Publications by authors named "Yusuke Kuroda"

62 Publications

Comparison of acute inhalation toxicity of sulfuric acid by the inhalation and intratracheal instillation methods.

J Toxicol Pathol 2021 Jul 24;34(3):269-273. Epub 2021 Apr 24.

Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

Recently, intratracheal instillation has been focused on as a simple, low-cost alternative to the inhalation method. In this study, intratracheal instillation of sulfuric acid, a typical acidic compound, was performed to compare the acute toxicity of acidic compounds that could cause damage to the respiratory system between intratracheal instillation and inhalation. Sulfuric acid was administered to male rats at doses of 0.7, 2, 7, 20, and 60 mg/kg by dividing the total dose into four doses. General condition and body weight were examined up to 14 days after administration, and macropathological and histopathological examinations were performed. The half-lethal dose was then estimated. All animals administered 20 and 60 mg/kg sulfuric acid and one animal administered 2 mg/kg sulfuric acid died within 4 h after administration. No abnormalities were observed in other animals. At 20 and 60 mg/kg, multiple red foci or diffuse red areas were macroscopically observed in the lungs. In these lesions, histopathologically, clefts between the mucosal epithelium and basement membrane and necrosis of the alveolar epithelium were observed. Deaths in these groups may have resulted from lung injury. No notable changes were observed in other animals. Therefore, the half-lethal dose of sulfuric acid by intratracheal instillation was estimated as 7-20 mg/kg. The acute toxicity by intratracheal instillation was evaluated with two-fold sensitivity since the exposure at the half-lethal sulfuric acid concentration in inhalation studies was calculated as 43.2 mg/kg.
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http://dx.doi.org/10.1293/tox.2020-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280304PMC
July 2021

A case report of RccHan: WIST rat with multiple neoplastic and non-neoplastic proliferative lesions.

J Toxicol Pathol 2021 Jul 30;34(3):251-259. Epub 2021 Apr 30.

Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.
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http://dx.doi.org/10.1293/tox.2021-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280308PMC
July 2021

Swim bladder tumor in the young adult scoliotic medaka ().

J Toxicol Pathol 2021 Apr 28;34(2):157-160. Epub 2021 Feb 28.

Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

A swim bladder tumor was detected in one scoliotic medaka aged 22 weeks. The tumor was located in the dorsal abdominal cavity, with maximum dimension of 1,850 × 1,500 µm. No swim bladder lumen was identified, and the region where the swim bladder lumen would have been located, was replaced with adipose tissues. The tumor was a non-invasive, expansile, and encapsulated solid mass with a few cysts, and comprised a homogenous population of well-differentiated, densely packed, gas glandular epithelium-like cells. The tumor mass was connected to a rete mirabile that showed a hyperplastic capillary plexus; however, the tumor cells did not invade the rete mirabile, thereby revealing that the tumor was an adenoma originating from the gas glandular epithelium of the swim bladder. Since proliferative lesions in the swim bladder have been reported in some teleosts with skeletal deformations, including medaka, the occurrence of a spontaneous swim bladder tumor in teleosts is considered to be closely associated with various types of skeletal deformation, and spinal curvature in particular.
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http://dx.doi.org/10.1293/tox.2020-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100251PMC
April 2021

The interaction of competition and terrain on pacing during cross-county running races in junior athletes.

Res Sports Med 2021 Mar 30:1-11. Epub 2021 Mar 30.

Massey University, College of Health, School of Sport, Exercise and Nutrition, Palmerston North, New Zealand.

The aim of this study was to assess pacing during cross-country racing in relation to race length, surface-terrain and racing dynamics. Athletes ( = 148) competed for school teams (U15, U17, U20) over 2.9, 4.2, 6.3 km, respectively. The course lap (2.067 m) was timed using UHF-RFID and divided into six sections based on surface-terrain and length (549, 619, 207, 338, 150, 156m). Overall pace differed between races (4.56 ± 0.30, 4.42 ± 0.38, 4.40 ± 0.31 m∙s, =0.042) but not for the top-20 of each race (=0.174). Moreover, within lap pacing followed a repeated reverse-"J"-parabolic strategy for all races. Race length (no. of laps) and category affected pacing with regards to finish position banding (1st-10th, 11th-20th) where effect size differences showed large to extremely large (1.21 - >4.00) difference between top-10 and other bands. Exceptions to this included the finish sprint where it was typically trivial-moderate (<0.2-1.2) and in key areas where social facilitation occurred. Athlete/coaches need to be aware of between and within lap variations in pace/effort, the effects of race dynamics, and spectator influences, while all athletes need to be educated as part of their training to run their own optimal strategy for best performance.
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http://dx.doi.org/10.1080/15438627.2021.1906675DOI Listing
March 2021

Swim bladder tumors in the wavy medaka ().

J Toxicol Pathol 2021 Jan 30;34(1):107-111. Epub 2020 Oct 30.

Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

Swim bladder tumors were detected in three out of 28 wavy medakas aged about 2 years old, all of which displayed abnormal swimming patterns caused by their spinal curvature. The tumors were located in the dorsal abdominal cavity. The swim bladder lumen was not detected in the region where it was originally assumed to be located, and that region was replaced with adipose tissue. The tumors were non-invasive, expansile, and encapsulated solid masses composed of a homogenous population of well-differentiated, densely packed, gas glandular epithelium-like cells. The tumor masses were connected to the rete mirabile, but the tumor cells did not infiltrate into them. Histopathologically, these tumors were diagnosed as adenomas originating from the gas glandular epithelium of the swim bladder. Spontaneous swim bladder tumors are rare in medaka, with an incidence of 0.02%; however, in the present study of wavy medaka, the incidence was much higher (10.7%). The long-term physical effects on the gas gland caused by swim bladder deformation considered to be a secondary effect of the spinal curvature may be an important factor in the proliferation of the gas glandular epithelium in the wavy medaka, resulting in the higher incidence of swim bladder tumors.
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http://dx.doi.org/10.1293/tox.2020-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890170PMC
January 2021

Effect of sampling time on somatic and germ cell mutations induced by acrylamide in gpt delta mice.

Genes Environ 2021 Feb 17;43(1). Epub 2021 Feb 17.

Division of Genetics and Mutagenesis, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501, Japan.

Background: Acrylamide (AA) is a rodent carcinogen and classified by the IARC into Group 2A (probable human carcinogen). AA has been reported to induce mutations in transgenic rodent gene mutation assays (TGR assays), the extent of which is presumed to depend on exposure length and the duration of expression after exposure. In particular, it is not clear in germ cells. To investigate mutagenicity with AA in somatic and germ cells at different sampling times, we conducted TGR assays using gpt delta transgenic mice.

Results: The male gpt delta mice at 8 weeks of age were treated with AA at 7.5, 15 and 30 mg/kg/day by gavage for 28 days. Peripheral blood was sampled on the last day of the treatment for micronucleus tests and tissues were sampled for gene mutation assays at day 31 and day 77, those being 3 and 49 days after the final treatment (28 + 3d and 28 + 49d), respectively. Another group of mice was treated with N-Ethyl-N-nitrosourea (ENU) at 50 mg/kg/day by intraperitoneal administration for 5 consecutive days and tissues were sampled at the day 31 and day 77 (5 + 26d and 5 + 72d). Frequencies of micronucleated erythrocytes in the peripheral blood significantly increased at AA doses of 15 and 30 mg/kg/day. Two- to three-fold increases in gpt mutation frequencies (MFs) compared to vehicle control were observed in the testes and lung treated with 30 mg/kg/day of AA at both sampling time. In the sperm, the gpt MFs and G:C to T:A transversions were significantly increased at 28 + 3d, but not at 28 + 49d. ENU induced gpt mutations in these tissues were examined at both 5 + 26d and 5 + 72d. A higher mutant frequency in the ENU-treated sperm was observed at 5 + 72d than that at 5 + 26d.

Conclusions: The gpt MFs in the testes, sperm and lung of the AA-treated mice were determined and compared between different sampling times (3 days or 49 days following 28 day-treatment). These results suggest that spermatogonial stem cells are less sensitive to AA mutagenicity under the experimental condition. Prolonged expression time after exposure to AA to detect mutagenicity may be effective in somatic cells but not in germ cells.
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http://dx.doi.org/10.1186/s41021-021-00175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890838PMC
February 2021

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

ACS Catal 2020 Mar 16;10(5):2929-2941. Epub 2020 Jan 16.

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo -hydroxy--lactams under mild, visible light conditions using a Norrish-Yang process to affect -functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo -hydroxy--lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.
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http://dx.doi.org/10.1021/acscatal.9b04551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872151PMC
March 2020

Personality and motivational predictors of well-being and coping during COVID-19: A reversal theory analysis.

Pers Individ Dif 2021 Jun 28;175:110703. Epub 2021 Jan 28.

Massey University, School of Agriculture and Environment, Private Bag 11 222, Palmerston North 4442, New Zealand.

This study used reversal theory to examine motivational predictors of well-being and coping during the COVID-19 pandemic in 2020. 149 UK based respondents completed an online survey including measures of demographics, well-being, coping, motivational style, and dominance. Well-being was predicted by optimism (positively), autic and mastery (negatively) dominances, by alloic sympathy, optimism and paratelic motivation styles (positively), and, negatively by arousal seeking, arousability and pessimism. Coping was positively predicted by optimism and negativism dominances and by negativist, paratelic and telic motivations, and, negatively by arousability and pessimism. Using motivational dominances, indirect support was identified for the link between psychodiversity and well-being, but not coping. Findings suggest that well-being and, to a lesser degree, coping could be enhanced by encouraging individuals to experience a range of motivations, possibly focusing on those identified here as significant predictors. Future research needs to determine the context specificity of these findings and explore psychodiversity, well-being and coping using both metamotivational states and composite profiles incorporating the full range of motivational constructs.
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http://dx.doi.org/10.1016/j.paid.2021.110703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843147PMC
June 2021

Dural Arteriovenous Fistula Formation as Eagle Jugular Syndrome: A Case Report and Literature Review.

World Neurosurg 2020 12 3;144:154-161. Epub 2020 Sep 3.

Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.

Background: An elongated styloid process can less frequently lead to symptomatic compression of the internal jugular vein (IJV). We present the first case of dural arteriovenous fistula (DAVF) in association with compressed IJV by an elongated styloid process.

Case Description: A 77-year-old woman presented with pulsating tinnitus. DAVF at the right hypoglossal canal was diagnosed, and she underwent transvenous embolization. The shunt flow was reduced, and the symptom disappeared after transvenous embolization. However, 2 years and 8 months later, retrograde sinus drainage from the residual shunt was asymptomatically found on magnetic resonance imaging, and angiography revealed progression of IJV stenosis caused by an elongated styloid process. Subsequently, she underwent a second transvenous embolization, and the arteriovenous shunt was almost completely obliterated.

Conclusions: The present case suggests that venous hypertension by compressed IJV can induce the development of DAVF. It is helpful for the diagnosis and treatment of DAVF to keep in mind the possibility of IJV stenosis owing to an elongated styloid process.
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http://dx.doi.org/10.1016/j.wneu.2020.08.214DOI Listing
December 2020

C-C Bond Cleavage Approach to Complex Terpenoids: Development of a Unified Total Synthesis of the Phomactins.

J Am Chem Soc 2020 09 31;142(36):15536-15547. Epub 2020 Aug 31.

Department of Chemistry, University of California, Berkeley, California 94720, United States.

The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C-C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C-C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C-C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.
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http://dx.doi.org/10.1021/jacs.0c07316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771649PMC
September 2020

Intracranial-Intracranial Bypass Using a Y-Shaped Artery Graft for Growing Unruptured Gemella morbillorum Infectious Aneurysm on Artery Supplying Sensory Cortex.

World Neurosurg 2020 10 17;142:328-333. Epub 2020 Jul 17.

Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Background: Vascular reconstruction is required to treat infectious intracranial aneurysms (IIAs) on arteries supplying the eloquent area. However, extracranial-intracranial bypass is sometimes impossible because IIAs are frequently located distally on arteries and the length of a donor artery is limited. We report a rare case of an unruptured Gemella morbillorum IIA, which was successfully treated by intracranial-intracranial (IC-IC) bypass using a Y-shaped superficial temporal artery (STA) interposition graft.

Case Description: A 52-year-old man presented with heart failure and an unruptured IIA in the right anterior parietal artery because of acute G. morbillorum endocarditis. The patient was treated with urgent replacement of cardiac valves and antibiotic therapy. However, the IIA increased in size during the following 1 month, and therefore was treated surgically to prevent the rupture. End-to-side IC-IC bypass using a Y-shaped STA graft followed by aneurysmal trapping was performed to overcome the limited length of the STA as a donor artery to prevent cerebral ischemia in the artery territory and to avoid direct injury to the sensory cortex adhering tightly to the IIA. Postoperative courses were uneventful, and he recovered from the infectious diseases.

Conclusions: This case suggests that end-to-side IC-IC bypass using a Y-shaped STA graft can be a good option for surgical treatment of IIAs, which are located in eloquent areas.
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http://dx.doi.org/10.1016/j.wneu.2020.07.056DOI Listing
October 2020

Intestinal ganglioneuroma in a neonatal Japanese black calf - Short communication.

Acta Vet Hung 2020 03 8;68(1):49-52. Epub 2020 May 8.

1Department of Veterinary Pathology, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate, 020-8550, Japan.

A 1-day-old male calf presented with clinical signs of severe progressive abdominal distension. Abdominal radiographic and ultrasonic images revealed several loop-like structures in the small intestine, which were indicative of gas retention. Experimental laparotomy was performed. However, the calf died during surgery. At necropsy, a round, well-circumscribed mass (3 × 3 × 2.5 cm) was found in the jejunal wall, and the jejunal lumen was narrowed. The mass was firm and had white to grey appearance on the cut surface. Histologically, the submucosa and the muscle layer were diffusely thickened due to abundance of neural tissues comprising several fascicles of nerve fibres and large aggregates of ganglion cells. Some ganglion cells contained basophilic Nissl substances in their cytoplasm. Immunohistochemically, these cells were positive for S-100 and synaptophysin. Ultrastructural examination revealed that the neoplastic ganglion cells contained dense core vesicles in the cytoplasm. Based on these findings, the neoplastic lesion was diagnosed as ganglioneuroma in the jejunum.
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http://dx.doi.org/10.1556/004.2020.00012DOI Listing
March 2020

Author Correction: Deconstructive diversification of cyclic amines.

Nature 2020 Apr;580(7803):E6

Department of Chemistry, University of California, Berkeley, CA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-020-2132-0DOI Listing
April 2020

The effects of β-naphthoflavone on rat placental development.

J Toxicol Pathol 2019 Oct 20;32(4):275-282. Epub 2019 Aug 20.

Veterinary Clinical Pathology, Faculty of Veterinary Medicine Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.

The morphological effects of β-naphthoflavone (β-NF) on placental development in pregnant rats were examined. β-NF, administered to pregnant rats intraperitoneally at 15 mg/kg bw from gestation day (GD) 9 to GD 14, had no effect on maternal body weight gain, mortality, or clinical sign. In the β-NF-exposed rats, intrauterine growth retardation (IUGR) rates increased on GDs 17 and 21, although there was no effect on fetal mortality rate, fetal or placental weight, or external fetal abnormality. Histopathologically, β-NF induced apoptosis and inhibition of cell proliferation of the trophoblastic septa in the labyrinth zone, resulting in its poor development. In the basal zone, β-NF induced spongiotrophoblast apoptosis and delayed glycogen islet regression, resulting in their cystic degeneration. β-NF-induced CYP1A1 expression was detected in the endothelial cells of the fetal capillaries in the labyrinth zone and in the endothelial cells of the spiral arteries in the metrial gland, but not in any trophoblasts. This indicates that CYP1A1 is inducible in the endothelial cells of the fetal capillaries in the labyrinth zone, and that these cells have an important role in metabolizing CYP1A1 inducers crossing the placental barrier.
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http://dx.doi.org/10.1293/tox.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831496PMC
October 2019

Clinical and neurophysiological variability in Andersen-Tawil syndrome.

Muscle Nerve 2019 12 9;60(6):752-757. Epub 2019 Oct 9.

Department of Neurology, Dokkyo Medical University, Tochigi, Japan.

Introduction: Andersen-Tawil syndrome (ATS) is characterized by a triad of periodic paralysis, ventricular arrhythmias, and dysmorphism. However, patients often lack one or more of these features.

Methods: Clinical and neurophysiological features were reviewed of five members in two families with heterozygous mutations in KCNJ2 (R218Q and R67W).

Results: Only one patient had all features of the triad of ATS. One patient had low-set ears, and the others had minor anomalies. Bidirectional ventricular tachycardias were seen in two patients. Two patients (R67W) never had episodes of paralysis. The long exercise test was abnormal in three patients with episodes of paralysis, but normal in two without paralytic episodes.

Discussion: ATS patients without skeletal muscle symptoms can have normal neurophysiological examinations. They can show variability in phenotype or the severity of arrhythmias. Such variability among patients who share the same gene mutations may result in underdiagnosis of ATS.
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http://dx.doi.org/10.1002/mus.26705DOI Listing
December 2019

Asymmetric Formal Synthesis of (+)-Catharanthine via Desymmetrization of Isoquinuclidine.

Org Lett 2019 05 25;21(10):3750-3754. Epub 2019 Apr 25.

Graduate School of Pharmaceutical Sciences , Chiba University , 1-8-1, Inohana , Chuo-ku, Chiba 260-8675 , Japan.

Although (+)-catharanthine is an attractive alkaloid for both clinical research and organic synthetic chemistry, only a limited number of approaches for its catalytic asymmetric synthesis exist. Herein, we describe a novel strategy for synthesizing a chiral intermediate of (+)-catharanthine via phosphoric acid-catalyzed asymmetric desymmetrization of a meso-isoquinuclidine possessing a 1,3-diol unit that was synthesized by a formal amide insertion reaction.
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http://dx.doi.org/10.1021/acs.orglett.9b01198DOI Listing
May 2019

Deconstructive diversification of cyclic amines.

Nature 2018 12 31;564(7735):244-248. Epub 2018 Oct 31.

Department of Chemistry, University of California, Berkeley, CA, USA.

Deconstructive functionalization involves carbon-carbon (C-C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis and olefin metathesis have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp)-C(sp) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp)-N and C(sp)-C(sp) single-bond cleavage followed by C(sp)-halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.
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http://dx.doi.org/10.1038/s41586-018-0700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317721PMC
December 2018

Isolation, synthesis and bioactivity studies of phomactin terpenoids.

Nat Chem 2018 09 30;10(9):938-945. Epub 2018 Jul 30.

Department of Chemistry, University of California, Berkeley, CA, USA.

Studies of secondary metabolites (natural products) that cover their isolation, chemical synthesis and bioactivity investigation present myriad opportunities for discovery. For example, the isolation of novel secondary metabolites can inspire advances in chemical synthesis strategies to achieve their practical preparation for biological evaluation. In the process, chemical synthesis can also provide unambiguous structural characterization of the natural products. Although the isolation, chemical synthesis and bioactivity studies of natural products are mutually beneficial, they are often conducted independently. Here, we demonstrate the benefits of a collaborative study of the phomactins, diterpenoid fungal metabolites that serve as antagonists of the platelet activating factor receptor. Our isolation of novel phomactins has spurred the development of a bioinspired, unified approach that achieves the total syntheses of six congeners. We also demonstrate in vitro the beneficial effects of several phomactins in suppressing the rate of repopulation of tumour cells following gamma radiation therapy.
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http://dx.doi.org/10.1038/s41557-018-0084-xDOI Listing
September 2018

Application of 2'-O-(2-N-Methylcarbamoylethyl) Nucleotides in RNase H-Dependent Antisense Oligonucleotides.

Nucleic Acid Ther 2018 10 18;28(5):307-311. Epub 2018 Jul 18.

1 Department of Life Science and Technology, Tokyo Institute of Technology , Yokohama, Japan .

An RNase H-dependent antisense oligonucleotide (ASO), having the 2'-O-(2-N-methylcarbamoylethyl) (MCE) modification, was evaluated in vitro and in vivo. The antisense activities of an ASO having the MCE modification were comparable with those of an ASO having the 2'-O-methoxyethyl (MOE) modification in both in vitro and in vivo experiments. In contrast, the hepatotoxic potential of the ASO having the MCE modification was lower than that of the ASO having the MOE modification. Thus, these findings suggested that the MCE modification could be used as an alternative to the MOE modification.
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http://dx.doi.org/10.1089/nat.2018.0738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157346PMC
October 2018

Deconstructive fluorination of cyclic amines by carbon-carbon cleavage.

Science 2018 07;361(6398):171-174

Department of Chemistry, University of California, Berkeley, CA 94720, USA.

Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp)-C(sp) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp)-C(sp) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late-stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks.
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http://dx.doi.org/10.1126/science.aat6365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287955PMC
July 2018

Comparison of metamotivational dominance and cultural identity between Japanese National Team and Māori All Blacks rugby players.

Heliyon 2017 Nov 1;3(11):e00454. Epub 2017 Dec 1.

Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan.

This pilot study used a reversal theory framework to examine metamotivational dominance of rugby players on the Māori All Blacks (MABs) squad of New Zealand and the Japanese National Team (JNT). Since the two groups have different cultural team demographics, cultural identity was also examined. Twenty six players from the MABs and 31 from the JNT completed questionnaires on metamotivational dominance and cultural identity. In terms of metamotivational dominance, the findings indicated that the MABs were more playful minded and spontaneous oriented than the JNT. Regarding cultural identity, the JNT showed a greater knowledge of their own culture and higher comfort level in their cultural context, while the MABs felt more positive and willing to sustain their own culture. The motivational personality differences between the teams may reflect the style of play that is valued within each team culture that is, flair, spontaneity and high-risk play within Māori rugby, and structure, team unity and conformity within the JNT. This suggests that metamotivational dominance of teams and players is influenced by the cultural identity of both the individuals and the group, which may have a further impact on team cohesion and performance.
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http://dx.doi.org/10.1016/j.heliyon.2017.e00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727547PMC
November 2017

Effect of dibutyltin on placental and fetal toxicity in rat.

J Toxicol Sci 2017 ;42(6):741-753

Courses of Veterinary Laboratory Medicine, School of Veterinary Medicine, Faculty of Agriculture, Tottori University.

In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.
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http://dx.doi.org/10.2131/jts.42.741DOI Listing
March 2018

Cortical bone trajectory screw fixation versus traditional pedicle screw fixation for 2-level posterior lumbar interbody fusion: comparison of surgical outcomes for 2-level degenerative lumbar spondylolisthesis.

J Neurosurg Spine 2018 01 10;28(1):57-62. Epub 2017 Nov 10.

1Department of Orthopaedic Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo; and.

OBJECTIVE The cortical bone trajectory (CBT) screw technique is a new nontraditional pedicle screw (PS) insertion method. However, the biomechanical behavior of multilevel CBT screw/rod fixation remains unclear, and surgical outcomes in patients after 2-level posterior lumbar interbody fusion (PLIF) using CBT screw fixation have not been reported. Thus, the purposes of this study were to examine the clinical and radiological outcomes after 2-level PLIF using CBT screw fixation for 2-level degenerative lumbar spondylolisthesis (DS) and to compare these outcomes with those after 2-level PLIF using traditional PS fixation. METHODS The study included 22 consecutively treated patients who underwent 2-level PLIF with CBT screw fixation for 2-level DS (CBT group, mean follow-up 39 months) and a historical control group of 20 consecutively treated patients who underwent 2-level PLIF using traditional PS fixation for 2-level DS (PS group, mean follow-up 35 months). Clinical symptoms were evaluated using the Japanese Orthopaedic Association (JOA) scoring system. Bony union was assessed by dynamic plain radiographs and CT images. Surgery-related complications, including symptomatic adjacent-segment disease (ASD), were examined. RESULTS The mean operative duration and intraoperative blood loss were 192 minutes and 495 ml in the CBT group and 218 minutes and 612 ml in the PS group, respectively (p < 0.05 and p > 0.05, respectively). The mean JOA score improved significantly from 12.3 points before surgery to 21.1 points (mean recovery rate 54.4%) at the latest follow-up in the CBT group and from 12.8 points before surgery to 20.4 points (mean recovery rate 51.8%) at the latest follow-up in the PS group (p > 0.05). Solid bony union was achieved at 90.9% of segments in the CBT group and 95.0% of segments in the PS group (p > 0.05). Symptomatic ASD developed in 2 patients in the CBT group (9.1%) and 4 patients in the PS group (20.0%, p > 0.05). CONCLUSIONS Two-level PLIF with CBT screw fixation for 2-level DS could be less invasive and result in improvement of clinical symptoms equal to those of 2-level PLIF using traditional PS fixation. The incidence of symptomatic ASD and the rate of bony union were lower in the CBT group than in the PS group, although these differences were not significant.
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http://dx.doi.org/10.3171/2017.5.SPINE161154DOI Listing
January 2018

Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes.

Biochem Biophys Rep 2017 Mar 11;9:245-256. Epub 2017 Jan 11.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

Andersen-Tawil syndrome (ATS) is a rare inherited channelopathy. The cardiac phenotype in ATS is typified by a prominent U wave and ventricular arrhythmia. An effective treatment for this disease remains to be established. We reprogrammed somatic cells from three ATS patients to generate induced pluripotent stem cells (iPSCs). Multi-electrode arrays (MEAs) were used to record extracellular electrograms of iPSC-derived cardiomyocytes, revealing strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Ca imaging of cells loaded with the Ca indicator Fluo-4 enabled us to examine intracellular Ca handling properties, and we found a significantly higher incidence of irregular Ca release in the ATS-iPSC-derived cardiomyocytes than in control-iPSC-derived cardiomyocytes. Drug testing using ATS-iPSC-derived cardiomyocytes further revealed that antiarrhythmic agent, flecainide, but not the sodium channel blocker, pilsicainide, significantly suppressed these irregular Ca release and arrhythmic events, suggesting that flecainide's effect in these cardiac cells was not via sodium channels blocking. A reverse-mode NaCaexchanger (NCX) inhibitor, KB-R7943, was also found to suppress the irregular Ca release, and whole-cell voltage clamping of isolated guinea-pig cardiac ventricular myocytes confirmed that flecainide could directly affect the NCX current (I). ATS-iPSC-derived cardiomyocytes recapitulate abnormal electrophysiological phenotypes and flecainide suppresses the arrhythmic events through the modulation of I.
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http://dx.doi.org/10.1016/j.bbrep.2017.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614591PMC
March 2017

Posterior lumbar interbody fusion with cortical bone trajectory screw fixation versus posterior lumbar interbody fusion using traditional pedicle screw fixation for degenerative lumbar spondylolisthesis: a comparative study.

J Neurosurg Spine 2016 Nov 27;25(5):591-595. Epub 2016 May 27.

Department of Orthopaedic Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo; and.

OBJECTIVE Several biomechanical studies have demonstrated the favorable mechanical properties of the cortical bone trajectory (CBT) screw. However, no reports have examined surgical outcomes of posterior lumbar interbody fusion (PLIF) with CBT screw fixation for degenerative spondylolisthesis (DS) compared with those after PLIF using traditional pedicle screw (PS) fixation. The purposes of this study were thus to elucidate surgical outcomes after PLIF with CBT screw fixation for DS and to compare these results with those after PLIF using traditional PS fixation. METHODS Ninety-five consecutive patients underwent PLIF with CBT screw fixation for DS (CBT group; mean followup 35 months). A historical control group consisted of 82 consecutive patients who underwent PLIF with traditional PS fixation (PS group; mean follow-up 40 months). Clinical status was assessed using the Japanese Orthopaedic Association (JOA) scale score. Fusion status was assessed by dynamic plain radiographs and CT. The need for additional surgery and surgery-related complications was also evaluated. RESULTS The mean JOA score improved significantly from 13.7 points before surgery to 23.3 points at the latest follow-up in the CBT group (mean recovery rate 64.4%), compared with 14.4 points preoperatively to 22.7 points at final follow-up in the PS group (mean recovery rate 55.8%; p < 0.05). Solid spinal fusion was achieved in 84 patients from the CBT group (88.4%) and in 79 patients from the PS group (96.3%, p > 0.05). Symptomatic adjacent-segment disease developed in 3 patients from the CBT group (3.2%) compared with 9 patients from the PS group (11.0%, p < 0.05). CONCLUSIONS PLIF with CBT screw fixation for DS provided comparable improvement of clinical symptoms with PLIF using traditional PS fixation. However, the successful fusion rate tended to be lower in the CBT group than in the PS group, although the difference was not statistically significant between the 2 groups.
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http://dx.doi.org/10.3171/2016.3.SPINE151525DOI Listing
November 2016

Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions at sp -Hybridized Carbon Atoms: Kinetic Resolution of β-Amino Alcohols by p-Methoxybenzylation.

Angew Chem Int Ed Engl 2016 10;55(42):13137-13141

Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.

A catalytic strategy was developed for asymmetric substitution reactions at sp -hybridized carbon atoms by using a chiral alkylating agent generated in situ from trichloroacetimidate and a chiral phosphoric acid. The resulting chiral p-methoxybenzyl phosphate selectively reacts with β-amino alcohols rather than those without a β-NH functionality. The use of an electronically and sterically tuned chiral phosphoric acid enables the kinetic resolution of amino alcohols through p-methoxybenzylation with good enantioselectivity.
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http://dx.doi.org/10.1002/anie.201607208DOI Listing
October 2016

Embryonic type Na channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome.

Sci Rep 2016 Sep 28;6:34198. Epub 2016 Sep 28.

Department of Cardiology, Keio University School of Medicine, Japan.

SCN5A is abundant in heart and has a major role in I. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that I of mutated SCN5A is decreased and SCN3B augmented I of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039759PMC
http://dx.doi.org/10.1038/srep34198DOI Listing
September 2016

Fixation Strength of Caudal Pedicle Screws after Posterior Lumbar Interbody Fusion with the Modified Cortical Bone Trajectory Screw Method.

Asian Spine J 2016 Aug 16;10(4):639-45. Epub 2016 Aug 16.

Department of Orthopaedic Surgery, Kansai Rosai Hospital, Amagasaki, Japan.

Study Design: Clinical case series.

Purpose: In the posterior lumbar interbody fusion (PLIF) procedure in our institute, the cephalad screw trajectory follows a mediolateral and caudocephalad directed path according to the original cortical bone trajectory (CBT) method. However, the starting point of the caudal screw is at the medial border of the pedicle on an articular surface of the superior articular process, and the trajectory takes a mediolateral path parallel to the cephalad endplate. The incidence of caudal screw loosening after PLIF with this modified CBT screw method was investigated, and significant risk factors for caudal screw loosening were evaluated.

Overview Of Literature: A biomechanical study of this modified caudal screw trajectory using the finite element method reported about a 20% increase in uniaxial yield pullout load compared with the traditional trajectory. However, there has been no clinical study concerning the fixation strength of this modified caudal screw trajectory.

Methods: The subjects were 193 consecutive patients who underwent single-level PLIF with modified CBT screw fixation. Caudal screw loosening was checked in computed tomography at 6 months after surgery, and screw loosening was defined as a radiolucency of 1 mm or more at the bone-screw interface.

Results: The incidence of caudal screw loosening after lumbosacral PLIF (46.2%) was significantly higher than that after floating PLIF (6.0%). No significant differences in sex, brand of the instruments, and diameter and length of the caudal screw were evident between patients with and without caudal screw loosening. Patients with caudal screw loosening were significantly older at the time of surgery than patients without caudal screw loosening.

Conclusions: Fixation strength of the caudal screw after floating PLIF with this modified CBT screw technique was sufficiently acceptable. Fixation strength after the lumbosacral procedure was not.
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http://dx.doi.org/10.4184/asj.2016.10.4.639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995245PMC
August 2016

Surgical outcomes after laminoplasty for cervical spondylotic myelopathy in patients with renal dysfunction and/or aortic arch calcification.

J Neurosurg Spine 2016 Oct 27;25(4):444-447. Epub 2016 May 27.

Department of Orthopaedic Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan.

OBJECTIVE The authors recently reported that the presence of chronic kidney disease (CKD) and/or extended abdominal aortic calcification was associated with significantly worse clinical outcomes after posterior lumbar interbody fusion. CKD is one of the highest risk factors for systemic atherosclerosis. Therefore, impaired blood flow due to atherosclerosis could exacerbate degeneration of the cervical spine and neural tissue. However, there has been no report of a study evaluating the deleterious effects of CKD and atherosclerosis on the outcomes after decompression surgery for cervical compression myelopathy. The purpose of this study was thus to examine whether CKD and systemic atherosclerosis affect surgical outcomes after laminoplasty for cervical spondylotic myelopathy (CSM). METHODS The authors analyzed data from 127 consecutive cases involving patients who underwent laminoplasty for CSM and met their inclusion criteria. Stage 3-4 CKD was present as a preoperative comorbidity in 44 cases. Clinical status was assessed using the Japanese Orthopaedic Association (JOA) cervical myelopathy evaluation questionnaire before surgery and 2 years postoperatively. As a marker of systemic atherosclerosis, the presence of aortic arch calcification (AoAC) was assessed on preoperative chest radiographs. RESULTS AoAC was found on preoperative chest radiographs in 40 of 127 patients. Neither CKD nor AoAC had a statistically significant deleterious effect on preoperative JOA score. However, CKD and AoAC were significantly associated with reductions in both the JOA score recovery rate (mean 36.1% in patients with CKD vs 44.7% in those without CKD; 26.0% in patients with AoAC vs 48.9% in those without AoAC) and the change in JOA score at 2 years after surgery (mean 2.3 points in patients with CKD vs 3.1 points in those without CKD; 2.1 points for patients with AoAC vs 3.2 points for those without AoAC). A multivariate regression analysis showed that AoAC was a significant independent predictor of poor outcome with respect to both for the difference between follow-up and preoperative JOA scores and the JOA score recovery rate. CONCLUSIONS CKD and AoAC were associated with increased rates of poor neurological outcomes after laminoplasty for CSM, and AoAC was a significant independent predictive factor for poor outcome.
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http://dx.doi.org/10.3171/2016.3.SPINE151411DOI Listing
October 2016

Histopathology of a wavy medaka.

J Toxicol Pathol 2016 Apr 15;29(2):115-8. Epub 2016 Feb 15.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Shiraoka, Saitama 349-0294, Japan.

Wavy medakas are medakas that exhibit spinal curvature characterized by dorsoventrally curved vertebrae. We found a spontaneous wavy medaka in our experimental stock and subjected it to a histopathological examination. Macroscopically, the wavy medaka's spine formed an M shape, and its vertebrae displayed a dorsoventral curvature that started at the third vertebral bone. Microscopically, the vertebral cavities were filled with fibrous tissue, which was similar to that seen in the central parts of the intervertebral discs of a normal medaka. The vertebral joints were composed of vacuolated notochord cells without intervertebral disc formation. These changes were also observed in the caudal region, which exhibited less curvature. In the normal medaka, the intervertebral discs form via the regression of the notochord that plays a key role in the development of vertebrae and disc formation. We concluded that notochordal subinvolution had induced intervertebral disc dysplasia, leading to lordokyphosis, in the wavy medaka.
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http://dx.doi.org/10.1293/tox.2015-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866008PMC
April 2016
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