Publications by authors named "Masahiro Ito"

419 Publications

Retrieval and Investigation of Data on SARS-CoV-2 and COVID-19 Using Bioinformatics Approach.

Adv Exp Med Biol 2021 ;1318:839-857

Advanced Life Sciences Program, Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.

Sudden emergence and a rapid outbreak of SARS-CoV-2 accompanied by a devastating impact on the economy and public health has driven extensive scientific mobilization to study and elucidate the various associated concerns about SARS-CoV-2. Bioinformatics plays a crucial role in addressing and providing solutions to questions about SARS-CoV-2. It helps shorten the duration for the vaccine development process and the discovery of potential clinical interventions through the simulation and information retrieval, and the development of well-ordered information hubs and resources, which are essential to derive data and meaningful findings from the current massive information about SARS-CoV-2. Advanced algorithms in this field also provide approaches that are essential to elucidate the relationship, origin, and evolutionary process of SARS-CoV-2. Here, we report essential bioinformatics entities, such as database and platform development, molecular evolution and phylogenetic analyses, and vaccine designs, that are useful to solve the SARS-CoV-2 conundrum.
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http://dx.doi.org/10.1007/978-3-030-63761-3_47DOI Listing
January 2021

Essential updates 2019/2020: Multimodal treatment of localized pancreatic adenocarcinoma: Current topics and updates in survival outcomes and prognostic factors.

Ann Gastroenterol Surg 2021 Mar 8;5(2):132-151. Epub 2021 Mar 8.

Department of Gastroenterological Surgery Bantane Hospital Fujita Health University School of Medicine Nagoya Aichi Japan.

Overall survival of patients with localized pancreatic ductal adenocarcinoma (PDAC) is extremely poor. Therefore, the establishment of multimodal treatment strategies is indispensable for PDAC patients because surgical treatment alone could not contribute to the improvement of survival. In this review article, we focus on the current topics and advancement of the treatments for localized PDAC including resectable, borderline resectable, and locally advanced PDAC in accordance with the articles mainly published from 2019 to 2020. Reviewing the articles, the recent progress of multimodal treatments notably improves the prognosis of patients with localized PDAC. For resectable PDAC, neoadjuvant chemo or chemoradiation therapy, rather than upfront surgery, plays a key role, especially in patients with a large tumor, poor performance status, high tumor marker levels, peripancreatic lymph nodes metastasis, or neural invasion suspected on preoperative imaging. For borderline resectable PDAC, neoadjuvant treatments followed by surgery is a desirable approach, and maintenance of immunonutritional status during the treatments are also important. For locally advanced disease, conversion surgery has a central role in improving a survival outcome; however, its indication should be standardized.
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http://dx.doi.org/10.1002/ags3.12427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034700PMC
March 2021

Introduction of histological classification and cytology reporting format of the Japanese General Rules for the Description of Thyroid Cancer with a special focus on the differences of the WHO Histological Classification and The Bethesda System of Thyroid Cytology.

Endocr J 2021 Apr 13. Epub 2021 Apr 13.

Thyroid Examination Expert Committee, Diagnostic Criteria Subcommittee for the Fukushima Health Management Survey, Fukushima Medical University, Fukushima 960-1295, Japan.

Histological classification and cytology reporting format described in General Rules for the Description of Thyroid Cancer, the 8 edition (2019) (the Japanese General Rules) were briefly introduced. Moreover, the differences between "the Japanese General Rules", and WHO Histological Classification, the 4 edition (2017) and The Bethesda System for Reporting Thyroid Cytopathology, the 2 edition (2018) were also explained. The Japanese General Rules did not accept the borderline lesions of thyroid tumor which were newly shown in WHO Histological Classification. We believe it is not necessary to introduce these borderline lesions in daily practice in Japan. Borderline lesions were proposed for avoiding over-surgery for thyroid cancer patients. In the United States, when the patient is diagnosed as malignant on cytology, total thyroidectomy is generally recommended. However, there is no over-surgery in Japan, because surgeons have several choices of treatment for thyroid cancer patients. This article is the first that the Japanese General Rules was shown by foreign language. Therefore, this will be advantageous to us when we present our opinion concerning histology and cytology of thyroid tumor to the world.
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http://dx.doi.org/10.1507/endocrj.EJ21-0077DOI Listing
April 2021

The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling.

Evol Bioinform Online 2021 15;17:11769343211003079. Epub 2021 Mar 15.

Advanced Life Sciences Program, Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.

is a highly variable genomic region of SARS-CoV-2. Although non-essential and the precise functions are unknown, it has been suggested that this protein assists in SARS-CoV-2 replication in the early secretory pathway and in immune evasion. We utilized the binding partners of SARS-CoV-2 proteins in human HEK293T cells and performed genome-wide phylogenetic profiling and clustering analyses in 446 eukaryotic species to predict and discover ORF8 binding partners that share associated functional mechanisms based on co-evolution. Results classified 47 ORF8 binding partner proteins into 3 clusters (groups 1-3), which were conserved in vertebrates (group 1), metazoan (group 2), and eukaryotes (group 3). Gene ontology analysis indicated that group 1 had no significant associated biological processes, while groups 2 and 3 were associated with glycoprotein biosynthesis process and ubiquitin-dependent endoplasmic reticulum-associated degradation pathways, respectively. Collectively, our results classified potential genes that might be associated with SARS-CoV-2 viral pathogenesis, specifically related to acute respiratory distress syndrome, and the secretory pathway. Here, we discuss the possible role of ORF8 in viral pathogenesis and in assisting viral replication and immune evasion via secretory pathway, as well as the possible factors associated with the rapid evolution of ORF8.
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http://dx.doi.org/10.1177/11769343211003079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970180PMC
March 2021

Overlapping and non-overlapping roles of the class-I histone deacetylase-1 corepressors LET-418, SIN-3, and SPR-1 in Caenorhabditis elegans embryonic development.

Genes Genomics 2021 May 19;43(5):553-565. Epub 2021 Mar 19.

Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan.

Background: Histone deacetylase (HDAC)-1, a Class-I HDAC family member, forms three types of complexes, the nucleosome remodeling deacetylase, Sin3, and CoREST complexes with the specific corepressor components chromodomain-helicase-DNA-binding protein 3 (Mi2/CHD-3), Sin3, and REST corepressor 1 (RCOR1), respectively, in humans.

Objective: To elucidate the functional relationships among the three transcriptional corepressors during embryogenesis.

Methods: The activities of HDA-1, LET-418, SIN-3, and SPR-1, the homologs of HDAC-1, Mi2, Sin3, and RCOR1 in Caenorhabditis elegans during embryogenesis were investigated through measurement of relative mRNA expression levels and embryonic lethality given either gene knockdown or deletion. Additionally, the terminal phenotypes of each knockdown and mutant embryo were observed using a differential-interference contrast microscope. Finally, the functional relationships among the three corepressors were examined through genetic interactions and transcriptome analyses.

Results: Here, we report that each of the corepressors LET-418, SIN-3, and SPR-1 are expressed and have essential roles in C. elegans embryonic development. Our terminal phenotype observations of single mutants further implied that LET-418, SIN-3, and SPR-1 play similar roles in promoting advancement to the middle and late embryonic stages. Combined analysis of genetic interactions and gene ontology of these corepressors indicate a prominent overlapping role among SIN-3, SPR-1, and LET-418 and between SIN-3 and SPR-1.

Conclusion: Our findings suggest that the class-I HDAC-1 corepressors LET-418, SIN-3, and SPR-1 may cooperatively regulate the expression levels of some genes during C. elegans embryogenesis or may have some similar roles but functioning independently within a specific cell.
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http://dx.doi.org/10.1007/s13258-021-01076-1DOI Listing
May 2021

DiRect: Site-directed mutagenesis method for protein engineering by rational design.

Biochem Biophys Res Commun 2021 Apr 13;551:107-113. Epub 2021 Mar 13.

Laboratory for Cellular Structural Biology, RIKEN Center for Biosystems Dynamics Research (BDR), 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan; Laboratory for Biomolecular Structure and Dynamics, RIKEN Quantitative Biology Center (QBiC), 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. Electronic address:

Site-directed mutagenesis (SDM), an indispensable method in molecular biology and protein engineering, is rather time-consuming and laborious. Protein engineering, especially that of enzymes, nowadays increasingly relies on rational design approaches in which both SDM and protein expression are the bottlenecks because they are generally based on the recombinant DNA technology. Here, we developed a new PCR-based mutagenesis method, DiRect, that achieves high performance in product quality (≥99% substitution) without recombinant DNA technology. We applied DiRect in combination with a cell-free protein expression system to an industrially relevant enzyme, nicotinamide adenine dinucleotide phosphate-dependent 3-quinuclidinone reductase from Rhodotorula rubra. In a single round of screening, 90 newly designed mutant proteins were produced within two days, and an unreported mutant (Q135I) exhibiting much higher thermostability than the wild-type enzyme was successfully identified within one extra day. Thus, DiRect is a simple, efficient, and potentially scalable SDM method.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.021DOI Listing
April 2021

Complete Genome Sequence of sp. Strain 32K, Isolated from Soil as a Mixed Single Colony with sp. Strain ME121.

Microbiol Resour Announc 2021 Mar 11;10(10). Epub 2021 Mar 11.

Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.

sp. strain 32K, an aerobic Gram-negative bacterium, was isolated from soil in Japan. Here, we report the complete genome sequence of this bacterium, which has a 5.4-Mbp genome sequence, containing 4,919 protein-coding sequences.
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http://dx.doi.org/10.1128/MRA.00019-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953281PMC
March 2021

Significance of abnormal 53BP1 expression as a novel molecular pathologic parameter of follicular-shaped B-cell lymphoid lesions in human digestive tract.

Sci Rep 2021 Feb 4;11(1):3074. Epub 2021 Feb 4.

Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.

The digestive tract is a common site of extranodal malignant lymphomas (MLs) and benign lymphoid lesions (BLs). TP53-binding protein 1 (53BP1) expression has been widely investigated in class switch recombination but rarely in human lymphoid tissues with respect to tumorigenesis. We previously reported that immunofluorescence (IF) analysis of 53BP1 nuclear foci (NF), reflecting DNA double strand breaks, is useful for estimating genomic instability in different tumor types. In this study, we evaluated the potential of IF-based analysis of 53BP1 expression in differentiating MLs from BLs. We examined 231 biopsied tissue samples of primary MLs and BLs in the digestive tract. The 53BP1 immunoreactivity pattern was determined by multicolor IF. Compared to BLs, MLs showed a high frequency of abnormal 53BP1 expression (p < 0.0001). Statistically, abnormal 53BP1 expression is an effective test for distinguishing follicular lymphomas from BLs (specificity 98.6%, sensitivity 86.8%) and for distinguishing small B-cell lymphomas from BLs (specificity 98.3%, sensitivity 77.6%). Furthermore, a high frequency of abnormal 53BP1 expression was associated with "high-risk" MALT lymphomas, which exhibited t(11;18)(q21;21) (p = 0.0145). Collectively, these results suggest that IF-based analysis of 53BP1 expression in biopsy samples is a promising technique for diagnosing MLs in the digestive system.
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http://dx.doi.org/10.1038/s41598-021-82867-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862599PMC
February 2021

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Brain Dev 2021 Apr 9;43(4):505-514. Epub 2021 Jan 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.

Results: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.

Conclusion: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
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http://dx.doi.org/10.1016/j.braindev.2020.12.006DOI Listing
April 2021

Assembling a library of typical surgery video clips to construct a system for assessing the surgical difficulty of laparoscopic cholecystectomy.

J Hepatobiliary Pancreat Sci 2021 Mar 28;28(3):255-262. Epub 2021 Jan 28.

Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.

Background: To explore best practices for acute cholecystitis, it is necessary to construct a system to assess the difficulty of laparoscopic cholecystectomy (LC) based on intraoperative findings. In this study, multiple evaluators assessed videos of LC to assemble a library of typical video clips for 25 intraoperative findings.

Methods: We have previously identified 25 items that contribute to surgical difficulty in LC. For each item, roughly 30-second video clips were submitted from videos of LC performed at member institutions. We then selected one typical video from the collected clips based on simple tabulation of the instances of agreement. Inter-rater agreement was assessed with Fleiss's κ and Gwet's agreement coefficient (AC).

Results: Except in the case of two assessment items ("edematous change" and "easy bleeding"), κ or AC significantly exceeded 0.5 and the typical videos were judged to be applicable. For the two remaining items, the evaluation was repeated after clarifying the definitions of positive and negative findings. Eventually, they were recognized as typical. The completed video clip library contains 31 clips and is divided into five categories (http://www.jshbps.jp/modules/project/index.php?content_id=13).

Conclusions: This clip library may be highly useful in clinical settings as a more objective standard for assessing surgical difficulty in LC.
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http://dx.doi.org/10.1002/jhbp.871DOI Listing
March 2021

Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios.

Thyroid 2020 Dec 3. Epub 2020 Dec 3.

Department of Thyroid Endocrinology, Fukushima Medical University, Fukushima, Japan.

A significant increase in the incidence of papillary thyroid carcinoma (PTC) in subjects exposed to radiation at a young age is a well-documented health consequence of the Chernobyl accident. The ongoing Thyroid Ultrasound Examination (TUE) program in children and adolescents of Fukushima Prefecture in Japan also indicated a high prevalence of PTC although its attribution to radiation exposure is a subject of debate. The objective of this study was to perform histopathological analysis of tumor architecture and invasive properties in (i) radiogenic post-Chernobyl and sporadic PTCs from Ukraine, and (ii) PTCs in patients from Fukushima and other Prefectures of Japan of comparable age groups. The Ukrainian radiogenic PTCs included 245 PTCs from patients who resided in three highly I-contaminated regions and 165 sporadic PTCs diagnosed in residents of the same regions who were born after the accident and therefore not exposed to radioiodine. The Japanese series included 115 PTCs detected during the preliminary and the first full-scale surveys of the TUE in Fukushima and 223 PTCs from patients resident in other Prefectures. All of the subjects were included in the main statistical analysis. Three additional analyses were performed limiting the subjects to children, adolescents, and adults. Ukrainian radiogenic PTC was characterized by the higher frequency of tumors with a dominant solid-trabecular growth pattern and higher invasiveness, more frequent extrathyroidal extension, lymphatic/vascular invasion, regional and distant metastases when compared with sporadic Ukrainian PTC. The integrative "invasiveness score," based on five cancer characteristics, was also higher in the radiogenic group. The differences were most pronounced in children. In contrast, no significant differences in tumor morphology or invasiveness were observed between the two Japanese groups or the three age subgroups. The only statistically significant findings were the higher proportion of male patients, smaller mean tumor size, and higher frequency of T1b tumors in the Fukushima group. The difference in morphological features that indicate biological behavior of PTC between the radiation-related and sporadic groups from Ukraine, together with the lack of such in the two groups from Japan, strongly suggest a nonradiogenic etiology of PTC from Fukushima and other Prefectures.
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http://dx.doi.org/10.1089/thy.2020.0308DOI Listing
December 2020

Incidence, predictive factors and severity of methotrexate-related liver injury in rheumatoid arthritis: a longitudinal cohort study.

Rheumatol Adv Pract 2020 5;4(2):rkaa020. Epub 2020 Jun 5.

Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan.

Objectives: The aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition.

Methods: We used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis.

Results: We followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine-Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced.

Conclusion: Aggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.
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http://dx.doi.org/10.1093/rap/rkaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585403PMC
June 2020

[A Case of Metachronous Liver Metastasis of Gallbladder Cancer Successfully Treated by Hepatectomy after Chemotherapy].

Gan To Kagaku Ryoho 2020 Oct;47(10):1501-1504

Dept. of Surgery, School of Medicine, Fujita Health University Bantane Hospital.

We present the case of a 66-year-old female diagnosed with gallbladder cancer that was initially discovered with contrast enhanced computed tomography. The primary gall bladder tumor displayed heterogeneous enhancement. The patient underwent cholecystectomy with full-thickness excision of the gallbladder cancer. After 3 rounds of adjuvant chemotherapy with the oral fluoropyrimidine derivative, S-1(administered for 4 weeks at 120 mg/day and then stopped for 2 weeks), a metastasis measuring 15 mm in diameter emerged within hepatic segment 5. The chemotherapy regimen was altered to include 6 months of combination therapy with gemcitabine(1,000 mg/m2)and cisplatin(25 mg/m2)given once every week for 2 weeks and then stopped for 1 week. The hepatic metastasis decreased in size to 8 mm in diameter, and a partial liver resection was performed. After hepatectomy, the patient remains alive and without disease recurrence.
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October 2020

Serum kynurenine levels are a novel biomarker to predict the prognosis of patients with hepatocellular carcinoma.

PLoS One 2020 21;15(10):e0241002. Epub 2020 Oct 21.

Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Nagasaki, Japan.

Background: We examined serum kynurenine levels in patients with chronic hepatitis C virus infection, and the relationship between serum kynurenine and prognosis in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C.

Methods: We retrospectively analyzed 604 patients with HCC diagnosed between January 1999 and December 2015, and 288 patients without HCC who were seen at the National Hospital Organization Nagasaki Medical Center between October 2014 and November 2017. The association between serum kynurenine and prognosis was evaluated using the Cox's proportional hazards regression analysis.

Results: Patients with HCC had significantly higher values of serum kynurenine than patients without HCC (median: 557.1 vs. 464.2 ng/mL, p<0.001). Five-year survival rates of HCC patients with serum kynurenine ≥900 (n = 65), 600-899 (n = 194), and <600 ng/mL (n = 345) were 30.6%, 47.4%, and 61.4%, respectively (p = 0.001, log-rank test). Multivariate analysis identified serum kynurenine as an independent predictor for prognosis of HCC patients. The hazard ratio of serum kynurenine ≥900, and 600-899 compared with serum kynurenine <600 ng/mL were 1.91 (p<0.001) and 1.37 (p = 0.015), respectively.

Conclusions: A high level of serum kynurenine correlated with poor prognosis of HCC. Serum kynurenine levels may be a novel biomarker to predict the prognosis of patients with HCC. The development of drugs that inhibit kynurenine production is expected to help improve the prognosis of patients with HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241002PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577466PMC
December 2020

Metabolites Produced by sp. 32K Promote Biofilm Formation in Coculture with sp. ME121.

Biology (Basel) 2020 Sep 13;9(9). Epub 2020 Sep 13.

Graduate School of Life Sciences, Toyo University, Oura-gun, Gunma 374-0193, Japan.

Previously, we reported that the coculture of motile sp. ME121 and non-motile sp. 32K, isolated from the same soil sample, displayed accelerated motility of strain ME121 due to an extracellular polysaccharide (EPS) produced by strain 32K. Since EPS is a major component of biofilms, we aimed to investigate the biofilm formation in cocultures of the two strains. The extent of biofilm formation was measured by a microtiter dish assay with the dye crystal violet. A significant increase in the amount of biofilm was observed in the coculture of the two strains, as compared to that of the monocultures, which could be due to a metabolite produced by strain 32K. However, in the coculture with strain 32K, using or , there was no difference in the amount of biofilm formation as compared with the monoculture. Elevated biofilm formation was also observed in the coculture of strain ME121 with , which was isolated from a different soil sample. , isolated from another soil sample, showed a significant increase in biofilm formation when cocultured with , but not with strain 32K. We also found that the culture supernatants of strains 32K and accelerated the motility of strains ME121 and , wherein culture supernatant of significantly increased the motility of , as compared to that by the culture supernatant of strain 32K. These results indicated that there was a positive relationship between accelerated motility and increased biofilm formation in spp. This is the first study to report that the metabolites from spp. could specifically modulate the biofilm-forming ability of spp. spp. biofilms are capable of inhibiting the biofilm formation of mycobacteria, which are opportunistic pathogens that cause problems in infectious diseases. Thus, the metabolites from the culture supernatant of spp. have the potential to contribute to the environment in which increased biofilm production of Methylobacterium is desired.
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http://dx.doi.org/10.3390/biology9090287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563137PMC
September 2020

Cervical Superficially Invasive Squamous Cell Carcinoma With Supraclavicular Lymph Node Metastasis: A Case Report.

Int J Gynecol Pathol 2021 Jan;40(1):78-83

Typically, local spread and lymph-vascular space invasion (LVSI) occur before lymph node (LN) and distant metastases during the progression of uterine cervical cancer. The prognostic value of LVSI in cervical superficially invasive squamous cell carcinoma (SISCC) is still debated. We encountered a rare case of cervical SISCC without LVSI presenting with multiple LN metastases, including pelvic, para-aortic, and left supraclavicular LNs. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus confirmed the relationship of the cervical SISCC and pelvic LN metastases. Aspiration cytology of the left supraclavicular LN showed squamous cell carcinoma and our final diagnosis was uterine cervical squamous cell carcinoma, stage IVB. The patient underwent adjuvant chemotherapy. Although relapse was observed at the vaginal stump and in pelvic and para-aortic LNs, chemotherapy and radiotherapy were effective. The patient is alive without disease 40 mo after initial treatment. This is the first case report of cervical SISCC without LVSI presenting with supraclavicular LN metastasis, which contributes to our understanding of the value of LVSI. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus were useful in confirming the relationship of cervical SISCC and its metastases. As cervical SISCC with LN metastasis is rare, multi-institutional joint research is needed to clarify its prognosis and appropriate treatment.
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http://dx.doi.org/10.1097/PGP.0000000000000679DOI Listing
January 2021

The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.

J Clin Endocrinol Metab 2020 12;105(12)

Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.

Background: Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features.

Methods: We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC).

Results: The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ± 6.8 mm) than in wild-type BRAF cases (20.9 ± 10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis.

Conclusions: The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.
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http://dx.doi.org/10.1210/clinem/dgaa573DOI Listing
December 2020

Evaluation of the simulator with automatic irrigation control system designed for countermeasures of internal contamination in dental unit water lines.

Heliyon 2020 Jun 10;6(6):e04132. Epub 2020 Jun 10.

Department of Pathophysiology - Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

The prevention of nosocomial infections is an imperative task. The dental chair unit (DCU) is an indispensable device used in dental treatment. However, it is known that the dental unit water line (DUWL) can become contaminated with biofilm, consisting mainly of heterotrophic bacteria (HB). Recently, the International Organization for Standardization specified the methods for testing DUWL contamination management. On these grounds, a simulator reproducing DUWL was prepared to standardize the examination method of the DUWL contamination.

Objectives: To evaluate the reproducibility of the DUWL simulator, monitor the DUWL contamination states, and test the efficacy of a commercial decontaminant for DUWL.

Methods: The DUWL simulator was assembled by a DCU manufacturing company. The simulator's DUWL was filled with tap water (TW), and left for approximately one year. Neutral electrolyzed water (NEW) was used as a decontaminant for DUWL. Both TW and NEW were passed through DUWL in a timely manner simulating daily dental treatment. Water was sampled from the air turbine hand piece weekly for 4 weeks and used for HB culture. Contamination status was evaluated by measuring bacterial adenosine triphosphate release and by culturing on Reasoner's 2A medium.

Results: The DUWL released contaminated water had a bacterial count of over 6 × 10 cfu/mL. After passing NEW through DUWL for 1 week, the count drastically decreased to its basal level and remained steady for 4 weeks. However, TW showed no effect on DUWL decontamination throughout the examination periods.

Conclusions: The DUWL simulator could be useful to examine the efficacy of the decontaminant for DUWL and development of new methods in DUWL contamination management.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298401PMC
June 2020

Resection of pancreatic and splenic metastases from alveolar soft part sarcoma: a case report.

Surg Case Rep 2020 Jun 17;6(1):139. Epub 2020 Jun 17.

Department of Gastroenterological Surgery, Fujita Health University Bantane Hospital, 3-6-10 Otobashi, Nakagawa-ku, Nagoya, Aichi, 454-8509, Japan.

Background: We present a case of pancreatic and splenic metastases following alveolar soft part sarcoma (ASPS), which was successfully treated by surgery.

Case Presentation: A 41-year-old male was referred to our hospital in 2012. Computed tomography (CT) showed the presence of a pancreatic tumor. In 2002, the patient had undergone surgical resection of an ASPS of the anal region. In 2009, during follow-up, CT revealed lung metastases, which prompted surgical resection of the lung, followed by resection of the head skin in 2011. Abdominal ultrasonography (US) revealed the presence of isodense masses sized 34 mm in the pancreatic head and 60 mm within the spleen. The contrast-enhanced US revealed a solitary lesion with enhancement. Contrast-enhanced CT revealed solitary lesions with enhancement within the pancreatic head, spleen, and liver. The patient underwent metastasectomies from the pancreas, spleen, and liver. The patient was discharged on postoperative day 22 without recurrence for 18 months after metastasectomy. Twelve years after primary resection and 2 years after metastasectomy, the patient died as a consequence of multiple metastases.

Conclusions: We have presented a rare case of pancreatic and spleen metastases from ASPS. Resection by radical metastasectomy was successful without morbidity. Thus, for improved survival of patients with multiple metastases from ASPS, metastasectomy may be indicated. If multiple metastases are resectable, surgical approaches may be the preferred treatment.
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http://dx.doi.org/10.1186/s40792-020-00907-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300166PMC
June 2020

Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors.

Cancer Sci 2020 Aug 30;111(8):2814-2823. Epub 2020 Jun 30.

Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A noncanonical mitophagy system has recently been identified, and mitochondria-eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs; its expression was defective not only in oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. Expression of MIEAP was not correlated with methylation status of the 5'-UTR of the gene. Our functional analysis showed that exogenously induced MIEAP, but not PARK2, reduced the amounts of abnormal mitochondria, as indicated by decreased reactive oxygen species levels, mitochondrial DNA / nuclear DNA ratios, and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, ie impaired MIEAP-mediated noncanonical mitophagy.
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http://dx.doi.org/10.1111/cas.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419045PMC
August 2020

MotP Subunit is Critical for Ion Selectivity and Evolution of a K-Coupled Flagellar Motor.

Biomolecules 2020 04 29;10(5). Epub 2020 Apr 29.

Graduate School of Life Sciences, Toyo University, Oura-gun, Gunma 374-0193, Japan.

The bacterial flagellar motor is a sophisticated nanomachine embedded in the cell envelope. The flagellar motor is driven by an electrochemical gradient of cations such as H, Na, and K through ion channels in stator complexes embedded in the cell membrane. The flagellum is believed to rotate as a result of electrostatic interaction forces between the stator and the rotor. In bacteria of the genus and related species, the single transmembrane segment of MotB-type subunit protein (MotB and MotS) is critical for the selection of the H and Na coupling ions. Here, we constructed and characterized several hybrid stators combined with single Na-coupled and dual Na- and K-coupled stator subunits, and we report that the MotP subunit is critical for the selection of K. This result suggested that the K selectivity of the MotP/MotS complexes evolved from the single Na-coupled stator MotP/MotS complexes. This finding will promote the understanding of the evolution of flagellar motors and the molecular mechanisms of coupling ion selectivity.
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http://dx.doi.org/10.3390/biom10050691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277484PMC
April 2020

Isolation and identification of the antimicrobial substance included in tempeh using Rhizopus stolonifer NBRC 30816 for fermentation.

Int J Food Microbiol 2020 Jul 22;325:108645. Epub 2020 Apr 22.

Department of Pathophysiology - Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama 700-8525, Japan. Electronic address:

In this study, we focus on the antimicrobial properties of tempeh, a soybean fermented food, against oral bacteria. Tempeh showed antimicrobial activity against dental caries pathogenic bacterium Streptococcus mutans at a final concentration of 1 mg/mL. An antimicrobial substance contained in tempeh was present in the 100 kDa or greater fraction generated by ultrafiltration, but it was found not to be proteinaceous by native-PAGE, SDS-PAGE and protein degradation tests. Next, when the fraction was purified with an ODS column, the 80% and 100% methanol eluates showed antimicrobial activity against S. mutans. The 100% methanol eluate was further subjected to a 2nd column purification, and isolation of the target was confirmed by HPLC. When the isolated material was analyzed by ESI-MS, the m/z was 279.234. Further analysis by Raman spectroscopy revealed a peak similar to linoleic acid. This substance also possessed antimicrobial properties equivalent to linoleic acid.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2020.108645DOI Listing
July 2020

A Factor Produced by sp. 32K Accelerated the Motility of sp. ME121.

Biomolecules 2020 04 16;10(4). Epub 2020 Apr 16.

Graduate School of Life Sciences, Toyo University, Oura-gun, Gunma 374-0193, Japan.

Motile sp. ME121 and non-motile sp. 32K were isolated from the same soil sample. Interestingly, ME121 was significantly more motile in the coculture of ME121 and 32K than in the monoculture of ME121. This advanced motility of ME121 was also observed in the 32K culture supernatant. A swimming acceleration factor, which we named the K factor, was identified in the 32K culture supernatant, purified, characterized as an extracellular polysaccharide (5-10 kDa), and precipitated with 70% ethanol. These results suggest the possibility that the K factor was directly or indirectly sensed by the flagellar stator, accelerating the flagellar rotation of ME121. To the best of our knowledge, no reports describing an acceleration in motility due to coculture with two or more types of bacteria have been published. We propose a mechanism by which the increase in rotational force of the ME121 flagellar motor is caused by the introduction of the additional stator into the motor by the K factor.
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http://dx.doi.org/10.3390/biom10040618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226442PMC
April 2020

Draft Genome Sequence of Calcium-Dependent sp. Strain TCA1, Isolated from a Hot Spring Containing a High Concentration of Calcium Ions.

Microbiol Resour Announc 2020 Apr 9;9(15). Epub 2020 Apr 9.

Graduate School of Life Sciences, Toyo University, Itakura-machi, Gunma, Japan

Calcium-dependent sp. strain TCA1 was newly isolated from a water sample from a hot spring containing a high concentration of calcium ions. Here, we report the draft genome sequence of this bacterium, which may be the basis for research on calcium ion homeostasis.
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http://dx.doi.org/10.1128/MRA.00145-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380538PMC
April 2020

Cold shock proteins improve E. coli cell-free synthesis in terms of soluble yields of aggregation-prone proteins.

Biotechnol Bioeng 2020 06 26;117(6):1628-1639. Epub 2020 Mar 26.

Laboratory for Cellular Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.

Protein folding is usually slowed-down at low temperatures, and thus low-temperature expression is an effective strategy to improve the soluble yield of aggregation-prone proteins. In this study, we investigated the effects of a variety of cold shock proteins and domains (Csps) on an Escherichia coli cell extract-based cell-free protein synthesis system (CF). Most of the 12 Csps that were successfully prepared dramatically improved the protein yields, by factors of more than 5 at 16°C and 2 at 23°C, to levels comparable to those obtained at 30°C. Their stimulatory effects were complementary to each other, while CspD and CspH were inhibitory. The Csps' effects correlated well with their Pfam CSD family scores (PF00313.22). All of the investigated Csps, except CspH, similarly possessed RNA binding and chaperon activities and increased the messenger RNA amount irrespective of their effect, suggesting that the proper balance between these activities was required for the enhancement. Unexpectedly, the 5'-untranslated region of cspA was less effective as the leader sequence. Our results demonstrated that the use of the Csps presented in this study will provide a simple and highly effective strategy for the CF, to improve the soluble yields of aggregation-prone proteins.
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http://dx.doi.org/10.1002/bit.27326DOI Listing
June 2020

Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV.

Infect Genet Evol 2020 07 3;81:104272. Epub 2020 Mar 3.

Advanced Life Sciences Program, Graduate School of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan; Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan. Electronic address:

The seventh novel human infecting Betacoronavirus that causes pneumonia (2019 novel coronavirus, 2019-nCoV) originated in Wuhan, China. The evolutionary relationship between 2019-nCoV and the other human respiratory illness-causing coronavirus is not closely related. We sought to characterize the relationship of the translated proteins of 2019-nCoV with other species of Orthocoronavirinae. A phylogenetic tree was constructed from the genome sequences. A cluster tree was developed from the profiles retrieved from the presence and absence of homologs of ten 2019-nCoV proteins. The combined data were used to characterize the relationship of the translated proteins of 2019-nCoV to other species of Orthocoronavirinae. Our analysis reliably suggests that 2019-nCoV is most closely related to BatCoV RaTG13 and belongs to subgenus Sarbecovirus of Betacoronavirus, together with SARS coronavirus and Bat-SARS-like coronavirus. The phylogenetic profiling cluster of homolog proteins of one annotated 2019-nCoV protein against other genome sequences revealed two clades of ten 2019-nCoV proteins. Clade 1 consisted of a group of conserved proteins in Orthocoronavirinae comprising Orf1ab polyprotein, Nucleocapsid protein, Spike glycoprotein, and Membrane protein. Clade 2 comprised six proteins exclusive to Sarbecovirus and Hibecovirus. Two of six Clade 2 nonstructural proteins, NS7b and NS8, were exclusively conserved among 2019-nCoV, BetaCoV_RaTG, and BatSARS-like Cov. NS7b and NS8 have previously been shown to affect immune response signaling in the SARS-CoV experimental model. Thus, we speculated that knowledge of the functional changes in the NS7b and NS8 proteins during evolution may provide important information to explore the human infective property of 2019-nCoV.
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http://dx.doi.org/10.1016/j.meegid.2020.104272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106073PMC
July 2020

Prevention of postprandial hypotension-related syncope by caffeine in a patient with long-standing diabetes mellitus.

Endocr J 2020 Jun 28;67(6):585-592. Epub 2020 Feb 28.

Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan.

A 74-year-old man who had type 2 diabetes mellitus of a duration of 20 years was admitted for syncope after eating a high carbohydrate meal. Although he had had episodes of pallor or syncope after carbohydrate-rich meals, such as with large amounts of white rice, several times within a year and he had been taken to hospitals emergently, the etiology of these episodes had remained unclear despite his undergoing several studies. Studies did show severe orthostatic hypotension during the head-up tilt test and a decrease in the coefficient of variation of the R-R interval (CVR-R) on resting electrocardiogram, suggesting severe autonomic nervous dysfunction. Because of the episodes of syncope after eating a carbohydrate-rich meal, we investigated whether he had postprandial hypotension (PPH). The 75 g oral glucose tolerance test revealed a significant decrease in his postprandial blood pressure by about 40 mmHg, leading to the diagnosis of PPH. The carbohydrate-rich meal test induced syncope with systolic blood pressure under 40 mmHg. Then 150 mg caffeine was administered before a second carbohydrate-rich meal. The marked decline in postprandial blood pressure was suppressed and plasma noradrenaline levels were gradually increased over a period of 60 minutes. Caffeine could be useful for prevention of postprandial hypotension-related syncope.
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http://dx.doi.org/10.1507/endocrj.EJ19-0370DOI Listing
June 2020

Tree of motility - A proposed history of motility systems in the tree of life.

Genes Cells 2020 Jan;25(1):6-21

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan.

Motility often plays a decisive role in the survival of species. Five systems of motility have been studied in depth: those propelled by bacterial flagella, eukaryotic actin polymerization and the eukaryotic motor proteins myosin, kinesin and dynein. However, many organisms exhibit surprisingly diverse motilities, and advances in genomics, molecular biology and imaging have showed that those motilities have inherently independent mechanisms. This makes defining the breadth of motility nontrivial, because novel motilities may be driven by unknown mechanisms. Here, we classify the known motilities based on the unique classes of movement-producing protein architectures. Based on this criterion, the current total of independent motility systems stands at 18 types. In this perspective, we discuss these modes of motility relative to the latest phylogenetic Tree of Life and propose a history of motility. During the ~4 billion years since the emergence of life, motility arose in Bacteria with flagella and pili, and in Archaea with archaella. Newer modes of motility became possible in Eukarya with changes to the cell envelope. Presence or absence of a peptidoglycan layer, the acquisition of robust membrane dynamics, the enlargement of cells and environmental opportunities likely provided the context for the (co)evolution of novel types of motility.
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http://dx.doi.org/10.1111/gtc.12737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004002PMC
January 2020

Identification of a selective DDX3X inhibitor with newly developed quantitative high-throughput RNA helicase assays.

Biochem Biophys Res Commun 2020 03 15;523(3):795-801. Epub 2020 Jan 15.

Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan. Electronic address:

The DEAD-box family of RNA helicases plays essential roles in both transcriptional and translational mRNA degradation; they unwind short double-stranded RNA by breaking the RNA-RNA interactions. Two DEAD-box RNA helicases, eukaryotic translation initiation factor 4A3 (eIF4A3) and DEAD-box helicase 3 (DDX3X), show high homology in the ATP-binding region and are considered key molecules for cancer progression. Several small molecules that target eIF4A3 and DDX3X have been reported to inhibit cancer cell growth; however, more potent compounds are required for cancer therapeutics, and there is a critical need for high-throughput assays to screen for RNA helicase inhibitors. In this study, we developed novel fluorescence resonance energy transfer-based high-throughput RNA helicase assays for eIF4A3 and DDX3X. Using these assays, we identified several eIF4A3 allosteric inhibitors whose inhibitory effect on eIF4A3 ATPase showed a strong correlation with inhibitory effect on helicase activity. From 102 compounds that exhibited eIF4A3 ATPase inhibition, we identified a selective DDX3X inhibitor, C1, which showed stronger inhibition of DDX3X than of eIF4A3. Small-molecule helicase inhibitors can be valuable for clarifying the molecular machinery of DEAD-box RNA helicases. The high-throughput quantitative assays established here should facilitate the evaluation of the helicase inhibitory activity of compounds.
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http://dx.doi.org/10.1016/j.bbrc.2019.12.094DOI Listing
March 2020

Genome-Wide Analysis of Whole Human Glycoside Hydrolases by Data-Driven Analysis in Silico.

Int J Mol Sci 2019 Dec 13;20(24). Epub 2019 Dec 13.

Advanced Life Sciences Program, Graduate School of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.

Glycans are involved in various metabolic processes via the functions of glycosyltransferases and glycoside hydrolases. Analysing the evolution of these enzymes is essential for improving the understanding of glycan metabolism and function. Based on our previous study of glycosyltransferases, we performed a genome-wide analysis of whole human glycoside hydrolases using the UniProt, BRENDA, CAZy and KEGG databases. Using cluster analysis, 319 human glycoside hydrolases were classified into four clusters based on their similarity to enzymes conserved in chordates or metazoans (Class 1), metazoans (Class 2), metazoans and plants (Class 3) and eukaryotes (Class 4). The eukaryote and metazoan clusters included - and -glycoside hydrolases, respectively. The significant abundance of disordered regions within the most conserved cluster indicated a role for disordered regions in the evolution of glycoside hydrolases. These results suggest that the biological diversity of multicellular organisms is related to the acquisition of - and -linked glycans.
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http://dx.doi.org/10.3390/ijms20246290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940844PMC
December 2019