or FRT and was useful for quickly validating various floxed or Flrted alleles in conditional mice., The universal PCR primer set specific to loxP and FRT has been developed and can be used for quickly validating various floxed or Flrted alleles in conditional mice.
- Published
- 2021
42. Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice
- Author
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Haruhiko Koseki, Mitsuyuki Nakata, Keita Terui, Takeshi Saito, Hideo Yoshida, Tetsuya Mitsunaga, Shuichi Hiraoka, Lisa Fujimura, Youichi Teratake, Yukiko Ohara, Akemi Sakamoto, and Masahiko Hatano
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pathology ,Science ,Kinesins ,Megacolon ,Biology ,Enteric Nervous System ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,Animal disease models ,Intestine, Small ,medicine ,Animals ,Glial Cell Line-Derived Neurotrophic Factor ,Gene ,Animal breeding ,Mice, Knockout ,Neurons ,Mice, Inbred BALB C ,Multidisciplinary ,Disease model ,Proto-Oncogene Proteins c-ret ,NADPH Dehydrogenase ,Hyperplasia ,medicine.disease ,Survival Analysis ,Phenotype ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Medicine ,Histopathology ,Enteric nervous system ,Signal transduction ,Function (biology) ,Signal Transduction - Abstract
The Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, −/−) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.
- Published
- 2021
43. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors
- Author
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Kalarickal V. Dileep, Minoru Yoshida, Divya M. Sivaraman, Akiko Nakata, Miyuki Kato-Murayama, Akihiro Ito, Kam Y. J. Zhang, Jay W. Shin, Mikako Shirouzu, Naoki Sakai, and Kentaro Ihara
- Subjects
Scaffold ,medicine.drug_class ,Amyloid beta ,Carboxamide ,02 engineering and technology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Piperidines ,Alzheimer Disease ,Structural Biology ,Cell Line, Tumor ,medicine ,Humans ,Moiety ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Virtual screening ,Amyloid beta-Peptides ,biology ,Chemistry ,Brain ,Active site ,General Medicine ,Aminoacyltransferases ,021001 nanoscience & nanotechnology ,Pyrrolidonecarboxylic Acid ,Molecular Docking Simulation ,biology.protein ,Piperidine ,Pharmacophore ,0210 nano-technology - Abstract
Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC50 = 34 μM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.
- Published
- 2021
44. Association between external female genital mutilation and securing paternity in a spider
- Author
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Kensuke Nakata
- Subjects
0106 biological sciences ,Female circumcision ,Spider ,biology ,05 social sciences ,Cyclosa ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Sexual conflict ,External genitalia ,behavior and behavior mechanisms ,0501 psychology and cognitive sciences ,Animal Science and Zoology ,050102 behavioral science & comparative psychology ,Mating ,Association (psychology) ,reproductive and urinary physiology ,Ecology, Evolution, Behavior and Systematics ,Demography - Abstract
Males sometimes injure their partner physically or physiologically during mating. While harmful mating is assumed to incur fitness costs, it is thought to confer increased paternity for males; this advantage may have driven the evolution of harmful mating. To date, two spider species are known to exhibit external female genital mutilation (EFGM), in which males remove a scape, a small projection on female's external genitalia, to secure their paternity. This study investigated whether a similar phenomenon occurs in Cyclosa ginnaga to assess whether EFGM is commonly associated with paternity securing in spiders. Two consecutive staged mating using a unmated female and two males was conducted and female genitalia was inspected after mating. Results showed that while EFGM occurred among C. ginnaga, the mutilation rate was less than half that of the two previously studied species. Mated females, irrespective of whether they experienced mutilation, attacked the second males that courted them. Consequently, most mating trials ended without successful copulation due to the retreat of the second male, and EFGM was seldom responsible for the failure of the second mating. These results do not support the hypothesis that EFGM evolved because it secured paternity for mutilator males.
- Published
- 2021
45. MCM10 compensates for Myc‐induced DNA replication stress in breast cancer stem‐like cells
- Author
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Toyoaki Natsume, Satoshi Inoue, Noriko Gotoh, Asako Sasahara, Masahiko Tanabe, Takayuki Enomoto, Rojas-Chaverra N. Marcela, Tatsunori Nishimura, Kuniko Horie-Inoue, Kana Tominaga, Masato T. Kanemaki, Kei-Ichiro Tada, Koji Okamoto, Satoko Ishikawa, Mengjiao Li, Arinobu Tojo, Yutaka Suzuki, Takahiko Murayama, Kazuhiro Ikeda, Sumio Sugano, Kaoru Yamawaki, Yuta Kogure, Yasuto Takeuchi, Masahide Seki, Masao Yano, Asuka Nakata, and Tetsuo Ohta
- Subjects
DNA Replication ,0301 basic medicine ,cancer stem cell ,Cancer Research ,Primary Cell Culture ,Antineoplastic Agents ,Breast Neoplasms ,tumor spheroids ,Biology ,Origin of replication ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Cell, Molecular, and Stem Cell Biology ,Downregulation and upregulation ,Cancer stem cell ,Spheroids, Cellular ,Gene duplication ,Tumor Cells, Cultured ,medicine ,Humans ,Breast ,oncogenes and tumor‐suppressor genes ,Minichromosome Maintenance Proteins ,drug sensitivity/drug resistance‐relating factors/gene expression analysis ,DNA replication ,Cancer ,Original Articles ,MCM ,General Medicine ,medicine.disease ,DNA replication stress ,Up-Regulation ,anticancer drug resistance ,030104 developmental biology ,Oncology ,c‐Myc ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Neoplastic Stem Cells ,MCM10 ,Cancer research ,others ,Original Article ,Female ,Neoplasm Recurrence, Local ,DNA Damage - Abstract
Cancer stem‐like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c‐Myc expression induces stronger DNA replication stress in patient‐derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini‐chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c‐Myc. c‐Myc‐dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient‐derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S‐phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c‐Myc‐MCM10 axis for preventing drug resistance and recurrence of tumors., We provide evidence that upregulated c‐Myc expression induces stronger DNA replication stress in patient‐derived breast cancer stem‐like cells than in differentiated cancer cells. Our results suggest critical roles for mini‐chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress.
- Published
- 2021
46. GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma
- Author
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Akiyoshi Kakita, Sama Ahsan, Kensuke Tateishi, Takafumi Wataya, Makoto Oishi, Volker Hovestadt, Yu Kanemaru, Takashi Yamamoto, Michael D. Taylor, Junko Ito, Charles G. Eberhart, Masayasu Okada, Manabu Natsumeda, Satoshi Nakata, Hiroaki Miyahara, Fausto J. Rodriguez, Junko Hirato, Yukihiko Fujii, Jun Watanabe, Yoshihiro Tsukamoto, Takanori Nozawa, Mario L. Suvà, Junichi Yoshimura, and Hitoshi Takahashi
- Subjects
animal structures ,Cell ,Nerve Tissue Proteins ,Zinc Finger Protein GLI1 ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Zinc Finger Protein Gli3 ,GLI1 ,GLI3 ,medicine ,Humans ,Hedgehog Proteins ,Cerebellar Neoplasms ,neoplasms ,Neurons ,Medulloblastoma ,integumentary system ,biology ,Oncogene ,Wnt signaling pathway ,Cell Differentiation ,General Medicine ,medicine.disease ,nervous system diseases ,Wnt Proteins ,medicine.anatomical_structure ,Neurology ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,biology.protein ,Neuron differentiation ,Immunohistochemistry ,Neurology (clinical) ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
- Published
- 2021
47. Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model
- Author
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Mitsugu Fujita, Hayato Takeuchi, Masahiro Aoki, Teruaki Fujishita, Naoya Hashimoto, Chiami Moyama, Yoshinobu Takahashi, Seisuke Tanigawa, Susumu Nakata, Shota Ando, Hiromi, Takumi Yamanaka, and Yasushi Kojima
- Subjects
0301 basic medicine ,endocrine system ,Cancer Research ,animal structures ,Zinc Finger Protein Gli2 ,Biology ,Stem cell marker ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,GLI2 ,Neurosphere ,medicine ,Animals ,Humans ,Gene silencing ,Molecular Biology ,Cell Proliferation ,Brain Neoplasms ,Gene Expression Profiling ,fungi ,Wnt signaling pathway ,LGR5 ,Prognosis ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Stem cell ,Glioblastoma ,Carcinogenesis - Abstract
The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although the properties of Lgr5-positive GSCs remain unclear. Here, the Sleeping-Beauty transposon-induced glioblastoma model was used in Lgr5-GFP knock-in mice identify GFP-positive cells in neurosphere cultures from mouse glioblastoma tissues. Global gene expression analysis showed that Gli2 was highly expressed in GFP-positive GSCs. Gli2 knockdown using lentiviral-mediated shRNA downregulated Hedgehog-related and Wnt signaling pathway-related genes, including Lgr5; suppressed tumor cell proliferation and invasion capacity; and induced apoptosis. Pharmacological Gli inhibition with GANT61 suppressed tumor cell proliferation. Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.
- Published
- 2021
48. Effects of zinc on tissue uptake and toxicity of lead in Sprague Dawley rat
- Author
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Yared B. Yohannes, Andrew Kataba, Haruya Toyomaki, Shouta M.M. Nakayama, Mayumi Ishizuka, Hokuto Nakata, and Yoshinori Ikenaka
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,chemistry.chemical_element ,Apoptosis ,Zinc ,Toxicology ,medicine.disease_cause ,Antioxidants ,Rats, Sprague-Dawley ,Internal medicine ,Testis ,medicine ,Animals ,oxidative stress ,lead ,Full Paper ,General Veterinary ,biology ,toxicity ,Enzyme assay ,Rats ,Endocrinology ,chemistry ,Lead acetate ,Catalase ,Toxicity ,biology.protein ,zinc co-administration ,Oxidative stress ,Peroxidase - Abstract
Lead (Pb) exposure occurs together with other metals including zinc (Zn). This study investigated the impact of Zn on Pb tissue accumulation and Pb-induced toxicities. Animals (n=6 rats per group) were exposed to lead acetate (PbAc) or a combination of PbAc and zinc acetate (ZnAc) under the following groups: control (deionized water), low PbAc [12 mg/kg PbAc (3 mg PbAc/rat/day)], low PbAc-ZnAc [12 mg/kg PbAc (3 mg PbAc/rat/day) + 0.2 mg ZnAc/rat/48 hr], high PbAc [120 mg/ kg ( 30 mg PbAc/rat/day)], and high PbAc- ZnAc [120 mg/ kg ( 0 mg PbAc/rat/ day) + 1 mg ZnAc/rat/48 hr] for 8 weeks. A significant reduction in body weight gain was observed in the high PbAc group relative to the control group. Muscles and testes both had reduced and increased Pb uptake in low PbAc-ZnAc and high PbAc-ZnAc groups compared to PbAc only groups, respectively. Bone Pb levels in the high PbAc-ZnAc group were lower than the high PbAc group. Zinc co-administration attenuated Pb-induced inhibition of delta aminolaevulinic acid dehydratase enzyme and enhanced catalase enzyme activity at a high level of exposure. Moreover, ZnAc seems to have minimized the effects of Pb-induced mRNA dysregulation in antioxidant and antiapoptotic enzymes encoding genes. Heme oxygenase- 1 was downregulated in the kidney and brain in the low PbAc group. Liver glutathione peroxidase and thioredoxin reductase-1 were downregulated in the high PbAc group. These findings suggest that zinc co-administration with lead may partially mitigate against Pb-induced toxicities.
- Published
- 2021
49. Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis
- Author
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Qianxing Mo, Paul A. Nakata, Jimmonique Donelson, Ninghui Cheng, George G. Rodney, Kendal D. Hirschi, Lingfei Wang, Ghislain Breton, Xander H.T. Wehrens, and Jin Wang
- Subjects
Male ,Cardiac function curve ,endocrine system ,medicine.medical_specialty ,Glucose uptake ,Mice, Obese ,Cardiomegaly ,Biology ,Diet, High-Fat ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Transcriptome ,Mice ,Glutaredoxin ,Internal medicine ,medicine ,Animals ,Myocytes, Cardiac ,Obesity ,cardiac energy metabolism ,Molecular Biology ,Glutaredoxins ,Ecology, Evolution, Behavior and Systematics ,Heart Failure ,Mice, Knockout ,Ejection fraction ,Gene Expression Profiling ,Fatty Acids ,nutritional and metabolic diseases ,glutaredoxin ,Cell Biology ,medicine.disease ,Oxidative Stress ,Endocrinology ,Heart failure ,Energy Metabolism ,transcriptome ,Oxidation-Reduction ,Diet-induced obese ,Oxidative stress ,Research Paper ,Developmental Biology - Abstract
Obesity is often associated with metabolic dysregulation and oxidative stress with the latter serving as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of the major antioxidant systems in the heart. Although Grx3 has been shown to act as an endogenous negative regulator of cardiac hypertrophy and heart failure, its metabolic impact on cardiac function in diet-induced obese (DIO) mice remains largely unknown. In the present study, analysis of Grx3 expression indicated that Grx3 protein levels, but not mRNA levels, were significantly increased in the hearts of DIO mice. Cardiac-specific Grx3 deletion (Grx3 CKO) mice were viable and grew indistinguishably from their littermates after being fed a high fat diet (HFD) for one month, starting at 2 months of age. After being fed with a HFD for 8 months (starting at 2 months of age); however, Grx3 CKO DIO mice displayed left ventricular systolic dysfunction with a significant decrease in ejection fraction and fractional shortening that was associated with heart failure. ROS production was significantly increased in Grx3 CKO DIO cardiomyocytes compared to control cells. Gene expression analysis revealed a significant decline in the level of transcripts corresponding to genes associated with processes such as fatty acid uptake, mitochondrial fatty acid transport and oxidation, and citrate cycle in Grx3 CKO DIO mice compared to DIO controls. In contrast, an increase in the level of transcripts corresponding to genes associated with glucose uptake and utilization were found in Grx3 CKO DIO mice compared to DIO controls. Taken together, these findings indicate that Grx3 may play a critical role in redox balance and as a metabolic switch in cardiomyocytes contributing to the development and progression of heart failure.
- Published
- 2021
50. Integrin α2β1 plays an important role in the interaction between human articular cartilage-derived chondrocytes and atelocollagen gel
- Author
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Seira Sato, Ken Nakata, Shohei Oyama, Kosuke Ebina, Yoshihito Tachi, Takashi Kanamoto, Sanae Kuroda, Minami Hikida, Takeo Mazuka, and Tsuyoshi Nakai
- Subjects
0301 basic medicine ,Cartilage, Articular ,Scaffold ,Knee Joint ,Protein subunit ,Science ,Integrin ,Integrin alpha2 ,Matrix metalloproteinase ,Regenerative Medicine ,Article ,Cell membrane ,Biomaterials ,03 medical and health sciences ,0302 clinical medicine ,Chondrocytes ,Gene expression ,Osteoarthritis ,medicine ,Extracellular ,Humans ,Cells, Cultured ,Cell Proliferation ,Multidisciplinary ,biology ,Cell growth ,Chemistry ,Matrix Metalloproteinases ,Cell biology ,Extracellular Matrix ,030104 developmental biology ,medicine.anatomical_structure ,Cartilage ,030220 oncology & carcinogenesis ,biology.protein ,Medicine ,Collagen ,Integrin alpha2beta1 ,Integrin alpha Chains - Abstract
Although atelocollagen gel is used as a scaffold for culturing human articular cartilage-derived chondrocytes, little is known about cell–gel interactions. In this study, we investigated the mechanism via which atelocollagen gel affects human articular cartilage-derived chondrocytes. Two types of three-dimensional cultures of human articular cartilage-derived chondrocytes (i.e., with and without atelocollagen gel) were compared. While the amount of atelocollagen gel in culture gradually decreased with time, it promoted the expression of matrix metalloproteinases (MMPs) during the early stages of culture. Genome-wide differential gene expression analysis revealed that cell membrane- and extracellular matrix-related genes were highly ranked among up- and down-regulated groups in cells cultured in the presence of atelocollagen gel. Among the integrin family of genes, the expression of integrin subunit alpha 2 and integrin subunit alpha 10 was significantly increased in the presence of atelocollagen gel. Blocking α2β1 integrin with the specific inhibitor BTT 3033 had a significant effect on cell proliferation, MMP expression, and cell shape, as well as on the response to mechanical stimulation. Taken together, our findings indicate that the α2β1 integrin pathway plays an important role in the interaction of atelocollagen gel with human articular cartilage-derived chondrocytes and may be a potential therapeutic target for articular cartilage disorders.
- Published
- 2021
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