Publications by authors named "Yasuo Mori"

317 Publications

MrgprB4 in trigeminal neurons expressing TRPA1 modulates unpleasant sensations.

J Pharmacol Sci 2021 Aug 28;146(4):200-205. Epub 2021 Apr 28.

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch behaviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone application or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensations may modulate unpleasant sensations on the cheek via MrgprB4.
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http://dx.doi.org/10.1016/j.jphs.2021.04.006DOI Listing
August 2021

Extreme deformability of insect cell membranes is governed by phospholipid scrambling.

Cell Rep 2021 Jun;35(10):109219

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Kyoto 615-8510, Japan. Electronic address:

Organization of dynamic cellular structure is crucial for a variety of cellular functions. In this study, we report that Drosophila and Aedes have highly elastic cell membranes with extremely low membrane tension and high resistance to mechanical stress. In contrast to other eukaryotic cells, phospholipids are symmetrically distributed between the bilayer leaflets of the insect plasma membrane, where phospholipid scramblase (XKR) that disrupts the lipid asymmetry is constitutively active. We also demonstrate that XKR-facilitated phospholipid scrambling promotes the deformability of cell membranes by regulating both actin cortex dynamics and mechanical properties of the phospholipid bilayer. Moreover, XKR-mediated construction of elastic cell membranes is essential for hemocyte circulation in the Drosophila cardiovascular system. Deformation of mammalian cells is also enhanced by the expression of Aedes XKR, and thus phospholipid scrambling may contribute to formation of highly deformable cell membranes in a variety of living eukaryotic cells.
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http://dx.doi.org/10.1016/j.celrep.2021.109219DOI Listing
June 2021

TRPM7 is an essential regulator for volume-sensitive outwardly rectifying anion channel.

Commun Biol 2021 May 20;4(1):599. Epub 2021 May 20.

National Institute for Physiological Sciences, Okazaki, Japan.

Animal cells can regulate their volume after swelling by the regulatory volume decrease (RVD) mechanism. In epithelial cells, RVD is attained through KCl release mediated via volume-sensitive outwardly rectifying Cl channels (VSOR) and Ca-activated K channels. Swelling-induced activation of TRPM7 cation channels leads to Ca influx, thereby stimulating the K channels. Here, we examined whether TRPM7 plays any role in VSOR activation. When TRPM7 was knocked down in human HeLa cells or knocked out in chicken DT40 cells, not only TRPM7 activity and RVD efficacy but also VSOR activity were suppressed. Heterologous expression of TRPM7 in TRPM7-deficient DT40 cells rescued both VSOR activity and RVD, accompanied by an increase in the expression of LRRC8A, a core molecule of VSOR. TRPM7 exerts the facilitating action on VSOR activity first by enhancing molecular expression of LRRC8A mRNA through the mediation of steady-state Ca influx and second by stabilizing the plasmalemmal expression of LRRC8A protein through the interaction between LRRC8A and the C-terminal domain of TRPM7. Therefore, TRPM7 functions as an essential regulator of VSOR activity and LRRC8A expression.
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http://dx.doi.org/10.1038/s42003-021-02127-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137958PMC
May 2021

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program.

Transplant Cell Ther 2021 May 5. Epub 2021 May 5.

Japan Marrow Donor Program, Aichi Medical University School of Medicine, Nagakute, Japan.

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.
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http://dx.doi.org/10.1016/j.jtct.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098035PMC
May 2021

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist-induced orofacial dyskinesia.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Department of Molecular Pharmacology, Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.
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http://dx.doi.org/10.1172/jci.insight.145632DOI Listing
May 2021

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Br J Haematol 2021 Apr 6. Epub 2021 Apr 6.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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http://dx.doi.org/10.1111/bjh.17456DOI Listing
April 2021

V for versatility: TRPV4 Ca entry channel plays multiple roles in invadosome regulation.

Authors:
Yasuo Mori

Cell Calcium 2021 Jun 4;96:102387. Epub 2021 Mar 4.

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan. Electronic address:

Several Ca-permeable cation channels attract attention for their mechanotransducer function to evoke Ca signals in cell invasion. Vellino et al., have clarified the versatility of the osmo-sensing TRPV4 channel in regulating invadosome functions: TRPV4 detects and integrates multiple cellular and environmental cues, triggering Ca signals and molecular interactions that modulate coupling between acto-adhesion and extracellular matrix degradation.
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http://dx.doi.org/10.1016/j.ceca.2021.102387DOI Listing
June 2021

Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis.

Biol Pharm Bull 2021 ;44(3):431-436

Graduate School of Pharmaceutical Sciences, Kyushu University.

Non-alcoholic steatohepatitis (NASH) is a disease that has progressed from non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6 (TRPC3/6), reportedly participate in the development of fibrosis in cardiovascular and renal systems. We hypothesized that TRPC3/6 may also participate in NASH fibrosis. We evaluated the effects of TRPC3 or TRPC6 functional deficiency in a NASH mouse model using choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Wild-type (WT) and TRPC3 or TRPC6 gene-deficient (KO) mice were fed with CDAHFD or standard diet for 6 weeks. The CDAHFD-induced body weight loss in TRPC6 KO mice was significantly lower compared with WT mice with CDAHFD. CDAHFD treatment significantly increased TRPC3 mRNA expression level and tissue weight in WT liver, which were suppressed in TRPC3 KO mice. However, either systemic deletion of TRPC3 or TRPC6 failed to attenuate liver steatosis, inflammation and fibrosis. These results imply that TRPC3 and TRPC6 are unlikely to be involved in liver dysfunction and fibrosis of NASH model mice.
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http://dx.doi.org/10.1248/bpb.b20-00903DOI Listing
January 2021

Deficiency of the RIβ subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats.

Sci Rep 2021 Jan 21;11(1):2039. Epub 2021 Jan 21.

Laboratory of Animal Nutrition, Department of Animal Science, Faculty of Agriculture, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 243-0034, Japan.

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral-CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function.
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http://dx.doi.org/10.1038/s41598-021-81515-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820254PMC
January 2021

A molecular cell atlas of the human lung from single-cell RNA sequencing.

Nature 2020 11 18;587(7835):619-625. Epub 2020 Nov 18.

Department of Biochemistry, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.

Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles, it has been difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.
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http://dx.doi.org/10.1038/s41586-020-2922-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704697PMC
November 2020

Transient Receptor Potential Ankyrin 1 Mediates Hypoxic Responses in Mice.

Front Physiol 2020 22;11:576209. Epub 2020 Oct 22.

Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel that is broadly expressed in sensory pathways, such as the trigeminal and vagus nerves. It is capable of detecting various irritants in inspired gasses and is activated during hypoxia. In this study, the role of TRPA1 in hypoxia-induced behavioral, respiratory, and cardiovascular responses was examined through four lines of experiments using TRPA1 knockout (KO) mice and wild type (WT) littermates. First, KO mice showed significantly attenuated avoidance behavior in response to a low (15%) oxygen environment. Second, the wake-up response to a hypoxic ramp (from 21 to 10% O in 40 s) was measured using EEG electrodes. WT mice woke up within 30 s when oxygen was at 13-14%, but KO mice did not wake up until oxygen levels reached 10%. Histological analysis confirmed that mild (13% O) hypoxia resulted in an attenuation of trigeminal neuronal activation in KO mice. Third, the ventilatory response to hypoxia was measured with whole body plethysmography. KO mice showed attenuated responses to mild hypoxia (15% O) but not severe hypoxia (10% O). Similar responses were observed in WT mice treated with the TRPA1 blocker, AP-18. These data clearly show that TRPA1 is necessary for multiple mild hypoxia (13-15% O)-induced physiological responses. We propose that TRPA1 channels in the sensory pathways innervating the airway can detect hypoxic environments and prevent systemic and/or cellular hypoxia from occurring.
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http://dx.doi.org/10.3389/fphys.2020.576209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642990PMC
October 2020

Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study.

Ann Hematol 2021 Jan 5;100(1):197-208. Epub 2020 Nov 5.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
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http://dx.doi.org/10.1007/s00277-020-04310-0DOI Listing
January 2021

Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data.

Bone Marrow Transplant 2021 Apr 2;56(4):853-862. Epub 2020 Nov 2.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.
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http://dx.doi.org/10.1038/s41409-020-01082-zDOI Listing
April 2021

Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice.

Eur J Pharmacol 2021 Jan 22;891:173671. Epub 2020 Oct 22.

Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Nakano, Tokyo, 164-8530, Japan. Electronic address:

Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca-permeable channel. The activation of TRPM2 by HO causes cell death in various types of cells. 5-Fluorouracil (5-FU) is an important anticancer drug, but myelosuppression is one of the most frequent adverse effects. The involvement of oxidative stress in 5-FU-induced myelosuppression has been reported, and bone marrow cells are known to express TRPM2. The aim of this study was to investigate whether TRPM2 is involved in 5-FU-induced myelosuppression. Enhancement of HO-induced intracellular Ca concentration ([Ca]) increase by 5-FU treatment was observed in human embryonic kidney 293 (HEK) cells stably expressing TRPM2 but not in HEK cells, indicating that 5-FU stimulates TRPM2 activation. In CD117 positive cells from wild type (WT) mouse bone marrow, 5-FU also enhanced the HO-induced [Ca] increases, but not in cells from Trpm2 knockout (KO) mice. In the CFU-GM colony assay, the 5-FU-induced reduction of colony number was alleviated by Trpm2 deficiency. Moreover, the reduction of leukocytes in blood by administration with 5-FU in WT mice was also alleviated in Trpm2 KO mice. The activation of TRPM2 in bone marrow cells seems to be involved in 5-FU-induced myelosuppression.
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http://dx.doi.org/10.1016/j.ejphar.2020.173671DOI Listing
January 2021

A Rapid Shift from Chronic Hyperoxia to Normoxia Induces Systemic Anaphylaxis via Transient Receptor Potential Ankyrin 1 Channels on Mast Cells.

J Immunol 2020 12 23;205(11):2959-2967. Epub 2020 Oct 23.

Laboratory of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan;

Extensive activation of mast cells is the major switch that triggers systemic anaphylaxis, resulting in the subsequent release of anaphylactic mediators into circulation. We previously demonstrated that rapid changes in oxygen tension lead to mast cell degranulation, and the released tryptase triggers retinal angiogenesis in a murine oxygen-induced retinopathy model. However, whether a rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk factor for systemic anaphylaxis remains unknown. In this study, we demonstrated that the relative hypoxia stress induces systemic mast cell activation via transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads to hypothermia and increased vascular permeability in adult mice. Although mast cell-deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms following a rapid sift to normoxia, preinjection with bone marrow-derived cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice restored anaphylactic responses. In addition, we found that the rapid reductions in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor. Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms. Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylactic shock without Ag-Ab reactions. These findings introduce a potential role for oxygen in inducing mast cell-dependent anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for anoxic diseases.
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http://dx.doi.org/10.4049/jimmunol.2000149DOI Listing
December 2020

Uterine relapse of Philadelphia chromosome-negative acute lymphoblastic leukemia.

J Clin Exp Hematop 2020 ;60(3):103-107

Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan.

The relapse of acute lymphoblastic leukemia (ALL) usually involves the bone marrow, with the central nervous system being the most frequent extramedullary site. The relapse of ALL in the female genital organs, particularly the uterus, is markedly rare. We report such a patient who developed relapse in the bone marrow and uterus. The uterine lesion, which presented as abnormal uterine bleeding, consisted of a mass on MRI and proliferation of ALL cells on histology. MRI revealed a heterogeneous high-intensity mass (T2-WI/D-WI) with a diameter of 6.8 cm, a notable decrease in the apparent diffusion coefficient (ADC), and mild enhancement by contrast enhancement study. Histological findings of the uterine cervix demonstrated the infiltration of ALL. The patient achieved remission by allogeneic haplo-identical hematopoietic stem-cell transplantation, but died of complications of the transplantation. This case suggested that attention should be paid to the uterus as a site of extramedullary relapse. In addition, abnormal uterine bleeding, which is a common sign of hormonal imbalance and hormone replacement therapy after chemotherapy, may be an initial sign of extramedullary recurrence. To confirm uterine relapse as an intractable disease, the accumulation of more cases is required.
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http://dx.doi.org/10.3960/jslrt.20016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596908PMC
January 2021

Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients.

Int J Hematol 2020 Oct 31;112(4):466-476. Epub 2020 Aug 31.

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.
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http://dx.doi.org/10.1007/s12185-020-02934-6DOI Listing
October 2020

O-Dependent Protein Internalization Underlies Astrocytic Sensing of Acute Hypoxia by Restricting Multimodal TRPA1 Channel Responses.

Curr Biol 2020 09 16;30(17):3378-3396.e7. Epub 2020 Jul 16.

Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan. Electronic address:

Hypoxia sensors are essential for regulating local oxygen (O) homeostasis within the body. This is especially pertinent within the CNS, which is particularly vulnerable to O deprivation due to high energetic demand. Here, we reveal hypoxia-monitoring function exerted by astrocytes through an O-regulated protein trafficking mechanism within the CNS. Strikingly, cultured mouse astrocytes isolated from the parafacial respiratory group (pFRG) and retrotrapezoid nucleus (RTN) region are capable of rapidly responding to moderate hypoxia via the sensor cation channel transient receptor potential (TRP) A1 but, unlike multimodal sensory neurons, are inert to hyperoxia and other TRPA1 activators (carbon dioxide, electrophiles, and oxidants) in normoxia. Mechanistically, O suppresses TRPA1 channel activity by protein internalization via O-dependent proline hydroxylation and subsequent ubiquitination by an E3 ubiquitin ligase, NEDD4-1 (neural precursor cell-expressed developmentally down-regulated protein 4). Hypoxia inhibits this process and instantly accumulates TRPA1 proteins at the plasma membrane, inducing TRPA1-mediated Ca influx that triggers ATP release from pFRG/RTN astrocytes, potentiating respiratory center activity. Furthermore, astrocyte-specific Trpa1 disruption in a mouse brainstem-spinal cord preparation impedes the amplitude augmentation of the central autonomic respiratory output during hypoxia. Thus, reversible coupling of the TRPA1 channels with O-dependent protein translocation allows astrocytes to act as acute hypoxia sensors in the medullary respiratory center.
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http://dx.doi.org/10.1016/j.cub.2020.06.047DOI Listing
September 2020

Correction to: Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep;112(3):431-432

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

In the original publication of the article, the "CNS involvement" in the last row under the column "Total N=50" has been published incorrectly. The correct Table 1 is given in this correction.
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http://dx.doi.org/10.1007/s12185-020-02932-8DOI Listing
September 2020

Ion channelopathies to bridge molecular lesions, channel function, and clinical therapies.

Pflugers Arch 2020 07;472(7):733-738

Department of Synthetic Chemistry and Biological Chemistry, Laboratory of Molecular Biology, Kyoto University, Kyoto, 615-8510, Japan.

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http://dx.doi.org/10.1007/s00424-020-02424-yDOI Listing
July 2020

Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep 10;112(3):349-360. Epub 2020 Jun 10.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 10/L (high risk) or < 3 × 10/L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.
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http://dx.doi.org/10.1007/s12185-020-02911-zDOI Listing
September 2020

Fluorescence detection of the nitric oxide-induced structural change at the putative nitric oxide sensing segment of TRPC5.

Bioorg Med Chem 2020 04 17;28(8):115430. Epub 2020 Mar 17.

Institute of Advanced Energy, Kyoto University, Uji, Kyoto 611-0011, Japan. Electronic address:

The plausible nitric oxide (NO)-sensing module of TRPC5 was incorporated in a enhanced green fluorescent protein (EGFP) to evaluate its conformational change as an optical response upon the reaction with NO. Two cysteine residues located in the NO-sensing module have been proposed to form a disulfide bond through S-nitrosylation of the thiol group by NO. Modification of the cysteine residues by NO resulted a ratiometric change of EGFP emission through transducing the conformational change of NO-sensing module to the EGFP chromophore. The oxidized form of NO-sensing module fused EGFP changed the intensity of emission spectra upon reduction of the disulfide bond at the NO-reactive module. The NO-sensing module fused EGFP in its reduced form avidly reacted with NO and realized the ratiometric fluorescence intensity changes depending on the formation of disulfide bond. These results support the notion that NO induces a conformational change at the putative NO-sensing segment of TRPC5, and provide a prototype for the genetically encoded cellular NO sensors.
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http://dx.doi.org/10.1016/j.bmc.2020.115430DOI Listing
April 2020

Disrupted tongue microbiota and detection of nonindigenous bacteria on the day of allogeneic hematopoietic stem cell transplantation.

PLoS Pathog 2020 03 9;16(3):e1008348. Epub 2020 Mar 9.

Section of Preventive and Public Health Dentistry, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.

Disruption of the intestinal microbiota caused by intensive chemotherapy, irradiation and antibiotics can result in development of severe gut graft-versus-host disease and infectious complications, leading to poorer outcomes among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the oral cavity is also densely colonized by indigenous microorganisms, the bacterial composition in allo-HSCT recipients remains unclear. We determined the tongue microbiota composition of 45 patients with hematological disorders on the day of transplantation and compared them to 164 community-dwelling adults. The V1-V2 regions of the 16S rRNA gene sequences demonstrated that the allo-HSCT recipients had less diverse and distinct microbiota from that of community-dwelling adults. The full-length 16S rRNA gene sequences identified 146 bacterial taxa in the microbiota of allo-HSCT recipients, of which 34 bacterial taxa did not correspond to bacteria primarily inhabiting the oral cavity deposited in the expanded Human Oral Microbiome Database. Notably, the detection of Staphylococcus haemolyticus and/or Ralstonia pickettii was significantly associated with a higher risk of mortality during the follow-up period. These results demonstrate that the oral cavity of allo-HSCT recipients is colonized by a disrupted microbiota on the day of transplantation and suggest that detection of specific nonindigenous taxa could be a predictor of transplant outcome.
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http://dx.doi.org/10.1371/journal.ppat.1008348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082065PMC
March 2020

Successful allogeneic stem cell transplantation in a case with acute myeloid leukemia and invasive Schizophyllum commune rhinosinusitis.

J Infect Chemother 2020 May 5;26(5):506-509. Epub 2020 Mar 5.

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Schizophyllum commune, a basidiomycete fungus, is a quite rare cause of invasive sinusitis for which no standard treatment has yet been established. We report herein a 59-year-old woman who developed S. commune rhinosinusitis after remission induction chemotherapy for her acute myeloid leukemia. No causative microorganisms were identified in the sinus lavage fluid culture, whereas nucleotide sequencing of the internal transcribed spacer region using endoscopic sinus biopsy specimen could confirm the pathogen as S. commune. Liposomal amphotericin B and voriconazole (VRCZ) treatment ameliorated both her clinical symptoms and laboratory findings. The patient was successfully treated with allogeneic stem cell transplantation, under continuous VRCZ administration, without aggravation of S. commune sinusitis. Molecular diagnosis and prompt intervention with suitable antifungal drugs may be crucial to manage this rare infectious complication.
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http://dx.doi.org/10.1016/j.jiac.2019.12.013DOI Listing
May 2020

Structure determination of the human TRPV1 ankyrin-repeat domain under nonreducing conditions.

Acta Crystallogr F Struct Biol Commun 2020 Mar 2;76(Pt 3):130-137. Epub 2020 Mar 2.

Graduate School of Science and Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan.

TRPV1, a member of the transient receptor potential (TRP) channels family, has been found to be involved in redox sensing. The crystal structure of the human TRPV1 ankyrin-repeat domain (TRPV1-ARD) was determined at 4.5 Å resolution under nonreducing conditions. This is the first report of the crystal structure of a ligand-free form of TRPV1-ARD and in particular of the human homologue. The structure showed a unique conformation in finger loop 3 near Cys258, which is most likely to be involved in inter-subunit disulfide-bond formation. Also, in human TRPV1-ARD it was possible for solvent to access Cys258. This structural feature might be related to the high sensitivity of human TRPV1 to oxidants. ESI-MS revealed that Cys258 did not form an S-OH functionality even under nonreducing conditions.
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http://dx.doi.org/10.1107/S2053230X20001533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057350PMC
March 2020

Increasing Diluent Volume Decreases Bendamustine-Induced Venous Irritation without Reducing the Therapeutic Efficacy.

Biol Pharm Bull 2020 ;43(3):488-492

Department of Pharmacy, Kyushu University Hospital.

The intravenous injection of bendamustine often induces venous irritation, which reduces patients' QOL. We previously reported that the dilution of the final volume of bendamustine from 250 to 500 mL significantly decreased the incidence of venous irritation. However, the influence of this change on the therapeutic efficacy of bendamustine remains unclear. Therefore, the aim of this study was to evaluate the efficacy and safety profiles of bendamustine at different dilutions of the final volume, comparing with the correspondences of previous studies. Thirty-four patients, who received a total of 161 courses of bendamustine and rituximab chemotherapy, were included in this study. The overall response rate of this regimen was 94.1% in this study, which was comparable to that reported in the BRB study (94.2%, a phase II study of bendamustine plus rituximab therapy in Japanese patients). Additionally, the median progression-free survival was not inferior to that reported in the BRB study. Bendamustine-induced venous irritation was observed in 17.6% of the patients during the first treatment cycle administered at a final volume of 500 mL, and was found to be lower than that observed in the control, where bendamustine was administered at a final volume of 250 mL (85.7%). These results suggest that diluting bendamustine to 500 mL, but not to 250 mL, reduces the incidence of venous irritation without a negative impact on its therapeutic efficacy; thus, this simple strategy may be beneficial to ensure efficacy and safety in patients receiving regimens including bendamustine.
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http://dx.doi.org/10.1248/bpb.b19-00826DOI Listing
September 2020

Phase I/II study of bortezomib, lenalidomide, and dexamethasone treatment for relapsed and refractory multiple myeloma.

Int J Hematol 2020 May 24;111(5):673-680. Epub 2020 Jan 24.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse.
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http://dx.doi.org/10.1007/s12185-020-02833-wDOI Listing
May 2020

Current Status and Needs of Long-Term Follow-Up Clinics for Hematopoietic Cell Transplantation Survivors: Results of a Nationwide Survey in Japan.

Biol Blood Marrow Transplant 2020 05 18;26(5):949-955. Epub 2020 Jan 18.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

With increasing focus on the importance of long-term survivorship care after allogeneic hematopoietic cell transplantation (allo-HCT), more institutions have been establishing long-term follow-up (LTFU) clinics. Currently, however, with varying volumes of HCT procedures and resources, there is no standardized operation of these clinics in HCT centers. We conducted a nationwide questionnaire survey to characterize the current operation of LTFU clinics in Japan. We targeted 271 HCT centers (189 adult and 82 pediatric) that registered allo-HCT cases to the national transplant registry database. The response rate was 69%, and 117 of the 188 participating centers (62%) had an established LTFU clinic. The most frequent reason cited for not operating an LTFU clinic was a "lack of human resources," especially nurses. Most centers with an LTFU clinic targeted allo-HCT recipients, although autologous HCT survivors were followed up at 18% of adult centers and 48% of pediatric centers. Ninety-two percent of centers did not terminate LTFU at a specific time point, and 56% recommended that patients visit the LTFU clinic beyond 5 years after HCT. Fifteen of 20 pediatric centers indicated that they did not routinely refer survivors who underwent HCT at a young age to an adult HCT center for their adulthood LTFU. We found that staffing and standard practices varied widely among centers, and that most centers continued to see long-term HCT survivors at their own outpatient clinics. The development of common LTFU tools may help standardize LTFU practices and facilitate efficient transitions.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.008DOI Listing
May 2020

Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.

Gastroenterology 2020 05 10;158(6):1626-1641.e8. Epub 2020 Jan 10.

Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.

Background & Aims: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca-selective ion channel, in an international cohort of patients and in mice.

Methods: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca imaging assays. CP was induced by repeated injections of cerulein in TRPV6 mice.

Results: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10). TRPV6 mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis.

Conclusions: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca balance in pancreatic cells. TRPV6 regulates Ca homeostasis and pancreatic inflammation.
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http://dx.doi.org/10.1053/j.gastro.2020.01.005DOI Listing
May 2020

Ryanodine receptor mutations (G4946E and I4790K) differentially responsible for diamide insecticide resistance in diamondback moth, Plutella xylostella L.

Insect Biochem Mol Biol 2020 03 18;118:103308. Epub 2019 Dec 18.

School of Agriculture, Utsunomiya University, Utsunomiya, Tochigi, 321-8505, Japan. Electronic address:

This study examined diamondback moth (Plutella xylostella) strains showing high-level resistance to cyantraniliprole (KA17 strain) and to flubendiamide and chlorantraniliprole (KU13 strain). The LC value of the KA17 strain against cyantraniliprole was ca. 100-fold higher than that of the KU13 strain. The KA17 strain also exhibited high-level resistance to chlorantraniliprole and flubendiamide equivalent to those in the KU13 strain. The KU13 strain showed a higher LC value against cyantraniliprole than the susceptible strains. However, the LC value of the KU13 strain against cyantraniliprole was below the agriculturally recommended concentration. Subsequent QTL analysis using ddRAD-seq identified the resistance responsible regions of the KA17 and KU13 strains with different diamide resistance profiles. Ryanodine receptor (RyR) gene was included in the identified regions. Single nucleotide polymorphism calling in the RyR gene using RNA-seq found previously reported G4946E (amino acid mutation from glycine to glutamic acid at amino acid position 4946) and novel I4790K (amino acid mutation from isoleucine to lysine at amino acid position 4790) mutations, respectively, in the RyR of the KU13 and KA17 strains. Functional significance of I4790K in the resistance was confirmed in calcium imaging of the human embryonic kidney 293T cell line expressing Bombyx mori RyR with the mutation. This reporting is the first describing I4790K as a fundamental mechanism responsible for the resistance to the diamides including cyantraniliprole. From this study, we also report up-regulated expression of some degradation enzymes and that of the RyR gene in the KA17 and KU13 strains based on results of RNA-seq data analysis.
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http://dx.doi.org/10.1016/j.ibmb.2019.103308DOI Listing
March 2020