Publications by authors named "Tatsuya Hattori"

46 Publications

Comparison of the safety and efficacy between the prone split-leg and Galdakao-modified supine Valdivia positions during endoscopic combined intrarenal surgery: A multi-institutional analysis.

Int J Urol 2021 Aug 3. Epub 2021 Aug 3.

Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Objectives: To evaluate the safety and efficacy of the prone split-leg and the Galdakao-modified supine Valdivia positions during endoscopic combined intrarenal surgery.

Methods: A multi-institutional, retrospective cohort study was conducted between January 2014 and December 2018. The stone-free and complication rates were compared between the prone split-leg and the Galdakao-modified supine Valdivia positions. Anatomical variations were evaluated using contrast-enhanced computed tomography imaging.

Results: In total, 118 and 100 patients underwent endoscopic combined intrarenal surgery in the prone split-leg and Galdakao-modified supine Valdivia positions, respectively. Renal punctures in the prone split-leg position were predominantly executed through the lower calyces (78.0%), whereas those in the Galdakao-modified supine Valdivia position were primarily performed through the middle calyces (64.0%; P < 0.001). Surgical duration in the prone split-leg position was significantly shorter than that in the Galdakao-modified supine Valdivia position (106.5 vs 126.0 min; P = 0.0459). There were no significant differences in the stone-free rate between the two positions (78.8% vs 76.0%; P = 0.629). Incidences of urinary tract injury (P = 0.033) and febrile urinary tract infection (23.7% vs 10.0%; P = 0.011) in the prone split-leg position were significantly higher than that in the Galdakao-modified supine Valdivia position. The tilt of the major renal axis was significantly greater in the prone position than the corresponding values in the oblique position (19.4° vs 8.5°; P = 0.019).

Conclusions: Anatomical variation might result in the differences of renal puncture calyx. Endoscopic combined intrarenal surgery in the Galdakao-modified supine Valdivia position may bring equal stone-free status, with a longer surgical time but fewer complications including febrile urinary tract infection and urinary tract injury than the prone split-leg position.
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http://dx.doi.org/10.1111/iju.14655DOI Listing
August 2021

The First Case Report of Robot-Assisted Fluoroscopy-Guided Renal Access During Endoscopic Combined Intrarenal Surgery.

J Endourol Case Rep 2020 29;6(4):310-314. Epub 2020 Dec 29.

Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

During percutaneous nephrolithotomy (PCNL) and endoscopic combined intrarenal surgery (ECIRS), obtaining renal access is the most critical step to achieving effective treatment without major intraoperative complications. Among a variety of methods attempted to improve the access, robot-assisted fluoroscopy-guided (RAFG) renal access has been introduced to mitigate technical human errors and overcome challenging learning curves. In this study, we present our first experience with an automated needle targeting with an X-ray (ANT-X) device for minimally invasive (mini-) ECIRS. A 75-year-old healthy woman with a 6.0 cm left kidney stone was referred to our hospital for surgical treatment. The patient underwent mini-ECIRS utilizing RAFG renal access without complication, and the stone was completely removed. The ureteral stent and transurethral catheter were removed on postoperative day 2, and the patient was discharged on postoperative day 3. There were no residual fragments detected by CT as of 3 months after the surgery. To our knowledge, this is the first report of the effective use of RAFG mini-ECIRS for a kidney stone. The overall outcome was positive, indicating the feasibility of ANT-X use for PCNL and ECIRS.
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http://dx.doi.org/10.1089/cren.2020.0125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803196PMC
December 2020

Microscopic pulmonary tumor embolism from adenocarcinoma of the prostate.

IJU Case Rep 2020 Sep 18;3(5):161-165. Epub 2020 Jun 18.

Department of Nephro-urology Nagoya City University Graduate School of Medical Sciences Nagoya Japan.

Introduction: Microscopic pulmonary tumor embolisms from prostate cancer are extremely rare. In this case of prostate cancer, microscopic pulmonary tumor embolism developed during androgen deprivation therapy.

Case Presentation: A 56-year-old man was diagnosed with prostate cancer and underwent androgen deprivation therapy. Three months after starting treatment, he noticed shortness of breath and developed acute progressive dyspnea. He was diagnosed with pulmonary hypertension; however, the cause was not found. His dyspnea was progressive and he died 40 days after the onset of symptoms. Autopsy proved that the cause of pulmonary hypertension was microscopic pulmonary tumor emboli from prostate cancer. Furthermore, histology revealed differences in the androgen receptors in the prostate and emboli, with significantly greater Ki-67 expression in the emboli than in the prostate.

Conclusion: Prostate cancer proliferated in the pulmonary artery after hematogenous metastasis, caused vascular occlusion, and formed microscopic pulmonary tumor embolisms.
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http://dx.doi.org/10.1002/iju5.12159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469864PMC
September 2020

Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.

Medicine (Baltimore) 2020 Aug;99(35):e21576

Nagoya University Graduate School of Medicine, Brain and Mind Research Center, Nagoya.

Background: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects.

Methods: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment.

Results: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 μM; Post = 38.1 μM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ± 9.3; Post = 24.7 ± 10.8; mean ± SD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment.

Conclusions: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.
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http://dx.doi.org/10.1097/MD.0000000000021576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458241PMC
August 2020

Targeting the ESCRT-III component CHMP2A for noncanonical Caspase-8 activation on autophagosomal membranes.

Cell Death Differ 2021 02 17;28(2):657-670. Epub 2020 Aug 17.

Department of Pediatrics, Penn State College of Medicine, Hershey, PA, 17033, USA.

Autophagosomal membranes can serve as activation platforms for intracellular death-inducing signaling complexes (iDISCs) to initiate Caspase-8-dependent apoptosis. In this study, we explore the impact of ESCRT-III-dependent phagophore closure on iDISC assemblies and cell death in osteosarcoma and neuroblastoma cells. Inhibition of phagophore closure by conditional depletion of CHMP2A, an ESCRT-III component, stabilizes iDISCs on immature autophagosomal membranes and induces Caspase-8-dependent cell death. Importantly, suppression of the iDISC formation via deletion of ATG7, an E1 enzyme for ubiquitin-like autophagy-related proteins, blocks Caspase-8 activation and cell death following CHMP2A depletion. Although DR5 expression and TRAIL-induced apoptosis are enhanced in CHMP2A-depleted cells, the canonical extrinsic pathway of apoptosis is not responsible for the initiation of cell death by CHMP2A depletion. Furthermore, the loss of CHMP2A impairs neuroblastoma tumor growth associated with decreased autophagy and increased apoptosis in vivo. Together, these findings indicate that inhibition of the ESCRT-III-dependent autophagosome sealing process triggers noncanonical Caspase-8 activation and apoptosis, which may open new avenues for therapeutic targeting of autophagy in cancer.
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http://dx.doi.org/10.1038/s41418-020-00610-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862398PMC
February 2021

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

Neurobiol Aging 2021 01 2;97:146.e1-146.e13. Epub 2020 Jul 2.

Department of Neurology, Jikei University Katsushika Medical Center, Tokyo, Japan.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.017DOI Listing
January 2021

The effects of 28-day early-life exposure to triphenyl phosphate (TPhP) on odor preference and sexual behavior in female rats.

J Appl Toxicol 2020 12 22;40(12):1614-1621. Epub 2020 Jun 22.

Laboratory of Animal Behavior and Environmental Science, Graduate School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan.

Many chemical substances are detectable in house dust, and they are consequently taken into our bodies via the mouth and nose. Triphenyl phosphate (TPhP), a flame retardant that has an estrogen-like effect in vitro, is present in house dust at high concentrations. Estrogen exposure during development has significant influences on reproductive behavior in rodents, and its effects persist until maturity. In the present study, we investigated the effect of early life exposure to TPhP on the reproductive behavior of female rats. Oral treatment with TPhP (25 or 250 mg/kg), ethinyl estradiol (EE; 15 μg/kg) as a positive control, or sesame oil as a negative control, were given to female rats (from birth to 28 days of age). The 8-week-old rats were bilaterally ovariectomized. At 12-15 weeks of age, the rats were subjected to odor preference and sexual behavior tests. In the odor preference test, the oil group showed significantly higher preference for male odor than female odor, but the low-dose TPhP treatment group lost the preference for male odor, indicating a possible outcome of early life TPhP exposure on sexual recognition. In the sexual behavior test, both the EE and TPhP treatment groups displayed significantly less proceptive behavior. These results suggest that early life exposure to TPhP disturbs the normal sexual behavior of female rats.
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http://dx.doi.org/10.1002/jat.4021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687172PMC
December 2020

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Brain 2020 04;143(4):1190-1205

Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awaa064DOI Listing
April 2020

VPS37A directs ESCRT recruitment for phagophore closure.

J Cell Biol 2019 10 13;218(10):3336-3354. Epub 2019 Sep 13.

Department of Pediatrics, Penn State College of Medicine, Hershey, PA

The process of phagophore closure requires the endosomal sorting complex required for transport III (ESCRT-III) subunit CHMP2A and the AAA ATPase VPS4, but their regulatory mechanisms remain unknown. Here, we establish a FACS-based HaloTag-LC3 autophagosome completion assay to screen a genome-wide CRISPR library and identify the ESCRT-I subunit VPS37A as a critical component for phagophore closure. VPS37A localizes on the phagophore through the N-terminal putative ubiquitin E2 variant domain, which is found to be required for autophagosome completion but dispensable for ESCRT-I complex formation and the degradation of epidermal growth factor receptor in the multivesicular body pathway. Notably, loss of VPS37A abrogates the phagophore recruitment of the ESCRT-I subunit VPS28 and CHMP2A, whereas inhibition of membrane closure by CHMP2A depletion or VPS4 inhibition accumulates VPS37A on the phagophore. These observations suggest that VPS37A coordinates the recruitment of a unique set of ESCRT machinery components for phagophore closure in mammalian cells.
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http://dx.doi.org/10.1083/jcb.201902170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781443PMC
October 2019

TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion.

Cell Rep 2019 08;28(7):1744-1757.e5

Department of Pediatrics, Penn State University College of Medicine, Hershey, PA, USA; Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA. Electronic address:

During autophagy, phagophores grow into double-membrane vesicles called autophagosomes, but the underlying mechanism remains unclear. Here, we show a critical role of Atg2A in phagophore expansion. Atg2A translocates to the phagophore at the mitochondria-associated ER membrane (MAM) through a C-terminal 45-amino acid domain that we have termed the MAM localization domain (MLD). Proteomic analysis identifies the outer mitochondrial membrane protein TOM40 as a MLD-interacting partner. The Atg2A-TOM40 interaction is responsible for MAM localization of Atg2A and requires the TOM receptor protein TOM70. In addition, Atg2A interacts with Atg9A by a region within its N terminus. Inhibition of either Atg2A-TOM40 or Atg2A-Atg9A interactions impairs phagophore expansion and accumulates Atg9A-vesicles in the vicinity of autophagic structures. Collectively, we propose a model that the TOM70-TOM40 complex recruits Atg2A to the MAM for vesicular and/or non-vesicular lipid transport into the expanding phagophore to grow the size of autophagosomes for efficient autophagic flux.
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http://dx.doi.org/10.1016/j.celrep.2019.07.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701867PMC
August 2019

Rare case of Richter syndrome with testicular involvement successfully obtained good prognosis with rapid operation and immunochemotherapy.

IJU Case Rep 2019 Jul 17;2(4):232-235. Epub 2019 Jun 17.

Department of Nephro-Urology Graduate School of Medical Sciences Nagoya City University Nagoya Aichi Japan.

Introduction: Richter syndrome refers to the transformation from chronic lymphocytic leukemia to assaultive lymphoma, often a diffuse large B-cell lymphoma, and has a greatly poor prognosis. Richter syndrome is characterized by rapidly growing lymphadenopathy but rarely presents with extra-nodal involvement, common sites being the digestive tract, lungs, kidneys, and central nervous system. However, Richter syndrome with testicular involvement is extremely rare.

Case Presentation: Herein we report a very scare case of a male at the age of 72 with Richter syndrome and testicular involvement, diagnosed by the investigation of bilateral scrotal swellings. The patient had attained disease-free survival for over a year with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and the intrathecal administration of chemotherapeutic agents after diagnosis by immediate orchiectomy.

Conclusion: An early pathological diagnosis by immediate orchiectomy and the early initiation of induction immunochemotherapy may be good prognostic factors in Richter syndrome involving the testes.
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http://dx.doi.org/10.1002/iju5.12096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292090PMC
July 2019

An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure.

Nat Commun 2018 07 20;9(1):2855. Epub 2018 Jul 20.

Department of Pediatrics, Penn State College of Medicine, Hershey, PA, 17033, USA.

The mechanism of phagophore closure remains unclear due to technical limitations in distinguishing unclosed and closed autophagosomal membranes. Here, we report the HaloTag-LC3 autophagosome completion assay that specifically detects phagophores, nascent autophagosomes, and mature autophagic structures. Using this assay, we identify the endosomal sorting complexes required for transport (ESCRT)-III component CHMP2A as a critical regulator of phagophore closure. During autophagy, CHMP2A translocates to the phagophore and regulates the separation of the inner and outer autophagosomal membranes to form double-membrane autophagosomes. Consistently, inhibition of the AAA-ATPase VPS4 activity impairs autophagosome completion. The ESCRT-mediated membrane abscission appears to be a critical step in forming functional autolysosomes by preventing mislocalization of lysosome-associated membrane glycoprotein 1 to the inner autophagosomal membrane. Collectively, our work reveals a function for the ESCRT machinery in the final step of autophagosome formation and provides a useful tool for quantitative analysis of autophagosome biogenesis and maturation.
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http://dx.doi.org/10.1038/s41467-018-05254-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054611PMC
July 2018

Severe hyposmia and aberrant functional connectivity in cognitively normal Parkinson's disease.

PLoS One 2018 5;13(1):e0190072. Epub 2018 Jan 5.

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

Objective: Severe hyposmia is a risk factor of dementia in Parkinson's disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear.

Methods: We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs).

Results: Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke's Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH.

Conclusion: PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190072PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755765PMC
January 2018

Early-life exposure to Tris(1,3-dichloroisopropyl) phosphate induces dose-dependent suppression of sexual behavior in male rats.

J Appl Toxicol 2018 05 22;38(5):649-655. Epub 2017 Dec 22.

Laboratory of Animal Behavior and Environmental Science, School of Agriculture, Meiji University, Kanagawa, 214-8571, Japan.

Exposure to endocrine-disrupting chemicals may adversely affect animals, particularly during development. Tris(1,3-dichloroisopropyl) phosphate (TDCIPP) is an organophosphate with anti-androgen function in vitro that is present in indoor dust at relatively high concentrations. In male rats, androgens are necessary for the development of reproductive organs, as well as the endocrine and central nervous systems. However, we currently do not know the exact effects of TDCIPP exposure through suckling on subsequent reproductive behavior in males. Here, we show that TDCIPP exposure (25-250 mg kg via oral administration over 28 consecutive days post-birth) suppressed male sexual behavior and reduced testes size. These changes were dose-dependent and appeared first in adults rather than in juveniles. These results demonstrate that TDCIPP exposure led to normal body growth and appearance in juveniles, but disrupted the endocrine system and physiology in adults. Therefore, assays should be performed using adult animals to ensure accuracy, and to confirm the influence of chemical substances given during early mammalian life.
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http://dx.doi.org/10.1002/jat.3569DOI Listing
May 2018

Sex differences in olfactory-induced neural activation of the amygdala.

Behav Brain Res 2018 07 2;346:96-104. Epub 2017 Dec 2.

Companion Animal Research, School of Veterinary Medicine, Azabu University, Sagamihara 252-5201, Japan. Electronic address:

Olfactory signals, including the scent of urine, are thought to be processed by specific brain regions, such as the medial amygdala (Me), and regulate sexual behavior in a sex-dependent manner. We aimed to reveal the sex-specific neural circuit from the accessory olfactory bulb (AOB) to Me by using a transgenic mouse. We quantified the long-lasting green fluorescent protein (GFP) expression profile, which was controlled by the c-fos promotor in a sex-dependent manner by the scent of urine. Female urine predominantly activated neurons of the posterodorsal medial amygdala (MePD) in male mice and the posteroventral medial amygdala (MePV) in female mice. Male urine, in contrast, generated the opposite pattern of activation in the Me. Secondary, the selective artificial activation of these circuits was used to examine their specific behavioral function, by using a dual Cre-loxP viral infection. AAV-hSyn-FLEX-hM3Dq-EGFP-the designer receptor exclusively activated by a designer drug-was infused into the AOB after infection with trans-synaptic AAV(DJ)-CMV-mCherry-2A-Cre-TTC into either the MePD or the MePV. Double virus-transfected mice were injected with hMDq activator and their sexual behavior was monitored. However, selective activation of sex-dependent circuits, i.e., the AOB-MePD or AOB-MePV, did not significantly alter mounting or attack behavior in male mice. There were clear sex differences in the pheromone conveying circuits in the AOB-Me of mice. The sex-dependent functional activation of the Me, however, no effect on behavior. This suggests that a diverse number of nuclei and brain areas are likely to function in concert to successfully facilitate sexual and aggressive behaviors.
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http://dx.doi.org/10.1016/j.bbr.2017.11.034DOI Listing
July 2018

Exocrine Gland-Secreting Peptide 1 Is a Key Chemosensory Signal Responsible for the Bruce Effect in Mice.

Curr Biol 2017 Oct 12;27(20):3197-3201.e3. Epub 2017 Oct 12.

Companion Animal Research, School of Veterinary Medicine, Azabu University, Sagamihara 252-5201, Japan. Electronic address:

The Bruce effect refers to pregnancy termination in recently pregnant female rodents upon exposure to unfamiliar males [1]. This event occurs in specific combinations of laboratory mouse strains via the vomeronasal system [2, 3]; however, the responsible chemosensory signals have not been fully identified. Here we demonstrate that the male pheromone exocrine gland-secreting peptide 1 (ESP1) is one of the key factors that causes pregnancy block. Female mice exhibited high pregnancy failure rates upon encountering males that secreted different levels of ESP1 compared to the mated male. The effect was not observed in mice that lacked the ESP1 receptor, V2Rp5, which is expressed in vomeronasal sensory neurons. Prolactin surges in the blood after mating, which are essential for maintaining luteal function, were suppressed by ESP1 exposure, suggesting that a neuroendocrine mechanism underlies ESP1-mediated pregnancy failure. The single peptide pheromone ESP1 conveys not only maleness to promote female receptivity but also the males' characteristics to facilitate memorization of the mating partner.
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http://dx.doi.org/10.1016/j.cub.2017.09.013DOI Listing
October 2017

Generation of monoclonal antibodies against mitocryptide-2: toward a new strategy to investigate the biological roles of cryptides.

J Pept Sci 2017 Jul 29;23(7-8):610-617. Epub 2017 Mar 29.

Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.

We recently identified a novel family of neutrophil-activating peptides including mitocryptide-1 and mitocryptide-2 (MCT-2) that are endogenously produced from various mitochondrial proteins. Among them, MCT-2 is an N-formylated pentadecapeptide derived from mitochondrial cytochrome b and is found to promote neutrophilic migration and phagocytosis efficiently. Signaling mechanisms of neutrophil activation by MCT-2 have been investigated at the cellular level, and MCT-2 has been demonstrated to be an endogenous specific ligand for formyl peptide receptor-2 (also referred to as formyl peptide receptor-like 1). It was also found that MCT-2 promoted neutrophilic functions via the activation of G proteins and phosphorylation of ERK1/2 consecutively. However, the physiological production, distribution, and functions of MCT-2 are not yet elucidated. Here, to investigate the roles of MCT-2 in vivo, we generated monoclonal antibodies (mAbs) against human MCT-2 (hMCT-2) that have two different characteristics. One mAb, NhM2A1, not only bound to the region of positions 10-15 of hMCT-2 but also recognized its C-terminal cleavage site that is presumably produced upon enzymatic hydrolysis of cytochrome b, indicating that NhM2A1 specifically interacts with hMCT-2 but not its parent protein. Moreover, we succeeded in acquiring a specific neutralizing mAb, NhM2A5, which blocks the bioactivities of hMCT-2. Specifically, NhM2A5 inhibited hMCT-2-induced β-hexosaminidase release in neutrophilic/granulocytic differentiated HL-60 cells by binding to the region of positions 5-12 of hMCT-2. Functional analysis using obtained mAbs that specifically recognize hMCT-2 but not its parent protein, cytochrome b, and that neutralize bioactivities of hMCT-2 is expected to reveal the physiological roles of MCT-2, which are presently very difficult to investigate. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/psc.3000DOI Listing
July 2017

Self-Exposure to the Male Pheromone ESP1 Enhances Male Aggressiveness in Mice.

Curr Biol 2016 05 14;26(9):1229-34. Epub 2016 Apr 14.

Companion Animal Research, School of Veterinary Medicine, Azabu University, Sagamihara 252-5201, Japan. Electronic address:

Exocrine gland-secreting peptide 1 (ESP1) released into male tear fluids is a male pheromone that stimulates sexually receptive behavior in female mice via the vomeronasal sensory system. ESP1 also induces c-Fos expression in male brain regions distinct from those in females. However, behavior in males following ESP1 exposure has not been examined. In the present study, we show that ESP1, in conjunction with unfamiliar male urine, enhances male aggression via the specific vomeronasal receptor V2Rp5. In addition, male mice that secrete ESP1 but lack V2Rp5 exhibit a lower level of aggressiveness than do mice that express V2Rp5. These results suggest that ESP1 not only acts as a male pheromone in both sexes but also serves as an auto-stimulatory factor that enhances male aggressiveness by self-exposure. Finally, re-activation of ESP1-induced c-Fos-positive neurons by using the designer receptor exclusively activated by designer drug (DREADD) approach resulted in enhancement of sexual and aggressive behaviors in female and male mice, respectively, indicating that sexually dimorphic activation in the brain is a neural basis for the sex-specific behavioral responses to ESP1.
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http://dx.doi.org/10.1016/j.cub.2016.03.029DOI Listing
May 2016

Anaerobic Growth of Haloarchaeon Haloferax volcanii by Denitrification Is Controlled by the Transcription Regulator NarO.

J Bacteriol 2016 Jan 19;198(7):1077-86. Epub 2016 Jan 19.

Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka, Japan Department of Environment and Energy Systems, Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan

Unlabelled: The extremely halophilic archaeon Haloferax volcanii grows anaerobically by denitrification. A putative DNA-binding protein, NarO, is encoded upstream of the respiratory nitrate reductase gene of H. volcanii. Disruption of the narO gene resulted in a loss of denitrifying growth of H. volcanii, and the expression of the recombinant NarO recovered the denitrification capacity. A novel CXnCXCX7C motif showing no remarkable similarities with known sequences was conserved in the N terminus of the NarO homologous proteins found in the haloarchaea. Restoration of the denitrifying growth was not achieved by expression of any mutant NarO in which any one of the four conserved cysteines was individually replaced by serine. A promoter assay experiment indicated that the narO gene was usually transcribed, regardless of whether it was cultivated under aerobic or anaerobic conditions. Transcription of the genes encoding the denitrifying enzymes nitrate reductase and nitrite reductase was activated under anaerobic conditions. A putative cis element was identified in the promoter sequence of haloarchaeal denitrifying genes. These results demonstrated a significant effect of NarO, probably due to its oxygen-sensing function, on the transcriptional activation of haloarchaeal denitrifying genes.

Importance: H. volcanii is an extremely halophilic archaeon capable of anaerobic growth by denitrification. The regulatory mechanism of denitrification has been well understood in bacteria but remains unknown in archaea. In this work, we show that the helix-turn-helix (HTH)-type regulator NarO activates transcription of the denitrifying genes of H. volcanii under anaerobic conditions. A novel cysteine-rich motif, which is critical for transcriptional regulation, is present in NarO. A putative cis element was also identified in the promoter sequence of the haloarchaeal denitrifying genes.
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http://dx.doi.org/10.1128/JB.00833-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800875PMC
January 2016

Mitochondrial protein-derived cryptides: Are endogenous N-formylated peptides including mitocryptide-2 components of mitochondrial damage-associated molecular patterns?

Biopolymers 2016 Nov;106(4):580-7

Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.

Recently, much attention has been paid to "nonclassical" bioactive peptides, which are fragmented peptides simultaneously produced during maturation and degradation of various functional proteins. We identified many fragmented peptides derived from various mitochondrial proteins including mitocryptide-1 and mitocryptide-2 that efficiently activate neutrophils. These endogenous, functionally active, fragmented peptides are referred to as "cryptides." Among them, mitocryptide-2 is an N-formylated cryptide cleaved from mitochondrial cytochrome b that is encoded in mitochondrial DNA (mtDNA). It is known that 13 proteins encoded in mtDNA are translated in mitochondria as N-formylated forms, suggesting the existence of endogenous N-formylated peptides other than mitocryptide-2. Here, we investigated the effects of N-formylated peptides presumably cleaved from mtDNA-encoded proteins other than cytochrome b on the functions of neutrophilic cells to elucidate possible regulation by endogenous N-formylated cryptides. Four N-formylated cryptides derived from cytochrome c oxidase subunit I and NADH dehydrogenase subunits 4, 5, and 6 among 12 peptides from mtDNA-encoded proteins efficiently induced not only migration but also β-hexosaminidase release, which is an indicator of neutrophilic phagocytosis, in HL-60 cells differentiated into neutrophilic cells. These activities were comparable to or higher than those induced by mitocryptide-2. Although endogenous N-formylated peptides that are contained in mitochondrial damage-associated molecular patterns (DAMPs) have yet to be molecularly identified, they have been implicated in innate immunity. Thus, N-formylated cryptides including mitocryptide-2 are first-line candidates for the contents of mitochondrial DAMPs to promote innate immune responses. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 580-587, 2016.
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http://dx.doi.org/10.1002/bip.22788DOI Listing
November 2016

Successful acquisition of a neutralizing monoclonal antibody against a novel neutrophil-activating peptide, mitocryptide-1.

Biochem Biophys Res Commun 2015 Jul 17-24;463(1-2):54-9. Epub 2015 May 15.

Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan. Electronic address:

Mitocryptide-1 (MCT-1) is a novel neutrophil-activating peptide derived from mitochondrial cytochrome c oxidase subunit VIII, and its physiological role and involvement in various diseases have not yet been elucidated. Generating neutralizing antibodies against the function of MCT-1 is of particular importance for investigating its physiological and pathophysiological roles, because MCT-1 is a fragmented peptide of its mother protein and hence it is very difficult to manipulate its expression level genetically without affecting expression of the mother protein. Here, we report the successful generation of a neutralizing monoclonal antibody (MAb) against MCT-1. This MAb, designated NM1B1, which specifically bound to the region of positions 9-22 of MCT-1, showed concentration-dependent inhibition of MCT-1-induced migration and β-hexosaminidase release in neutrophilic/granulocytic differentiated HL-60 cells. Thus, NM1B1, as a neutralizing MAb against MCT-1, could elucidate not just the physiological regulatory mechanisms of MCT-1 but also its pathophysiological involvement in various inflammatory diseases in vivo.
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http://dx.doi.org/10.1016/j.bbrc.2015.05.016DOI Listing
August 2015

Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice.

Proc Natl Acad Sci U S A 2015 Jan 6;112(3):E311-20. Epub 2015 Jan 6.

Department of Functional Neuroscience, Osaka Bioscience Institute, Osaka 565-0874, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.
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http://dx.doi.org/10.1073/pnas.1416723112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311817PMC
January 2015

Cryptides: biologically active peptides hidden in protein structures.

Nihon Yakurigaku Zasshi 2014 Nov;144(5):234-8

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http://dx.doi.org/10.1254/fpj.144.234DOI Listing
November 2014

Sexual attractiveness of male chemicals and vocalizations in mice.

Front Neurosci 2014 5;8:231. Epub 2014 Aug 5.

Department of Animal Science and Biotechnology, Graduate School of Veterinary Medicine, Azabu University Kanagawa, Japan.

Male-female interaction is important for finding a suitable mating partner and for ensuring reproductive success. Male sexual signals such as pheromones transmit information and social and sexual status to females, and exert powerful effects on the mate preference and reproductive biology of females. Likewise, male vocalizations are attractive to females and enhance reproductive function in many animals. Interestingly, females' preference for male pheromones and vocalizations is associated with their genetic background, to avoid inbreeding. Moreover, based on acoustic cues, olfactory signals have significant effects on mate choice in mice, suggesting mate choice involves multisensory integration. In this review, we synopsize the effects of both olfactory and auditory cues on female behavior and neuroendocrine functions. We also discuss how these male signals are integrated and processed in the brain to regulate behavior and reproductive function.
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http://dx.doi.org/10.3389/fnins.2014.00231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122165PMC
August 2014

Single osteotomy at the radial diaphysis for congenital radioulnar synostosis.

J Hand Surg Am 2014 Aug 2;39(8):1553-7. Epub 2014 Jul 2.

Hand Department, Japanese Red Cross Hospital Nagoya Daiichi, Nagoya; Hattori Orthopedic Dermatology Clinic, Aichi, Japan.

Purpose: To report the effectiveness of single derotation osteotomy at the radial diaphysis for the treatment of congenital radioulnar (RU) synostosis.

Methods: Since 2000, we performed 35 radial diaphysis osteotomies on 17 boys and 9 girls younger than 9 years old (average, 5 y). The radius was cut at the midshaft and manually rotated to a neutral position. A long-arm cast was applied for 4 to 6 weeks. Complications of surgeries were recorded, and pre- and postoperative forearm position was measured.

Results: The average postoperative follow-up was 5 years. The patient age at the final follow-up ranged from 5 to 19 years. There were no major surgery-related complications. The average forearm position was improved from 72° pronation before surgery to neutral after surgery, except 2 forearms. Elbow flexion and extension showed no change. All parents noted that daily activities were improved after surgery, and they found the surgical scar in the midforearm acceptable.

Conclusions: Single osteotomy at the radial diaphysis was effective for correcting pronation deformity in congenital RU synostosis in children younger than 9 years. Complications were few, and the correction was maintained through midterm follow-up.

Type Of Study/level Of Evidence: Therapeutic IV.
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http://dx.doi.org/10.1016/j.jhsa.2014.05.018DOI Listing
August 2014

Impairment of interstrain social recognition during territorial aggressive behavior in oxytocin receptor-null mice.

Neurosci Res 2015 Jan 12;90:90-4. Epub 2014 Jun 12.

Companion Animal Research, School of Veterinary Medicine, Azabu University, Sagamihara 252-5201, Japan.

In humans, oxytocin has been shown to be involved in in-group cooperative behaviors and out-group aggression. Studies have also demonstrated that oxytocin plays a pivotal role in social recognition. However, no empirical research has investigated the effect of oxytocin on in-group and out-group aggressiveness. We employed a resident-intruder paradigm to assess the ability of resident male mice to discriminate intruder male strain differences. We found that resident male mice exhibited higher frequencies of attack bites against intruders of different strains than against intruders of their own strain. Subsequently, we examined whether the interstrain recognition was regulated by the oxytocin system using oxytocin receptor (OTR)-null mice. OTR wild-type or heterozygous residents displayed higher aggression toward intruders of a strain different from their own (C57BL/6J). On the other hand, OTR-null residents exhibited greater aggression toward intruders of the same strain compared to OTR wild-type or heterozygous residents, and aggression levels were not different compared to those exhibited toward other strains. Our findings demonstrated that the oxytocin system contributes to interstrain social recognition in territorial aggression in male mice, implying that one function of oxytocin is to promote an in-group "tend-and-defend" response, such as in-group favoritism, which could be evolutionarily conserved in mammals.
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http://dx.doi.org/10.1016/j.neures.2014.05.003DOI Listing
January 2015

Flexor pollicis longus reconstruction using the palmaris longus in anterior interosseus nerve syndrome.

Hand Surg 2014 ;19(2):189-92

Department of Orthopedic Surgery, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.

In anterior interosseus nerve syndrome, reconstruction of the paralyzed flexor pollicis longus is occasionally required. Traditionally, the brachioradialis has been used as a motor, but we utilised the palmaris longus, which is expendable. The palmaris longus tendon was transferred in an end-to-side manner, leaving the flexor pollicis longus in situ. The procedure was performed in three patients. All patients regained a full range of thumb interphalangeal joint motion and an average 90% of the pinch strength. The only complication noted was thenar pain due to the adhesion of the palmar branch of the median nerve with the transferred tendon in one patient. This can be avoided if the interlacing suture was placed more proximally. Palmaris longus transfer is a simple technique that gives a satisfactory result.
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http://dx.doi.org/10.1142/S021881041450018XDOI Listing
December 2014

Comparison of test methods for detecting metallo-β-lactamase-producing Gram-negative bacteria.

Jpn J Infect Dis 2013 ;66(6):512-8

Department of Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine.

The recent increase in gram-negative bacteria coproducing multiple classes of β-lactamases has made it difficult to accurately identify metallo-β-lactamase (MBL) producers. In the present study, six methods for detecting MBL producers were compared using 56 gram-negative bacterial isolates that produce various β-lactamases. Sodium mercaptoacetic acid (SMA) and EDTA were used as inhibitors for a double-disk synergy test (DDST), and antimicrobial agents, including ceftazidime (CAZ), imipenem, and meropenem (MEPM), along with the distance between the disks, were compared. The Etest(®), dry-plate DPD1(®), Cica-Beta(®), and modified Hodge test were also compared. Among the six methods compared, DDST using the SMA disk showed the highest sensitivity (Se) and specificity (Sp). In DDST, the clearest appearance of growth inhibition was observed when the distance between the disks was maintained at approximately 5 mm. A combination of CAZ and SMA successfully detected only MBL-producing isolates (Se, 87.5%; Sp, 100%), and MEPM exhibited the best performance in combination with SMA in the detection of MBL producers coproducing other classes of β-lactamases such as CTX-M- and CMY-type enzymes (Se, 79.1%; Sp, 100%). DDST using SMA and CAZ and/or MEPM is a simple, specific, and cost-effective method to screen MBL producers in routine clinical laboratory testing.
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http://dx.doi.org/10.7883/yoken.66.512DOI Listing
August 2014

Mouse embryonic stem cells cultured under serum- and feeder-free conditions maintain their self-renewal capacity on hydroxyapatite.

Mater Sci Eng C Mater Biol Appl 2014 Jan 25;34:214-20. Epub 2013 Sep 25.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan. Electronic address:

New tissue engineering techniques based on embryonic stem (ES) cells and artificial scaffolds are required for regenerative medicine. Because artificial scaffolds can regulate the differentiation states of ES cells, compatibility between the cells and artificial scaffolds is important. To our knowledge, this study is the first report showing that mouse ES (mES) cells can be maintained in undifferentiated state on hydroxyapatite coated with gelatin. In contrast to previous studies, our culture medium was serum-free and included a GSK-3 inhibitor. Under these conditions, mES colony morphology was similar to that of an undifferentiated state; mES cells expressed the pluripotent-specific factors Oct-3/4 and Nanog, and they maintained the ability to differentiate into the three germ layers. Moreover, a GSK-3 inhibitor blocked the expression of integrin subunits that bind to laminin which are known to induce the differentiation of mES cells. These findings indicate that mES cells can be cultured under serum- and feeder-free conditions and maintained in an undifferentiated state on a composite with hydroxyapatite and that this composite can be used to control the differentiation of stem cells.
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http://dx.doi.org/10.1016/j.msec.2013.09.012DOI Listing
January 2014

Radiocapitellar impingement due to residual deformities after a Bado type III Monteggia fracture-dislocation in a pediatric patient: a case report.

J Shoulder Elbow Surg 2013 May 13;22(5):e19-21. Epub 2013 Mar 13.

Department of Orthopedic Surgery, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.

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http://dx.doi.org/10.1016/j.jse.2013.01.025DOI Listing
May 2013
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