視覚野においてT型Ca²⁺チャネル依存性長期増強を引き起こすためにはTNFαが必要である

Monocular deprivation produces depression and potentiation of visual responses evoked in visual cortical neurons by stimulation of deprived and nondeprived eyes, respectively, during the critical period of ocular dominance plasticity. Our previous studies suggested that T-type Ca²⁺ channel-dependent long-term potentiation (LTP), induced by 2 Hz stimulation, mediates the potentiation of visual responses. However, it was proposed that the experience-dependent response potentiation is mediated by tumor necrosis factor-α (TNFα)-dependent homeostatic synaptic scaling but not by Hebbian synaptic plasticity, because the potentiation was absent in TNFα knockout (TNFα-KO) mice. In this study, we investigated whether TNFα is required for LTP induced by 2 Hz stimulation using visual cortical slices prepared from critical period mice and rats. The production of LTP was prevented by pharmacological blockade of TNFα in rats and mice. LTP production was also prevented by an inhibitor of TNFα-converting enzyme that converts membrane-bound TNFα to soluble TNFα. In TNFα-KO mice, LTP did not occur and was rescued by exogenous soluble TNFα. Soluble TNFα was required for LTP production only during a restricted time window soon after 2 Hz stimulation. These results strengthen the view that T-type Ca²⁺ channel-dependent LTP contributes to the potentiation of nondeprived eye responses following monocular deprivation.博士（医学）・乙第1401号・平成29年6月28日Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved

BALB/c-Fcgr2b−/−Pdcd1−/− mouse expressing anti-urothelial antibody is a novel model of autoimmune cystitis

We report the impact of anti-urothelial autoantibody (AUAb) on urinary bladder phenotype in BALB/c mice deficient of the FcγRIIb and PD-1. AUAb was present in serum samples from approximately half of the double-knockout (DKO) mice, as detected by immunofluorescence and immunoblots for urothelial proteins including uroplakin IIIa. The AUAb-positive DKO mice showed degeneration of urothelial plaque and umbrella cells, along with infiltration of inflammatory cells in the suburothelial layer. TNFα and IL-1β were upregulated in the bladder and the urine of AUAb-positive DKO mice. Voiding behavior of mice was analyzed by the Voided Stain on Paper method. 10-week-old and older AUAb-positive DKO mice voided significantly less urine per void than did wild type (WT) mice. Furthermore, administration of the AUAb-containing serum to WT mice significantly reduced their urine volume per void. In summary, this report presents a novel comprehensive mouse model of autoimmune cystitis

Initial periodontal treatment affects nucleotide-binding domain leucine-rich repeat-containing protein 3 inflammasome priming in peripheral blood mononuclear cells

Objective: Accumulating evidence suggests an association between periodontitis and several systemic diseases, such as atherosclerosis. In the lesions of these diseases, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and caspase-1 form inflammasome complex, which leads to the functional maturation of interleukin (IL)-1β via cleavage of caspase-1 in macrophages. IL-1β plays a critical role in the etiology of these diseases; however, inflammasome priming?specifically, IL-1β and NLRP3 upregulation?is necessary for effective IL-1β production. We investigated the effect of initial periodontal treatment on the inflammasome priming of peripheral blood mononuclear cells (PBMCs). Methods: Twenty-two patients with chronic periodontitis were enrolled in this study and given initial periodontal treatment. Peripheral blood samples were collected at baseline and re-evaluation (41.1 ± 29.1 d after the treatment), and the relative expression of IL-1β, and three inflammasome components, ASC, NLRP3 and Caspase-1, mRNA was determined using quantitative reverse transcription PCR. PBMCs were stimulated with silica crystals, and the IL-1β secretion was measured via enzyme-linked immunosorbent assay. Results: Probing pocket depth and bleeding on probing (BOP) were significantly improved after the treatment. Expression of IL-1β and ASC in the PBMCs decreased after the treatment. PBMCs stimulated with silica crystals secreted IL-1β. The treatment attenuated IL-1β secretion by PBMCs in low BOP percentages group whereas IL-1β secretion was increased in high BOP percentages group. Conclusion: Periodontal treatment altered the inflammasome priming status of the PBMCs, however, the effects on systemic diseases need to be further investigated

Dental Calculus Stimulates Interleukin-1beta Secretion by Activating NLRP3 Inflammasome in Human and Mouse Phagocytes

Dental calculus is a mineralized deposit associated with periodontitis. The bacterial components contained in dental calculus can be recognized by host immune sensors, such as Toll-like receptors (TLRs), and induce transcription of proinflammatory cytokines, such as IL-1beta. Studies have shown that cellular uptake of crystalline particles may trigger NLRP3 inflammasome activation, leading to the cleavage of the IL-1beta precursor to its mature form. Phagocytosis of dental calculus in the periodontal pocket may therefore lead to the secretion of IL-1beta, promoting inflammatory responses in periodontal tissues. However, the capacity of dental calculus to induce IL-1beta secretion in human phagocytes has not been explored. To study this, we stimulated human polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) with dental calculus collected from periodontitis patients, and measured IL-1beta secretion by ELISA. We found that calculus induced IL-1beta secretion in both human PMNs and PBMCs. Calculus also induced IL-1beta in macrophages from wild-type mice, but not in macrophages from NLRP3- and ASC-deficient mice, indicating the involvement of NLRP3 and ASC. IL-1beta induction was inhibited by polymyxin B, suggesting that LPS is one of the components of calculus that induces pro-IL-1beta transcription. To analyze the effect of the inorganic structure, we baked calculus at 250 degrees C for 1 h. This baked calculus failed to induce pro-IL-1beta transcription. However, it did induce IL-1beta secretion in lipid A-primed cells, indicating that the crystalline structure of calculus induces inflammasome activation. Furthermore, hydroxyapatite crystals, a component of dental calculus, induced IL-1beta in mouse macrophages, and baked calculus induced IL-1beta in lipid A-primed human PMNs and PBMCs. These results indicate that dental calculus stimulates IL-1beta secretion via NLRP3 inflammasome in human and mouse phagocytes, and that the crystalline structure has a partial role in the activation of NLRP3 inflammasome

Detrusor overactivity induced by intravesical application of adenosine 5 '-triphosphate under different delivery conditions in rats

Objectives. We investigate the effects of intravesical application of adenosine 5'-triphosphate (ATP) on bladder activity to elucidate the role of urothelial barrier function and ecto-ATPase activity in the ATP-mediated mechanism inducing detrusor overactivity. Methods. Continuous cystometry by an intravesical catheter inserted from the bladder dome was performed in conscious female rats. Results. ATP solutions adjusted to pH 6.0 did not elicit significant detrusor overactivity at a concentration of 60 mM. However, in bladders pretreated with protamine sulfate (10 mg/mL) to increase urothelial permeability, ATP solution (pH 6.0) induced detrusor overactivity by decreasing the intercontraction intervals. These irritant effects of ATIP after protamine treatment were antagonized by P2X receptor antagonists, such as pyridoxal-5-phosphate-6-azophenyl-2',4-disulfonic acid (70 mu mol/kg) and 2',3'-O-(2,4,6, trinitrophenyl) ATP (30 mu mol/kg). These were also suppressed in rats pretreated with systemic capsaicin (125 mg/kg subcutaneously). Alpha,beta-methylene ATP (5 mM, pH 6.0) or ATP (60 mM, pH6) after intravesical infusion of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (5 mM, pH 6.0), an ecto-ATPase inhibitor, induced detrusor overactivity without protamine pretreatment, but the reduction in intercontraction intervals was smaller compared with that with ATP after protamine treatment. Conclusions. Low permeability of bladder epithelium and ecto-ATPase activity can prevent ATP activation of subepithelial P2X receptors to induce bladder overactivity. Thus, enhanced penetration of endogenous ATIP owing to urothelial damage may contribute to urinary frequency and bladder pain in hypersensitive bladder disorders such as interstitial cystitis.</p

Life-Threatening Infantile Diarrhea from Fluoroquinolone-Resistant Salmonella enteric Typhimurium with Mutations in Both gyrA and parC

Salmonella Typhimurium DT12, isolated from a 35-day-old infant with diarrhea, was highly resistant to ampicillin, tetracycline, chloramphenicol, streptomycin, gentamycin, sulfamethoxazole/trimethoprim, nalidixic acid, and fluoroquinolones. The patient responded to antibiotic therapy with fosfomycin. Multidrug-resistance may become prevalent in Salmonella infections in Japan, as shown in this first case of a patient infected with fluoroquinolone-resistant Salmonella

RETRACTED: The Chromatin-Remodeling Complex WINAC Targets a Nuclear Receptor to Promoters and Is Impaired in Williams Syndrome

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.Our paper reported that a chromatin-remodeling complex, WINAC, recruited the unliganded vitamin D receptor to promoters in cooperation with the transcription factor implicated in Williams syndrome, WSTF. The findings provided insights into the coordination between chromatin remodelers and sequence-specific transcription factors and pointed to a role of chromatin remodeling defects in Williams syndrome. We recently identified errors affecting several figure panels where original data were processed inappropriately such that the figure panels do not accurately report the original data. We believe that the most responsible course of action is to retract the paper. We sincerely apologize to the scientific community for any inconvenience that this might cause. The first author, H.K., declined to sign the retraction notice

Helium transport in the core and stochastic edge layer in LHD

Radial profiles of the density ratio of helium to hydrogen ions are measured using charge exchange spectroscopy with a two-wavelength spectrometer in the large helical device. Helium transport at the last closed flux surface (LCFS) and stochastic magnetic field layer outside the LCFS as well as in the core plasma is studied for a wide range of helium fractions, i.e. from hydrogen-dominated plasmas up to helium-dominated plasmas. The helium density profile becomes more peaked and inward convection velocity increases in the hydrogen-dominant plasma, while it becomes flat or hollow and the convection velocity is in the outward direction in the helium-dominant plasmas. The density gradient of helium at the LCFS is twice that of hydrogen and becomes steeper as the hydrogen becomes more dominant