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The mass production of radiation resistant magnets for the J-PARC external beam lines is discussed. A new remote handling system of beam line magnets named 'Chimney' is developed and used for magnets placed at the highest radiation area near the production target.

Indirect-cooling mineral-insulation magnet coils are developed for high radiation environment downstream of a production target. The current of DC 1000 A is fed to the solid-conductor mineral-insulator-cable (MIC) coils in vacuum by improving the structure of end parts of MICs and by increasing their emissivity.

A series of the R&D works on the radiation resistant magnets for the Japan Hadron Facility (JHF) project is conducted at the High Energy Accelerator Research Organization. The actual sized completely-inorganic radiation-resistance quadrupole magnet, designed for the 50 GeV proton beam transportation, is manufactured by using mineral insulation magnet cable (MIC).

Research having to do with radiation-resistant magnets is under way at the High Energy Research Organization (KEK), Tsukuba-shi, Japan. The research involves the Japan Hadron Facility (JHF), Japan's next-generation high-intensity accelerator project.

The development of radiation-resistant magnets for the Japan Hadron Facility Project is described.

We report here on R/D work concerning two types of radiation-resistant magnet coils, which were insulated using completely inorganic materials. Regarding the first coil, the electric insulator employed was a alumina long fiber and a ceramic binder. A new combination of adhesive agent, inorganic filler and alumina long fiber was found, which enabled us to form a strong insulation layer which does not peel off from a copper conductor. The magnet coil for 2000A excitation current was produced using this insulation method. The second coil is a mineral insulated cable (MIC) with a 3000A excitation current. This 3000A-class MIC has been manufactured as a short sample, and was tested concerning its electric insulation beth before and after bending.

In a high-intensity proton beam facility, beam line elements downstream of a production target are exposed to a huge amount of radiation and heat. A water-cooled beam collimator must be located between the target and the magnets, and the iron yokes of the magnets also have to be cooled by water. Moreover, beam pipes are closer to the beam than the magnet poles and more difficult to cool sufficiently without tritium production. Therefore, the magnets are placed in a large vacuum chamber, instead of using vacuum pipes located within the pole gaps. In order to reduce the residual radiation dose during maintenance, the chamber lid and feedthroughs are 4 meter above the beam line, and radiation-shielding blocks are also stacked in the chamber. We have tested magnet operation in vacuum using a dipole magnet with mineral-insulation-cable (MIC) coils and a nickel-coated yoke. A magnet with 2500-A-class hollow-conductor MIC coils has worked successfully with the current of DC 3000 A. The stability of operation in vacuum was confirmed by measuring the temperature with thermocouples and the magnetic field with a NMR probe. We have also succeeded in operating a 1000-A-class solid-conductor MIC coil in vacuum. [ABSTRACT FROM AUTHOR]

Background: We investigated the efficacy and safety of dupilumab in Japanese patients aged ≥6 months to <18 years old with moderate-to-severe atopic dermatitis not adequately controlled with existing therapies., Methods: In this randomized, double-blind, phase 3 study, patients received dupilumab (n = 30) or placebo (n = 32) with concomitant topical corticosteroids for 16 weeks, then all patients received dupilumab from 16 to 52 weeks. The primary endpoint was the proportion of patients with ≥75% improvement in Eczema Area and Severity Index (EASI) score from baseline (EASI-75) to Week 16. Key secondary endpoints included changes in EASI score, proportion of patients with investigator global assessment (IGA) scores of 0/1, and changes in worst daily itch numerical rating scale (NRS) scores (evaluated in patients aged ≥6 to <12 years [n = 35])., Results: At Week 16, more patients achieved EASI-75 with dupilumab than placebo (43.3% vs 18.8%; P = 0.0304), and the least squares mean (LSM) difference in percent change in EASI scores at Week 16 of dupilumab vs placebo was -39.4% (P = 0.0003). However, no significant difference in the proportion of patients achieving IGA scores of 0/1 at Week 16 with dupilumab versus placebo were seen (10.0% vs 9.4%; P = 0.8476). The percent change in worst daily itch NRS scores at Week 16 was higher with dupilumab (LSM difference: -33.3%; nominal P = 0.0117). Dupilumab was well tolerated; no new safety signals were identified., Conclusions: Dupilumab showed consistent efficacy and was well tolerated in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis previously insufficiently controlled with existing therapies., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Ovarian somatic tissues typically surround developing oocytes and play a crucial role in oogenesis across various metazoans, often displaying structural properties specific to their functions. However, there is an absence of evident structural modularity in the follicle epithelium of Myriapoda. We report here two structurally and developmentally distinct domains within the follicle epithelium of the Japanese pill millipede, Hyleoglomeris japonica. The follicle epithelium of H. japonica exhibits a thick cell mass at the apex of the follicle. These cells harbor abundant rough endoplasmic reticulum, mitochondria, Golgi complexes, and numerous microvilli, indicative of synthetic/secretory activities. Moreover, their height increases as oogenesis progresses. In contrast, another region of the epithelium lacks these features. Our findings highlight the presence of structural and functional modularity in the follicle epithelium of H. japonica. We suggest classifying the follicle epithelium of Myriapoda into three types: homogenous epithelia with enhanced synthetic activities, homogenous epithelia with diminished such activities, and heterogeneous epithelia with varying synthetic activities. These findings prompt a reevaluation of the nature of ovarian somatic tissues in Myriapoda as well as in Arthropoda., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest in this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.

Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A 33-year-old woman developed hypertensive emergency (268/168 mmHg) with renal failure and hypertensive retinopathy. Four hours after the initiation of antihypertensive therapy with the continuous infusion of nicardipine, her blood pressure (BP) decreased to 168/84 mmHg; however, the patient developed blindness. She was diagnosed with posterior ischemic optic neuropathy (PION). Her BP was maintained at approximately 175/90 mmHg until her vision improved. Olmesartan was initiated on day 13, and her BP decreased to approximately 135/95 mmHg without the re-exacerbation of vision loss. Although the prognosis of PION is poor, its early diagnosis and gradual antihypertensive therapy may help preserve the patient's vision.

During the production of orexin A and B from preproorexin, a common precursor protein, in hypothalamic orexin neurons, C-terminal peptide (herein called preproorexin C-peptide) is concomitantly produced via post-translational processing. The predicted three-dimensional structure of preproorexin C-peptide is similar among mammalian species, suggestive of a conserved function in the mammalian brain. However, C-peptide has long been regarded as a non-functional peptide. We herein examined the effects of rat and/or mouse preproorexin C-peptide on gene expression and cell viability in cultured rat cerebrocortical cells and on memory behavior in C57BL/6J mice. Rat and mouse C-peptides both increased brain-derived neurotrophic factor (Bdnf) mRNA levels. Moreover, C-peptide enhanced high K + -, glutamate-, and BDNF-induced increases in Bdnf mRNA levels without affecting forskolin-induced Bdnf expression. H-89, a protein kinase A inhibitor, blocked C-peptide-induced Bdnf expression, whereas rolipram, a phosphodiesterase inhibitor, enhanced this effect. Intracellular cyclic AMP concentrations were elevated by C-peptide. These results demonstrate that preproorexin C-peptide promoted Bdnf mRNA expression by a cyclic AMP-dependent mechanism. Eleven amino acids at the N terminus of rat preproorexin C-peptide exerted similar effects on Bdnf expression as full-length preproorexin C-peptide. Preproorexin C-peptide also exerted protective effects against CoCl 2 -induced neuronal cell death. An intracerebroventricular injection of mouse preproorexin C-peptide induced c-fos and Bdnf expression in the cerebral cortex and hippocampus and enhanced novel object recognition memory in mice. Collectively, the present results show that preproorexin C-peptide is a functional substance, at least in some pharmacological and neuronal settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Parasitic euglenids have rarely been studied. We found parasitic euglenids in two species of ostracods (Cyprinotus cassidula, Dolerocypris sinensis) and two species of rhabdocoels (Mesostoma lingua, Microdalyellia armigera) in a rice field. These parasites grew and proliferated inside the host body. These parasites had pellicle strips, one emergent flagellum, and a red stigma, but no chloroplasts, and showed euglenoid movement. Inside the living host, they did not have emergent flagella and moved only by euglenoid movement, but when the host died or the parasites were isolated from the host, they extended their flagella and switched to swimming movement. We conclude that the parasites found in the four hosts that we examined are of the same species, considering the morphological characteristics and identities in the nSSU and nLSU rDNA sequences of those parasites. Molecular phylogenetic analysis showed that the parasite formed a clade with the free-living photoautotrophic species of Euglenaformis, with moderate statistical support. Therefore, the parasite is a secondary osmotroph derived from a photoautotrophic ancestor. Based on the results of morphological observation and molecular phylogenetic analysis, we propose a new species of parasitic euglenid, Euglenaformis parasitica sp. nov., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise a new approach aiming at an improved supply of this scarce marine natural product; this compound is a cometabolite of the prototypical phosphatase inhibitor okadaic acid but still awaits detailed biological profiling. The revised entry starts from 2-deoxy-d-glucose; keys to success were a telescoped hemiacetal reduction/acetal cleavage and an exquisitely selective gold/Brønsted acid-cocatalyzed spiroacetalization.

Introduction: Malignant hypertension (mHTN) damages multiple target organs, including the kidneys. mHTN has been regarded as one of the causes of secondary thrombotic microangiopathy (TMA); however, a high prevalence of complement gene abnormalities was recently reported in cohorts of mHTN., Case Report: We herein describe a 47-year-old male who presented with severe hypertension, renal failure (serum creatinine (sCr): 11.6 mg/dL), heart failure, retinal hemorrhage, hemolytic anemia, and thrombocytopenia. Renal biopsy findings were consistent with acute hypertensive nephrosclerosis. The patient was diagnosed with secondary TMA associated with mHTN. However, his previous medical history of TMA of unknown origin and family history of atypical hemolytic uremic syndrome (aHUS) suggested as aHUS presenting mHTN, and genetic testing revealed a pathogenic C3 mutation (p.I1157T). The patient required plasma exchange and hemodialysis for 2 weeks and was able to withdraw from dialysis by antihypertensive therapy without eculizumab. Renal function gradually improved to a sCr level of 2.7 mg/dL under antihypertensive therapy for 2 years after the event. There was no recurrence, and renal function was preserved throughout a 3-year follow-up., Discussion: mHTN is a common presentation of aHUS. In cases of mHTN, abnormalities in complement-related genes may be involved in the development of the disease., Competing Interests: The authors have no conflict of interest to declare. Table 1.Laboratory findings on admission. Lab testResults (normal range)Peripheral blood   White blood cell count (/μL)7,500 (3,300 – 8,600)   Red blood cell count (×104/μL)329 (435 – 555)   Schistocytes (%)1 (< 1)   Hemoglobin (g/dL)10.3 (13.7 – 16.8)   Platelet count (×104/μL)5.2 (15.8 – 34.8)Blood chemistry   Total protein (g/dL)6.0 (6.6 – 8.1)   Albumin (g/dL)3.8 (4.1 –5.1)   Aspartate aminotransferase (U/L)20 (13 – 30)   Alanine aminotransferase (U/L)10 (10 – 42)   Lactate dehydrogenase (U/L)816 (124 –222)   Total bilirubin (mg/dL)1.0 (0.4 – 1.5)   Direct bilirubin (mg/dL)0.2 (0 – 0.4)   Uric acid (mg/dL)9.8 (3.7 – 7.8)   Blood urea nitrogen (mg/dL)106 (8 – 20)   Creatinine (mg/dL)11.57 (0.65 – 1.07)   Sodium (mEq/L)136 (138 – 145)   Potassium (mEq/L)3.6 (3.6 – 4.8)   Chloride (mEq/L)101 (101 – 108)   Ferritin (ng/mL)787.0 (34 – 370)   Brain natriuretic peptide (pg/mL)1,282.7 (0 – 18.4)   Plasma renin activity (ng/mL/hr)13 (0.3 – 2.9)   Plasma aldosterone concentration (pg/mL)285 (35.7 – 240)Serology   C-reactive protein (mg/dL)0.44 (0 – 0.14)   Immunoglobulin G (mg/dL)616 (861 – 1747)   Immunoglobulin A (mg/dL)126 (93 – 393)   Immunoglobulin M (mg/dL)36 (33 – 183)   Complement component 3 (mg/dL)82 (73 – 138)   Complement component 4 (mg/dL)31 (11 – 31)   50% hemolytic complement activity (U/mL)> 65 (29 – 47)   Haptoglobin (mg/dL)< 10   ADAMTS13 activity (%)52 (> 0.78)   ADAMTS13 inhibitor (BU/mL)0.5 (< 0.5)   Direct Coombs–Urinalysis   Occult blood3+   Protein (g/gCr)6.23   N-acetyl-D-glucosaminidase (U/gCr)21.0 (0.9 – 2.4)   β-2-microglobulin (μg/gCr)9788.4 (4 – 180)Sediments   Red blood cells (/high-power field)10 – 19ADAMS13 = a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13. Figure 1Clinical course. SBP = systolic blood pressure; DBP = diastolic blood pressure; sCr = serum creatinine; Plt = platelet count; LD = lactate dehydrogenase.Figure 2Renal biopsy findings. A: Ischemic glomeruli and global sclerotic glomeruli (arrow) were observed, and tubular atrophy and interstitial fibrosis were detected in 30% of the area (periodic acid methenamine staining, original magnification × 40). B: A globally sclerotic glomerulus shown in (A) indicated by an arrow (periodic acid methenamine staining, original magnification × 400). C, D: In glomeruli, there were mild ischemic changes, but no thrombi (C: periodic acid-Schiff staining, original magnification × 400, D: periodic acid methenamine staining, original magnification × 400). E, F: An interlobular artery exhibited “onion skin” with a narrowing lumen (E: periodic acid-Schiff staining, original magnification × 100, F: Elastica-Masson staining, original magnification × 100). G, H: There were no deposits of IgG (G) or C3 (H) on direct immunofluorescence microscopy (original magnification × 200). I: Slight subendothelial edema (arrowheads) was observed on electron microscopy (original magnification × 18,000)., (© Dustri-Verlag Dr. K. Feistle.)

The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5- trans -disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.

Purpose: This study compared concentric-eccentric coupled (CON-ECC), concentric-only (CON), and eccentric-only (ECC) resistance training of the elbow flexors for their effects on muscle strength and hypertrophy., Methods: Non-resistance-trained young adults were assigned to one of the four groups: CON-ECC (n = 14), CON (n = 14) and ECC (n = 14) training groups, and a control group (n = 11) that had measurements only. The training group participants performed dominant arm elbow flexor resistance training in extended elbow joint angles (0°-50°) twice a week for 5 weeks. The total training volume (dumbbell weight × number of contractions) in CON-ECC (5745 ± 1020 kg) was double of that in CON (2930 ± 859 kg) and ECC (3035 ± 844 kg), because 3 sets of 10 contractions were performed for both directions in CON-ECC. Maximum voluntary isometric (MVC-ISO), concentric (MVC-CON), and eccentric contraction (MVC-ECC) torque of the elbow flexors and biceps brachii and brachialis muscle thickness (MT) were measured at baseline, and 3-9 days post-last training session., Results: No significant changes in any measures were evident for the control group. The CON-ECC and ECC groups showed increases (P < 0.05) in MVC-ISO (12.0 ± 15.7% and 11.3 ± 10.8%, respectively) and MVC-ECC torque (12.5 ± 18.3%, 16.2 ± 11.0%) similarly. Increases in MVC-CON torque (P < 0.05) were evident for the CON-ECC (17.5 ± 13.5%), CON (10.5 ± 12.8%), and ECC (14.2 ± 10.4%) groups without a significant difference among groups. MT increased (P < 0.01) after CON-ECC (10.6 ± 5.4%) and ECC (9.7 ± 7.2%) similarly, but not significantly after CON (2.5 ± 4.8%)., Conclusions: ECC training increased muscle strength and thickness similarly to CON-ECC training, despite the half training volume, suggesting that concentric contractions contributed little to the training effects., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)